JPH07258199A - Urea derivative - Google Patents

Abstract

PURPOSE:To obtain the novel compound having an acyl coenzyme A cholesterol acyl transferase inhibitory effect and a protective effect against oxidative change of a low-density lipoprotein and useful for prevention and therapy of arterial sclerosis, etc. CONSTITUTION:A compound of the formula I [R1 and R2 are H, a halogen, a 1 to 6C alkoxy; R3 and R4 are H, a 1 to 8C alkyl, a cyclo-3 to 8C alkyl, an aryl-1 to 6C alkyl, etc.; R5 and R7 are H, a 1 to 6C akyl; R6 is formula OR8 or a group of the formula II (R8 is H, a 1 to 6C alkyl or a group of the formula III); OCH2O may be formed between R6 and R7 and condensed with a phenyl ring; X is N or methine; A is a bonding group of the formula IV, formula V (R9 is H, a 1 to 6C alkyl, a 1 to 6C alkylcarbonyl, etc.), etc.] or its pharmaceutically permissible salt. For example, N-(4-dimethyl- aminophenol)-2-(3-heptylureido)benzamide. In the case of A in a compound of the formula I is a group of the formula IV, this compound can be synthesized by converting a compound of the formula VI to its acid chloride and subsequently reacting a compound of the formula VII (R9 is H, etc.) therewith.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel urea derivative, a method for producing the same, and a pharmaceutical composition containing the derivative. In particular, the present invention provides a compound having an acylcoenzyme A cholesterol acyltransferase (hereinafter abbreviated as ACAT) inhibitory activity and a protective ability against oxidative changes of low density lipoprotein (hereinafter abbreviated as LDL).

[0002]

2. Description of the Related Art In recent years, there has been a strong interest in the relationship between an increase in blood cholesterol level and health status. It has been pointed out that the cholesterol level in blood is related to the amount of cholesterol deposited in the vascular system, and that the cholesterol deposit in the vascular system causes ischemic diseases such as arteriosclerosis. Although drugs that lower the amount of cholesterol in the blood have been developed so far, such drugs have been effective in controlling the cholesterol level in the blood to an appropriate level, but in the digestive tract, It was ineffective in absorbing cholesterol and suppressing cholesterol deposition on the blood vessel wall.

By the way, ACAT is an enzyme that catalyzes the synthesis of acyl coenzyme A and cholesterol into cholesterol ester, and plays an important role in the metabolism of cholesterol and absorption in the digestive tract. And A
CAT is present at the site of intestinal mucosal cells, and is considered to act when esterifying dietary cholesterol and taking it up. On the other hand, the cholesterol deposited on the blood vessel wall is esterified cholesterol, and the cholesterol accumulated in foamed macrophages, which plays an important role in the formation of atherosclerotic lesions, is also esterified. It is cholesterol. And
The enzyme that catalyzes the esterification of cholesterol at these sites is also ACAT. Therefore, this AC
By inhibiting the action of AT, it is possible to suppress the intake of dietary cholesterol into the body and further suppress the production of cholesterol ester at a specific cell site.

As such a compound having an ACAT inhibitory activity, a urea derivative having a structure similar to that of the compound of the present invention is disclosed in, for example, JP-A-2-188568 and JP-A-2-
No. 92950. However, although the drugs shown in these known documents have an ACAT inhibitory activity, they exert a different action on the oxidative alteration of LDL which causes foaming of macrophages important for the formation of atherosclerotic plaque. It does not affect.

[0005]

By the way, foam cells, which play an important role in the formation of atherosclerotic plaque, are incorporated into macrophages by LDL that has undergone oxidative alteration, and as a result, the macrophages become foamed. It was done. It has been reported by Diane W. Morel et al. (ARTERIOSCLEROSIS, 4) that LDL that has undergone oxidative deterioration causes foaming of macrophages and plays an important role in the formation of atherosclerotic plaques. Volume, Pages 357-364, 1984
Furthermore, the prevention of oxidative alteration of LDL causes regression of atherosclerotic plaques by TORU KITA et al. (Proc. Natl. Acad. Sci. USA, 84, 5928-5931).
Page, 1987). Therefore, suppressing the oxidative deterioration of LDL in addition to the above-described ACAT inhibitory action is extremely important for the formation of atherosclerotic plaques, prevention of their expansion, and their regression.

From the above, a substance having an ACAT inhibitory activity and capable of suppressing oxidative alteration of LDLs at the same time lowers blood cholesterol level and at the same time oxidizes LDL cholesterol deposited in blood vessels or tissues. It is effective for the formation of atherosclerotic lesions, the prevention of their expansion, and their regression by suppressing the physical alteration, and therefore, the development of a drug having such properties is needed.

[0007]

In order to solve the above problems, the inventors of the present invention, as a result of diligent research, suppress the absorption of cholesterol from the intestinal tract by the ACAT inhibitory action, lower the cholesterol level in the blood, By suppressing the accumulation of cholesterol ester in blood vessel wall, arteriosclerotic lesion and macrophage, and by having a protective effect against oxidative alteration of LDL involved in foam formation of macrophage, formation and expansion of atherosclerotic lesion The present invention has been completed by discovering a novel urea derivative that is effective in suppressing the above-mentioned phenomenon and its regression. The present invention is to provide a novel urea derivative having an ACAT inhibitory action and an antioxidant action at the same time. These compounds are effective in the prevention and treatment of hypercholesterolemia, arteriosclerosis and the like.

That is, the present invention provides the following general formula (1):

[Chemical 8] (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a halogen atom, or a (C ₁ -C ₆ ) alkoxy group, R ₃ and R ₄ are the same or different, and a hydrogen atom, (C ₁ -C 6 ₈ ) alkyl group, cyclo (C ₃ -C ₈ ) alkyl group, aryl (C
₁ -C ₆₎ alkyl group (the aryl moiety is optionally halogen atom, (C ₁ -C ₆₎ may alkyl group, be mono- or disubstituted with (C ₁ -C ₆₎ alkoxy group), diaryl (C ₁ ~C ₆₎ alkyl group, a pyridyl (C ₁ ~
C ₆ ) alkyl group, (C ₁ -C ₆ ) alkyl group optionally substituted with diazabicyclo (C ₇ -C ₁₀ ) alkyl group, adamantyl group, aryl (C ₁ -C ₆ ) alkyl group substituted 5 or 6 optionally represent a piperidyl group, or R ₃ and R ₄ together with the nitrogen atom to which they are attached are optionally substituted with a (C ₁ -C ₆ ) alkyl group. Represents a membered monocyclic heterocyclic group, R ₅ and R ₇ are the same or different and represent a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, and R ₆ is a group represented by the formula:

[Chemical 9] (In the formula, R ₈ is a hydrogen atom, a (C ₁ -C ₆ ) alkyl group,

[Chemical 10] (Wherein R ₃ is the same as the above), or R ₆ and R ₇ together are —O—CH ₂ —O—.
To form a nitrogen atom or a methine group, and A is of the formula

[Chemical 11] (In the formula, R ₉ is a hydrogen atom, a (C ₁ -C ₆ ) alkyl group,
(C ₁ -C ₆ ) alkylcarbonyl group, geranyl group,

[Chemical 12] And m and n each independently represent an integer of 0 to 2). In addition, R ₁
To alkyl groups and alkoxy moieties of each of the substituents represented by R ₉ to R ₉ may be linear or branched) and a pharmaceutically acceptable salt thereof.

The present invention also relates to an ACAT inhibitor containing a compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Examples of the halogen atom represented by R ₁ and R ₂ in the general formula (1) of the above-mentioned urea derivative of the present invention include fluorine, chlorine, bromine and iodine, and the (C ₁ -C ₆ ) alkoxy group is , Methoxy,
Ethoxy, propoxy, iso-propoxy, butoxy, i
Examples thereof include so-butoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.

R in the general formula (1) of the above-mentioned urea derivative
Examples of the (C ₁ -C ₈ ) alkyl group represented by ₃ and R ₄ include
Methyl, ethyl, propyl, iso-propyl, butyl, i
so-butyl, sec-butyl, tert-butyl, pentyl, i
Examples thereof include so-pentyl, tert-pentyl, neopentyl, hexyl, 2-methylpentyl, 2-ethylpentyl, 4-methylhexyl, heptyl and octyl groups, and the cyclo (C ₃ -C ₈ ) alkyl group includes cyclo. Propyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples thereof include a cycloheptyl group and a cyclooctyl group. Examples of the aryl (C ₁ -C ₆ ) alkyl group include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl,
5-phenylpentyl, 6-phenylhexyl, 3-phenylhexyl, 2-naphthylmethyl, 2-naphthylethyl, 2-methylbenzyl, 4-ethylbenzyl, 3-
Chlorobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-chlorophenethyl, 3,4-dimethoxyphenethyl group and the like, and diaryl Examples of the (C ₁ -C ₆ ) alkyl group include diphenylmethyl, 2,2-diphenylethyl, 3,3-diphenylpropyl, 4,4-diphenylbutyl, 4,6-diphenylhexyl group, and pyridyl ( C ₁ ~
As the C ₆ ) alkyl group, 2-pyridylmethyl, 3-
Pyridylmethyl, 2- (2-pyridyl) ethyl, 2-
Examples thereof include (3-pyridyl) propyl and 4- (2-pyridyl) butyl groups, and the diazabicyclo (C ₇ -C ₁₀ ) alkyl group is 3,9-diazabicyclo [3.3.1].
Non-7-yl, 3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl, 3-ethyl-9-methyl-3,9-diazabicyclo [3.3.1] Nona-7-
And 3-methyl-9-propyl-3,9-diazabicyclo [3.3.1] non-7-yl group and the like, which may be substituted with an aryl (C ₁ -C ₆ ) alkyl group. Examples of the piperidyl group include benzylpiperidyl, phenethylpiperidyl, 3-phenylpropylpiperidyl, 4-phenylbutylpiperidyl, 5-phenylpentylpiperidyl, 6-phenylhexylpiperidyl group, and R ₃ and R ₄ are bonded to each other. Together with the nitrogen atom, it may be substituted with a (C ₁ -C ₆ ) alkyl group,
Examples of the 5- or 6-membered monocyclic heterocyclic group include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrrolyl, pyrazolyl, imidazolyl, piperidyl, piperazinyl,
2-methylpyrrolidinyl, 3-methylpyrazolidinyl,
2-methylimidazolidinyl, 3-methylpyrrolyl, 2
-Ethylpiperidyl, 4-ethylpiperazinyl group and the like can be mentioned.

R ₅ , R ₇ , R ₈ and R ₉ (C ₁ to
The C ₆₎ alkyl groups include methyl, ethyl, propyl, iso- propyl, butyl, iso- butyl, sec- butyl, tert- butyl, pentyl, iso- pentyl, tert-
Examples thereof include pentyl, neopentyl, hexyl and 2-methylpentyl groups. Examples of the (C ₁ -C ₆ ) alkylcarbonyl group represented by R ₉ include acetyl, propionyl,
Examples include butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups.

The present invention includes all isomers, stereoisomers, metabolites, and metabolic precursors which are possible with the compound of the general formula (1). The compound represented by the general formula (1) of the present invention can be produced by various conventional methods, for example, the methods shown below.

(A) The linking group A is

[Chemical 13] (Wherein R ₉ represents a hydrogen atom, an alkyl group or a geranyl group), the general formula (2a)

[Chemical 14] (Wherein R ₁ , R ₂ and X are the same as above) are reacted with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride and the like to give the corresponding general formula (2)
b)

[Chemical 15] (Wherein R ₁ , R ₂ and X are the same as defined above), and then the compound represented by the general formula (3) in the presence of an acid binder in an organic solvent.

[Chemical 16] (Wherein R ₅ , R ₆ and R ₇ are the same as above, and R ₉ represents a hydrogen atom, an alkyl group or a geranyl group), or a compound represented by the general formula (2a) In an organic solvent, the compound represented by the formula (3) and dicyclohexylcarbodiimide, 1-ethyl-
By the method of reacting using a condensing agent such as 3- (3-diethylaminopropyl) carbodiimide, the compound represented by the general formula (4)

[Chemical 17] After the compound represented by, is reduced by using zinc, iron, tin, tin (II) chloride in an acidic solution such as hydrochloric acid or acetic acid, or in an alcohol solvent such as methanol or ethanol, palladium-carbon By reducing the nitro group by a method of catalytic hydrogenation using a catalyst such as platinum oxide

[Chemical 18] A compound represented by is obtained. In addition to this, the general formula (6) RNC
When the isocyanate represented by O (R represents R ₃ or R ₄ , R ₃ and R ₄ are the same as above) is reacted in an organic solvent under ice cooling to room temperature, the urea derivative represented by the general formula (1) Is manufactured. The production process of the compound of the present invention by the above reaction is shown in the following scheme 1.

[0014]

[Chemical 19]

(B) The linking group A is

[Chemical 20] (Wherein R ₉ represents a hydrogen atom, an alkyl group or a geranyl group), the general formula (8a)

[Chemical 21] (Wherein R ₅ , R ₆ and R ₇ are the same as above) and reacted with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, etc.
b)

[Chemical formula 22] (Wherein R ₅ , R ₆ and R ₇ are the same as above), and then the compound represented by the general formula (7) in the presence of an acid binder in an organic solvent.

[Chemical formula 23] (Wherein R ₁ , R ₂ and X are as defined above, Y represents NR ₉ or OH, and R ₉ represents a hydrogen atom, an alkyl group or a geranyl group). Alternatively, the compound represented by the general formula (8a) and the compound represented by the general formula (7) are reacted in an organic solvent with a condensing agent such as dicyclohexylcarbodiimide, to give a compound represented by the general formula (9a) or (9b). )

[Chemical formula 24] Or a compound represented by the general formula (8a) is reacted with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or the like, and a corresponding acid chloride represented by the general formula (8b). After that, in the presence of an acid binder in an organic solvent, the general formula (10)

[Chemical 25] (Wherein R ₁ , R ₂ , X and Y are the same as above), or the compound represented by the general formula (8a) and the compound represented by the general formula (10) are reacted. According to the method of reacting with a condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3-diethylaminopropyl) carbodiimide in an organic solvent, the compound represented by the general formula (1
1a) or (11b)

[Chemical formula 26] After the compound represented by, is reduced by using zinc, iron, tin, tin (II) chloride in an acidic solution such as hydrochloric acid or acetic acid, or in an alcohol solvent such as methanol or ethanol, palladium-carbon The nitro group is reduced by a method of catalytic hydrogenation using a catalyst such as platinum oxide to obtain the compound represented by the general formula (9a) or (9b). The isocyanate represented by the general formula (6) RNCO is reacted with this in an organic solvent under ice cooling to room temperature to give the general formula (1)
The urea derivative represented by is produced.

Further, the compound represented by the general formula (9a) or (9b) is reacted with phenyl chloroformate in an organic solvent in the presence of an acid binder at room temperature under ice cooling and at room temperature.
a) or (12b)

[Chemical 27] The compound of the general formula (13)

[Chemical 28] The urea derivative represented by the general formula (1) is also produced by reacting the compound represented by the formula (wherein R ₃ and R ₄ are the same as above) in an organic solvent under heating at 50 to 150 ° C. The process for producing the compound of the present invention by the above reaction is described in the following Scheme 2
Shown in.

[0017]

[Chemical 29]

Further, the general formula (14)

[Chemical 30] (In the formula, R ₁ , R ₂ or X is the same as above, Z is NH ₂ ,
A compound represented by the general formula (15a) by reacting a compound represented by OH and NO ₂ ) with an isocyanate represented by the general formula (6) in an organic solvent under ice cooling and at room temperature.

[Chemical 31] Or a compound represented by the general formula (14) and phenyl chloroformate in an organic solvent,
In the presence of an acid binder, the compound of general formula (16)

[Chemical 32] When the compound represented by the formula (15b) is reacted with the compound represented by the formula (13),

[Chemical 33] A compound represented by is obtained. When Z is a nitro group in the compound represented by the general formula (15a) or (15b), it is reduced with zinc, iron, tin, tin (II) chloride in an acidic solution such as hydrochloric acid or acetic acid. Method or methanol,
The nitro group is reduced to an amino group by catalytic hydrogenation using a catalyst such as palladium-carbon or platinum oxide in an alcohol solvent such as ethanol. Then, the compound represented by the general formula (8a) is reacted with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or the like to give the corresponding acid chloride represented by the general formula (8b), and then in an organic solvent, In the presence of an acid binder, the general formula (15a)
Or a method of reacting with the compound represented by (15b),
Alternatively, the compound represented by the general formula (8a) and the general formula (15)
a) or a compound represented by (15b) in an organic solvent,
Dicyclohexylcarbodiimide, 1-ethyl-3-
The urea derivative represented by the general formula (1) is produced by a reaction method using a condensing agent such as (3-diethylaminopropyl) carbodiimide. The production process of the compound of the present invention by the above reaction is shown in the following scheme 3.

[0019]

[Chemical 34]

(C) The linking group A is

[Chemical 35] [Wherein R ₉ represents a hydrogen atom, an alkyl group, an alkylcarbonyl group, a geranyl group or —CONHR ₃ (R ₃ is the same as the above)], the general formula (17)

[Chemical 36] (Wherein R ₁ , R ₂ , m and X are the same as defined above, and Q represents a halogen atom, a paratoluenesulfonyl group or a methanesulfonyl group) and a compound represented by the general formula (18)

[Chemical 37] (Wherein R ₅ , R ₆ , R ₇ , R ₉ and n are the same as above) and reacted in an organic solvent in the presence of an acid binder at room temperature to under heating to reflux. )

[Chemical 38] In the acidic solution such as hydrochloric acid and acetic acid, zinc, iron, tin, a method of reducing with tin (II) chloride or the like, or in an alcohol solvent such as methanol or ethanol,
A nitro group is reduced to an amino group by a method of catalytic hydrogenation using a catalyst such as palladium-carbon, platinum oxide, etc.

[Chemical Formula 39] The compound represented by the formula (6) is reacted with the isocyanate represented by the general formula (6) RNCO in an organic solvent at room temperature under ice-cooling to produce the urea derivative represented by the general formula (1). Further, when R ₉ is a hydrogen atom in the compound represented by the general formula (1), the isocyanate represented by the general formula (6) is reacted in an organic solvent under ice-cooling at room temperature to give the compound represented by the general formula (1) ), A urea derivative in which R ₉ is CONHR ₃ (R ₃ is the same as above) is produced. When R ₉ is a hydrogen atom in the compound represented by the general formula (1), R _{9 in the} general formula (1) is reacted with an acid chloride or an acid anhydride in an organic solvent at room temperature under ice cooling. A urea derivative that is an alkylcarbonyl group is produced. The production process of the compound of the present invention by the above reaction is shown in the following scheme 4.

[0021]

[Chemical 40]

The compound represented by the general formula (5) or the general formula (9a) is reduced with sodium borohydride-boron trifluoride in an ether solvent such as diethyl ether, tetrahydrofuran or dioxane under ice cooling. General formula (21a) or general formula (21b)

[Chemical 41] The compound represented by the formula (6) is reacted with an isocyanate represented by the general formula (6) RNCO in an organic solvent at room temperature under ice-cooling to produce a urea derivative represented by the general formula (1). Further, in the compound represented by the general formula (1), R ₉
Is a hydrogen atom, the compound represented by the general formula (6) is reacted with an isocyanate in an organic solvent at room temperature under ice-cooling to give R _{9 in the} general formula (1) as CONHR ₃ (R ₃ is the same as above). ) Is produced. When R ₉ is a hydrogen atom in the compound represented by the general formula (1), R _{9 in the} general formula (1) is reacted with an acid chloride or an acid anhydride in an organic solvent at room temperature under ice cooling. A urea derivative that is an alkylcarbonyl group is produced. The process for producing the compound of the present invention by the above reaction is shown in the following scheme 5.

[0023]

[Chemical 42]

(D) When the linking group A is --O-(CH ₂ ) _3- , the compound represented by the general formula (10)

[Chemical 43] (Wherein R ₁ , R ₂ and X are the same as defined above and Y represents OH) and the compound represented by the general formula (22)

[Chemical 44] (Wherein R ₅ , R ₆ , R ₇ and Q are the same as above) are reacted in an organic solvent in the presence of an acid binder at room temperature to under reflux with heating to give a compound of the general formula (23)

[Chemical formula 45] In the acidic solution of hydrochloric acid, acetic acid, etc., zinc, iron, tin, a method of reducing with tin (II) chloride, etc., or in an alcohol solvent such as methanol, ethanol, palladium-carbon, oxidation A nitro group is reduced to an amino group by a catalytic hydrogenation method using a catalyst such as platinum to give a compound of the general formula (24)

[Chemical formula 46] After the compound represented by the formula (1) is reacted with the isocyanate represented by the general formula (6) in an organic solvent under ice-cooling at room temperature, the urea derivative represented by the general formula (1) is produced.

Further, the compound represented by the general formula (24) is reacted with phenyl chloroformate in an organic solvent in the presence of an acid binder under ice-cooling at room temperature to give the general formula (25).

[Chemical 47] The urea derivative represented by the general formula (1) can be produced by reacting the compound represented by the formula (13) with a compound represented by the formula (13) in an organic solvent under heating at 50 to 150 ° C.

The compound of the present invention obtained by the above reaction is shown in the following scheme 6.

[Chemical 48]

The organic solvent used in each of the above reaction steps includes aliphatic hydrocarbon solvents such as hexane, petroleum ether and cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methylene chloride, chloroform, Halogen-based solvents such as carbon tetrachloride and dichloroethane,
An ether solvent such as ethyl ether, isopropyl ether, tetrahydrofuran or dioxane, a ketone solvent such as acetone or methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide or the like can be used. As the acid binder, inorganic basic substances such as sodium hydride, potassium hydroxide, sodium carbonate and potassium carbonate, and secondary amines such as diisopropylamine, triethylamine, methylmorpholine,
Examples thereof include organic basic substances such as tertiary amines such as pyridine.

The acid addition salt of the compound represented by the general formula (1) of the present invention is a pharmacologically acceptable salt, for example, hydrochloride, hydrobromide, hydroiodide, sulfuric acid. Inorganic acid salts such as salts and phosphates, and organic acids such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate. Examples include salt.

The compound of the present invention can be administered orally or parenterally, usually in the form of a pharmaceutical preparation. The form of the pharmaceutical preparation includes tablets, capsules, troches, syrups, granules, powders, injections, suspensions and the like. Further, it can be made into a double-layer tablet or a multi-layer tablet together with other drugs. Further, the tablets may be tablets coated with a usual coating as necessary, for example, sugar-coated tablets, enteric-coated tablets and film-coated tablets.

In the case of preparing a solid preparation, solid additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, gum arabic, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol, stearic acid. , Magnesium stearate, talc and the like are used. When preparing a semi-solid formulation,
Vegetable or synthetic wax or fat is used. In the case of liquid preparations, liquid additives such as sodium chloride aqueous solution, sorbitol, glycerin, olive oil, almond oil, propylene glycol, ethyl alcohol and the like are used.

The amount of active ingredient in these formulations is 0.
0001 to 100% by weight, suitably 0.001 to 50% by weight for formulations for oral administration and 0.0001 to 10% by weight for injectable formulations. The administration method and dose of the compound of the present invention are not particularly limited and may be appropriately selected depending on various dosage forms, disease grade, patient age, sex, etc., but the daily dose of the active ingredient is 0.01 mg. ~ 1000 mg. No toxicity is observed within this range.

Specific synthetic methods of the compounds of the present invention will be shown below as examples. Example 1 N- (4-Dimethylaminophenyl) -2- (3-heptylureido) benzamide

[Chemical 49] (1) A mixture of 2-nitrobenzoic acid (10 g) and thionyl chloride (11 ml) was heated under reflux for 2 hours, concentrated to dryness, this mixture was dissolved in dichloromethane (80 ml), triethylamine (10 ml) was added, and N, N was added. A solution of dimethyl-1,4-phenylenediamine (9.0 g) in dichloromethane (10 ml) was added dropwise under ice cooling, and the mixture was stirred for 2 hours while gradually returning to room temperature. After distilling off the solvent, it was once dissolved in ethyl acetate (800 ml), washed with water, saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was crystallized from ethyl acetate to give N- (4-dimethylaminophenyl). ) -2-Nitrobenzamide (11 g, 64%) was obtained. (2) N- (4-dimethylaminophenyl) -2-nitrobenzamide (3.0 g) in ethanol (30 ml)
Add a catalytic amount of 10% palladium carbon to the suspension,
Catalytic reduction was carried out at room temperature at 2.5 atm for 4 hours. After filtering the catalyst, the solvent was evaporated and the residue was crystallized from chloroform-ethyl acetate to give N- (4-dimethylaminophenyl) -2-aminobenzamide (2.2 g, 79%). (3) N- (4-dimethylaminophenyl) -2-aminobenzamide (1.5 g) in dichloromethane (20 m
l) To the solution, under ice-cooling, heptyl isocyanate (2.4 g)
Was added, and the mixture was stirred overnight while gradually returning to room temperature. The solvent was distilled off, crystallized from chloroform-ethyl acetate, and N
-(4-Dimethylaminophenyl) -2- (3-heptylureido) benzamide (1.6 g, 69%) was obtained. mp. 178-180 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 10.05 (1H, s), 8.34 (1H, d, J = 8H
z), 8.20 (1H, s), 7.29-7.50 (4H, m), 6.93 (1H, t, J = 7Hz), 6.7
6 (2H, d, J = 9Hz), 4.58 (1H, t, J = 5Hz), 3.21-3.26 (2H, m), 2.9
6 (6H, s), 1.28-1.53 (10H, m), 0.88 (3H, t, J = 6Hz) IR (cm ^-1 ) 3340,2930,1680,1640,1520,1450,1340,1300,1
230,820,750 (4) N- (4-dimethylaminophenyl) -2-
(3-heptylureido) benzamide (0.70 g)
To an ethanol (10 ml) solution was added 4N-hydrochloric acid / ethyl acetate solution (0.48 ml) under ice cooling, and the mixture was concentrated to dryness and N
An amorphous solid of-(4-dimethylaminophenyl) -2- (3-heptylureido) benzamide monohydrochloride (0.77 g, 99%) was obtained.

Example 2 1- (4-dimethylaminophenyl) -1- {2- (3
-Heptylureido) benzyl} -3-heptylurea

[Chemical 50] (1) A suspension of lithium aluminum hydride (0.61 g) in THF (30 ml) was added with TH of N- (4-dimethylaminophenyl) -2-aminobenzamide (2.0 g).
The F (20 ml) solution was added dropwise under ice cooling and then heated to reflux. A small amount of water was added dropwise thereto under ice cooling, the insoluble matter was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane. Thus, N- (2-aminobenzyl) -N ', N'-dimethyl-1,4-phenylenediamine (1.1 g, 56%) was obtained. (2) To a solution of N- (2-aminobenzyl) -N ', N'-dimethyl-1,4-phenylenediamine (0.6 g) in dichloromethane (10 ml) was added heptyl isocyanate (0.4 g) under ice cooling. Then, the mixture was stirred overnight while gradually returning to room temperature. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (chloroform: ethyl acetate = 20:
Purified in 1), 1- (4-dimethylaminophenyl)
-1- {2- (3-heptylureido) benzyl} -3
-Amorphous solid of heptylurea (0.55 g, 44
%) Was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.31 (s, 1H), 8.36 (d, 1H, J = 8Hz),
7.20-7.25 (m, 1H), 6.50-6.77 (m, 6H), 5.17 (t, 1H, J = 5Hz),
4.70 (s, 2H), 4.33 (t, 1H, J = 6Hz), 3.10-3.31 (m, 4H), 2.96
(s, 6H), 0.82-1.66 (m, 26H) IR (cm ^-1 ) 2920,2850,1720,1630,1520,1480,1460,1300,1
230 (3) 1- (4-dimethylaminophenyl) -1-
{2- (3-heptylureido) benzyl} -3-heptylurea (0.5 g) was used in the same reaction procedure as in Example 1 (4) to give 1- (4-dimethylaminophenyl).
-1- {2- (3-heptylureido) benzyl} -3
-Amorphous solid of heptylurea monohydrochloride (0.49
g, 92%).

Example 3 N- (4-dimethylaminophenyl) -N-geranyl-
2- (3-heptylureido) benzamide

[Chemical 51] (1) A mixture of 2-nitrobenzoic acid (2.3 g) and thionyl chloride (2.5 ml) was heated under reflux for 2 hours and concentrated to dryness. This mixture was dissolved in dichloromethane (20 ml) and triethylamine (2.3 ml). A solution of N, N-dimethyl-N'-geranyl-1,4-phenylenediamine (4.0 g) in dichloromethane (10 ml) was added dropwise under ice cooling, and the mixture was stirred for 2 hours while gradually returning to room temperature.
The reaction solution was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give N- (4-dimethylamino). Phenyl) -N-geranyl-2-nitrobenzamide oil (5.6 g, 9
5%) was obtained. (2) N- (4-Dimethylaminophenyl) -N-geranyl-2-nitrobenzamide (2.5 g) was dissolved in ethanol (35 ml), and 1N-hydrochloric acid water (6.5 ml) was added,
Iron powder (1.3 g) was added, and the mixture was heated with stirring for 2 hours. The insoluble matter was filtered off, the solvent was distilled off, the solution was neutralized with a 10% sodium hydroxide solution, and then extracted with ethyl acetate, washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. Purification with (hexane: ethyl acetate = 3: 1) gave 1.3 g (58%) of an oily product of N- (4-dimethylaminophenyl) -N-geranyl-2-aminobenzamide. (3) N- (4-dimethylaminophenyl) -N-.
To a solution of geranyl-2-aminobenzamide (0.8 g) in dichloromethane (10 ml) was added heptylisocyanate (0.56 g) under ice cooling, and the mixture was stirred overnight while gradually returning to room temperature. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purified in 1), N- (4-dimethylaminophenyl)
An oil of -N-geranyl-2- (3-heptylureido) benzamide (0.98 g, 89%) was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 8.55 (1H, br.s), 8.04 (1H, d, J = 8H
z), 7.14 (1H, br.s), 6.46-6.81 (6H, m), 5.33 (1H, br.s), 5.0
3-5.05 (1H, m), 4.77 (2H, br.s), 4.43 (1H, br.s), 3.21-3.27
(2H, m), 2.88 (6H, s), 0.87-2.13 (26H, m) IR (cm ^-1 ) 3350,2920,1620,1590,1520,1450,1230 (4) N- (4-dimethylamino Phenyl) -N-geranyl-2- (3-heptylureido) benzamide (0.91 g) was subjected to the same reaction procedure as in Example 1 (4) to give N- (4-dimethylaminophenyl) -N-geranyl-2-. (3-heptylureido) benzamide 1
An amorphous solid of the hydrochloride salt (0.95 g, 98%) was obtained.

Example 4 1- [2- {N- (4-dimethylaminophenyl) -N
-Geranylaminomethyl} phenyl] -3-heptylurea

[Chemical 52] (1) N, N-dimethyl-N'-geranyl-N'-
(2-Nitrobenzyl) -1,4-phenylenediamine (1.0 g) was dissolved in ethanol (20 ml) and 1N-
Hydrochloric acid water (2.5 ml) and iron powder (0.6 g) were added, and the mixture was heated with stirring for 2 hours. The insoluble matter was filtered off, the solvent was distilled off, the solution was neutralized with a 10% sodium hydroxide solution, extracted with ethyl acetate, washed with water,
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), N- (2-aminobenzyl) -N-geranyl-N. Oil of ', N'-dimethyl-1,4-phenylenediamine (0.58 g,
62%) was obtained. (2) N- (2-aminobenzyl) -N-geranyl-
Heptylisocyanate (0.3 g) was added to a dichloromethane (10 ml) solution of N ', N'-dimethyl-1,4-phenylenediamine (0.54 g) under ice cooling, and the mixture was stirred overnight while gradually returning to room temperature. . The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 3: 1), 1- [2- {N-
An oily product of (4-dimethylaminophenyl) -N-geranylaminomethyl} phenyl] -3-heptylurea (0.62 g, 85%) was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 8.82 (1H, d, J = 12Hz), 7.75 (1H, t,
J = 8Hz), 6.69-7.26 (7H, m), 4.99-5.20 (2H, m), 4.32-4.35 (1
H, m), 4.16 (2H, s), 3.59 (2H, d, J = 6Hz), 3.12-3.18 (2H, m),
2.88 (6H, s), 0.86-2.04 (26H, m) IR (cm ^-1 ) 3320,2930,2850,1650,1550,1520,1450,1240 (3) 1- [2- {N- (4- Dimethylaminophenyl) -N-geranylaminomethyl} phenyl] -3-heptylurea (0.6 g) was used in the same manner as in Example 1 (4) to give 1- [2- {N- (4-dimethylaminophenyl)-. N-geranylaminomethyl} phenyl] -3-heptylurea dihydrochloride amorphous solid (0.7 g, 99
%) Was obtained.

Example 5 1- [2- {N-geranyl-N- (3,4-methylenedioxyphenyl) aminomethyl} phenyl] -3-heptylurea

[Chemical 53] The title compound was obtained by the same reaction procedure as in Example 4. ¹ H-NMR (δ ppm, CDCl ₃ ) 8.29 (1H, d, J = 19Hz), 7.89 (1H, t,
J = 9Hz), 6.43-7.28 (6H, m), 5.91 (2H, d, J = 3Hz), 4.97-5.18
(2H, m), 4.32-4.35 (1H, m), 4.16 (2H, s), 3.62 (2H, d, J = 6H
z), 3.12-3.18 (2H, m), 0.86-2.15 (26H, m) IR (cm ^-1 ) 3340,2940,2850,1640,1560,1510,1500,1220,1
050

Example 6 N- {2- (3-heptylureido) phenyl} -3,
5-di-t-butyl-4-hydroxybenzamide and N- {2- (3-heptylureido) phenyl} -3,
5-di-t-butyl-4-{(N-heptyl) carbamoyloxy} benzamide

[Chemical 54] (1) To a solution of 3,5-di-t-butyl-4-hydroxybenzoic acid (5.0 g) in methylene chloride (20 ml) was added dicyclohexylcarbodiimide (2.17 g), and the mixture was stirred overnight at room temperature. Triethylamine (2.1m
l), 4-dimethylaminopyridine (0.37 g) and o-phenylenediamine (1.08 g) were added, and the mixture was stirred at room temperature overnight. The insoluble material was filtered, the filtrate was concentrated, the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1), and crystallized from diisopropyl ether to give N- (2-aminophenyl) -3,5-di −
1.10 g of t-butyl-4-hydroxybenzamide
(32%) was obtained. (2) n-caprylic acid (0.32 g), diphenylphosphoryl azide (0.53 ml) and triethylamine (0.34 ml) in toluene (5 ml) at room temperature for 3 hours,
Furthermore, it stirred at 80-90 degreeC for 2 hours. Under ice cooling,
N- (2-aminophenyl) -3,5-di-t-butyl-4-hydroxybenzamide (0.51 g) was added,
Stir for 3 hours while gradually returning to room temperature. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1), and N-
{2- (3-heptylureido) phenyl} -3,5-
Crystals of di-t-butyl-4-hydroxybenzamide (0.25 g, 35%)

Mp95-100 ° C. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.93 (1H, br.s), 7.84 (2H, s), 7.6
4 (1H, d, J = 7Hz), 7.09-7.04 (2H, m), 6.87 (1H, t, J = 7Hz), 6.6
2 (1H, br.d), 5.64 (1H, s), 5.28 (1H, br.s), 3.09 (2H, q-lik
e, J = 7Hz), 1.48 (18H, s), 1.44-1.20 (10H, m), 0.85 (3H, t, J =
7Hz) IR (cm ^-1 ) 3336,2956,2928,1638,1600,1561,1516,1430,1
307,1236,1114,751 and N- {2- (3-heptylureido) phenyl}-
Crystals of 3,5-di-t-butyl-4-{(N-heptyl) carbamoyloxy} benzamide (0.28 g, 3
0%). mp 120-122 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.87 (1H, br.s), 7.93 (2H, s), 7.7
4 (1H, d, J = 8Hz), 7.08 (1H, t, J = 8Hz), 6.98-6.90 (2H, m), 6.8
4 (1H, br.s), 5.17 (1H, br.t), 3.29 (2H, q-like, J = 6Hz), 3.0
9 (2H, q-like, J = 6Hz), 1.43-1.20 (38H, m), 0.90 (3H, t, J = 6H
z), 0.86 (3H, t, J = 6Hz) IR (cm ^-1 ) 3374,2954,2930,1712,1680,1644,1544,1520,1
422,1246,1199,752

Example 7 N- [2- {3- (2,2-diphenylethyl) ureido} phenyl] -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 55] The title compound was obtained by the same reaction procedure using 3,3-diphenylpropionic acid in place of n-caprylic acid in Example 6. mp 198-200 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.74 (1H, s), 7.83 (2H, s), 6.96 (1
H, s), 6.54-7.49 (14H, m), 5.64 (1H, s), 5.18-5.20 (1H, m),
4.15 (1H, t, J = 8Hz), 3.79 (2H, dd, J = 8,6Hz), 1.48 (18H, s) IR (cm ^-1 ) 3620,3314,2958,1639,1545,1431,1309, 1233,7
55,701

Example 8 N- {2- (3,3-dibenzylureido) phenyl}
-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 56] (1) N- (2-aminophenyl) -3,5-di-t
-Butyl-4-hydroxybenzamide (0.85g)
And diishipropylamine (0.39 ml) were suspended in dichloromethane (20 ml), and phenyl chloroformate (1
A solution of 6.8 g) in dichloromethane (30 ml) was added dropwise. After stirring overnight at room temperature, this reaction solution was washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1), and hexane-
Crystallized from ethyl acetate to give phenyl N- {2-
(3,5-di-t-butyl-4-hydroxybenzoylamino) phenyl} carbamate (12.6 g, 49
%) Was obtained. (2) Phenyl N- {2- (3,5-di-t-butyl-4-hydroxybenzoylamino) phenyl} carbamate (1.6 g) and dibenzylamine (0.7 g) were dissolved in benzene (10 ml). The mixture was stirred at 70-80 ° C for 2 hours. The reaction solution was washed with a 2N aqueous sodium hydroxide solution and a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by a silica gel column and crystallized from ether. N- {2-
(3,3-Dibenzylureido) phenyl} -3,5-di-t-butyl-4-hydroxybenzamide (0.47)
g, 23%). mp187-189 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.53 (1H, s), 7.79 (2H, s), 7.56 (1
H, dd, J = 8,1Hz), 7.25-7.14 (11H, m), 7.10-6.90 (3H, m), 5.5
9 (1H, s), 4.57 (4H, s), 1.45 (18H, s) IR (cm ^-1 ) 3620,3220,1638,1602,1524,1500,1454,1436,1
381,1238,748,700

Example 9 1- [N- {2- (3,5-di-t-butyl-4-hydroxybenzamido) phenyl} carbamoyl] -4-
Methylpiperazine

[Chemical 57] The title compound was obtained by the same reaction procedure using N-methylpiperazine instead of dibenzylamine in Example 8. mp169-171 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.51 (1H, s), 7.99 (1H, s), 7.80 (2
H, s), 7.28-7.24 (1H, m), 7.13 (1H, d, J = 8Hz), 6.87-6.73 (2
H, m), 5.64 (1H, s), 3.53 (4H, t, J = 5Hz), 2.39 (4H, t, J = 5Hz),
1.52 (18H, s) IR (cm ^-1 ) 3630,3540,3310,2960,2800,1645,1600,1530,1
435,, 1305,1260,1240,1110,1005,755

Example 10 N- {2- (3-cyclopentyl) ureido} phenyl-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 58] The title compound was obtained by the same reaction procedure using cyclopentylamine instead of dibenzylamine in Example 8. mp195-197 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.65 (1H, s), 7.83 (2H, s), 7.67 (1
H, d, J = 7Hz), 7.12-7.06 (1H, m), 6.96-6.90 (2H, m), 6.86-6.
80 (1H, m), 5.63 (1H, s), 4.96 (1H, d, J = 7Hz), 4.08-3.94 (1H,
m), 1.96-1.81 (2H, m), 1.72-1.02 (6H, m), 1.49 (s, 18H) IR (cm ^-1 ) 3640,3630,3330,2960,1640,1580,1530,1440,1
320,1228,896,750

Example 11 N- {2- (3-adamantyl) ureido} phenyl-
3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 59] The title compound was obtained by the same reaction procedure using 1-adamantylamine instead of dibenzylamine of Example 8. mp204-205 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.79 (1H, s), 7.87 (2H, s), 7.63 (1
H, dd, J = 8Hz, 2Hz), 7.07 (1H, ddd, J = 8Hz, 8Hz, 2Hz), 6.90 (1
H, ddd, J = 8Hz, 8Hz, 2Hz), 6.80-6.73 (2H, m), 5.63 (1H, s), 4.
80 (1H, s), 2.00 (3H, br.s), 1.87 (6H, d, J = 2Hz), 1.61 (1H, d,
J = 3Hz), 1.50 (18H, s) IR (cm ^-1 ) 3630,3360,3310,2915,1685,1640,1600,1555,1
520,1485,1435,1300,1240,755

Example 12 N- [2- {3-benzyl-3- (2-pyridylmethyl) ureido} phenyl] -3,5-di-t-butyl-
4-hydroxybenzamide

[Chemical 60] The title compound was obtained by the same reaction procedure using 2- (N-benzylaminomethyl) pyridine in place of the dibenzylamine of Example 8. mp162-163 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.85 (1H, br.s), 8.51 (1H, d, J = 4H
z), 7.93-7.86 (3H, m), 7.56 (1H, ddd, J = 8Hz, 8Hz, 2Hz), 7.25
-7.07 (10H, m), 6.90 (1H, d, J = 7Hz), 5.56 (1H, s), 4.67 (2H,
s), 4.42 (2H, br.s), 1.44 (18H, s) IR (cm ^-1 ) 3640,3500,3270,2960,1645,1600,1540,1480,1
430,1314,1236,764

Example 13 N- {2- (3-heptyl-3-methyl) ureido} phenyl-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical formula 61] The title compound was obtained by the same reaction procedure using N-methylheptylamine in place of the dibenzylamine of Example 8. mp156-157 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.43 (1H, br.s), 7.84 (2H, s), 7.5
5-7.50 (1H, m), 7.29-7.24 (1H, m), 7.17-7.11 (1H, m), 7.06-
7.00 (2H, m), 5.62 (1H, s), 3.32 (2H, d, J = 8Hz), 2.99 (3H, s),
1.58-1.50 (2H, m), 1.50 (18H, m), 1.31-1.16 (8H, m), 0.86 (3
H, t, J = 7Hz) IR (cm ^-1 ) 3625,3605,3260,2960,2930,1635,1600,1520,1
490,1435,1310,1235,750

Example 14 1- [2- {N- (3,5-di-t-butyl-4-hydroxybenzyl) aminomethyl} phenyl] -3-heptylurea

[Chemical formula 62] (1) To a suspension of sodium borohydride (2.72 g) in tetrahydrofuran (80 ml) was added BF3. E
t2O (8.86 ml) was added dropwise and the mixture was stirred for 30 minutes. Under ice cooling, N- (2-aminophenyl) -3,5-di-t was added.
-Butyl-4-hydroxybenzamide (3.06 g)
Was added little by little, and the mixture was stirred overnight while gradually returning to room temperature.
After adding 6N hydrochloric acid to this and heating under reflux for 30 minutes, the solvent was distilled off, poured into water and neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give crystals of (2-aminophenyl) -3,5-di-t-butyl-4-hydroxybenzylamine (2. 00g,
68%). (2) n-caprylic acid (0.15 g), diphenylphosphoryl azide (0.28 ml) and triethylamine (0.21 ml) in toluene (5 ml) at room temperature for 3 hours,
Further, the mixture is stirred at 80 to 90 ° C for 2 hours. Under ice cooling,
(2-Aminophenyl) -3,5-di-t-butyl-4-
A solution of hydroxybenzylamine (0.34 g) in toluene (5 ml) was added, and the mixture was stirred overnight while gradually returning to room temperature. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give 1- [2- {N- (3,5-di-t-butyl-4-hydroxy). Benzyl) aminomethyl} phenyl]
Crystals of -3-heptylurea (0.31 g, 64%) were obtained. mp135-138 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.21 (1H, t, J = 7Hz), 7.12 (2H, s),
7.11 (1H, d, J = 7Hz), 6.78 (1H, d, J = 7Hz), 6.71 (1H, t, J = 7H
z), 5.53 (1H, br.s), 5.20 (1H, s), 4.60 (1H, br.t), 4.45 (1H,
br.s), 4.17 (2H, br.s), 3.16 (2H, q-like, J = 7Hz), 1.50-1.4
0 (20H, m), 1.35-1.20 (8H, m), 0.86 (3H, t, J = 7Hz) IR (cm ^-1 ) 3634,3324,2954,2928,1639,1568,1504,1432,1
236,746

Example 15 1- [2- {N-acetyl-N- (3,5-di-t-butyl-4-hydroxybenzyl) aminomethyl} phenyl] -3-heptylurea

[Chemical formula 63] 1- [2- {N- (3,5-di-t-butyl-4-hydroxybenzyl) aminomethyl} phenyl] -3-heptylurea (0.23 g), 4-dimethylaminopyridine (0.02 g) and Triethylamine (0.14 ml) was dissolved in toluene (5 ml), and acetic anhydride (0.05 m) was added under ice cooling.
l) was added, and the mixture was stirred overnight while gradually returning to room temperature. The solvent was distilled off, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid, washed with aqueous sodium hydrogen carbonate solution, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, distilled off the solvent, and crystallized from hexane.
1- [2- {N-acetyl-N- (3,5-di-t-butyl-4-hydroxybenzyl) aminomethyl} phenyl] -3-heptylurea (0.24 g, 96%) was obtained. mp125-128 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 8.40 (1H, d, J = 8Hz), 7.36 (1H, br.
s), 7.29 (1H, t, J = 8Hz), 6.95 (2H, s), 6.85 (1H, t, J = 8Hz), 6.
69 (1H, d, J = 8Hz), 5.86 (1H, br.s), 5.19 (1H, s), 5.03 (1H, b
rd, J = 14Hz), 4.46 (1H, br.d, J = 14Hz), 3.16 (2H, m), 1.84 (3
H, s), 1.35 (18H, s), 1.40-1.20 (10H, m), 0.86 (3H, t, J = 7Hz) IR (cm ^-1 ) 3360,2954,2928,1692,1627,1548,1456 , 1286,1
231,1101,749

Example 16 N- {2- (3-heptylureido) phenyl} -N-
Methyl-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 64] (1) n-Caprylic acid (1.44 g), diphenylphosphoryl azide (2.80 ml) and triethylamine (2.09 ml) were stirred in toluene (10 ml) at room temperature for 3 hours and further at 80-90 ° C for 2 hours. . This was ice-cooled and N-methyl-1,2-phenylenediamine (1.22
g) is added, and the mixture is stirred overnight while gradually returning to room temperature. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2
-(3-heptyl) ureidophenyl 3,5-di-t-
Crystals of butyl-4-hydroxybenzoate (1.58)
g, 63%). This crystal (0.50 g), 3,5-
Di-t-butyl-4-hydroxybenzoic acid (0.50
g) and dicyclohexylcarbodiimide (0.42)
g) was stirred in dichloromethane (5 ml) at room temperature overnight. The insoluble material was removed by filtration, the solvent was evaporated, and the residue was crystallized from hexane to give N- {2- (3-heptylureido) phenyl} -N-methyl-3,5-di-t-butyl- 4-Hydroxybenzamide (2.31 g, 93%)
Got mp 193-196 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 8.38 (1H, d, J = 7Hz), 8.14 (1H, br.
s), 7.11 (1H, t, J = 7Hz), 6.96 (2H, br.s), 6.89 (1H, br.s), 6.
64 (1H, t, J = 7Hz), 6.54 (1H, t, J = 7Hz), 5.22 (1H, s), 3.35 (2
H, m), 3.17 (3H, br.s), 1.50-1.25 (10H, m), 1.14 (18H, s), 0.
89 (3H, t, J = 9Hz) IR (cm ^-1 ) 3358,2951,2926,1697,1617,1544,1455,1416,1
373,1300,1235,1102

Example 17 N- {2- (3-Cyclopentyl) ureido-5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 65] (1) 4-methoxy-2-nitroaniline (15.0
g) and diisopropylamine (16.2 ml) were dissolved in dichloromethane (300 ml), and a solution of phenyl chloroformate (16.8 g) in dichloromethane (30 ml) was added dropwise under ice cooling. After stirring overnight at room temperature, this reaction solution was washed with water, saturated saline solution, dried over anhydrous magnesium sulfate, the solvent was distilled off and crystallized from hexane to give a crystal of phenyl 4-methoxy-2-nitrophenylcarbamate ( 12.6
g, 49.1%). (2) Phenyl 4-methoxy-2-nitrophenyl carbamate (1.1 g) and cyclopentylamine (0.1 g).
37 g) was dissolved in xylene (10 ml) and then heated under reflux for 2 hours. After cooling, the precipitated crystals were filtered, washed with xylene and dried to give 1- (4-methoxy-2-nitrophenyl) -3-cyclopentylurea crystals (0.97 g,
87%). (3) 1- (4-methoxy-2-nitrophenyl)-
A catalytic amount of 10% palladium carbon was added to a suspension of 3-cyclopentylurea (0.96 g) in ethanol (15 ml), and the mixture was catalytically reduced at room temperature at 1 to 2.5 atm for 2 hours. After filtering the catalyst, the solvent was distilled off and crystallized from benzene and hexane to give 1- (2-amino-4-methoxyphenyl)-
3-Cyclopentylurea (0.79 g, 93%) was obtained. (4) 1- (2-amino-4-methoxyphenyl)-
3-Cyclopentylurea (0.66 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (0.59 g), 3,5-di-t-butyl-4
-Hydroxybenzoic acid (0.78g) was dissolved in dichloromethane (70ml) and stirred at room temperature overnight. The reaction mixture was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was crystallized from ethyl acetate to give N-
{2- (3-Cyclopentyl) ureido-5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide (0.92 g, 71%) was obtained. mp204-205 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.27 (1H, br.s), 7.79 (2H, s), 7.6
3 (1H, br.s), 6.91 (1H, d, J = 9Hz), 6.58 (1H, dd, J = 9Hz, 3Hz),
6.33 (1H, br.s), 5.63 (1H, s), 4.66 (1H, d, J = 7Hz), 3.95-4.0
7 (1H, m), 3.77 (3H, s), 1.85-1.92 (2H, m), 1.51-1.58 (4H,
m), 1.48 (18H, s), 1.21-1.30 (2H, m) IR (cm ^-1 ) 3630,3300,2950,1650,1540,1320,1240,1220,1
070,1040

Example 18 N- {2- (3-heptylureido) -5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical formula 66] The title compound was obtained by the same reaction procedure using heptylamine instead of cyclopentylamine of Example 17. mp 150-151 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.35 (1H, br.s), 7.79 (2H, s), 7.6
7 (1H, br.s), 6.86 (1H, d, J = 9Hz), 6.57 (1H, dd, J = 9Hz, 3Hz),
6.36 (1H, br.s), 5.64 (1H, s), 4.82 (1H, s), 3.79 (3H, s), 3.1
1-3.16 (2H, m), 1.48 (18H, s), 1.20-1.26 (10H, m), 0.84 (3H,
t, J = 7Hz) IR (cm ^-1 ) 3400,2880,2870,1640,1560,1520,1430,1300,1
240

Example 19 N- {2- (3-adamantylureido) -5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical formula 67] The title compound was obtained by the same reaction procedure using 1-adamantylamine in place of cyclopentylamine of Example 17. mp 198-199 ° C ¹ H-NMR (δ ppm, DMSO) 10.38 (1H, br.s), 7.78 (1H, br.s),
7.73 (2H, s), 7.55 (1H, br.s), 7.24 (1H, d, J = 2Hz), 7.15 (1H,
d, J = 9Hz), 6.69 (1H, dd, J = 9Hz, 2Hz), 6.26 (1H, br.s), 3.72
(3H, s), 1.99-2.05 (3H, m), 1.90-1.99 (6H, m), 1.53-1.68 (6
H, m), 1.43 (18H, s) IR (cm ^-1 ) 3400,2880,2860,1680,1640,1520,1430,1300,1
280,1240

Example 20 N- {2- (3,3-dibenzylureido) -5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 68] The title compound was obtained by the same reaction procedure using dibenzylamine instead of cyclopentylamine of Example 17. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.82 (1H, s), 7.86 (2H, s), 7.15-
7.36 (11H, m), 6.99 (1H, s), 6.68 (1H, d, J = 9Hz), 6.54 (1H, d
d, J = 9Hz, 3Hz), 5.59 (1H, s), 4.56 (4H, s), 3.62 (3H, s), 1.44
(18H, s) IR (cm ^-1 ) 3600,3250,2950,1640,1600,1520,1500,1450,1
430,1300,1240,700

Example 21 N- {2- (3-heptyl-3-methylureido) -5
-Methoxyphenyl} -3,5-di-t-butyl-4-
Hydroxybenzamide

[Chemical 69] The title compound was obtained by the same reaction procedure using N-methylheptylamine in place of the cyclopentylamine of Example 17. mp152-153 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.70 (1H, br.s), 7.86 (2H, s), 7.2
9 (1H, d, J = 3Hz), 7.06 (1H, d, J = 9Hz), 6.84 (1H, s), 6.59 (1H,
dd, J = 9Hz, 3Hz), 5.61 (1H, s), 3.65 (3H, s), 3.31 (2H, t, J = 8H
z), 2.98 (3H, s), 1.50 (18H, s), 1.20-1.30 (10H, m), 0.86 (3
H, t, J = 7Hz) IR (cm ^-1 ) 3470,3270,2880,2870,1610,1520,1420,1240

Example 22 1- [N- {2- (3,5-di-t-butyl-4-hydroxybenzamido) phenyl} carbamoyl] -4-
Methylpiperazine

[Chemical 70] The title compound was obtained by the same reaction procedure using N-methylpiperazine instead of cyclopentylamine of Example 17. mp 160-161 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.56 (1H, s), 7.84 (2H, s), 7.51 (1
H, s), 7.02-7.05 (2H, m), 6.54 (1H, dd, J = 9Hz, 3Hz), 5.63 (1
H, s), 3.53 (4H, t, J = 5Hz), 3.45 (3H, s), 2.41 (4H, t, J = 5Hz),
2.31 (3H, s), 1.51 (18H, s) IR (cm ^-1 ) 3450,3250,2950,1640,1600,1500,1440,1300,1
260,1240,1090,1000 Then, by the same reaction operation as in Example 1 (4), 1
Crystals of-[N- {2- (3,5-di-t-butyl-4-hydroxybenzamido) phenyl} carbamoyl] -4-methylpiperazine monohydrochloride were obtained. mp184-185 ℃

Example 23 N- [2- {3- (2-pyridylmethyl) ureido}-
5-Methoxyphenyl] -3,5-di-t-butyl-4
-Hydroxybenzamide

[Chemical 71] The title compound was obtained by the same reaction procedure using 2- (aminomethyl) pyridine instead of cyclopentylamine of Example 17. mp181-182 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.65 (1H, s), 8.34 (1H, d, J = 4Hz),
7.79 (2H, s), 7.63 (1H, s), 7.46 (1H, t, J = 7Hz), 7.26 (1H, s),
7.13 (1H, d, J = 8Hz), 7.05-7.12 (1H, m), 6.88 (1H, d, J = 9Hz),
6.56 (, H, dd, J = 9Hz, 2Hz), 6.11 (1H, br.s), 5.60 (1H, s), 4.4
9 (2H, d, J = 5Hz), 3.75 (3H, s), 1.41 (18H, s) IR (cm ^-1 ) 3400,2950,1640,1600,1520,1430,1320,1240,1
200,1110

Example 24 N- [2- {3-benzyl-3- (2-pyridylmethyl) ureido} -5-methoxyphenyl] -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 72] Instead of the cyclopentylamine of Example 17, 2- (N
The title compound was obtained by the same reaction procedure using -benzylaminomethyl) pyridine. mp165-166 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 10.00 (1H, br.s), 8.49 (1H, d, J = 4
Hz), 7.90 (2H, s), 7.64 (1H, d, J = 2Hz), 7.54-7.58 (1H, m), 7.
12-7.22 (7H, m), 7.03 (1H, d, J = 9Hz), 6.89 (1H, d, J = 8Hz), 6.
69 (1H, dd, J = 9Hz, 3Hz), 5.57 (1H, s), 4.66 (2H, s), 4.42 (2H,
s), 3.82 (3H, s), 1.44 (18H, s) IR (cm ^-1 ) 3450,2950,1650,1600,1530,1480,1420,1260,1
240. Then, by the same reaction operation as in Example 1 (4), N
-[2- {3-benzyl-3- (2-pyridylmethyl)
Ureido} -5-methoxyphenyl] -3,5-di-t
Crystals of -butyl-4-hydroxybenzamide monohydrochloride were obtained. mp142-144 ℃

Example 25 N- [2- {3- (3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) ureido} -5-
Methoxyphenyl] -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical formula 73] Instead of the cyclopentylamine of Example 17, 7-amino-3,9-dimethyl-3,9-diazabicyclo [3.3.
1] The title compound was obtained by the same reaction procedure using nonane. mp210-211 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 8.84 (1H, br.s), 8.10 (1H, d, J = 2H
z), 7.75 (2H, s), 7.26 (1H, s), 7.11 (1H, d, J = 8Hz), 6.69 (1H,
dd, J = 8Hz, 3Hz), 5.65 (1H, s), 5.64 (1H, s), 4.25 (1H, t, J = 7H
z), 3.84 (3H, s), 2.68 (2H, br.s), 2.40 (3H, s), 2.26-2.35 (6
H, m), 1.61-1.67 (3H, m), 1.48 (18H, s), 1.25 (2H, d, J = 14Hz) IR (cm ^-1 ) 3420,3250,2950,1650,1530,1500,1430 , 1260,1
240. Then, by the same reaction operation as in Example 1 (4), N
-[2- {3- (3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) ureido} -5-methoxyphenyl] -3,5-di-t-butyl Crystals of -4-hydroxybenzamide dihydrochloride were obtained. mp265-270 ℃

Example 26 N- {2- (3-benzyl-3-cycloheptylureido) -5-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 74] The title compound was obtained by the same reaction procedure using N-benzylcycloheptylamine in place of the cyclopentylamine of Example 17. mp125-130 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.94 (1H, s), 7.89 (2H, s), 7.48 (1
H, s), 7.33-7.18 (5H, m), 6.53-6.41 (2H, m), 6.34-6.22 (1H,
m), 5.60 (1H, s), 4.48 (2H, s), 4.48-4.36 (1H, m), 3.69 (3H,
s), 1.95-1.85 (2H, m), 1.72-1.50 (10H, s), 1.50 (18H, s) IR (cm ^-1 ) 3420,3400,3280,2928,1640,1602,1516,1238,6
97

Example 27 N- [2- {3-Cycloheptyl-3- (2-pyridylmethyl) ureido} -5-methoxyphenyl] -3,5
-Di-t-butyl-4-hydroxybenzamide

[Chemical 75] Instead of the cyclopentylamine of Example 17, 2- (N
The title compound was obtained by the same reaction procedure using -cycloheptylaminomethyl) pyridine. mp165-166 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 10.12 (1H, br.s), 9.63 (1H, br),
8.48 (1H, d, J = 5Hz), 7.90 (2H, s), 7.73-7.65 (2H, m), 7.31 (1
H, d, J = 8Hz), 7.27-7.20 (1H, m), 7.01 (1H, d, J = 9Hz), 6.65 (1
H, dd, J = 10Hz, 3Hz), 5.57 (1H, s), 4.45 (2H, s), 4.40-4.31 (1
H, m), 3.82 (3H, s), 1.84-1.74 (2H, m), 1.73-1.50 (10H, m),
1.49 (18H, s) IR (cm ^-1 ) 3470,3240,2928,1662,1635,1599,1522,1469,1
426,1400,1304,1239

Example 28 N- [2- {3- (2,4-difluorobenzyl) -3
-(2-Pyridylmethyl) ureido} -5-methoxyphenyl] -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 76] 2- {N instead of cyclopentylamine of Example 17
The title compound was obtained by the same reaction procedure using-(2,4-difluorobenzyl) aminomethyl} pyridine. mp176-178 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.84 (1H, br.s), 9.63 (1H, br), 8.
46 (1H, d, J = 4Hz), 7.86 (2H, s), 7.66-7.58 (2H, m), 7.28-7.1
6 (2H, m), 7.12-7.06 (2H, m), 6.78-6.66 (2H, m), 6.53-6.46
(1H, m), 5.58 (1H, s), 4.66 (2H, s), 4.43 (2H, s), 3.82 (3H,
s), 1.44 (18H, s) IR (cm ^-1 ) 3520,3300,2958,1645,1611,1545,1537,1507,1
484,1428,1238,850

Example 29 N- [2- {3-benzyl-3- (3-pyridylmethyl) ureido} -5-methoxyphenyl] -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 77] Instead of the cyclopentylamine of Example 17, 3- (N
The title compound was obtained by the same reaction procedure using -benzylaminomethyl) pyridine. mp 120-128 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.64 (1H, s), 8.48-8.42 (2H, m),
7.81 (2H, s), 7.55-7.46 (2H, m), 7.26-7.07 (7H, m), 6.89 (1
H, d, J = 9Hz), 6.56 (1H, dd, J = 9.3Hz), 5.64 (1H, s), 4.58 (2H,
s), 4.50 (2H, s), 3.55 (3H, s), 1.45 (18H, s) IR (cm ^-1 ) 3430,3230,2960,1640,1620,1524,1215,1110,7
13,700

Example 30 N- {5-fluoro-2- (3-heptylureido) phenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 78] (1) 4-Fluoro-2-nitroaniline (1.56
g), heptyl isocyanate (1.41 g) and 4-
Dimethylaminopyridine (0.37g) was added to toluene (5m
In 1), the mixture was stirred at 80-90 ° C for 5 hours. This solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, washed with sodium hydrogen carbonate solution, washed with water, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained crystals are washed with hexane 1
-(4-Fluoro-2-nitrophenyl) -3-heptylurea (1.95 g, 66%) was obtained. (2) 1- (4-fluoro-2-nitrophenyl)-
3-Heptylurea (1.49g) in ethanol (10m
l) Add a catalytic amount of 10% palladium carbon to the suspension,
Catalytic reduction was carried out for 5 hours at room temperature at 1 to 2.5 atm. The catalyst was filtered, the solvent was distilled off, and the residue was crystallized from hexane to give 1- (2
-Amino-4-fluorophenyl) -3-heptylurea (1.26 g, 95%) was obtained. (3) 1- (2-amino-4-fluorophenyl)-
3-Cyclopentylurea (1.07 g), 3,5-di-
t-Butyl-4-hydroxybenzoic acid (1.00 g) and dicyclohexylcarbodiimide (0.99 g) were stirred in dichloromethane (35 ml) at room temperature for 3 hours. The insoluble material was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1) to give N- {5-fluoro-2-
(3-heptylureido) phenyl} -3,5-di-t
-Butyl-4-hydroxybenzamide crystal (1.3
5g, 68%) was obtained. mp 192-194 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 10.02 (1H, br.s), 7.82 (2H, s), 7.
75 (1H, m), 6.98 (1H, br.s), 6.65 (1H, m), 6.57 (1H, m), 5.66
(1H, s), 5.21 (1H, br.s), 3.12 (2H, d, J = 6Hz), 1.50-1.40 (2
H, m), 1.47 (18H, s), 1.30-1.20 (8H, m), 0.85 (3H, t, J = 6Hz) IR (cm ^-1 ) 3628,3346,2954,2928,1640,1532,1430 , 1237

Example 31 N- {2- (3-adamantylureido) -5-fluorophenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 79] The title compound was obtained by the same reaction procedure using 1-adamantyl isocyanate instead of heptyl isocyanate of Example 30. mp182-185 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.62 (1H, br.s), 7.82 (2H, s), 7.6
6 (1H, dd, J = 10Hz, 3Hz), 6.91 (1H, dd, J = 9Hz, 6Hz), 6.88 (1H,
m), 6.38 (1H, br.s), 5.66 (1H, s), 4.53 (1H, br.s), 2.02 (3H,
br.s), 1.89 (6H, br.s), 1.64 (6H, br.s), 1.50 (18H, s) IR (cm ^-1 ) 3604,3404,3262,2908,1649,1615,1543,1433 , 1
238,756

Example 32 N- {5-fluoro-2- (3-heptyl-3-methylureido) phenyl} -3,5-di-t-butyl-4-
Hydroxybenzamide

[Chemical 80] (1) 4-Fluoro-2-nitroaniline (1.56
g) and diisopropylamine (1.68 ml) were dissolved in dichloromethane (20 ml), and phenyl chloroformate (1.51 g) was added dropwise under ice cooling. After stirring overnight at room temperature,
The reaction solution was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was crystallized from diisopropyl ether to give crystals of phenyl 4-fluoro-2-nitrophenylcarbamate (0.79 g, 29%). ) Got. (2) Phenyl 4-fluoro-2-nitrophenyl carbamate (0.70 g) and N-methylheptylamine (0.33 g) were dissolved in xylene (5 ml) and heated under reflux for 2 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1).
The oily substance of 1- (4-fluoro-2-nitrophenyl) -3-heptyl-3-methylurea was obtained. (3) Suspend this in ethanol (15 ml) and add 10%
A catalytic amount of palladium carbon was added, and catalytic reduction was performed at room temperature at 1 to 2.5 atm for 2 hours. The catalyst was filtered off, the solvent was distilled off, and 1- (2-amino-4-fluorophenyl) -3-
Heptyl-3-methylurea oil (0.82 g, 9
9%) was obtained. (4) 1- (2-amino-4-fluorophenyl)-
3-heptyl-3-methylurea (0.82 g), 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride (0.67 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.88 g) were dissolved in dichloromethane (10 ml) at room temperature. Stir overnight. The reaction solution was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain N- {5- Fluoro-2- (3-heptyl-
3-Methylureido) phenyl} -3,5-di-t-butyl-4-hydroxybenzamide (0.84 g, 56
%) Was obtained. mp164-167 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.80 (1H, br.s), 7.82 (2H, s), 7.3
0-7.20 (2H, m), 7.12 (1H, dd, J = 9Hz, 6Hz), 6.55 (1H, m), 5.64
(1H, s), 3.32 (2H, d, J = 7Hz), 3.00 (3H, s), 1.60-1.40 (20H,
m), 1.35-1.20 (8H, m), 0.86 (3H, t, J = 7Hz) IR (cm ^-1 ) 3424,3274,2956,2924,2854,1633,1609,1526,1
432,1315,1241,1112

Example 33 N- {4,5-dichloro-2- (3-heptylureido) phenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 81] (1) 4,5-dichloro-2-nitroaniline (2.0
7 g), heptyl isocyanate (1.41 g) and 4
-Dimethylaminopyridine (0.37g) was stirred in toluene (5ml) at 80-90 ° C for 5 hours. The solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, washed with sodium hydrogen carbonate solution, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: Purification in 1) gave 1- (4,5-dichloro) phenyl-3-heptylurea crystals (2.00 g, 58%). (2) To a suspension of 1- (4,5-dichloro) phenyl-3-heptylurea (1.74 g) in ethanol (10 ml), a catalytic amount of 10% palladium carbon was added to give 1-2.
Catalytic reduction was carried out at room temperature at 5 atm for 5 hours. The catalyst was filtered, the solvent was evaporated, and the residue was crystallized from methanol to give 1- (2-amino-4,5-dichlorophenyl) -3-heptylurea (0.54 g, 34%). (3) 1- (2-amino-4,5-dichlorophenyl) -3-cyclopentylurea (0.48 g), 3,5
-Di-t-butyl-4-hydroxybenzoic acid (0.38
g) and dicyclohexylcarbodiimide (0.37)
g) was stirred in dichloromethane (35 ml) at room temperature for 3 hours. The insoluble material was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give N- {4,5-dichloro-2- (3-heptyl). Ureido) phenyl} -3,
Crystals of 5-di-t-butyl-4-hydroxybenzamide (1.35 g, 68%) were obtained. mp209-212 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 10.16 (1H, br.s), 7.86 (2H, s), 7.
65 (1H, s), 7.52 (1H, br.s), 6.85 (1H, br.s), 5.69 (1H, s), 4.
99 (1H, br.s), 3.15 (2H, q, J = 6Hz), 1.60-1.40 (20H, m), 1.40
-1.20 (8H, m), 0.87 (3H, t, J = 6Hz) IR (cm ^-1 ) 3610,3425,3294,2954,1662,1638,1526,1235

Example 34 N- {2- (3-adamantylureido) -4,5-dichlorophenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical formula 82] The title compound was obtained by the same reaction procedure using 1-adamantyl isocyanate in place of the heptyl isocyanate of Example 33. mp203-207 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.96 (1H, br.s), 8.19 (1H, s), 7.8
8 (1H, br.s), 7.79 (2H, s), 7.57 (1H, s), 7.53 (1H, s), 6.69 (1
H, br.s), 2.01 (3H, br.s), 1.92 (6H, br.s), 1.62 (6H, br.s),
1.43 (18H, s) IR (cm ^-1 ) 3618,3320,2916,2850,1640,1631,1575,1313,1
244,1233

Example 35 N- {4,5-dichloro-2- (3-heptyl-3-methylureido) phenyl} -3,5-di-t-butyl-
4-hydroxybenzamide

[Chemical 83] The title compound was obtained by the same reaction procedure using 4,5-dichloro-2-nitroaniline instead of 4-fluoro-2-nitroaniline of Example 32. mp187-190 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.97 (1H, br.s), 8.07 (1H, br.s),
7.88 (2H, s), 7.39 (1H, s), 7.27 (1H, s), 5.65 (1H, s), 3.34 (2
H, m), 3.03 (3H, s), 1.60-1.50 (20H, m), 1.40-1.20 (8H, m),
0.87 (3H, t, J = 6Hz) IR (cm ^-1 ) 3500,2954,2928,1634,1590,1526,1493,1427,1
320,1234,1116

Example 36 N- {2- (3-heptylureido) -4-methoxyphenyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 84] (1) 4-methoxy-2-nitroaniline (1.68
g) 3,5-Di-t-butyl-4-hydroxybenzoic acid (2.50 g) and dicyclohexylcarbodiimide (2.06 g) were stirred in dichloromethane (12 ml) at room temperature for 6 days. After removing insolubles by filtration and distilling off the solvent,
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) and crystallized from hexane-ethyl acetate to give N- (4-methoxy-2-nitrophenyl) -3,5-di-t. -Butyl-4-hydroxybenzamide (1.56 g, 39%) was obtained. (2) N- (4-methoxy-2-nitrophenyl)-
A catalytic amount of 10% palladium carbon was added to a solution of 3,5-di-t-butyl-4-hydroxybenzamide (1.50 g) in ethanol (10 ml), and catalytic reduction was carried out at room temperature at 1 to 2.5 atm for 5 hours. The catalyst was filtered off, the solvent was distilled off, and the residue was crystallized from hexane-ethyl acetate to give N- (2-amino-4-methoxyphenyl) -3,5-di-t-butyl-
4-Hydroxybenzamide (0.79 g, 57%) was obtained. (3) n-caprylic acid (0.32 g), diphenylphosphoryl azide (0.53 ml) and triethylamine (0.34 ml) in toluene (5 ml) at room temperature for 3 hours,
Furthermore, it stirred at 80-90 degreeC for 2 hours. Under ice cooling,
N- (2-amino-4-methoxyphenyl) -3,5-
Di-t-butyl-4-hydroxybenzamide (0.4
4 g) is added, and the mixture is stirred overnight while gradually returning to room temperature.
The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform), and N- {2- (3-
Heptylureido) -4-methoxyphenyl} -3,5
An amorphous solid of -di-t-butyl-4-hydroxybenzamide (0.57 g, 93%) was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 10.02 (1H, s), 7.88 (2H, s), 7.39
(1H, d, J = 9Hz), 7.31 (1H, s), 6.61 (1H, dd, J = 9Hz, 3Hz), 6.01
(1H, s), 5.64 (1H, s), 5.17 (1H, br.s), 3.36 (3H, s), 3.03 (2
H, td, J = 6Hz, 8Hz), 1.48 (18H, s), 1.40-1.20 (10H, m), 0.87
(3H, t, J = 7Hz) IR (cm ^-1 ) 3630,3300,1632,1516,1432,1237

Example 37 2- (3-heptylureido) phenyl 3,5-di-t
-Butyl-4-hydroxybenzoate

[Chemical 85] n-Caprylic acid (1.44 g), diphenylphosphoryl azide (2.80 ml) and triethylamine (2.09 m)
l) in toluene (10 ml) at room temperature for 3 hours, then 8
Stir at 0-90 ° C for 2 hours. This is ice-cooled, o-aminophenol (1.09 g) is added, and the mixture is stirred overnight while gradually returning to room temperature. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1) to give 1- (2-hydroxyphenyl)
Crystals of -3-heptylurea (1.58 g, 63%) were obtained. The crystals (0.50 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.50 g) and dicyclohexylcarbodiimide (0.42 g) were stirred in dichloromethane (5 ml) at room temperature overnight. The insoluble material was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 10: 1) to give 2- (3-heptyl) ureidophenyl 3,
Crystals of 5-di-t-butyl-4-hydroxybenzoate (0.58 g, 60%) were obtained. mp 160-162 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 8.04 (2H, m), 7.77 (1H, d, J = 8Hz),
7.26 (1H, m), 7.17 (2H, m), 6.12 (1H, br.s), 5.84 (1H, s), 4.6
4 (1H, br.t), 3.16 (2H, q-like, J = 7Hz), 1.60-1.40 (20H, m),
1.40-1.20 (8H, m), 0.86 (3H, t, J = 7Hz) IR (cm ^-1 ) 3312,2958,2928,1736,1720,1645,1600,1552,1
305,1223,1178,1101

Example 38 2- (3-heptylureido) phenyl 3,5-di-t
-Butyl-4-{(N-heptyl) carbamoyloxy} benzoate

[Chemical 86] o-Nitrophenol (1.39 g), 3,5-di-t-
A mixture of butyl-4-hydroxybenzoic acid (2.50 g) and trifluoroacetic anhydride (8.5 ml) was stirred overnight at room temperature. This was poured into ice water, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and crystallized from diisopropyl ether to give 2-nitrophenyl 3,5- The-
t-Butyl-4-hydroxybenzoate (2.60
g, 70%). A catalytic amount of 5% palladium carbon was added to a solution of the crystals (1.11 g) in ethanol (10 ml), and catalytic reduction was carried out at room temperature at 1 to 2.5 atm for 5 hours. After filtering the catalyst, the solvent was distilled off and 2-aminophenyl 3,5
Crystals of -di-t-butyl-4-hydroxybenzoate (0.86 g, 84%) were obtained. n-caprylic acid (0.3
2 g), diphenylphosphoryl azide (0.53 ml) and triethylamine (0.34 ml) in toluene (5 ml)
The mixture is stirred at room temperature for 3 hours and at 80-90 ° C for 2 hours. This was ice-cooled and 2-aminophenyl 3,5-di-t
-Butyl-4-hydroxybenzoate (0.51 g)
Is added, and the mixture is gradually warmed to room temperature and stirred overnight. The solvent was distilled off and the residue was purified by silica gel column to give 2
-(3-heptylureido) phenyl 3,5-di-t-
Butyl-4- {N- (heptyl) carbamoyloxy}
An amorphous solid of benzoate (0.18 g, 19%) was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 7.80-7.78 (3H, m), 7.24 (1H, d, J =
7Hz), 7.19-7.10 (3H, m), 5.26 (1H, br.t), 5.18 (1H, br.t),
3.31-3.21 (4H, m), 1.50-1.20 (38H, m), 0.90-0.80 (6H, m) IR (cm ^-1 ) 3314,2960,2930,1721,1525,1198,1117,749

Example 39 N- {2- (3-heptylureido) -3-pyridyl}
-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 87] (1) 2-amino-3-nitropyridine (1.39
g), heptyl isocyanate (1.41 g) and 4-
Dimethylaminopyridine (0.37g) was added to toluene (5m
In 1), the mixture was stirred at 100-110 ° C for 5 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1-
Crystals of (3-nitro-2-pyridyl) -3-heptylurea (1.03 g, 37%) were obtained. (2) To a suspension of 1- (3-nitro-2-pyridyl) -3-heptylurea (1.00 g) in ethanol (10 ml), a catalytic amount of 10% palladium carbon was added, and 1-2.
Catalytic reduction was carried out at room temperature at 5 atm for 5 hours. The catalyst was filtered, the solvent was distilled off, and the residue was crystallized from hexane to give 1- (3-amino-2-pyridyl) -3-heptylurea (0.89 g,
99%). (3) 1- (3-amino-2-pyridyl) -3-heptylurea (0.80 g), 3,5-di-t-butyl-4
-Hydroxybenzoic acid (0.80 g) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide
Monohydrochloride (0.67g) in dichloromethane (35ml)
The mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give N- {2- (3-heptylureido) -3-pyridyl}. An amorphous solid (1.34 g, 87%) of -3,5-di-t-butyl-4-hydroxybenzamide was obtained. ¹ H-NMR (δ ppm, CDCl ₃ ) 9.58 (1H, br.s), 9.48 (1H, br.s),
9.06 (1H, br.s), 8.34 (1H, dd, J = 8Hz, 1Hz), 7.96 (1H, dd, J = 5
Hz, 1Hz), 7.87 (2H, s), 6.97 (1H, dd, J = 8Hz, 5Hz), 5.59 (1H,
s), 2.86 (2H, q, J = 6Hz), 1.44 (18H, s), 1.40-1.10 (10H, m),
0.85 (3H, t, J = 6Hz) IR (cm ^-1 ) 3622,3250,2956,2926,1679,1564,1424,1311,1
236,1114

Example 40 N- {2- (3-adamantylureido) -3-pyridyl} -3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 88] The title compound was obtained by the same reaction procedure using 1-adamantyl isocyanate in place of the heptyl isocyanate of Example 39. mp 198-202 ° C ¹ H-NMR (δ ppm, CDCl ₃ ) 9.55 (1H, br.s), 9.24 (1H, br.s),
8.38 (1H, br.s), 8.25 (1H, dd, J = 6Hz, 2Hz), 7.97 (1H, dd, J = 5
Hz, 2Hz), 7.89 (2H, s), 6.96 (1H, dd, J = 6Hz, 5Hz), 5.58 (1H,
s), 1.90-1.70 (9H, m), 1.60-1.40 (24H, m) IR (cm ^-1 ) 3732,3266,2908,1681,1562,1455,1319,1237

Example 41 N- {3- (3-heptylureido) -4-pyridyl}
-3,5-di-t-butyl-4-hydroxybenzamide

[Chemical 89] (1) 3,4-Diaminopyridine (1.09 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) in toluene (10 ml),
The mixture was stirred at 50-60 ° C for 5 hours. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol = 4: 1), and crystals of 1- (4-amino-3-pyridyl) -3-heptylurea (1.
09 g, 37%) was obtained. (2) 1- (4-amino-3-pyridyl) -3-heptylurea (0.50 g), 3,5-di-t-butyl-4
-Hydroxybenzoic acid (0.60 g) and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide
Monohydrochloride (0.46 g) in dichloromethane (10 ml)
Inside, stirred at room temperature overnight. The reaction solution was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give N- {3-.
(3-Heptylureido) -4-pyridyl} -3,5-
Crystals of di-t-butyl-4-hydroxybenzamide (0.15 g, 16%) were obtained. mp177-180 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 10.58 (1H, br.s), 8.25 (1H, d, J = 5
Hz), 8.01 (2H, m), 7.89 (2H, s), 7.56 (1H, br.s), 5.69 (1H,
s), 5.52 (1H, br.s), 3.23 (2H, q-like, J = 4Hz), 1.81 (2H, m),
1.49 (18H, s), 1.39-1.21 (8H, m), 1.39-1.21 (3H, t, J = 7Hz) IR (cm ^-1 ) 3360,2954,2928,1646,1590,1510,1434,1317, 1
237,1113

Example 42 N- [2- {3- (1-benzyl-4-piperidyl) ureido} -5-methoxyphenyl] -3,5-di-t-
Butyl-4-hydroxybenzamide

[Chemical 90] The title compound was obtained by the same reaction procedure using 4-amino-1-benzylpiperazine instead of cyclopentylamine of Example 17. mp176-179 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 9.96 (1H, br.s), 7.82 (2H, s), 7.4
3 (1H, br.s), 7.33-7.06 (6H, m), 6.64 (1H, d, J = 8Hz), 6.45 (1
H, dd, J = 9,3Hz), 5.62 (1H, s), 5.17 (1H, br.d, J = 7Hz), 3.67
(3H, s), 3.62-3.50 (1H, m), 3.43 (2H, s), 2.78-2.68 (2H, m),
2.04-1.94 (2H, m), 1.78-1.68 (2H, m), 1.44 (18H, s), 1.34-
1.20 (2H, m) IR (cm ^-1 ) 3400,2950,1640,1525,1510,1430,1235,740,70
0

Example 43 1- (1-benzyl-4-piperidyl) -3- [2-
{3- (3,5-di-t-butyl-4-hydroxyphenyl) propoxy} phenyl] urea

[Chemical Formula 91] (1) 4- (3-bromopropyl) -2,6-di-t
-Butylphenol (1.20g), 2-nitrophenol (0.51g), potassium carbonate (1.01g) and a catalytic amount of sodium iodide in dimethylformamide (10g).
ml) at 60-70 ° C. for 1.5 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). , 4- {3- (2-nitrophenoxy) propyl} -2,6-di-t-butylphenol (1.05 g, 74%) was obtained. (2) 4- {3- (2-nitrophenoxy) propyl} -2,6-di-t-butylphenol (1.03 g)
A catalytic amount of 10% palladium carbon was added to a suspension of ethanol (30 ml) in Example 3 and catalytically reduced at 40 ° C. for 10 hours at 3 to 4 atmospheres. After filtering the catalyst, the solvent was distilled off and 4- {3- (2
-Aminophenoxy) propyl} -2,6-di-t-butylphenol was obtained. Dichloromethane (20m
It was dissolved in l) and diisopropylamine (0.75 ml) was added. Under ice cooling, add phenyl chloroformate (0.84).
g) was added dropwise. After stirring overnight at room temperature, the reaction solution was washed with water, saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1). 1
-(1-Benzyl-4-piperidyl) -3- [2- {3
-(3,5-Di-t-butyl-4-hydroxyphenyl) propoxy} phenyl] urea (1.23 g, 97
%) Was obtained. mp148-149 ℃ ¹ H-NMR (δ ppm, CDCl ₃ ) 7.95 (1H, dd, J = 7,2Hz), 7.35-7.2
0 (5H, m), 6.97 (2H, s), 6.96-6.90 (2H, m), 6.81 (1H, dd, J = 7,
2Hz), 6.70 (1H, s), 5.07 (1H, s), 4.56 (1H, d, J = 8Hz), 4.03 (2
H, t, J = 7Hz), 3.62-3.70 (1H, m), 3.48 (2H, s), 2.81 (2H, br.
d, J = 12Hz), 2.70 (2H, t, J = 8Hz), 2.15-2.09 (4H, m), 1.97 (2
H, br.d, J = 11Hz), 1.42 (18H, s), 1.50-1.35 (2H, m) IR (cm ^-1 ) 3636,3310,1641,1549,1451,1235,742

Pharmacological test For the compounds prepared according to the above examples, ACA
Tested for T inhibitory and antioxidant effects. 1. ACAT Inhibitory Action Method The enzyme preparation ACAT was prepared by the method of EE Largis (Journal o
f Lipid Research, 30, 681-690, 1989), and prepared from liver microsomal fractions of male rabbits.
Kazuichi NATORI and other methods (Japan, J. Pharmacol. 42
, Pp. 517-523, in accordance 1986) was calculated by measuring the production amount of labeled cholesterol ester from ^[1-14 C] oleoyl -CoA and endogenous cholesterol.

Results In Table 1 below, the amount of labeled cholesterol ester production inhibition (%) when the test compound was added at 10 ⁻⁷ M was measured by ACA.
It is shown as an index of T inhibitory action. The compounds are shown by the numbers in the examples. From Table 1, it is proved that the test compound has an excellent ACAT inhibitory action.

2. Antioxidant activity Method Human LDL was added in the presence of copper sulfate (5 × 10 ⁻⁶ M), with a compound (10 ⁻⁵ M) or in the absence of a compound to give 5
Incubate for hours. After incubation,
Method of Simon JT Mao et al. (J. Med. Chem. 34, 298-30
2 pages, 1991), the production of LDL by the formation of malondialdehyde (MDA), one of the products of lipid peroxides.
Evaluate the peroxidation of the family. The activity of the compounds showed a percentage inhibition of MDA production relative to the control.

Results Table 1 below shows that the test compounds significantly reduce lipid peroxide (MDA) production.

[0080]

[Table 1]

Finally, formulation examples containing the compound of the present invention as an active ingredient are shown below. Formulation Example 1 Tablets were manufactured by a conventional method according to the following formulation. [Formulation] Tablet (1 tablet) Compound of Example (8) 50 mg Hydroxypropyl cellulose 2 mg Wheat starch 10 mg Lactose 100 mg Magnesium stearate 3 mg Talc 3 mg

Formulation Example 2 According to the following formulation, capsules were produced by a conventional method. [Formulation] Capsule (1 tablet) Compound of Example (14) 200 mg Starch 8 mg Microcrystalline cellulose 23 mg Talc 8 mg Magnesium stearate 5 mg

Formulation Example 3 According to the following formulation, granules were manufactured by a conventional method. [Prescription] Granule (1 package) Compound of Example (36) 1 mg Lactose 99 mg Corn starch 50 mg Crystalline cellulose 50 mg Hydroxypropyl cellulose 10 mg Ethanol 9 mg

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/445 31/495 31/50 C07C 275/30 9451-4H C07D 213/75 237/20 237 / 22 295/20 A 317/66 471/08 (72) Inventor Victory Miura 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Masato Horimai Saitama 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Nisshin Seifun Co., Ltd. Pharmaceutical Research Institute (72) Norio Oshida 5-3-1 Tsurugaoka, Oi-cho, Irima-gun, Saitama Nisshin Seifun Co., Ltd. In the laboratory (72) Shigeru Hiramoto 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. (72) Inventor Koichi Katsuyama 5 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Prefecture 3-1-1 Nisshin Flour Milling Co., Ltd. In-house Pharmaceutical Research Institute (72) Inventor Fumihisa Nakata 5-3 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Institute (72) Nobusuke Kinoshita Tsuru Oi-cho, Iruma-gun, Saitama Prefecture 5-3-1 Kugaoka Pharmaceutical Research Laboratory, Nisshin Seifun Co., Ltd. (72) Inventor Yoko Tsukada 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd.

Claims (9)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a halogen atom, or a (C ₁ -C ₆ ) alkoxy group, and R ₃ and R ₄ are the same or different, and a hydrogen atom, (C ₁ -C 6 ₈ )
Alkyl group, cyclo (C ₃ -C ₈ ) alkyl group, aryl (C ₁ -C ₆ ) alkyl group (wherein the aryl moiety is a halogen atom, (C ₁ -C ₆ ) alkyl group, (C ₁
C ₆ ) alkoxy group may be mono- or di-substituted, diaryl (C ₁ -C ₆ ) alkyl group, pyridyl (C ₁ -C ₆ ) alkyl group, (C ₁ -C ₆ ) alkyl group optionally substituted diazabicyclo (C ₇ ~C ₁₀₎ alkyl group, an adamantyl group, an aryl (C ₁ ~C ₆₎ represent a good piperidyl group optionally substituted with an alkyl group,
Or, R ₃ and R ₄ together with the nitrogen atom to which they are bonded are a 5- or 6-membered monocyclic heterocyclic group which may be substituted with a (C ₁ -C ₆ ) alkyl group. And R ₅ and R ₇ are the same or different and each represent a hydrogen atom, (C ₁ to
Represents a C ₆ ) alkyl group, and R ₆ has the formula: (In the formula, R ₈ is a hydrogen atom, a (C ₁ -C ₆ ) alkyl group, and (Wherein R ₃ is the same as the above), or R ₆ and R ₇ together are —O—CH ₂ —O—.
To form a nitrogen atom or a methine group, and A is of the formula: (In the formula, R ₉ is a hydrogen atom, a (C ₁ -C ₆ ) alkyl group,
(C ₁ -C ₆ ) alkylcarbonyl group, geranyl group, And m and n each independently represent an integer of 0 to 2). In addition, R ₁
To an alkyl moiety or an alkoxy moiety of each substituent represented by R ₉ may be linear or branched, and a pharmaceutically acceptable salt thereof. 2. In the general formula (1), R ₃ and R ₄ are the same or different and each represents a hydrogen atom, (C ₁ -C ₇ ).
An alkyl group, a cyclo (C ₅ -C ₇ ) alkyl group, a benzyl group (the phenyl moiety may be mono- or di-substituted with a halogen atom in some cases), diphenyl (C ₁
~ C ₄ ) alkyl group, pyridyl (C ₁ -C ₄ ) alkyl group, diazabicyclononyl group optionally substituted with (C ₁ -C ₄ ) alkyl group, adamantyl group, benzylpiperidyl group, or Or, R ₃ and R ₄ together with the nitrogen atom to which they are attached represent a piperazinyl group optionally substituted with a (C ₁ -C ₄ ) alkyl group, and A is of the formula: (In the formula, R ₉ is a hydrogen atom, a (C ₁ -C ₆ ) alkyl group, an acetyl group, a geranyl group, and And m and n each independently represent an integer of 0 or 1). Incidentally, R
The alkyl moiety and alkoxy moiety of each substituent represented by _{1 to} R ₉ may be linear or branched, and the compound according to claim 1 and a pharmaceutically acceptable salt thereof. Salt. 3. A is --C (O) N (R ₉ )-or --N (R ₉ ).
The compound of claim 2 which is C (O)-. 4. The compound according to claim 2, wherein A is —OC (O) —. Wherein A is _{- (CH 2) m N (} R 9) (CH 2) n - A compound according to claim 2 which is. 6. The compound according to claim 2, wherein A is —O (CH ₂ ) ₃ —. 7. An ACAT inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and optionally a pharmaceutically acceptable carrier or excipient. 9. The pharmaceutical composition according to claim 8, which is used for preventing or treating hypercholesterolemia or arteriosclerosis.