WO1996026925A1 - Arylthioacetamide derivatives - Google Patents

Abstract

Arylthioacetamide derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof, wherein Ar represents phenyl, naphthyl or pyridyl optionally having one to four substituents selected from the group consisting of lower alkyl, lower alkoxy and halogeno; R1 represents hydrogen or lower alkyl; R?2 and R3¿ may be the same or different and each represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, mono(lower alkyl)amino or di(lower alkyl)amino, provided that the lower alkyl, lower alkoxy, lower alkylthio, mono(lower alkyl)amino or di(lower alkyl)amino may be substituted by pyrrolidino, etc. at arbitrary hydrogen atoms; n represents 0, 1 or 2; and X represents CH or N. The compounds inhibit ACAT to thereby suppress the formation of cholesterol esters, are expected to be usable as a remedy or preventive for hypercholesterolemia, hyperlipidemia, arteriosclerosis and cardiac diseases, etc. accompanying the same.

Description

 Description Arithioacetamide derivative Technical field

 The present invention relates to novel arylthioacetamide derivatives, and more particularly to arylthioacetamides which are useful in the field of medicine, particularly in the field of treatment and prevention of hypercholesterolemia, hyperlipidemia and arteriosclerosis. It relates to derivatives and their uses.

Background art

 In recent years, due to the aging of the population and changes in eating habits, it has been pointed out that arteriosclerosis and the accompanying frequency of various coronary and cerebral artery diseases have increased. A variety of factors are thought to contribute to the occurrence of arteriosclerosis, and elevated blood cholesterol in particular is considered to be one of the major causes. Therefore, many attempts have been made to develop cholesterol-lowering agents for the purpose of preventing and treating arteriosclerosis, and some of them have already been used clinically. Cholesterol in the living body is regulated by ingestion from the outside of the body by diet and biosynthesis in the body, and cholesterol in food is absorbed as free cholesterol, and cholesterol A 0 — Esterified by the action of acyltransferase (ACAT) and released into the blood as chylomicrons. Therefore, inhibition of ACAT is expected to suppress the absorption of dietary cholesterol from the intestine and reduce blood cholesterol levels. Atherosclerosis, on the other hand, is a condition caused by the accumulation and thickening of cholesterol esters in the arterial wall. It is known that the production of this cholesterol ester is catalyzed by ACAT. Therefore, inhibition of ACAT prevents the production and accumulation of cholesterol esters, and is expected to have the effect of suppressing and preventing the extension of arteriosclerosis.

The present invention provides a novel anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and a therapeutic and / or prophylactic agent for arteriosclerosis having ACAT inhibitory activity useful in the field of medicine. Disclosure of the invention

 The present inventors have found that an arylthioacetamide derivative represented by the following general formula [I] strongly inhibits ACAT activity and, as a result, inhibits cholesterol absorption, and completed the present invention. did.

 That is, according to the present invention, the general formula

_Ar

[In the formula, Ar represents a phenyl group, a naphthyl group or a pyridyl group which may have 1 to 4 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a halogen atom. R ′ represents a hydrogen atom or a lower alkyl group; R ² and R ³ may be the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group (However, any hydrogen atom of the lower alkyl group, lower alkoxy group, lower alkylthio group, mono-lower alkylamino group or di-lower alkylamino group is a morpholino group, a thiomorpholino group, an imidazolyl group, an amino group, Lower alkylamino group, di-lower alkylamino group, 1-piperazinyl group, 4-1-benzyloxycarbonyl—1-piperazinyl N, 0 and 1 may be substituted with a group selected from the group consisting of a group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a carbamoyl group and a hydroxyxethylmethylcarbamoyl group. Or X represents X or CH represents N], or an arylthioacetamide derivative or a pharmaceutically acceptable salt thereof.

 Next, definitions of various terms referred to in the description of this specification and specific examples thereof will be described.

 The term "lower" is used to mean that the group or compound to which it is attached has at most 6, preferably at most 5, carbon atoms.

Accordingly, a lower alkyl group is a straight or straight chain having 1-6, preferably 1-5, carbon atoms. Represents a branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc. No. The lower alkoxy group means a linear or branched alkoxy group having 1 to 6, preferably 1 to 5 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butkin, sec-butoxy group, tert-butoxy group, pentoxy group and the like.

 The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

 The lower alkylthio group means a linear or branched lower alkylthio group having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group. Group, butylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, hekinlthio group and the like.

 A mono-lower alkylamino group has 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms.

Means five linear or branched lower alkylthio groups, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino Group, isopentylamino group, hexylamino group and the like.

 The di-lower alkylamino group means a dialkylamino group having 1 to 6 carbon atoms, preferably 2 linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as a dimethylamino group. , Acetylamino, methylethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino, tert-butylmethylamino, ethylpentylamino, And an isopentylmethylamino group and a hexylmethylamino group.

A lower alkoxy group is a linear or branched lower alkoxycarbonyl group having 1 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, or an isocarbonyl group. Propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxy Examples include a carbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a hexyloxycarbonyl group, and the like.

 In order to more specifically disclose the compound of the present invention represented by the general formula [I], various symbols used in the general formula [I] will be more specifically described by giving preferable specific examples thereof. explain.

Ar represents a phenyl group, a naphthyl group or a pyridyl group which may have 1 to 4 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom, and specifically, , Phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 2-isopropylphenyl, 3-isopropylphenyl Phenyl group, 4-isopropylphenyl group, 2-butylphenyl group, 3-butylphenyl group, 2-pentylphenyl group, 2-hexylphenyl group, 3-hexylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl, 2-ethoxyquinyl, 3-ethoxyquinyl, 4-ethoxyphenyl 2-, 2-propoxyphenyl, 1-isopropoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-butoxyphenyl, 2-pentyl Oxyphenyl, 2-hexyloxyphenyl, 3-hexyloxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl Group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2.5-dimethylphenyl group, 2,6-dimethylphenyl group, 2 2,3-Jetylphenyl group, 2,4-Jetylphenyl group, 2,5-Jetylphenyl group, 2,6-Jetylphenyl group, 2_Ethyl-3-methylphenyl group, 2-Ethyl-4-methylphenyl group 2-ethyl-5-methylphenyl group, 2-ethyl-6-methylphenyl group, 2-methyl-3-propylphenyl group, 2-methyl-4-propylphenyl group, 2-methyl-5-propylphenyl group, 2-methyl-6-propylphenyl group Group, 6-butyl-2-methylphenyl group, 2-methyl-6-pentyl L-phenyl, 6-hexyl-2-methylphenyl, 2,6-ethylphenyl, 2-ethyl-3-propylphenyl, 2-ethyl-6-propylphenyl, 2,6-diisopropylphenyl, 2,6-diisopropylphenyl , 3-Dimethoxyphenyl group, 2,4-Dimethoxyphenyl group, 2,5-Dimethoxyphenyl group, 2,6-Dimethoxyphenyl group, 2,3-Diethoxyquinphenyl group, 2, 4-diethoxyquinenyl, 2,5-diethoxyphenyl, 2,6-ethoxyphenyl, 2-ethoxy-3-methoxyphenyl, 2-ethoxy-4-methoxyphenyl, 2-ethoxy-5-methoxyphenyl group, 2-ethoxy-1-6-methoxyphenyl group, 2-methoxy-3-propoxyphenyl group, 2-methoxy-4-propoxyphenyl group, 2-methoxy-5- Pro Poxyv 2-methoxy-6-propoxyphenyl group, 6-butoxy 2-methoxyphenyl group, 2-methoxy-6-pentyloxyphenyl group, 6-hexyloxy-1-methoxyphenyl group, 2, 6-diethoxyphenyl group, 2-ethoxyquin-3-bromoboxyl group, 2-ethoxy-6-propoxyphenyl group, 2,6-diisopropoxyphenyl group, 2,3-dichlorophenol 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 2,6-dichlorophenyl group, 2,3-dibromophenyl group, 2,4-dibromophenyl group, 2,5-dibromo Phenyl, 2,6-dibromophenyl, 2-bromo-3-chlorophenyl, 2-bromo-4-chlorophenyl, 2-bromo-5-chlorophenyl, 2-bromo-6-chlorophenyl Group, 2-methー 3-methoxyethoxy, 2-methyl-4-methoxyphenyl, 2-methyl-5-methoxyphenyl, 2-methyl-6-methoxyphenyl, 2-ethyl-3-methoxyphenyl, 2 —Ethyl-4-methoxyphenyl, 2-ethyl—5—Methoxyphenyl, 2-ethyl-16-methoxyphenyl, 2-methyl-3-propoxyphenyl, 2-methyl-4-propoxyfif Benzyl group, 2-ethyl-5-propoxyphenyl group, 2-ethyl-6-propoxyphenyl group, 2-methyl-3-butoxyphenyl group, 2-ethoxy-4-propylphenyl group, 2-ethoxy-5-propylpyruphenyl group , 2-ethoxy-6-propylphenyl group, 6-butyl-2-ethoxyphenyl group, 2-methoxy-1-pentylphenylphenyl Group, 6—hexyl-2-methoxyphenyl group, 2—ethyl-6—ethoxyphenyl group, 2—ethoxy-3—butoxyphenyl group, 2—ethyl-6—butoxyphenyl group, 2—pentyl-6—methoxyphenyl group, 2 —Chloro—3-methylphenyl, 2 —Chloro-4 monomethylphenyl, 2 —Chloro-5 monomethylphenyl, 2 —Chloro—6 —Methylphenyl, 2 —Chloro-3-ethylphenyl, 2 —Chloro— Ethylphenyl, 2-chloro-5-ethylphenyl, 2-chloro-6-ethylphenyl, 2-bromo-3-monomethylphenyl, 2-bromo-4-methylphenyl, 2-bromo-5-methylphenyl, 2-bromo- 6-methylphenyl group, 2-chloro-3-propylpropyl group, 2-chloro-4-propylphenyl , 2-chloro-5-propylphenyl, 2-chloro-6-propylphenyl, 6-butyl-2-chlorophenyl, 2-chloro-6-pentylphenyl, 2-chloro-6-hexyl Phenyl group, 2-bromo-6-ethylphenyl group, 3-bromo-2-ethylphenyl group, 2-bromo-6-ethylphenyl group, 2-chloro-3-methoxyphenyl group, 2-chloro-4-methoxyphenyl group , 2-chloro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-chloro-3-ethoxyethoxy, 2-chloro-4 monoethoxyphenyl, 2-chloro-5-ethoxyphenyl, 2-chloro-6-ethoxyphenyl group, 2-bromo-3-methoxyphenyl group, 2-bromo-4-methoxyphenyl group, 2-bromo-5-methoxy Ethyl, 2-bromo-6-methoxyphenyl, 2-chloro-3-propoxyphenyl, 2-chloro-4-propoxyphenyl, 2-chloro-5-propoxyphenyl Group, 2-chloro-6-propoxyphenyl, 6-butoxy-2-chlorophenyl, 2-chloro-6-pentyloxyphenyl, 6-hexyloxy 2-chlorophenyl, 2-bromo-6 —Ethokinphenyl group, 2-butamate 3 —Propoxyphenyl group, 2-bromo-6—Propoxyphenyl group, 2,3,4 —Trimethylphenyl group, 2,3,5-Trimethylphenyl group , 2,3,6-trimethylphenyl group, 2,4,6-trimethylphenyl group, 2-ethyl-3,4-dimethylphenyl group, 2-ethyl-3,5-dimethylphenyl group, 2- Ethyl—3,6-dimethylphenyl group, 2-Ethyl- 4,6-dimethylphenyl group, 2,3-dimethyl- 4-methylphenyl group, 2,3-dimethyl-5-methylphenyl group, 4-ethyl-2,6-dimethylphenyl group, 2,6-dimethyl-4-propyl Phenyl group, 2,6-dimethyl-4-isopropylphenyl group, 2,6-dimethyl-4-butylphenyl group, 2-chloro-4,6-dimethylphenyl group, 2-chloro-3,6-dimethylphenyl group, 2-chloro-4-ethyl-6-methylphenyl group, 2-butane 4,6-dimethylphenyl group, 2-bromo-4-ethyl-6-methylphenyl group, 2,6-dichloro-3-methylphenyl group, 2, 6 —Dichloro-1-methylphenyl group, 2,6-dichloro-3-ethylphenyl group, 2-bromo-6-chloro-3-methylphenyl group, 2-bromo-6-chloro-3-ethylphenyl group, 2-bromo — 6-chloro— 4-methylphenyl, 2-methoxy-3,4-dimethylphenyl, 2-methoxy-1,3-dimethylphenyl, 2-methoxy-3,6-dimethylphenyl , 2-Methoxy—4,6-dimethylphenyl, 2-ethoxyquin 3.4-dimethylphenyl, 2-ethoxy-3,5-dimethylphenyl, 2-ethoxy-3,6-dimethylphenyl Group, 2-ethoxy-1,4,6-dimethylphenyl group, 2,3-diethyl-4-methoxyphenyl group, 2,3-dimethyl-5-methoxyphenyl group, 4-ethoxy-1,2,6-dimethylphenyl group , 2.6-dimethyl-14-propoxyphenyl, 2,6-dimethyl-4-isopropoxyphenyl, 2,6-dimethyl-4-butoxyphenyl, 2-chloro-4-methoxy-6-methylphenyl , 2-Chloro-3-Methoxy C 6-methylphenyl, 2-chloro-4,1-ethoxy-6-methylphenyl, 2-bromo-14-methoxy-6-methylphenyl, 2-bromo-4-ethoxy-6-methylphenyl, 2, 6 —Dimethoxy-3-methylphenyl group, 2,6-Dimethoxy-4-methylphenyl group, 2,6-Dimethoxy-13-ethylphenyl group, 2-bromo-6-methoxy-3-methylphenyl group, 2-bromo-6— Methoxy-3-ethylphenyl group, 2-bromo-6-methoxy-4-methylphenyl group, 2,3,4,5-tetramethylphenyl group, 2,3,5,6-tetramethylphenyl group Substituted and unsubstituted fuiryl, 1-naphthyl, 2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-na 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl, 1-naphthyl -Methoxy 2-naphthyl, 6-methoxy-1 naphthyl, 2-chloro-1-naphthyl, 1-chloro-1-naphthyl, 6-chloro-1-naphthyl, 6-chloro- 2— Substituted and unsubstituted naphthyl groups such as naphthyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-21 Pyridyl group, 6-methyl-2-pyridyl group, 2-methyl-3-pyridyl group, 3-methyl-4-pyridyl group, 2-methoxy-14-pyridyl group, 3-methoxy-4-pyridyl group, 3—Methoxy—2-pyridyl group, 6—Methoxy 2— Lysyl, 3-chloro-2-pyridyl, 2-chloro-3-pyridyl, 3-chloro-4-pyridyl, 2-chloro-4-pyridyl, 3,5-dimethyl-4, pyridyl, 3 And substituted and unsubstituted pyridyl groups such as 1,5-dichloro-4-pyridyl group.

 R ′ represents a hydrogen atom or a lower alkyl group. Specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, Examples include an isopentyl group and a hexyl group.

R ² and R ³ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group (provided that the lower alkyl group, lower alkoxy group, Any hydrogen atom of a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino group is a pyrrolidino group, a morpholino group, a thiomorpholino group, an imidazolyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, 1 1 piperazinyl group, 4 benzyloxycarbonyl 1 1 piperazinyl group, hydroxyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxyl group, rubamoyl group and hydroxyxethylmethylcarnomomoyl group May be substituted with a group selected from) Specific examples of the grade alkyl group, methylation group, Echiru group, a propyl group, Isoburopiru group, butyl group, sec- Petit Le group, tert- butyl group, a pentyl group, isopentyl group, hexyl group or the like to Specific examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentylloquine, and isopentyloxy. And specific examples of lower alkylthio groups include methylthio, ethylthio, propylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like. Examples include a pentylthio group, an isopentylthio group, and a hexylthio group.

 The mono-lower alkylamino group means a linear or branched lower alkylthio group having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, such as a methylamino group, an ethylamino group, and a propylamino group. Isopropylamino group, butylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, hexylamino group and the like.

 The di-lower alkylamino group means a dialkylamino group having 1 to 6 carbon atoms, preferably 2 linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as a dimethylamino group. , Acetylamino, ethylmethylamino, methylpropylamino, ethylisopropylamino, butylmethylamino, sec-butylethylamino, tert-butylmethylamino, ethylpentylamino, And an isopentylmethylamino group and a hexylmethylamino group.

 The arylthioacetamide derivative of the above formula [I] may optionally be present in the form of an acid addition salt, and examples of such an acid addition salt include hydrochloride, hydrobromide, and iodine. Inorganic salts such as hydrides, sulfates, nitrates, perchlorates or phosphates; or, for example, p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate And organic acid salts such as tartrate, citrate, fumarate and maleate, and particularly preferably pharmaceutically acceptable non-toxic salts.

 Next, a method for producing the compound according to the present invention will be described.

The compound of the formula [I] of the present invention can be produced, for example, by the following production methods 1 to 3. Release 1

_{Ar - S (0) n -} CH 2 - COOH + NH 2 "

 ,

 [Π]

 [1Π]

Ar— S (0) _n — CH ₂

 [I]

Manufacturing method 2

 [IV]

 [V]

0

 II

Ar— S— CH ₂ — C-NH

ヽ to N R ³

[I J

Manufacturing method 3

[I _a ]

Ar—SO)) or _two CH ₂ —

[I _b ]

[Wherein, Y represents a leaving group, and Ar, R ′, R ² , R ³ , X and n have the above-mentioned meanings. ]

 In the above formula, specific examples of the leaving group represented by Y include, for example, a chlorine atom, a halogen atom such as a bromine atom or an iodine atom, a methanesulfonyloquine group or a P-toluenesulfonyloquine group. Organic sulfonyloxy group and the like can be mentioned.

 The above Production Methods 1 to 3 are all application examples of reactions well-known in the field of organic synthetic chemistry, and they are capable of selecting various reaction conditions in consideration of the physical properties of raw material compounds and the like.

 Hereinafter, each of the above-mentioned production methods that can be used for producing the compound [I] of the present invention will be described, but the production method of the compound [I] of the present invention is not limited thereto.

Production method 1 is a conventional amidation reaction in which a carboxylic acid compound [II] is condensed with a pyridylamine or pyrimidinylamine compound [III], and is the most general method that can be used for the synthesis of almost all the compounds of the present invention. is there. This reaction is usually carried out in a suitable solvent in an aromatic hydrocarbon such as benzene, toluene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane: halogens such as methylene chloride, chloroform or dichloroethane. Hydrocarbon; pyridine, dimethylformamide, case Using an aprotic polar solvent such as tonitrile or dimethyl sulfoxide; or a mixture thereof, usually using a carboxylic acid compound represented by the general formula [II] with a suitable condensation auxiliary, In an equimolar or excess mole, preferably in the range of 1 to 2 moles, and 0.5 to 2 moles or an excess, preferably 0.5 to 2 moles, of the amine compound represented by the general formula [III]. It can be produced by reacting in a molar range. As reaction conditions, the reaction temperature is generally about -7 (from TC to the boiling point of the solvent, preferably from about 120 ° C to about 150 ° C, and the reaction time is Usually, the reaction time can be from 5 minutes to 10 days, preferably from 1 to 24 hours Examples of the condensing aid include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid. Carbodimids such as chlorinated hydrochloride (EDCI) and diisopropyl carbodiimide: carbodildimidazole; organic acid chlorides such as chlorocarbonate carbonate, isopropyl chlorocarbonate, p-toluenesulfonic acid chloride and benzenesulfonic acid chloride; chloride Inorganic halogenating reagents such as thionyl, oxyphosphorus chloride, phosphorous pentachloride, phosphorous trichloride, phosphorous tribromide and the like. In order to proceed smoothly, the reaction can be carried out in the presence of a base. In this case, the base used is, for example, a hydrogenated metal such as sodium hydride, hydrogenated hydride or lithium hydride. For example, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium hydrogen carbonate Salts: or, for example, organic amines such as triethylamine or pyridine etc. These bases are generally used in an equimolar amount to the starting compounds [II] and [III] or Excess moles, preferably in the range of 1 to 5 moles.

Production method 2 is a well-known thiol alkylation reaction in the field of synthetic organic chemistry. According to the present invention, the target compound of the above formula [la] can be prepared in a solvent that does not affect the reaction, for example, in an aromatic hydrocarbon such as benzene, toluene or xylene: for example, an ether such as ethyl ether, tetrahydrofuran or dioxane. Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; e.g. ethanol and isopropanol Alcohols: An aprotic polar solvent such as dimethylformamide, acetonitrile or dimethyl sulfoxide; or a mixture thereof, is usually used to prepare a thiol compound represented by the general formula [IV], V] can be produced by reacting the alkylating agent with the amines in an equimolar amount or a small excess amount, preferably in a range of 1 to 2 mol.

 As the reaction conditions used in the above-mentioned production method 2, the reaction temperature is generally in a range from about −70 ° C. to the boiling point of the solvent, preferably from about 120 ° C. to about 150 ° C., The reaction time may be generally from 5 minutes to 10 days, preferably from 1 to 24 hours. In addition, it is generally advantageous to carry out these reactions in the presence of a base in order to smoothly carry out the reaction. In this case, as a base that can be used, for example, sodium hydride, lithium hydride or Alkali metal hydrides such as potassium hydride; Alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, lium hydroxide or hydroxide hydroxide; For example, sodium carbonate, carbonate Metal salts such as potassium carbonate and sodium bicarbonate; and organic amines such as triethylamine or pyridine. The amount of the base to be used is generally equimolar or excess, preferably in the range of 1 to 5 mol, based on the raw material compound of the formula [IV].

Production method 3 is a sulfide oxidation reaction well known in the field of synthetic organic chemistry. According to the present invention, the target compound of the above formula [ _Ib ] is used in a solvent that does not affect the reaction, for example, a halogenated hydrocarbon such as methylene chloride, chloroform or dichloroethane, or an aprotic solvent such as ethyl acetate. Acetic acid, water or a mixture thereof, using carboxylic acid peroxides such as metachloro-perbenzoic acid and peracetic acid; hydroperoxides such as hydrogen peroxide and tert-butyl hydroperoxide; periodic acid; Oxidizing agent such as inorganic peroxide for sulfide [ _Ia ]

It can be produced by reacting in a range of 0.5 to 10 mol, preferably 0.5 to 3 mol.

As the reaction conditions used in the above-mentioned Production method 3, the reaction temperature is generally in the range of −70 ° C. to the boiling point of the solvent, preferably in the range of about 120 ° C. to about 150 ° C. The reaction time can be from 5 minutes to 10 days, preferably 0.524 hours.

 The compound [I] of the present invention obtained in the above steps can be isolated and purified by a conventional separation means such as column chromatography, solvent extraction or recrystallization alone or in an appropriate combination. It is.

 The compounds represented by the general formulas [II] and [V] used in the above production methods 1 to 3 are produced and obtained by various production methods known in organic synthetic chemistry. For example, there are the following methods.

 (Formulation A)

1) BrCH ₂ COOR ^a

Ar-SH Ar-S (0) _n -CH ₂ COOH

 (2) mCPBA)

 [IV] 3) NaOH [Π]

(Formulation B)

 [VI]

 [V]

[Wherein, ^Ra represents a lower alkyl group, and Ar XYR ′ R ² R ³ and n have the above-mentioned meanings. ]

Further, the compounds of the formulas [III], [IV] and [VI] used in the above-mentioned production method 13 and production method AB may be purchased as a commercial product or disclosed in JP-A-62-174011. No. 268676 or JP-A-3- No. 120243, Production method (compound [111]), Journal, Ob american 'Chemical Society, J. Am. Chem. Soc., Vol. 100, p. 2149 (1978) (Compound [IV]) or a method analogous thereto, and further, can be produced by the production method described in Examples below.

 The compound of the present invention of the formula [I] extremely strongly inhibits ACAT in mammals, and is expected to be used as an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and furthermore as an anti-atherosclerotic agent It is a useful compound.

 In order to prove this, a test example will be described below.

 Pharmacological experiment 1

AC AT inhibitor

 Enzyme specimen A CAT was derived from human liver according to the method described in Clinica Chimica Acta, Smith et al., 158, 271 (11986). Cell line

Prepared from the microsomal fraction of He pG2. According to the method of AC AT activity above Smith [Sm i @ th] et is calculated by measuring the production amount of labeled cholesterol ester from [1 one ¹⁴ C] Oreiru C o A and exogenous cholesterol. Thus, the ACAT of the compound of the present invention is 0.

The inhibition rate (%) at each concentration was determined, and the results were measured simultaneously as a control compound. Melinamide (N- (α-methylbenzyl) linoleamide) and ΥΜ—17Ε (1,3-bis [[1-cyclo The following table shows the results for heptyl-3- (ρ-dimethylaminophenyl) perido] methyl] benzene 'dihydrochloride). Table 1 Inhibition of human ACAT

As is apparent from the above results, the compound of the present invention potently inhibits ACAT, and is therefore effective for treating and preventing diseases such as hypercholesterolemia, hyperlipidemia, and arteriosclerosis.

 The compound of the formula [I] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, it can be used to produce hypercholesterolemia, hyperlipidemia and arterial hyperlipidemia. It can be used for treatment and prevention of sclerosis. When the compound of the present invention is used clinically, it can be administered after formulating various preparations by adding pharmaceutically acceptable additives according to the dosage form. As the additives at this time, various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl Chilled cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, calcium phosphate anhydrous, cunic acid, trisodium citrate, hydroquinine propylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, Sugar fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light gay anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol Le, polyalkylene glycols, Ru include cyclo dextrin or hydroxypropyl cyclodextrin and the like.

Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or syrups, for example. And elixirs and liquid preparations such as injections, which can be prepared according to a usual method in the field of preparations. In the case of liquid preparations, they may be dissolved or suspended in water or another appropriate medium before use. In particular, in the case of an injection, it may be dissolved or suspended in a physiological saline solution or a glucose solution as necessary, and a buffer or a preservative may be added.

 These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight in the total preparation. These formulations may also contain other therapeutically effective compounds.

 When the compound of the present invention is used as an anti-hyperlipidemic agent, an anti-atherosclerotic agent or an anti-hypercholesterolemia agent, the dose and frequency of administration depend on the sex, age, weight, degree of symptoms and purpose of the patient. In general, for oral administration, 0.01 to 20 mg of Zkg per adult per day is divided into 1 to several doses, and for parenteral administration, 0.001 l It is preferred to administer 22 mgZkg in one or several divided doses. Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1

 Expression

Production of the compound represented by

 (1) 2,4-dichloro-3-nitro-6-methylpyridine

J. Heterocyc 1. Chem., Vol. 7, p. 389 (1970) Prepared by the method described in my own words. - two Toro - 4-arsenide Dorokishi - 6-methyl-2-pin Li Dong (1. 70 g, 10. Ommo l ) suspended to _{P0C 1 3 (6. 8 m 1} ) It was made cloudy and heated to 80 ° C. Anhydrous dimethylformamide (701) was added, and the mixture was heated and stirred at 110 ° C for 2 hours. The reaction mixture was poured into ice after cooling, it was made basic with N a OH, and extracted with CHC 1 _3. The organic layer was dried over MgSO _4, the residue obtained by concentration under reduced pressure, and purified by dry column flash chromatographed I i (Merck Silica gel 60 Roh CHC 1 _3), 2, 4 over dichloride port - 3 -Nitro-6-methylpyridine (817mg) as pale yellow powder

Ci guard o

 (2) 2-Mouth 3-throw 6-methyl-4-methylthiopyridine

To a solution of 2,4-dichloro-3-nitro-6-methylpyridine (1.30 g, 6.30 mmo 1) obtained in (1) in MeOH (30 ml) under ice cooling

MeSNa (15% aqueous solution, 2.94 ml) was added dropwise, and the mixture was stirred at the same temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, the residue CHC 1 ₃ - it was partitioned with H ₂ 0. The organic layer M MgSO, in vacuo and then concentrated to dryness and the residue dry column flash chromatography photography chromatography (hexane Merck Silica gel one _{60: CHC 1 3 = 1:} 1 → hexane: AcOE t = 3: 1 → CHC purification by 1 _3), 2-chloro over 3-nitro - give the 6-methyl-4-methylthiopyridine (1. 07 g) as a pale yellow powder.

 (3) 3-Nitro 6-methyl-4-methylthio-2- (2-morpholinoethylthio) pyridine

2-Chloro-3-nitro-6-methyl-4-methylthiopyridin (21.9 mg, 0.10 Ommo 1) obtained in (2) and biochemical pharmacology (Biochem em. Pharmacol) In a MeOH (2 ml) solution of (2-morpholinoethyl) isothironium dihydrochloride (31.5 mg) prepared by the method described in Vol. 46, p. 47 (1993) under a nitrogen atmosphere, 2M NaOH (0.20 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was vacuum 'concentrated and the residue AcOE t - distributed by H ₂ 0, dried out and the organic layer. The residue obtained by concentration under reduced pressure and purified by preparative TLC (Merck silica gel _{60 F 2 5 4 / CHC 13} : Me OH = 20: 1) to give the 3 twelve Torrox 6-methyl 4 Mechiruchio - 2- (2-Morpholinoethylthio) pyridine (25 mg) was obtained as a yellow powder. (4) 3-amino-6-methyl-4-methylthio-2- (2-morpholinoethylthio) pyridine

 3-Nitro-6-methyl-4-methylthio-2- (2-morpholinoethylthio) pyridine (24.7 mg, 0.075 mmo 1) obtained in (3) was dissolved in concentrated hydrochloric acid (0.40 ml) and tin dichloride was added. (49.8 mg) at room temperature

Stir for 30 minutes. Under ice-cooling, the reaction solution was neutralized with saturated N AHC 0 ₃ water and extracted with AcOE t. The organic layer N a ₂ S 0 ₄ at residue obtained by drying was concentrated under reduced pressure and purified by preparative TLC (Merck silica force gel _{6 0 F 254 ZC HC 13:} Me OH = 20: 1) with purified 3-amino-6-methyl-4-methylthio-1- (2-morpholinoethylthio) pyridine (20.6 mg) was obtained as a colorless oil.

(5) 3-amino-6-methyl-4-methylthio-2- (2-morpholinoethylthio) pyridine (20.6 mg, 0.0688 mmol) obtained in (4) and prepared by the method described in JP-A-4-268035 A solution of 2,6-dimethylphenylthioacetic acid (16.2 mg) in anhydrous pyridine (0.40 ml) was added to a solution of EDC I (1-ethyl-3- (3-dimethylaminopropyl) carpoimide) in a nitrogen atmosphere. Hydrochloride salt) (26.4 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in Ac OE t, washed with water, saturated NaHCO ₃ water, and dried over MgSO _4. Concentrated under reduced pressure to separate the residue obtained by partial TLC (Merck silica gel _{60 F 254 / CHC 1 3:} Me OH = 20: 1) to afford the title compound (25. 8 mg) as a colorless powder. mp: 170-173 ° C

High Resolution FAB- MS (m / e, ( C 23 H 3, N 3 0 2 S 3 + H) - as); Calculated: 478.1657

Measurements: 478. 1647

Ή-NMR (30 OMH z, CDC ", 5 ppm): 2.38 (3H, s), 2.46 (3 H, s), 2.50—2.58 (4 H, m), 2 58 1 2.67 (2H, m), 3.62 (2H, s), 3.28 (2H, dd, J = 6.6 Hz, 8.5 Hz), 2.62 (6H, s) , 3.68-3.75 (4 H, m), 6.65 (1 H, s), 7.03-7.18 (3 H, m), 7.74 (1H, brs)

R f: 0. 6 7 (Merck Silica gel _{6 0 F 254 CHC 1 3 Me} OH = 1 0: 1) in the same manner as in Example 1, to prepare the compound of Example 2-6.

 Example 2

 Expression

A compound represented by the formula:

mp: 1 3 3-1 3 7 ° C

High resolution FAB - MS (m / e, (C 24 H 33 N 3 0 2 S 3 + H) - as); Calculated: 4 9 2.1 8 1 3

Measured value: 4 9 2. 1 8 2 3

. Ή - NMR (3 0 0MH z, CDC 1 3, <5 p pm): 1. 8 7 (2 H, quint, J = 7. 2 H z) 2. 3 8 (3 H, s), 2 . 42-2.50 (6H, m), 2.46 (3H, s), 2.62 (6H, s), 3.17 (2H, t, J = 7 2 H z), 3.6 2 (2 H, s), 3.70-3.76 (4 H, m), 6.64 (1 H, s), 7.0 5 — 7 . 1 8 (3 H, m), 7.73 (1 H, brs)

1 ^ £ value: 0. 5 6 (manufactured by Merck & Co., Inc. silica gel _{6 0 F 254 ZC HC 1 3} : Me OH = 1 0: 1)

Example 3

formula

A compound represented by the formula:

High resolution FAB - MS (m / e, as _{+ (C 15 H 16 N 2} 0 S + H)); Calculated: 273.1062

Measurements: 273. 1065

Ή-NMR (30 OMH z, CDC 1 3, δ p pm): 2. 56 (6 H, s), 3. 49 (2H, s), 7. 01- 7. 1 7 (4 H, m) , 7.68 (1 H, dt, J = 1.8 Hz, 8.3 Hz), 8.13 (1 H, d, J =

8.3 Hz), 8.27 (1 H, d d, J = 1.0 Hz, 4.9 Hz),

8.81 (1 H, b r s)

1¾ £ value: 0.66 (Merck silica gel 60 F ₂₅₄ hexane:

Ac OE t = 1: 1)

Example 4

 Expression

A compound represented by the formula:

mp: 162-164 ° C

High Resolution FAB-MS (m / e, (C, 5 H, 6 N 2 0 S + H), as); Calculated: 273.1062

Measurements: 273. 1072

Ή-NMR (300 MHz, CDC 1 3, 5 pm): 2. 57 (6H, s), 3. 50 (2 H, s), 7. 1 1 - 7. 30 (4 H, m), 7 . 80 (1 H, brs), 8.07-8.11 (l H, m). 8.34 -8.40 (2 H, m)

1¾ £ values: 0. 1-7 (Merck Silica gel _{60 F 254 ZC HC 1 3:} Me OH = 50: 1)

 Example 5

 Expression

A compound represented by the formula:

mp: 130-135. C

High Resolution FAB- MS (mZe, (C, 5 H, 6 N 2 0 S + H) - as): Calculated: 273.1062

Measurements: 273. 1063

 Ή-NMR (300 MHz, CDC, (5 ppm): 2.54 (6H, s). 3.47 (2H, s), 7.10—7.20 (3H, m), 7.37

(2 H, d, J = 6.3 Hz), 8.23 (1 H, b rs), 8.47

(2H, d, J = 6.3Hz)

Scale value: 0.41 (Merck silica gel 60 F ₂ s ₄ ZCHC 13 ₃ : Me OH = 10: 1)

Example 6

 Expression

Compound c represented by mp: 171-173 ° C

High Resolution FAB- MS (m / e, ( C 16 H 18 N 2 0 S + H) + as); Calculated: 287.1218

 Measurements: 287. 1208

 Ή-NMR (30 OMH z, CDC ", 5 ppm): 2.51 (3 H, s), 2.56 (6H, s), 3.48 (2 H, s), 7.09-7 .2 1 (4H, m), 7.72 (1H, brs), 7.96 (1H, dd, J = 2.3Hz, 8.7Hz), 8.24 (1H, d, J = 2.3 Hz)

R l: 0.73 (Merck silica gel 60 F ₂₅₄ ZCHC I ₃ : Me OH = 10: 1)

Example 7

 Expression

Production of the compound represented by

(1) 3-Amino-2-chloro-6-methyl-4-methylthiopyridine Example 11 2-Chloro-3-nitro-6-methyl-4-methylinorethiopyridine obtained in (2) (41.5 mg, 0 (1. 90 mmol) in a solution of AcOEt (4 ml) was added 10% Pd-C (25 mg) and stirred vigorously at room temperature under a hydrogen atmosphere for 3 hours. The mixture was filtered and the catalyst was washed with MeOH. Combined, concentrated in vacuo and filtration liquid and the washing solution, the residue was purified by dry column flash chromatography grayed roughy (Merck Silica gel 60 Roh CHC 1 _3), 3- amino one 2- chloro 6-methyl-4-methylthiopyridine ( 32.8 mg) as a pale yellow powder.

 (2) 3-amino-6-methyl-1-methylthiopyridine

(1) obtained in 3-amino-2-chloro 6-methyl-4-methylthio pyridinium emissions (31. 3mg, 0. 166mmo l) 2N H 2 S0 4 in (1. 0 ml) was added zinc dust (43. 4 mg ) Was added and the mixture was heated and stirred at 70 ° C. for 1 hour. Anti After neutralizing the reaction solution with saturated NaHCO ₃ water, and extracted with Ac OE t. The organic layer was dried over N a ₂ S0 _4, the residue obtained by concentration under reduced pressure and purified by preparative TLC (Merck silica force gel _{60 F 254 / CHC 13: Me} OH = 1 0: 1) was purified by And 3-amino 6-methyl-4-methylthiopyridine (21.7 mg) were obtained as a pale orange powder.

 (3) The title compound was synthesized in the same manner as in Example 1- (5) using 3-amino-6-methyl-4-methylthiopyridine obtained in (2).

High resolution FAB - MS (m / e, as _{(C, 7 H 2 .N 2} 0 S 2 + H) '); Calculated: 3 33.1 095

Measurements: 333.1 1 082

'H-NMR (300 MH z , CDC 1 3, 5 pm): 2. 48 (3H, s), 2. 5 3 (3 H, s), 2. 5 8 (6 H, s), 3. 5 7 (2 H, s), 6.99 (1 H, s), 7.08-7.19 (3H, m), 8.10

(1 H, b rs), 8.78 (1 H, s)

R f {g: 0.66 (silica gel 60 F ₂₅₄ ZC HC 13 from Merck: Me OH = 10: 1)

Example 8

 Expression

Production of the compound represented by

(1) 2-chloro-1--3-nitro-6-methyl-4-methoxypyridine Example 11 2,4-Dichloro-3-nitro-6-methylpyridine obtained in (1) (207 mg, 1. 0 Ommo 1) was added to the INNaOH-MeOH solution (5 ml) at 0 ° C, and the mixture was stirred at the same temperature for 1.5 hours. After neutralizing the reaction solution was concentrated under reduced pressure, the residue H ₂ 0 - partitioned A c OE t. The organic layer was dried over N a ₂ S 0 _4, the solvent was concentrated under reduced pressure, 2 - to give a chloro-3-two Bok low 6-methyl-4-menu Tokishipirijin. This was used for the next reaction without purification. (2) The title compound was synthesized using 2-chloro-3-nitro-6-methyl-4-methoxypyridine obtained in (1) and in the same manner as in Example 11 (2) to (5). .

 mp: 203-204 ° C

High-resolution FAB—MS (as m / e, (C ₁₈ H ₂₂ N ₂ 0 ₃ S + H)); Calculated: 347. 1 4 29

 Measured: 3 4 7.1 429

Ή-NMR (30 OMH z, CDC 1 3, <5 p pm): 2. 4 1 (3 H, s), 2. 5 9 (6 H, s), 3. 5 4 (2 H, s) , 3.80 (3 H, s), 3.89 (3H, s), 6.39 (1 H, s), 7.07-7.18 (3 H, m), 7. 50 (1 H, brs)

R f €: 0. 5 2 (Merck silica gel _{6 0 F254ZCHC 1 3: Me OH} = 50: 1) c prepared the compound of Example 9 in the same manner as in Example 8

Example 9

 Expression

A compound represented by the formula:

mp: 2 03-205 ° C

High Resolution FAB- MS (m / e, ( C '8 H 22 N 2 0 2 S 2 + H) - as): Calculated: 363.1 20 1

Measurements: 363.1 208

Ή-NMR (300 MHz, CDC 13 _> 5 ppm): 2.48 (3 H, s), 2.5 1 (3 H, s), 2.61 (6 H, s), 3. 5 9 (2 H, s), 3.78 (3 H, s), 6.47 (1 H, s), 7.08-7.17 (3H, m), 7.58 (1H, brs)

1¾ value: 0.36 (silica gel 60 F _{254 from} Merck, CHC 13 AcOEt = 10: 1) In the same manner as in Example 1, the compounds of Examples 10 to 25 were produced. Example 10

 Expression

A compound represented by the formula:

mp: 129- 134 ° C

High Resolution FAB- MS (m / e, ( C 18 H 22 N 2 0 S 3 + H) as a); Calculated: 379.0972

Measurements: 379.0995

Ή-NMR (300 MHz, CDC 1 3, 5 p pm):. 2. 39 (3 H, s) 2. 49 (3H, s), 2. 50 (3 H, s), 2. 62 (6 H, s), 3.63 (2H, s), 6.65 (1H, s), 7.08-7.20 (3H, m), 7.73 (1H, brs)

 R f value: 0.77 (Merck silica gel 60:

A c OE t = 4: 1)

Example 1 1

formula

A compound represented by the formula:

mp: 190-191 ° C

High Resolution FAB- MS (mZe, as _{+ (C 2 oH 26 N 2} 0 S 3 + H)); Calculated: 407.1286

Measurements: 407. 1299

Ή-NMR (30 OMH Z, CDC 1 3, <5 p pm): 0. 98 (3 H, t, J = 7. 5H z), 1. 77 (2 H, sext, J = 7. 5H z ), 2.39 (3 H, s), 2.50 (3 H, s), 2.62 (6 H, s), 2.69 (2H, t, J = 7.5 Hz), 3.63 (2H, s), 6.63 (1H, s), 7.12-7.15 (3H, m), 7.75 (1H, s)

1¾ 1 "value: 0. 68 (Merck Silica gel _{60 F 254 / CHC 1 3:} A c OE t = 10: 1)

Example 12

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, 5p pm): 2. 36 (3H, s), 2. 47 (3 H, s), 2. 48 (3 H, s), 3. 86 (2 H, s), 6.63 (1 H, s), 7.20-7.36 (3H, m), 7.45 (2 H, d, J = 7.3 Hz), 8.06 (1 H , brs)

R f value: 0.62 (silica gel 60F ₂₅₄ ZE t ₂₀ manufactured by Merck) Example 13

 Expression

A compound represented by the formula:

High Resolution FAB- MS (m / e, ( C 22 H 2H N 3 0 2 S 3 + H) - as); Calculated: 464.1500

Measurements: 464. 1504

Ή-NMR (300MHz, CDC 1 3 5 p pm.): 2. 35 (3H, s), 2. 42 (3 Η, s), 2. 45 (3Η, s), 2. 45- 2. 55 (4 mm, m), 2.55-2.65 (2 mm, m), 3.19-3.29 (2 mm, m), 3.65-3.75 (4 mm, m), 3 85 (2 Η, s),

6.62 (1Η, s), 7.09-7.25 (3Η, m), 7.37 (1Η, d, J = 7.7Η), 8.03 (1Η, brs)

Rng: 0. 47 (Merck Silica gel _{60 F 254 ZC HC 1 3:} M e 0 H = 10: 1)

Example 14

 Expression

A compound represented by the formula:

High resolution FAB - MS (m / e, (C 22 H 29 N 3 0 3 S 3 + H) - ) Calculated value: 480.1449

Measurement value: 480. 1451 Ή-NMR (300 MHz, CDC 1 3, 5 p pm): 2. 34 (3 H, s), 2. 45 (3H, s), 2. 48 - 2. 57 (4 H, m), 2 . 59

(2H, t, J = 7.5Hz), 3.23 (2H, t, J = 7.5Hz), 3.67-3.76 (4H, m), 3.82 (1 H, s), 3.91

(3 H, s), 6.62 (1 H, s). 6.89 (1 H, dd, J = 1.2 Hz, 8.2 Hz), 6.97 (1 H, dt, J = 1.2 Hz, 7.7 Hz), 7.20-7.30 (1 H, m), 7.44 (1 H, dd, J-1.6 Hz, 7.7 Hz), 8. 25 (1 H, s)

R f: 0.49 (silica gel 60 F ₂₅₄ ZCHC 13: MeOH = 10: 1 by Merck)

Example 15

 Expression

A compound represented by the formula:

mp: 1 23-1 25 ° C

High resolution FAB-MS (as m / e, (C ₂ , H ₂₇ N ₃ 0 ₂ S ₂ + H)-) Calculated: 4 1 8. 1623

Measured value: 4 1 8. 1 6 1 7

 Ή-NMR (30 OMH z, CDC 1 (5 ppm): 2.48-2.55 (4 H, m), 2.59 (6H, s), 2.67 (2 H, t, J = 7.3 Hz), 3.40 (2 H, t, J = 73 Hz), 3.55 (2 H, s), 3.66-3.73 (4 H, m), 7. 06 (1 H, dd, J = 4.5 Hz, 7.8 Hz), 7.07-7.18 (3 H, m), 8.23 (1 H, dd, J = 1.7 Hz, 4.5 Hz), 8.30 (1 H, dd, J = 1.7 Hz, 7.8 Hz), 8.4 1 (1 H, brs)

R il: 0. 56 (Merck Silica gel 60 F2 ZCHC 1 _3: Me OH = 20 1)

Example 16

 Expression

A compound represented by the formula:

m p: 1 13-1 14 ° C

High Resolution FAB- MS (m / e, ( C 2, H 26 C 1 N 3 0 2 S 3 + H) - and with);

Calculated value: 484. 0954

Measurements: 484.0947

'H-NMR (300 MHz, CDC 1 3, (5p pm): 2. 34 (3H, s), 2. 45 (3H, s), 2. 49 - 2. 52 (4H, m), 2. 57 (2H, t, J = 7.5 Hz), 3.22 (2 H, t, J = 7.5 Hz), 3.69—3.72 (4H, m), 3.88 ( 2H, s), 6.62 (1H, s), 7.16 (1H, dt, J = 7.7Hz, 1.5Hz), 7.28 (1H, dt, J = 7.7 Hz, 1.5 Hz), 7.39 (1 H, dd, J = 7.7 Hz, 1.5 Hz), 7.42 (1 H, dd, J = 7.7 Hz, 1.5 Hz), 8.02 (1 H, s)

1¾ value: 0.59 (Merck silica gel _{60 F 254 ZCHC 1 3: M} e 0 H = 10: 1)

Example 17

formula

A compound represented by the formula:

 mp: 177-178 ° C

High resolution FAB - MS (mZe, (C 21 H 2e N 3 OS 3 + H) - ) Calculated value: 436.1551

 Measurements: 436. 1543

Ή-NMR (300MHz, CDC 1 3, (5 p pm): 2. 30 (6 H, s), 2. 37 (3H, s), 2. 46 (3H, s), 2. 53-2. 60

(2 H, m), 2.61 (6 H, s), 3.23-3.30 (2 H, m), 3.61 (2 H, s), 6.65 (1 H, s), 7.08-7.17

(3 H, m), 7.79 (1 H, b r s)

R i: 0. 53 (Merck Silica gel _{60 F 254 ZC HC 1 3:} Me OH = 5: 1)

Example 18

 Expression

A compound represented by the formula:

mp: 67-70 ° C

High-resolution FAB—MS (m / e, (C ₂ .H ₂₆ N ₄ 0 ₂ S ₃ + H) —); Calculated: 451. 1296

Measurement value: 45 1. 1294

Ή-NMR (30 OMH z, DMSO— d ₆ , δ ρ pm): 2.40 2.48 (4H, m), 2.41 (3 H, s), 2.44 (3 H, s), 2.5 (2H), 3.20 (2 H, brs), 3.58 (4H, t, J = 4.4Hz), 4.00 (2H, s), 6.90 (1H, s), 7.37 (2H, psd, J = 6.6Hz) , 8.40 (2 H, psd, J = 6.6 Hz)

R f II: 0. 58 (manufactured by Merck & Co., Inc. silica gel _{60 F 254 ZC HC 1 3:} Me OH = 10: 1)

Example 19

 Expression

A compound represented by the formula:

High Resolution FAB- MS (m / e, ( C 3 H 38 N 4 0 3 S 3 + H) - as.); Calculated: 61 1.2184

Measured value: 61 1.2 188

Ή-NMR (300 MHz, CDC 1 3, (5 p pm):. 2. 38 (3 H, s), 2. 46 (3H, s), 2. 46-2 51 (4H, m), 2 . 62

(6 H, s), 2.62-2.67 (2 Η, m), 3.25-3.30

(2Η, m), 3.51-3.53 (4H, m), 3.62 (2H, s), 5.14 (2H, s), 6.66 (1H, s). 7.13-7.15

(3 H, m), 7.34-7.37 (5 H, m), 7.73 (1 H, s) Ril: 0.79 (silica gel 60 F ₂₅₄ / CHC 1 _a : Merck) OH = 30: 1)

Example 20

formula

A compound represented by the formula:

 m p: 81-83 ° C

High Resolution FAB- MS (m / e (C 23 H 3 N 3 0 3 S 3 + H) - as..); Calculated: 494.1606

 Measurements: 494. 1612

Ή-NMR (300MHz, CDC 1 3, 5p pm):. 2. 43 (3H, s), 2. 48 (3H, s), 2. 51 -2 61 (4H, m), 2. 61 - 2 7 1 (2H, m), 2.66 (6H, s), 3.28—3.37 (2H, m), 3.51 (1H, d, J = 14.2Hz), 3. 69— 3.78 (4 H, m), 4.38 (1 H, d, J = 14.2 Hz), 6.68

(1H, s), 7.10 (2H, d, J = 7.5Hz), 7.29 (1H, t, J = 7.5Hz), 8.14 (1H, s )

R il: 0. 46 (Merck Silica gel _{60 F 254 / C HC 1 3} : M e 0 H = 10: 1)

Example 21

 Expression

A compound represented by the formula:

mp: 73-75 ° C

High Resolution FAB- MS (m / e, ( C 23 H 3I N 3 0 4 S 3 + H) - ) Calculated value: 510.1555 Measurements: 510. 1650

Ή-NMR (300 MHz, CDC 1 3, 5 p pm): 2. 40 (3H, s), 2. 47 (3 H, s), 2. 49 - 2. 59 (4 H. m), 2 59 — 2.69 (2H, m), 2.78 (6 H, s), 3.23-3.33

(2 H, m), 3.66-3.76 (4 H, m), 4.22 (2 H, s), 6.66 (1 H, s), 7.19 (2H, d, J = 7.6Hz), 7.37

(1 H, t, J = 7.6 Hz), 7.91 (1 H, s)

R li: 0. 4 1 (manufactured by Merck & Co., Inc. silica gel _{60 F 2 ^ ZC HC 1 3} : Me OH = 10: 1)

Example 22

 Expression

A compound represented by the formula:

mp: 77-79.5 ° C

High-resolution FAB—MS (m / e, (C ₂ , H ₂₉ N ₃ 0 ₃ S ₃ + H)-): Calculated value: 468. 1449

Measurements: 468. 1432

Ή-NMR (30 OMH z, CDC 1 3 (5 p pm):. 2. 33 (6 H, s), 2. 40 (3 H, s), 2. 47 (3H, s), 2. 59 (2H, t, J = 7.3Hz), 2.78 (6H, s), 3.29 (2H, t, J =

7.3Hz), 4.22 (2H, s), 6.66 (1H, s), 7.19 (2H, d, J = 7.6Hz), 7.37 (1H, t) , J = 7.6Hz),

8.04 (1 H, b r s)

R fig: 0. 37 (Merck Silica gel _{60 F 254 ZCHC 1 3: Me} OH = 5: 1)

Example 23 formula

A compound represented by the formula:

 mp: 63-66 ° C

High resolution FAB - MS (m / e, (C 20 H 27 N 3 O 3 S 3 + H) ' ) Calculated value: 454.1293

Measurements: 454.1303

Ή-NMR (30 OMH z, CDC 1 3, 5 p pm): 2. 33 (6H, s), 2. 38 (3 H, s), 2. 46 (3H, s), 2. 56-2 62 (2 H, m), 2.77 (3 H, s), 3.26-3.32 (2 H, m), 4.27 (2 H, s), 6.65 (1 H, s), 7.37 (2H, d, J

7.5 Hz), 7.39 (1 H, dd, J = 7.5 Hz, 7.9 Hz), 7.55 (1 H, dt, J = 1.3 Hz, 7.5 Hz) , 8.11 (1 H, brs), 8.16 (1 H, dd, J = 1.3 Hz, 7.9 Hz)

R f it: 0. 48 (Merck silica gel _{60 F 25il ZC HC 1 3 Me} 0H = 4: 1)

Example 24

 Expression

A compound represented by the formula:

mp: 77-80 ° C

High resolution FAB - MS (m / e, (C 22 H 31 N 3 0 3 S 3 + H) - as) Calculated value: 482. 1606

Measurements: 482. 1604

Ή-NMR (300MHz, CDC 1 3, 5 p pm): 1. 15 (3H, d, J = 6. 6H z), 2. 39 (9 H, s), 2. 47 (3H, s), 2.78 (6H, s), 2.75-2.9 (1 H, m), 3.05 (1 H, dd, J = 7.5 Hz, 13.3 Hz), 3.47 (1 H, dd, J = 5.5Hz, 13.3Hz), 4.24 (2H, s), 6.65 (1H, s), 7.18 (2H, d, J = 7.7H) z), 7.36 (1 H, t, J = 7.7 H z), 8.09 (1 H, brs)

Κ Πϋ: 0. 47 (manufactured by Merck & Co., Inc. silica gel _{60 F 254 ZCHC 1 3: Me} OH = 5: 1)

Example 25

 Expression

N (CH _¾ 3) No 2

A compound represented by the formula:

mp: 150-153 ° C

High Resolution FAB- MS (m / e, as _{* (C 2I H 29 N 3} 0 3 S 3 + H)): Calculated: 468.1449

Measurements: 468. 1432

Ή-NMR (300 MHz, CDC 13 _> 5 p pm): 2.30 (6 H, s), 2.47 (3 H, s), 2.49 (3H, s), 2.52-2 58 (2 H, m), 2.77 (6H, s), 2.97-3.03 (2H, m), 4.22 (2 H, s), 6.76 (1 H, s) , 7.18 (2H, d, J = 7.9 Hz), 7.35 (1 H, t, J = 7.9 Hz), 8.36 (1H, brs)

R f values: 0.69 (Merck Silica gel 60 F ₂₅₄ Roh CHC 1 _3: Me 0H = 5: 1) The compound of Example 26 was produced in the same manner as in Example 8.

Example 26

 Expression

A compound represented by the formula:

mp: 163-165. C

High resolution FAB - MS (mZe, (C 23 H 31 N 3 0 3 S 2 + H) ' ) Calculated value: 462.1885

Measurements: 462. 1889

 Ή-NMR (300 MHz, CDC 1 δ p p m 2.46 (3 H, s), 2.54 (4 H, t, J = 4.6 Hz), 25 8-2.66

(8H, m), 3.29 (2H, t, J = 7.5Hz) 3.58 (2H, s), 3.73 (4H, t, J = 4.6Hz), 3.78 ( 3H, s), 6.47 (1H, s), 7.13-7.15 (3H, m), 7.59

(1 H, s)

Shaku! ^ Value:. . 33 (manufactured by Merck & Co., Inc. silica gel _{60 F 254 / CHC 1 3:} Me OH = 30: 1)

Example 27

formula

 Production of the compound represented by

 (1) 3-Nitro 6-Methyl-4-methylthio-1- (3-Morpholinop)

Example 1 2-Chloro-3-nitro-6-methyl-4-methyl-0-thiopyridine (60. Omg, 0.274 mmol), 4- (3-aminopropyl) morpholine (59.3 mg) obtained in Example 1 (2) , 0.411 mmo 1) and triethylamine (48/1, 0.343 mmol) in EtOH (5 ml) were stirred at 80 ° C. for 2 hours under a nitrogen atmosphere. Reduced pressure the reaction solution 'was concentrated, and the residue was partitioned with Ac OE t- H ₂ 0, the organic layer was dried over Na ₂ S0 _4, vacuum' preparative was collected using concentrated s residue min TLC (Merck Ltd., silica gel 60 F ₂₅₄ Roh _{CHC l 3: Me OH = 18} : purified by l), 3-two Toro - 6-methyl - 4 Mechiruchio one (3-morpholinopropyl § amino) pyridinium gin (83. lmg) Obtained as a yellow powder.

 (2) A method similar to that of Example 1- (4) and (5) using the 3-nitro-6-methyl-4-methylthio-1 (3-mol0 holinopropylamino) pyridine obtained in (1). To synthesize the title compound.

 mp: 158-160 ° C

High Resolution FAB- MS (m / e, ( C 24 H 34 N, 0 2 S 2 + H) - as); Calculated: 475.2201

5 Measurements: 475.2220

Ή-NMR (300 MHz, DMS 0-d ₆ , 5 ppm): 1.6 1 (2H, qu int, J = 6.9 Hz), 2.25 (3H, s), 2.30 (3H, s ), 2.26-2.40 (6H, m), 2.54 (6H, s), 3.31 (2H, q, J = 6.9Hz), 3.52 (2H, s), 3 57o (4 H, d d. J = 5.6 Hz, 4.2 Hz), 5.26 (1 H, t, J = 6.9 Hz), 6.29 (1H, s), 7.15 (3H, s), 9.01 (1H.s)

R f values: 0.50 (Merck silica gel 60 HC 1 _3:

Me OH = 10: 1)

R f values: 0.84 (Merck silica gel _{60 F 2 5 4 ZC HC 1} 3: Me OH: Bok Riechiruamin = 10: 1: 1) to prepare the compound of Example 28 in the same manner as in Example 27 <

Example 28

 Expression

N (CH. 3)

A compound represented by the formula:

mp: 141-144 ° C

High resolution FAB-MS (as m / e, (C ₂₂ H ₃₂ N, OS ₂ + H)) Calculated: 433. 2096

Measurements: 433.2 106

Ή-NMR (300 MHz, CD ₃ OD, 5 ppm): 1.77 (2 H, quint, J = 6.9 Hz), 2.3-2.4 (2 H, m), 2.32 (3H, s), 2.34 (3H, s), 2.38 (6H, s), 2.60 (6 H, s), 3.2.3.3 (2H, m), 3.57 (2H, s), 6.35 (1 H, s), 7.05-7.21 (3 H, m)

R f value: 0.2 1 (silica gel 60 F ₂₅₄ CHC 13: MeOH = 3: 1 manufactured by Merck)

Example 29

formula

A compound represented by the formula:

 (1) 3-Nitro 6-methyl-4-methylthio-2- (3-morpholinop pill) pyridine

Example 11 2-chloro-3-nitro-6-methyl-4-monomethylthiopyridine (21.9 mg, 0.10 Ommo 1) and 4-propargyl morpholine (18.8 mg, 0 .15 Ommo l), KOAc (1 4.7 mg, 0.15 Ommo 1) and Pd (O) (PP h ₃ ) ₄ (5.8 mg, 0.005 mmo 1) to DMF (1.Oml) Add 70. The mixture was stirred at C for 12 hours. The mixture was concentrated under reduced pressure, AcOEt was added to the residue, and the mixture was filtered using celite. The filtrate was washed with saturated NaHCO ₃ water, and then dried down pressure concentrated Na ₂ S0 _4. The residue was purified by preparative TL C (Merck, silica gel _{6 0 F 254 CHC l 3:} Me OH = 1 5: 1) to give the 3-nitro one 6-methyl - 4 Mechiruchio one 2- (3-morpholino (Probenyl) pyridine (10.3 mg) was obtained as a pale brown oil.

 (2) 3-amino-6-methyl-4-methylthio-1- (3-morpholinop pill) pyridine

 MeOH (0.7 ml) of 3-nitro-6-methyl-4-methylthio-1- (3-morpholinopropenyl) pyridine (10. Omg, 0.0325 mmo1) obtained in (1) 10% Pd—C (8 mg) was added to the solution, and the mixture was stirred at room temperature under a hydrogen atmosphere for 14 hours. The mixture was filtered and the catalyst was washed with MeOH. The combined filtrate and washings were concentrated under reduced pressure to give 3-amino-6-methyl-4-methylthio-12- (3-morpholinopropyl) pyridine (6.8 mg) as a pale yellow oil.

(3) Using 3-amino-6-methyl-4-methylthio-12- (morpholinopropyl) pyridine obtained in (2) in the same manner as in Example 1- (5) The compound was synthesized.

High Resolution FAB- MS (m / e, ( C 24 H 33 N 3 0 2 S 2 + H) - as); Calculated: 460.2093

Measured value: 460. 2096

Ή-NMR (30 OMH z, CDC 1 3, 5 p pm): 1. 9 1 (2 H, quint, J = 6. 9H z), 2. 2 6 (2 H, t, J = 6. 9H z), 2.30-2.42 (4 H, m), 2.40 (2 H, s), 2.50 (3 H, s), 2.60 (6 H, s) ), 2.68 (2 H, t, J = 6.9 Hz), 3.57 (2H, s), 3.62-3.74 (4 H, m), 6.78 (1 H , s), 7.05-7.19 (3 H, m), 8.74 (1 H, brs)

 Ril: 0.45 (silica gel 60 Fz ZC H C13: MeOH = 10: 1 from Merck)

Example 30

 Expression

Production of the compound represented by

 (1) 2- (2-tert-butyldimethylsilyloxyshethylthio) -6-methyl-4-methylthio-3-nitropyridine

Example 1 2-Chloro-3-nitro-6-methyl-4-monomethylthiopyridine (50 Omg, 2.29 mmol I) and 2-tert-butyldimethylsilyloxyethanethiol (46 Omg, 2) obtained in (2) Under a nitrogen atmosphere, 2 MNaOH (1.20 ml) was added to a solution of .39 mmol) in MeOH (50 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue A c OE t - distributed by H ₂ 0, the organic layer was dried over N a ₂ S 0 _4. The residue obtained after concentration under reduced pressure was subjected to column chromatography (manufactured by Merck, silica gel 60). Noxane: AcOEt = 9: Purified by 1), and 2- (2-tert-butyldimethylsilyloxhexylthio) -16-methyl-4-methylthio-13-nitropyridine (690 mg) was obtained as a yellow oil. Obtained as a product.

 (2) N- [2- (2-tert-butyldimethylsilyloxyl) -6-methyl-1-methylthiopyridine-3-yl] 12- (2,6-dimethylphenylthio) Acetamide

 Using 2- (2-tert-butyldimethylsilyloxyshethylthio) —6-methyl-4-methylthio-13-2-nitropyridine obtained in (1), Example 7- (1) and Example 11 ( It was synthesized in the same manner as in 5).

 (3) THF of the compound (80 Omg. 1.53 mmol) obtained in (2)

(10 ml) Tetratyl ammonium fluoride (1.0 M THF solution 3. Oml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with AcOEt. The organic layer was dried over Na ₂ S0 _4, resulting et the residue was purified by column chromatography and concentrated under reduced pressure (Merck, silica gel _{60 CHC 1 3: Me OH =} 95: 1) to obtain the title compound ( 583 mg) as a colorless solid.

mp: 184—185. C

Ή-NMR (30 OMH z, CDC 1 3, δ p pm): 2. 40 (3 H, s), 2. 48 (3 H, s), 2. 62 (6 H, s), 3. 27 (2 H, dd, J = 4.9 Hz, 5.0 Hz), 3.63 (2 H, s), 3.94

(2H, dd, J = 4.9Hz, 5.0Hz), 5.29 (1H, brs), 6.70 (1H, s), 7.04-7.21 (3H, m), 7.80 (1 H, brs)

R f values: 0. 1 3 (Merck Silica gel _{60 F 254 ZCHC 1 3: M} e 0 H = 95: 5) was prepared compound of Example 31 in the same manner as in Example 30.

Example 31

formula CH ₃ S

No CH ₃

《》 One S (0) ₂ CH ₂

S (CH ₂ ) ₂ OH

A compound represented by CH _3.

 mp: 189- 190 ° C

High resolution FAB - MS (m / e, (C, 9 H 24 N 2 0 4 S 3 + H) - as); Calculated: 441.0976

Measured: 44 1. 0988

Ή-NMR (300 MHz, CDC 1 3, (5 p pm): 2. 42 (3H, s), 2. 49 (3 H, s), 2. 78 (6 H, s), 3. 28 ( 2 H, t, J = 5.0 Hz), 3.94 (2 H, t, J = 5.0 Hz), 4.22 (2 H, s) .6.71 (1 H, s), 7 20 (2 H, d, J = 7.6 Hz), 7.38 (1 H, t, J = 7.6 Hz), 8.01 (1 H, s)

R f IS: 0. 4 1 (Merck Silica gel _{60 F 2 5 4 ZC HC 1} 3: Me OH = 20: 1)

Example 32

 Expression

Production of the compound represented by

 (1) 2-Chloro-6-methyl-4-methylamino 3-dinitropyridine Example 2 In a solution of EtOH (2. Oml), add methylamine hydrochloride (55 mg, 0.8 Ommo 1) and triethylamine

(202 mg, 2.0 Ommo 1) and stirred in a sealed tube at 40 ° C for 12 hours did. The reaction was vacuum 'concentrated, the residue Ac OE t - distributed by H ₂ 0, the organic layer was dried over N a ₂ S 0 _4. Concentrated under reduced pressure to give the residue was purified by preparative TLC (Merck, silica gel 60 F ₂₅₄ / hexane: A c OE t = 4: 1) to give the 2-click Roro 6-methyl-4 one Mechirua Mi Bruno -3- Nitropyridine (64 mg) was obtained as a yellow powder.

 (2) Using the compound obtained in (1), the title compound was produced in the same manner as in Example 11 (3) to (5).

m p: 149.5-153. C

High resolution FAB—MS (as m / e, (C ₂ , H ₃₀ N, 0 S ₂ + H) —); Calculated: 4 19. 1939

Measurements: 4 19. 1937

Ή-NMR (30 OMH z, CDC 1 3, δ p pm): 2. 3 - 2. 4 (2H, m), 2. 34 (6 Η, s), 2. 38 (3Η, s), 2 60 (6 Η, s), 2.70 (3 Η, d, J = 5.5 Hz), 3.28 (2 Η, t, J = 7.0 Η ζ), 3.62 (2 Η, s) ), 4.12-4.21 (1Η, m), 6.18 (1Η, s), 7.10-7.20 (3Η, m),

8.07 (1 Η, b r s)

R f value: 0.25 (silica gel 60 F ₂₅₄ / CHC 1 e 0 H = 1: 1 from Menorek)

R f values: 0.62 (Merck silica gel _{60 F 2 5 4 CHC 1 Me} OH: Bok Riechiruami down = 50 5: 1)

Example 33

 Expression

CH ₃

Production of the compound represented by

(1) Ethyl 2- (3-nitro-6-methyl-4-methylthiopyridine 2-ylthio) acetate

 In a nitrogen atmosphere, a solution of 2-chloro-3-3-nitro-6-methyl-4-methylthiopyridine (150 mg, 0.686 mmol) in THF (3 ml) obtained in Example 1- (2) at 0 ° was added. Ethyl 2-mercaptoacetate (75.2 β \, 0.686 mm ο 1) and Na0Et (51.4 mg, 0.

755mmo 1) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue Ac OE t - partitioned with H ₂ 0. The organic layer was dried over Na ₂ S0 _4, reduced圧澳contraction to the resulting residue CHC 1 ₃ - recrystallized from hexane, Echiru 2 - (3 _ nitro one 6-methyl-4-methylthiopyridine one 2 —Ylthio) acetate (155 mg) was obtained as a yellow powder.

 (2) Using the compound obtained in (1), the title compound was synthesized in the same manner as in Example 7- (1) and Example 11- (5).

High Resolution FAB- MS (m / e, ( C 2, H 26 N 2 0 6 S 3 + H) - as); Calculated: 483.1082

Measured value: 483.1 088

'H—band R (300 MHz, CDC 13 ₍ <5 ppm): 1.27 (3 H, t, J = 7.3 Hz), 2.40 (3H, s), 2.44 (3 H, s), 2.77 (6H, s), 3.90 (2H, s), 4.19 (2H, q, J = 7.3Hz), 4.23 (2H, s), 6.66 (1H, s), 7.19 (2H, d, J = 7.3Hz), 7.37 (1H, d, J = 7.3Hz),

7.97 (1 H, s)

R i. 'O. 21 (Silica gel 60 F _{254 from} Merck: AcOEt = 2: 1)

Example 34

formula

Production of the compound represented by

 A mixture of the compound obtained in Example 33 (85 mg, 0.18 mmol) in EtOH (0.5 ml) -THF (0.5 ml) was mixed with 4 M at 0 ° C at 4 ° C.

NaOH (0.1ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture 1 M HC 1 was added CHC 1 was acidified ₃ - partitioned with H ₂ 0. Organic layer

The residue obtained after drying over Na ₂ SO ₄ and concentration under reduced pressure was purified by preparative TLC (manufactured by Merck, silica gel 60 F ₂₅₄ / CHC 13: MeOH = 10: 1) to give the title Compound (80 mg) was obtained as a colorless powder.

mp: 2 1 5— 2 1 6 (decomposition)

High Resolution _{FAB- MS (mZe, (C 19} H 22 N 2 0 5 S 3 + H) as a ^+); calculated: 4 5 5.0 7 6 9

Measured value: 4 5 5. 0 78 6

Ή-NMR (3 0 OMH z CD was _{1 3, 0 ppm 2 4 7} C3 H, s), 2. 5 5 (3 H, s), 2. 7 6 (6 H, s) 3 6 5 (2 H, s), 4.23 (2 H, s), 6.8 3 (1 H, s) 7 20 (2 H, d, J = 7.6 Hz), 7.37-7 . 3 9 (1 H, m), 8 • 15-8. 17 (1 H, brs)

R f value: 0.23 (silica gel 60 F ₂₅₄ ZC HC Me OH = 9: 1 made by Merck)

Example 3 5

formula

Production of the compound represented by

Of the compound obtained in Example 34 (4 Omg, 0. 088mmo l ) in DMF (lml) solution of, 0 ° C nitrogen棼囲air under, NH C l (5. 6mg) , NE t 3 (29. 4 1) , 1-hydroxyl 1 H-benzotriazole (16.2 mg) and EDC I (20.2 mg) were added, and the mixture was stirred at room temperature overnight. The residue of the reaction solution was concentrated under reduced pressure to give Ac OE t - distributed by H ₂ 0, the organic layer was dried over Na ₂ S0 _4. The residue obtained by concentration under reduced pressure was purified by preparative TLC (silica gel 60 F ₂₅ , / CHC 13: Me 0H = 30: 1, manufactured by Merck) to obtain the title compound (3 lmg) as a colorless powder. .

mp: 200-203 ° C (decomposition)

High Resolution FAB-MS (m / e, (C, 9 H 23 N 3 0 4 S 3 + H) - as); Calculated: 454.0929

Measurements: 454. 0965

 Ή-NMR (300 MHz, CDC ", 5 ppm): 2.44 (3 H, s), 2.50 (3 H, s), 2.78 (6 H, s), 3.81 (2 H , s), 4.23 (2 H, s), 5.25 (2 H, brs), 6.74 (1 H, s), 7.21 (2H, d, J = 7.6 Hz), 7.40 (1 H, d, J = 7.6 Hz), 8.07 (1 H, brs)

R il: 0.45 (Merck silica gel 60

_{HC 1 3: Me 0H = 10} : 1)

Example 36

formula

Production of the compound represented by

 MeOH of compound (4 Omg, 0.065 mmol) obtained in Example 19

(1.5 ml) —AcOEt (1.5 ml) palladium black was added to the mixed solution, and the mixture was stirred at room temperature for 21 hours under a hydrogen atmosphere. The mixture was filtered and the catalyst was washed with MeOH. Combined, concentrated in vacuo to濂液and washings prep residue TLC (Merck silica gel _{60 F 25, / CHC 1 3} : Me OH = 10: 1) to give the title compound (13 mg) Obtained as a pale yellow powder.

High Resolution FAB- MS (m / e, ( C 23 H 32 N 4 OS 3 + H) - as); Calculated: 477.1817

Measurements: 477. 1800

Ή-NMR (300 MH z, CDC 1 3, 5 p pm): 2. 39 (3H, s), 2. 45 (3Η, s), 2. 62 (6Η, s), 2. 67-2. 72

(6Η, m), 3.1 7-3.26 (6Η, m), 3.62 (2Η, s), 6.65 (1Η.s), 7.12-7.16 ( 3 Η, m) .7.7 3

(1 Η, s)

R il: 0. 04 (manufactured by Merck & Co., Inc. silica gel _{60 F 254 / CHC 1 3 ··} Me OH = 10: 1)

Example 37

 Expression

Production of the compound represented by (1) 4,6-bismethylthio-1-methyl-5-ditropyrimidine Journal of 'The' Chemikanore 'Society (J. Chem.

Soc) 4,6-Dichloro mouth-2-methyl-5-ditropyrimidine (200 mg, 0.96 111111101) prepared by the method described on page 3832 (1954). To the (41111) solution, Me SNa (15% aqueous solution, 0.90 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction was vacuum 'concentrated and the residue CHC 1 ₃ - was partitioned with H ₂ 0. The organic layer was dried over Na ₂ SO ₄ , reduced under reduced pressure, and the residue was reprecipitated from 1-hexane. 4.6-bismethylthio-2-methyl-5-ditropyrimidine (16 Omg) was yellowed. Obtained as crystals.

 (2) Using 4,6-bismethylthio-1-methyl-5-ditropyrimidine obtained in (1) in the same manner as in Examples 1- (3), (4) and (5) Compound was obtained.

mp: 146-148 ° C

High Resolution FAB- MS (m / e, ( C 22 H 3 .N 4 0 2 S 3 + H) - as): Calculated: 479.1607

Measurements: 479. 1589

'H- NMR (300 MHz, CDC 1 3, <5 p pm): 2. 49 (3 H, s), 2. 49 - 2. 55 (4H, m), 2. 58 (3H, s), 2.60-2.66 (2H, m), 2.62 (6H, s), 3.23—3.32 (2H, m), 3.61 (2H, s), 3.68—3 . 76 (4H, m), 7.04-7.20 (3 H, m), 7.66 (1 H, brs)

R f it: 0. 40 (Merck Silica gel _{60 F 254 / CHC 1 3:} M e 0 H = 10: 1) were prepared compounds of Examples 38 to 40 in the same manner as in Example 37. Example 38

formula

 A compound represented by the formula:

 mp: 265-266 ° C

High Resolution FAB- MS (m / e, ( C, 7 H 2, N 3 0 S 3 + H) - as); Calculated: 380.0925

 Measurement value: 380.0912

Ή-NMR (30 OMH z, CDC 1 3, <5ppm): 2. 49 (6H, s), 2. 60 (3 H, s), 2. 62 (6H, s), 3. 62 (2 H , s). 7. 04-7.19 (3H, m), 7.67 (1 H, brs)

R f values: 0.5 1 (Merck Silica gel _{60 F 2S4 C HC 1 3:} Me OH = 50: 1)

Example 39

 Expression

A compound represented by the formula:

m p: 151-153 ° C

High resolution FAB - MS (m / e, (C 20 H 28 N 4 OS 3 + H) ' ) Calculated value: 437.1504

Measurements: 437. 1486

Ή-NMR (300 MHz, CDC 1 3, 5 p pm): 2. 3 1 (6H, s), 2. 48 (3 H, s), 2. 53 - 2. 60 (2 H, m), 2.58 (3H, s), 2.61 (6 H, s), 3.28 (2H, t, J = 7. 3H z), 3.60 (2H, s), 7.13-7. 16 (3H, m), 7.66 (1 H, brs)

 R f value: 0.42 (Merck silica gel 60 H C 13:

Me OH = 10: 1)

Example 40

 Expression

N ^ O

A compound represented by the formula:

Ή-NMR (300 MHz, CDC 1 3, <5 p pm): 2. 50 (3 H, s), 2. 54 (4 H, t, J = 4. 7 H z), 2. 58 (3 H, s), 2.6 1-2.68 (2H, m), 2.77 (6H, s), 3.26-3.32 (2 H, m), 3.73 (4 H, t , J = 4.7 Hz), 4.22 (2 H, s), 7.20 (2H, d, J = 7.3 Hz), 7.38 (1 H, t, J = 7.3 Hz) , 7.95 (1 H, s)

R i: 0. 49 (Merck silica gel _{60 F 2 / CHC 1 3:} Me OH = 10: 1) to produce a compound of Example 41 in the same manner as in Example 30.

Example 41

 Expression

Compound c represented by Ή-NMR (300 MHz, CDC 1 3, <5 p pm): 2. 48 (3 H, s), 2. 5 1 (3 H, s), 2. 77 (6 H, s), 3. 1 0 (2 H, t, J = 5.7 Hz), 3.74 (2 H, t, J = 5.7 Hz), 4.24 (2 H, s), 6.8 1 (1 H, s ), 7.19 (2H, d, J = 7.7Hz), 7.38 (1H, t, J = 7.7Hz), 8.06 (1H, s)

R fi: 0. 25 (Merck Silica gel 60 F ₂₅₄ Bruno _{C HC 1 3: Me OH =} 20: 1) was prepared compound of Example 42 in the same manner as in Example 1.

Example 42

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, <5 p pm): 2. 29 (6 H, s), 2. 34 (6H, s), 2. 45 (3 H, s), 2. 50 — 2. 62

(4 H, m), 2.76 (6 H, s), 2.98 (2 H, dd, J = 6.2 Hz, 7.7 Hz), 3.27 (2 H, dd, J = 6.2 Hz, 7.7 Hz, 4.23 (2 H, s), 6.76 (1 H, s), 7.17

(2H, d, J = 7.6Hz), 7.35 (1H, t, J = 7.6Hz), 8.50 (1H, brs)

Length £ value: 0.17 (Merck silica gel 60

_{HC 1 3: Me OH = 1} : 1) Example 27 - (1) and Example 30 - (2), to prepare the compound of Example 43 in the same manner as in (3).

Example 43 formula

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, 5 p pm) 2. 37 (3H, s), 2. 40 (3H s), 2. 73 (6H s), 3. 55- 3. 57 (2 H m), 3.78-3.81 (2H, m), 4.22 (2 H, s),

5.53 (1H, brs), 6.28 (1Hs), 7.21 (2HdJ = 7.6Hz), 7.38 (1H, d, J = 7.6Hz) ), 7.57 (1 H, brs)

. R il 'O. 47 (Merck Silica gel _{60 F 254 ZC HC 1 3:} M e OH = 10: 1) Example 1 _c Example 44 to prepare the compound of Example 44 45 in the same manner as

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, 5 p pm) 2. 40 (3 H, s), 2. 55 (3H, s), 2. 78 (6H, s), 2. 95- 3. 00 (2 H, m) 3.35 (2 H, m), 4.23 (1 H, s) 6.66 (1 H, s 7.15-7.20 (7 H, m), 7 . 30-7. 40 (1 H, m) Example 45

 Expression

A compound represented by the formula:

High resolution FAB - MS (m / e, (C 2 2 H 26 N, 0 3 S 3 + H) - ) Calculated value: 491.1246

Measurements: 491. 1250

 Ή-NMR (30 OMH z, CDC 13, <p pm): 2.40 (3 H, s), 2.47 (3 H, s), 2.76 (2 H. d, J = 6.7 Hz), 4.25 (4H, m), 6.67 (1H, s), 6.95 (1H, brs), 7.00 (1H, brs), .17 (2 H, d, J = 7.7 Hz), 7.35 (1 H, t, J = 7 Hz), 7.87 (1 H, brs), 8.47 (1 H, brs)

R f 0.75 (Silica gel 6 OF, / CHC 1 Me OH = 10: 1, manufactured by Merck) The compounds of Examples 46 to 47 were prepared in the same manner as in Example 8, _c Example 46

 Expression

A compound represented by the formula:

Ή-NMR (300MHz, CDC 1 3, δ p pm): 1. 34 (6H, d, J = 6.0Hz), 2.46 (3H, s), 2.76 (3H, s), 3.20-3.30 (2H, m), 3.90-4. 40 (2 H, s), 4.19 (2H, s), 4.60 (1 H, m), 6.5 1 (1 H, s), 7.15-7.40 (3H, m) , 7.89 (1 H, brs)

Example 47

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC, 5 ppm): 2.40 (3 H, s), 2.45 (3H, s), 2.77 (6H, s), 2.95-3.05 (2 H, m), 3.25-3.35 (2H, m), 4.25 (2 H, s), 6.67 (1 H, s), 7.15-7.20 (2H, m m) 7.30-740 (1H, m) Example 48 to 50 were prepared in the same manner as in Example 29. _c Example 48

 Expression

A compound represented by the formula:

Ή-NMR (300MHz, CDC 1 3, 5 p pm): 1. 95 (2 H, tt, J = 5. 7 H z, 6. 8 H z), 2. 43 (3 H, s), 2 . 5 1 (3 H. s). 2.76 (1 H, s), 2.92 (2 H, t, J = 6. 8H z), 3.66 (2 H, t, J = 5.7 H z), 4.2 1 (1 H, s), 6.8 1 (1 H, s), 7.20 (2 H , d, J = 7.6Hz, 7.39 (1H, t, J = 7.6Hz), 8.28 (1H, brs)

. R f - 0. 1 6 (Merck Silica gel 60 F ₂₅₄ ZCHC 1 _3:

Me OH = 10: 1)

Example 49

 Expression

A compound represented by the formula:

Ή-NMR (300MHz, CDC 1 3, δ p pm): 1. 18 (3H, t, J = 7. 6Hz), 2. 48 (3H, s), 2. 53 (2H, q, J =

7.6Hz), 2.77 (6H, s), 3.30 (2H, t, J = 5.0Hz), 3.96 (2H, t, J = 5.0Hz), 4 2 1 (2 H, s), 5.38 (1 H, brs), 6.85 (1 H, s), 7.2 1

(2 H, d, J = 7.6 Hz), 7.40 (1 H, t, J = 7.6 Hz),

8.01 (1 H, s)

1¾ value: 0.22 (Merck silica gel _{60 F 254 ZC HC 1 3:} Me OH = 10: 1)

Example 50

 Expression

A compound represented by the formula: Ή-NMR (300MHz, CDC 1 3, 5 p pm): 1. 20 (3 H, t, J = 7. 6H z), 1. 98 (2 H, tt, J = 5. 6 H z, 6 6Hz), 2. 51 (3H, s), 2. 56 (2H, q, J = 7.6Hz), 2.75 (6H, s), 2. 9 8 (2H, t, J = 6.6Hz), 3.66 (2H, t, J = 5.6Hz), 4.20 (2H, s), 6.95 (1H, s ), 7.21 (2 H, d, J = 7.6 Hz), 7.40 (1 H, t. J = 7.6 Hz), 8.48 (1 H, s)

R i: 0. 33 (Merck Silica gel _{60 F 254 ZC HC 1 3 Me} OH = 10: 1) Example 30 _c Example compounds were prepared Example 5 1 61 in the same manner as 51

 Expression

A compound represented by the formula:

 Ή-NMR (30 OMH z CDC 13, 5 ppm): 2.42 (3 H, s), 2.48 (3 H, s), 2.76 (6 H, s), 2.85-3 00 (1 H, m), 3.20—3.30 (2 H, m), 3.70-4.00 (3H, m), 4.26 (2 H, s), 6.73 ( 1 H, s), 7.15-7.40 (3 H, m), 8.25 (1 H, brs)

Example 52

formula CH ₂ OH

 A compound represented by the formula:

 Ή-NMR (30 OMH z, CDC ", δ p pm): 2.77 (6H, s), 3.20-3.40 (2 H, m), 3.42 (3 H, s), 3 . 49

(3H, s), 3.50-3.70 (2 H, m), 3.90 (1 H, m), 4.23 (1 H, s), 6.72 (1 H, s) , 7.15-5.40

(3H, m), 8.10 (1H, brs), 8.60 (1H, brs) Example 53

 Expression

A compound represented by the formula:

 'H-NMR (30 OMH z CDC 13, <5 ppm): 2.47 (3H, s), 2.77 (6 H, s), 3.11 (2 H.m), 3.29 ( 2H, m), 3.78 (2H, m), 3.93 (2H, m), 4.24 (2H, s), 6.87 (1H, s), 7.18 (1 H, s), 7.2 1 (1 H, s), 7.38 (1 H, m), 8.20 (1 H, s)

Example 54

formula

A compound represented by the formula:

Ή-NMR (300 MHz, CDC 1 3, (5 p pm): 2. 35 (3 H, s), 2. 46 (3 H, s), 2. 84 (3 H, s), 3. 15 -3.25 (2 H, m), 3.73 (2H, s), 3.85-3.95 (2 H, m) .6.66 (1 H, s), 7.40-7. 90 (6 H, m), 8.60-8.70 (1 H, m)

Example 55

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, <5 p pm): 2. 4 1 (3 H, s), 2. 48 (3 H, s), 3. 00 (3 H, s), 3 20- 3.30 (2 H, m), 3.90-4.00 (2H, m), 4.40 (1 H, s), 6.70 (1 H, s). 8.10 (6 H, m), 8.90- 9.00 (1 H, m)

Example 56

formula

A compound represented by the formula:

Ή- NMR (3 00 MH z, CDC 1 3, 5 ppm): 1. 2 7 (1 2 H, d, J = 7. 0 H z), 2. 43 (3 H, s), 2. 50 (3 H, s), 3.20-3.30 (2H, m), 3.62 (2H, s),

3.90-4.00 (4H, m), 6.70 (1H, s), 7.20—7

70 (4 H, m)

Example 57

 Expression

A compound represented by the formula:

 Ή-NMR (30 OMH z, CDC ", 5 ppm): 1.47 (6 H, d, J = 6.5 Hz), 1.55 (6 H, d, J = 6.5 Hz), 2.67 (3H, s), 2.71 (3H, s), 3.45-3.55 (2 H, m), 3.70-3.80 (2 H, m), 4.10-4.20 (2H, m), 4.65 (2H, m), 6.94 (1 H, s), 7.40-7.70 (3 H, m), 8.55 (1 H, s)

Example 58

formula

A compound represented by the formula:

High resolution FAB - MS (m / e, (C, 8 H 23 N 3 0 2 S 3 + H) + ) Calculated value: 4 1 0.1 030

Measured value: 4 1 0.13

Ή-NMR (30 OMH z, CDC 1 3, (5 p pm): 2. 37 (3 H, s), 2. 4 6 (3 H, s), 2. 5 5 (6 H, s), 3.30 (2 H, m), 3.69 (2 H, s), 3.90 (2 H, m), 6.66 (1 H, s), 7.50 (1 H, m) , S), 8.3 1 (2 H, s)

R f value: 0.12 (silica gel 60 F ₂₅₄ ZAcOEt manufactured by Merck) Example 5 9

 Expression

A compound represented by the formula:

High Resolution FAB-MS (m / e, (C 2 .H 26 N 2 0 4 S 3 + H) - as); Calculated: 455.1 1 33

Measured value: 45 5.1 1 3 4

Ή-NMR (30 OMH z, CDC 1 3, <5 p pm): 2. 40 (3 H, s), 2. 4 7 (3 H, s), 2. 7 7 (6 H, s), 3.6 1 (2Η, t, J = 6.6Hz), 3.71 (2H, t, J = 6.6Hz), 3.88 (3H, s), 4.22 (2 H.s), 6.66 (1 H, s), 7.19 (2 H, d, J = 7.7 Hz), 7.37 (1 H, t, J = 7.7 H z), 7.87 (1 H, brs)

R f value: 0.26 (Merck silica gel 60 F ₂₅₄ ZA OE t: hebutane = 1: 1)

 Example 60

 Expression

A compound represented by the formula:

High resolution FAB - MS (m / e, (C.yH.eC 1 2 N 2 0, S 3 + H) - and with);

Calculated value: 480.9884

Measurements: 480. 9879

 Ή-NMR (30 OMH z, CDC 13, δ ρ m): 2.39 (3 Η, s), 2.47 (3 H, s), 3.26 (2 Η, dd, J = 5.ΟΗζ) , 5.5Hz), 3.92 (2H, t, J = 5.0Hz), 4.61 (22, s), 6.69 (1Η, s), 7.44 (1Η, s, J = 7.0 Η ζ), 7.51 (2Η, d, J = 7.OH), 7.97 (1 Η, brs)

R f: 0.70 (silica gel 60F ₂₅₄ / AcOEt manufactured by Merck) Example 61

 Expression

A compound represented by the formula:

High Resolution FAB- MS (m / e, as _{(C 20 H 26 N 2 O} 4 S 2 + H)); Calculated value: 455. 1 133

Measurements: 455. 1 138

Ή-NMR (300MHz, CDC 1 3, 5 p pm): 1. 27 (3 H, d, J = 7. 0H z), 2. 4 1 (3 H, s), 2. 48 (3 H, s), 2.77 (6 H, s), 3.19 (1 H, dd, J = 6.8 Hz, 14.5 Hz), 4.12 (1 H, m), 4.23 (2 H, s), 6.70 (1 H, s), 7.19 (2H, d, J = 7.5 Hz), 7.38 (1 H, d, J = 7.5 Hz) 8.02 (1 H, brs)

R f values: 0. 80 (Merck Silica gel 60 F ₂₅₄ ZAc OE t: § acetone = 4: 1) _c Example 62 The compound was prepared in Example 62, 63 by a method similar to Example 3 [delta]

 Expression

A compound represented by the formula:

 Ή-NMR (30 OMH z CDC 1 a, δ p pm): 2.43 (3 H, s), 2.75 (6H, s), 3.20-3.30 (4H, m), 3. 70 1 3.80 (2 H, m), 4.43 (1 H, s), 6.80 (1 H, s), 7.10-7.40 (4 H, m)

Example 63

formula

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, δ p pm): 2 3 7 (3 H, s), 2. 4 3 (3 H, s), 2. 7 3 (6 H, s), 3 . 2 2 (3 H, s), 3.05-3.90 (5 H, m), 3.95-4.20 (2 H, m), 4.30 (1 H, s ), 6.62 (1 H, s), 7.10-7.20 (2 H, m), 7.25-7.40 (1 H, m) By the same method as in Example 37. It was prepared compounds of examples. 64 to 66 _£ example 64

 Expression

/

 W — S (0)

 / No

2 OH

C ^H 3

A compound represented by the formula:

Ή-NMR (300 MH z, CDC 1 3, 5p pm): 2. 6 0 (3 H, s), 2. 7 7 (6 H, s), 3. 3 5 (4 H, t, J = 5.4 Hz), 3.55-3.70 (2 H, m), 3.85-3.95 (4 H, m), 4.22 (2 H, s), 7.2 1 (2 H, d, J = 7.7 Hz), 7.39

(1 H, t, J = 7.7 Hz), 8.08 (1 H, s)

R f values: 0. 2 8 (Merck Silica gel _{6 0 F 2 s 4 ZC HC} 1 3: Me OH = 95: 1)

Example 65

formula CH:

No CH ₃

One S (0) ₂ CH ₂

S CH ₂ CHOHCH ₂ OH

A compound represented by CH _3.

'Η- NMR (300 MHz, CDC 1 3, (5 p pm): 2. 52 (3H, s), 2. 62 (3 H, s), 2. 77 (6 H, s), 3. 26 (1 H, dd, J = 6.0 Hz, 14.8 Hz), 3.36 (1 H, dd, J = 5.3 Hz, 14.8 Hz), 3.6 1 (1 H, dd, J = 4.7 Hz, 1 1.

6 Hz), 3.65 (1 H, dd, J = 4.4 Hz, 1 1.6 Hz), 3.

93 (1 H, d d d d, J = 4.4 Hz, 4.7 Hz, 5.3 Hz, 6.

0 H z,), 4.22 (2 H, s), 7.2 1 (2 H, d, J = 7.

6H z), 7. 40 (1 H, t, J = 7. 6Hz), 8. 02 (1 H, s) R il: 0. 33 ( Merck Silica gel 60 F ₂₅₄ / CHC 1 _3:

Me OH = 10: 1)

Example 66

 Expression

A compound represented by the formula:

Ή-NMR (30 OMH z, CDC 1 3, (5 p pm): 2 5 1 (3 H, s), 2. 60 (3 H, s), 2. 77 (6 H, s), 3 32 (2 H, t, J = 5.3 Hz), 3.92 (2 H, dt, J = 4.7 Hz, 5.3 Hz), 4.12 (1 H, t, J = 4 7 Hz), 4.22 (2 H, s), 7.2 1 (2H, d, J = 7.7 Hz), 7.39 (1 H,, J = 7.7 Hz), 8 . 01 (1 H, s) 1 ^ £ value: 0.24 (Merck silica gel _{60 F 254 / CHC 1 3:} Me OH = 95: 1) m Bok of禾Iiffl ft

 The compound of the present invention, by inhibiting ACAT, suppresses the production of cholesterol ester, inhibits the absorption of cholesterol, lowers the blood cholesterol concentration, and further suppresses the accumulation of cholesterol ester in the blood vessel wall. . Therefore, it is expected to be effective as a therapeutic or preventive drug for hypercholesterolemia, hyperlipidemia, arteriosclerosis, and associated heart diseases.

Claims

The scope of the claims

 (1) General formula

[Wherein, Ar is a lower alkyl group, a lower alkoxy group, a halogen atom, and optionally has 1 to 4 substituents, a phenyl group, a naphthyl group, or a pyridyl group. R ¹ represents a hydrogen atom or a lower alkyl group; R ² and R ³ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono-lower alkylamino group or a di-lower alkylamino (However, any hydrogen atom of the lower alkyl group, lower alkoxy group, lower alkylthio group, mono-lower alkylamino group or di-lower alkylamino group is a pyrrolidino group, a morpholino group, a thiomorpholino group, an imidazolyl group , Amino group, mono-lower alkylamino group, di-lower alkylamino group, 1-piperazinyl group, 4-benzyloxycarbone 1 N may be substituted with a group selected from the group consisting of a piperazinyl group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a carboxy group, a phenol group, and a hydroxyethylmethylcarbamoyl group. Represents 0, 1 or 2, and X represents CH or N.] or a pharmaceutically acceptable salt thereof.

 (2) An aryl-coenzyme A cholesterol 0-acyltransferase inhibitor comprising the arylthioacetamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof. Agent.

 (3) A treatment for hypercholesterolemia, hyperlipidemia or arteriosclerosis, comprising the arylthioacetamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof. And Z or prophylactic.