JPH0532666A - Thienopyridine derivative, production thereof and acat inhibitor - Google Patents

Abstract

PURPOSE:To provide the subject new compounds useful as an acyl-CoA: a cholesterol acyltransferase inhibitor. CONSTITUTION:Compounds of formula I [Ring A is (substituted)benzene ring; Ring B is (substituted)thiophene ring; X is formula II (R<1> is H, alkyl or alkoxy; n is 0 or 1) or formula III (R<2> is H or alkyl); Y is direct bond,-NH-, 1-2C alkylene or-CH=CH-; R<3> is (substituted)hydrocarbon], e.g. N-[4-(2-chlorophenyl)-2- ethylthieno[2,3-b]pyridin-5-yl]-N'-(2,4-difluorophenyl)urea. The compounds of formula I can be obtained, e.g. by reacting a compound of formula IV with a compound of formula R<3>-Q<2> (One of Q<1> and Q<2> is-NH2 and the other is-NCO).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has excellent acyl-CoA:
The present invention relates to a thienopyridine derivative having a cholesterol acyltransferase (ACAT) inhibitory action.

[0002]

2. Description of the Related Art A thienopyridine derivative having a phenyl group at the 4-position counting from the pyridine nitrogen and having a nitrogen atom bonded at the 3-position has not been known so far, and is known as an arteriosclerotic agent or in blood. Whether it is useful as a cholesterol lowering agent has not been examined at all.

[0003]

The present invention has an excellent acyl-CoA: cholesterol acyltransferase inhibitory action and suppresses absorption of cholesterol from the intestinal tract and accumulation of cholesterol ester in the arterial wall in mammals, A novel drug useful as a preventive or therapeutic drug for hypercholesterolemia, atherosclerosis and various diseases caused by these (eg, ischemic heart disease such as myocardial infarction and cerebral infarction, cerebrovascular disorder such as stroke) The main object is to provide a thienopyridine derivative.
Further, it is an object of the present invention to provide an industrially excellent method for producing such a novel compound and a composition or agent useful as a medicine containing the novel compound.

[0004]

Means for Solving the Problems The present inventors have conducted various studies on thienopyridine derivatives, and as a result, have shown that they are novel compounds of the general formula:

[Chemical 10] [In the formula, the ring is a benzene ring which may have a substituent,
Ring B is an optionally substituted thiophene ring, and X is a formula

[Chemical 11] (In the formula, R ¹ represents hydrogen, an alkyl or alkoxy group,
Represents 0 or 1), or

[Chemical 12] (Wherein R ² represents hydrogen or an alkyl group), Y is a bond, —NH—, an alkylene group having 1 or 2 carbon atoms or —CH═CH—, and R ³ is a substituent. Represents a hydrocarbon group which may have. The thienopyridine derivative represented by the formula] or a salt thereof has a strong ACAT inhibitory action, and was found to be useful as a blood cholesterol lowering agent and a therapeutic agent for arteriosclerosis, and based on this, the present invention was completed.

That is, the present invention provides (1) a thienopyridine derivative (I) or a salt thereof, and (2) a general formula:

[Chemical 13] [In the formula, Q represents a carboxyl group which may be esterified or amidated, —NH ₂ or —NCO, and other symbols have the same meanings as described above. ] The compound or its salt represented by these, (3) General formula:

[Chemical 14] The compound represented by the formula or a salt thereof is reacted with the compound represented by the formula: R ³ -Q ² (IV) or a salt thereof:

[Chemical 15] A method for producing a thienopyridine derivative represented by or a salt thereof [in the above formula, ^one of Q ¹ and Q ² is —NH ₂ and the other is —NCO, and the other symbols have the same meanings as described above. ], (4) General formula:

[Chemical 16] [The symbols in the formulas have the same meanings as described above. And a salt thereof with the general formula: R ³ —Y ¹ —COOH (VII) [wherein Y ¹ is a bond, an alkylene group having 1 or 2 carbon atoms or —CH═CH—, R ³ Has the same meaning as above. ]
A general formula characterized by reacting with a compound represented by or a reactive derivative thereof:

[Chemical 17] [The symbols in the formulas have the same meanings as described above. ] A method for producing a thienopyridine derivative represented by the formula] or a salt thereof, and (5) an acyl CoA: cholesterol acyltransferase inhibitor comprising the thienopyridine derivative represented by the formula (I) or a salt thereof.

In the above formula, ring A represents a benzene ring which may have a substituent. Examples of such a substituent include a halogen atom, an alkyl group which may be halogenated, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, a C _1-3 acyloxy group (for example, , Formyloxy, acetoxy, propionyloxy groups, etc.), hydroxyl groups, di-C _1-6 alkylamino groups, mono-C _1-6 alkylamino groups and the like.
Examples of halogen as such a substituent include fluorine, chlorine, bromine and iodine. As the alkyl group which may be halogenated, for example, a linear or branched alkyl group having 1 to 6 carbon atoms and those having 1 to 5 halogen atoms as described above are used, For example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl , 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,
Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl,
6,6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like are frequently used. Examples of the optionally halogenated alkoxy and the optionally halogenated alkylthio group include, for example, a halogenated group formed by combining the aforementioned alkyl group or halogenated alkyl group with an oxygen atom and a sulfur atom, respectively. Optionally alkoxy group, optionally halogenated alkylthio group and the like are used, and examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,
Alkyl which may be halogenated, such as 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy, for example, methylthio, difluoromethylthio. An optionally halogenated alkylthio group such as trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio is often used. The-C _1-6
Examples of the alkylamino group include dimethylamino, methylethylamino, diethylamino, methylpropylamino, ethylpropylamino, dipropylamino and the like. Examples of the mono-C _1-6 alkylamino group include methylamino, ethylamino, propylamino and the like.

The substituents on ring A may be substituted at substitutable positions on the ring, and when there are two or more substituents, they may be the same or different, and the number thereof is 1 to 4. May be. Preferred examples of the ring A having a substituent include, for example, a halogen atom such as fluorine and chlorine at the 2-position,
C _1-4 alkyl group such as methyl and ethyl, methoxy group,
C _1-4 alkoxy group such as ethoxy group, etc. C _1-4 alkylthio group such as methylthio group is one substituted benzene ring. In the above formula, ring B represents a thiophene ring which may have a substituent, and the sulfur atom thereof may be at any position except the condensation position of the condensed ring (does not become a bridgehead atom of the condensed ring). Further, as the substituent, for example, a halogen atom, an alkyl group, a C _3-6 cycloalkyl group, a nitro group, an amino group, an acylamino group or the like is used. Examples of such halogen atoms include fluorine, chlorine, bromine and iodine. In addition, as the alkyl group, for example, a linear, branched or cyclic group having 1 to 6 carbon atoms is preferable, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. , Pentyl, isopentyl, neopentyl, hexyl and the like are used. Examples of the C _3-6 cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl and the like. As the acylamino group, those having 1 to 7 carbon atoms are preferable, and for example, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino and the like can be used. Such B ring substituents may be the same or different and may be 1 or 2
May exist, or adjacent carbon atoms on the B ring may be linked together with a group represented by-(CH ₂ ) q-- (q represents an integer of 3 to 5) to form a 5 to 7 membered ring. It may be formed.

In the above formula, R ³ represents a hydrocarbon group which may have a substituent. As the hydrocarbon group represented by R ³ , for example, an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl group or the like is used.
The alkyl group represented by R ³ has, for example, 1 carbon atom.
A straight chain, branched chain or cyclic group of 8 to 8 is preferred, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl. and cycloalkyl as, for example cyclopropyl, cyclopentyl, C _3-6 cycloalkyl such as cyclohexyl, cycloalkylalkyl the example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, C _3-6 cycloalkyl such as cyclohexyl methyl Alkyl-C _1-3 alkyl is used.
The aryl group represented by R ³ is preferably an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl. Examples of the aralkyl group represented by R ³ include
Benzyl, 1-phenylethyl, 2-phenylethyl,
1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, diphenylmethyl and the like having 7 to 16 carbon atoms
Aralkyl groups are preferred. Further, the alkyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl groups represented by R ³ may have 1 to 5 substituents which are the same or different. As such a substituent, for example, the substituents and the like used in the case of the ring A are preferably used, and those described below are used. As the aryl group represented by R ³ , for example, a phenyl group and the like are preferable, and the phenyl group has, as a substituent, for example, a halogen atom, an alkyl group, an alkoxy group, a dialkylamino group, a hydroxyl group, an acyloxy group, etc. Those having 1 to 5 halogen atoms (e.g., fluorine, chlorine, bromine, iodine), especially chlorine and fluorine are particularly preferable. Specifically, for example, 2,4- A difluorophenyl group and the like are preferable. As the alkyl group which the phenyl group may have, C _1-4 alkyl groups such as methyl, ethyl and isopropyl are preferably used, and as the alkyl-substituted phenyl group, particularly 2,6-dimethyl, 2,6
-Diethyl, 2-methyl-6-ethyl, 2-methyl-6
-Isopropyl, 2-ethyl-6-isopropyl, 2,6-diisopropylphenyl and the like are preferable. As the alkoxy group which the phenyl group may have, a C _1-4 alkoxy group such as methoxy and ethoxy is preferably used. As the dialkylamino group which the phenyl group may have, a di-C _1-5 alkylamino group such as dimethylamino, diethylamino, methylethylamino, dipropylamino and the like are preferably used. As the acyloxy group which the phenyl group may have, C _1-3 acyloxy groups such as formyloxy, acetoxy and propionyloxy are preferably used. Further, the above C _1-4 alkyl group, C _1-4 alkoxy group and hydroxyl group or C _1-3 acyloxy group (eg, formyloxy, acetoxy, etc.)
A phenyl group having, for example, 4-acetoxy-3,
5-dimethyl, 4-hydroxy-3,5-dimethyl, 4
-Acetoxy-3,5-dimethoxy or 4-hydroxy-3,5-dimethoxyphenyl group and the like are preferable as R ³ .

The aralkyl group represented by R ³ is particularly preferably a benzyl group or a 1-phenylethyl group,
It is preferable that 1 to 5 halogen atoms, alkyl groups, alkoxy groups, dialkylamino groups, hydroxyl groups and acyloxy groups are substituted on the benzene ring. Here, as the halogen atom, fluorine and chlorine are particularly preferable, and among them, a fluorine-substituted aralkyl group, particularly a 2,4-difluorobenzyl group is preferable. As the alkyl group, a C _1-4 alkyl group such as methyl, ethyl, isopropyl and tert-butyl is preferably used. As the alkoxy group, a C _1-4 alkoxy group such as methoxy and ethoxy is preferable. As the dialkylamino group, di-C _1-5 alkylamino such as dimethylamino, diethylamino, methylethylamino, dipropylamino and the like are preferably used. As the acyloxy group, a C _1-3 acyloxy group such as formyloxy, acetoxy and propionyloxy is preferably used. Benzyl having both a C _1-4 alkoxy group and a hydroxyl group or a C _1-3 acyloxy group (eg, formyloxy, acetoxy, etc.) is particularly preferred as R ³ , and examples thereof include 4-acetoxy-3,5-dimethyl, 4- Hydroxy-3,5-dimethyl, 4-acetoxy-3,5-dimethoxy or 4-hydroxy-3,5
-Dimethoxybenzyl and the like are preferable as R ³ . In the above formula, X is a formula

[Chemical 18] (In the formula, R ¹ represents hydrogen, an alkyl or alkoxy group,
Represents 0 or 1) or

[Chemical 19] (In the formula, R ² represents hydrogen or an alkyl group). The alkyl group represented by R ¹ and R ² is
Included are linear or branched ones having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

The alkoxy group represented by R ¹ has 1 carbon atom.
.About.6 straight or branched. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-
Butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like are used. X
Preferred examples of

[Chemical 20] Etc. In the above formula, Y represents a bond, -NH-, an alkylene group having 1 or 2 carbon atoms, or -CH = CH-.
Here, as the alkylene group having 1 or 2 carbon atoms, for example,

[Chemical 21] Etc. are used. A preferred example of Y is, for example, —NH
_{-, - CH 2 -, -} CH 2 CH 2 -, - it is a CH = CH- and the like.

The thienopyridine derivative represented by the formula (I) or a salt thereof can be produced, for example, by the following method. First, by reacting compound (III) or a salt thereof with compound (IV) or a salt thereof, compound (V) in which Y = -NH- in compound (I) or a salt thereof can be produced. Specifically, (1) general formula

[Chemical formula 22] [Wherein the symbols in the formula have the same meanings as described above] and a compound represented by the general formula R ³ —NH ₂ (V) [where the symbols in the formulas have the same meanings as described above] or a salt thereof. Compound (V) or a salt thereof is produced by reacting, or (2) the general formula

[Chemical formula 23] [Where the symbols in the formula have the same meanings as described above] or a compound or salt thereof is reacted with a compound represented by the general formula R ³ -NCO (XI) [where the symbols in the formulas have the same meanings as described above]. Thereby, compound (V) or a salt thereof can be produced. (3) Further, a compound (VI) or a salt thereof is reacted with a compound (VII) or a reactive derivative thereof to give a compound
Compound (VIII) or a salt thereof in which (Y) is a bond, an alkylene group having 1 or 2 carbon atoms, or -CH = CH- can be produced. (4) Further, by reducing the compound represented by Y = -CH = CH- or a salt thereof in the compound (I), Y = -CH ₂ C
The H ₂ — compound (I) or a salt thereof can be produced. Next, each of the above (1) to (4) will be described in detail.

Method (1): Compound (IX) and compound (X) or salts thereof (eg salts with mineral acids such as hydrochloric acid and sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid) When reacting with an acid, a salt with an organic acid such as maleic acid), it is usually carried out in a solvent. Such a solvent may be any solvent as long as it does not interfere with the reaction, for example,
Ethers (eg, ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene,
Xylene, etc., esters (eg, methyl acetate, ethyl acetate, etc.), N, N-dimethylformamide, dimethyl sulfoxide, etc. are preferably used. When compound (X) is used in the form of a salt, the reaction can be allowed to proceed significantly by optionally desalting. In this case, as the desalting agent, tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine, aromatic amines such as pyridine, picoline and N, N-dimethylaniline are preferably used. The amount of these amines used is
(X) 1 mol to 1 mol, preferably 1 to 3 mol
It is a molar equivalent. The reaction temperature is usually -10 ° C to 180 ° C,
It is preferably 0 ° C to 120 ° C. Reaction time is usually 15
Minutes to 40 hours, preferably 30 minutes to 20 hours. The amount of (X) or a salt thereof used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of (IX).

Method (2): Compound (VI) or a salt thereof (eg,
Salts with mineral acids such as hydrochloric acid, sulfuric acid or methanesulfonic acid,
Benzenesulfonic acid, toluenesulfonic acid, oxalic acid,
Salts with organic acids such as fumaric acid and maleic acid) and compounds (X
The reaction with I) is carried out under the same conditions as in the above method (1). When (VI) is used in the form of a salt, the same desalting agent used in the method (1) is used. The amount of compound (XI) to be used is generally 1 to 5 molar equivalents of (XI), preferably 1 to 3 molar equivalents, relative to 1 mole of (VI).

Method (3): Compound (VI) or a salt thereof (eg,
Salts with mineral acids such as hydrochloric acid, sulfuric acid or methanesulfonic acid,
Benzenesulfonic acid, toluenesulfonic acid, oxalic acid,
Salts with organic acids such as fumaric acid and maleic acid) and compounds (VI
When reacting with I), it is usually preferable to use an appropriate condensing agent, or to once convert (VII) into a reactive derivative of the carboxyl group and then react with (VI) or a salt thereof. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC) and diethyl cyanophosphate.
(DEPC), diphenylphosphoryl azide (DPPA) and the like are used. When using these condensing agents, usually,
Solvent (eg, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, N, N-
It is preferably carried out in dimethylformamide, dimethylsulfoxide). This reaction may be accelerated in the presence of a base, and is about -10 ° C to 100 ° C, preferably about 0 ° C to 6 ° C.
The reaction is carried out at 0 ° C. The reaction time is usually 1 to 96 hours,
It is preferably 1 to 72 hours. The amount of (VII) and the condensing agent to be used is 1 to 1 mol of (VI) or its salt, respectively.
It is 5 molar equivalents, preferably 1 to 3 molar equivalents. As the base, for example, alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine, pyridine and the like are used, and the amount thereof is 1 to 5 molar equivalents relative to 1 mole of (VI) or a salt thereof, preferably It is 1 to 3 molar equivalents.

Examples of the reactive derivative of (VII) include:
Acid halides (eg, chloride, bromide, etc.), acid anhydrides,
Mixed acid anhydride (e.g., anhydride with methyl carbonate, anhydride with ethyl carbonate, anhydride with isobutyl carbonate, etc.), active ester (e.g., ester with hydroxysuccinimide,
Ester with 1-hydroxybenzotriazole, N-
Hydroxyl-5-norbornene-2,3-dicarboximide ester, p-nitrophenol ester, 8-oxyquinoline ester, etc.) are used, and acid halides are particularly preferable. When the compound (VI) or a salt and a reactive derivative of (VII) are reacted, a solvent (e.g., chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine, N, N-dimethylformamide, etc.).
The reaction may be promoted in the presence of a base. Usually about -10
C. to 120.degree. C., preferably about 0.degree. C. to 100.degree. The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours
It's time. The amount of the reactive derivative of (VII) used is 1 to 5 molar equivalents, preferably 1
~ 3 molar equivalents. Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, and the like.
Alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate are used, and the amount thereof is 1 to 5 with respect to (VI) or 1 mol of the salt. It is a molar equivalent, preferably 1 to 3 molar equivalents. When a solvent immiscible with water is used in this reaction, water may be added to the reaction system to allow the reaction to proceed in a two-phase system.

Method (4): Y = -CH = C in compound (I)
A compound showing H- or a salt thereof is reduced to give Y = -CH.
₂ CH ₂ - can be converted to compounds shown (I) or a salt thereof. The reducing agent used is a metal hydride salt,
For example, lithium aluminum hydride, sodium borohydride, lithium borohydride, etc. are used, and the amount thereof is usually 0.5 with respect to 1 mol of compound (I) [Y = -CH = CH-] or a salt thereof. ~ 5 molar equivalents, preferably 0.1.
It is 5 to 2 molar equivalents. The reaction is usually performed in a solvent (eg, methanol, ethanol, ethyl ether, tetrahydrofuran, dioxane, etc.). The reaction temperature is generally -5 ° C to 120 ° C, preferably 0 ° C to 100 ° C.
The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. This reduction reaction can be performed using a metal and an acid, a metal and a base, or an alcohol, in addition to using the reducing agent. Such metals include zinc, tin,
When iron or the like is used, an acid (eg, hydrochloric acid, sulfuric acid, acetic acid, etc.) is mainly used as a hydrogen supply source. When using potassium, sodium, lithium or the like as a metal, a base (e.g., ammonia, ethylamine, dimethylamine, diethylamine, etc.) is mainly used as a hydrogen source, and alcohols (e.g., methanol, ethanol, propanol, etc.) ) Is also used. The amount of the metal used in this reaction is 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to 1 mol of compound (I) [Y = -CH = CH-] or a salt thereof. This reaction is usually performed in a solvent (eg, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc.), but the acid or base used may be used as a solvent. The reaction temperature is 0 ° C to 120 ° C, preferably 0 ° C to 80 ° C. Reaction time is usually 30 minutes to 12
The time is preferably 30 minutes to 6 hours.

This reduction reaction can also be carried out by a catalytic reduction reaction using a catalyst. As such a catalyst, for example, palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, rhodium carbon, etc. are used.
The reaction is usually performed in a solvent (eg, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethoxyethane, formic acid, acetic acid, N, N-dimethylformamide, etc.). The reaction is usually performed at atmospheric pressure to 20 atm, preferably atmospheric pressure to 5 atm. Reaction temperature is 0
C. to 100.degree. C., preferably 0.degree. C. to 80.degree. The reaction time is usually 30 minutes to 24 hours, preferably 30 minutes to 1
2 hours. In the case where the benzene ring in the compound (I) or a salt thereof produced by any of the above methods (1) to (4) contains a lower alkoxy group, it is optionally reacted with, for example, boron tribromide, It can also be converted to a hydroxyl group. This reaction is usually carried out in a solvent (e.g., dichloromethane,
(Chloroform, carbon tetrachloride, benzene, toluene, etc.)
The temperature is about -20 ° C to 80 ° C, preferably about 0 ° C to 30 ° C, and the amount of boron tribromide used is about 1 to 10 molar equivalents, preferably about 1 to 5 with respect to one lower alkoxy group. It is a molar equivalent. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

When the benzene ring in the compound (I) or its salt produced by any of the above methods (1) to (4) contains a hydroxyl group, it may be subjected to an alkylation or acylation reaction, if necessary. Each can be converted into an alkoxy or acyloxy group. The alkylation reaction is
In a solvent (eg, methanol, ethanol, propanol, dimethoxyethane, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, etc.), base
(Eg, organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide) in the presence of Alkane halide that may have a substituent (e.g., chloride, bromide, iodide, etc.),
It is carried out by reacting with an alkylating agent such as a sulfate ester or a sulfonate ester (eg, methane sulfonate, p-toluene sulfonate, benzene sulfonate, etc.). The reaction temperature is generally -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C. The amount of these alkylating agents used is about 1 to 5 per mol of the starting phenolic derivative.
It is a molar equivalent, preferably about 1 to 3 molar equivalents. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 1
2 hours. The acylation reaction is carried out by reacting the desired carboxylic acid or its reactive derivative. This reaction varies depending on the kind of the starting phenolic derivative, but is usually a solvent (eg, benzene, toluene, ethyl ether, ethyl acetate, chloroform, dichloromethane, dioxane, tetrahydrofuran, N, N-dimethylformamide, pyridine, etc.) In order to accelerate the reaction, an appropriate base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, triethylamine, pyridine, etc.) can be added. As the reactive derivative of carboxylic acid, acid anhydride, mixed acid anhydride, acid halide (eg, chloride, bromide) and the like are used. The amount of these acylating agents used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the starting phenolic derivative. The reaction temperature is generally 0 ° C to 150 ° C, preferably about 10 ° C to 100 ° C. The reaction time is usually 15 minutes to 12 hours, preferably 3 minutes.
0 minutes to 6 hours. When compound (I) can be obtained in a free state by the above method, for example, a mineral acid can be prepared by a conventional method.
(Eg, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (eg, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.) When compound (I) is obtained in the form of a salt, it can be converted into a free form or another salt according to a conventional method. The target compound (I) or a salt thereof obtained by the above method is purified and collected by using a separation / purification means known per se (eg, concentration, solvent extraction, crystallization, column chromatography, recrystallization, etc.). be able to.

The compound (I) or a pharmaceutically acceptable salt thereof has an excellent inhibitory effect on acyl-CoA: cholesterol acyltransferase (ACAT), and its acute toxicity and toxicity by continuous administration are weak. ACAT is an enzyme involved in the esterification of higher fatty acid ester of cholesterol in cells, and is known to play an important role in the absorption of cholesterol ester in the small intestine. Therefore, the ACAT inhibitory substance inhibits absorption of dietary cholesterol from the intestinal tract, suppresses elevation of blood cholesterol level, suppresses accumulation of intracellular cholesterol ester in arteriosclerotic lesions, and prevents progression of atherosclerosis. be able to. Therefore, the compound (I) of the present invention or a salt thereof having an excellent ACAT inhibitory activity is therefore highly effective in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, horse, cow, sheep, monkey, human, etc.). It is useful as a safe prophylactic / therapeutic agent for cholesterolemia, atherosclerosis, and diseases caused by these (eg, ischemic heart disease such as myocardial infarction and cerebrovascular disorder such as cerebral infarction / stroke). . In addition, the compound (I) or a salt thereof includes those exhibiting a lipid peroxide production inhibitory action (antioxidant action). It is known that lipid peroxidation in the living body is closely related to the onset of arteriosclerosis and ischemic diseases in the brain and cardiovascular system. Therefore, a compound having both an ACAT inhibitory action and an antioxidant action
Since (I) or its salt can prevent and treat various vascular lesions caused by blood cholesterol and lipid peroxide, it is highly useful as a pharmaceutical. When the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as the above-mentioned pharmaceutical product, it is mixed with an appropriate pharmacologically acceptable carrier, excipient or diluent to obtain powder or granules. It can be administered orally or parenterally in the form of tablets, capsules, injections, etc., but it is more preferably administered orally when used for the purpose of inhibiting absorption of cholesterol. The dose varies depending on the type of compound (I) or a salt thereof, the route of administration, symptoms, age of the patient, etc., but when administered orally to an adult patient with hypercholesterolemia, the daily dose is the body weight. About 0.005 to 50 mg per kg, preferably about 0.05 to 10
mg, more preferably about 0.2-4 mg, preferably divided into 1 to 3 divided doses per day. Compound of the present invention
The starting compound (VI) or (IX) for producing (I) or a salt thereof can be industrially advantageously produced by, for example, the method shown below or a method analogous thereto.

[0020]

[Chemical formula 24] [Wherein R ² 'and R ⁴ are alkyl groups, and X'is

[Chemical 25] , Z represents a leaving group, and other symbols have the same meanings as described above.]

[0021]

[Chemical formula 26] [In the formula, R ⁵ and R ⁶ are the same or different and each represents an alkyl group, a phenyl group or a benzyl group, or R ⁵ and R ⁶ may be linked to each other to form a ring with an adjacent nitrogen atom. Other symbols have the same meaning as above]

[0022]

[Chemical 27] [In the formula, R ¹ 'represents hydrogen or an alkyl group, R ⁷ represents an alkyl group, and other symbols have the same meanings as above]

[Method A] The alkyl group represented by R ² 'and R ⁴ is preferably one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. In this method, an aminobenzoylthiophene derivative (XII) is reacted with a malonic acid diester (XVI), or (XII) is reacted with a compound (XIII), followed by dehydration ring closure using a base (XV).
Can be manufactured. When (XV) is produced from (XII) and (XVI), it is usually carried out by heating without a solvent. At this time, piperidine, pyrrolidine, triethylamine, 1,
5-diazabicyclo [4,3,0] non-5-ene (DB
N) 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) or other amines, or potassium fluoride, fluorine It is preferably carried out in the presence of cesium chloride, tetrabutylammonium fluoride or the like. The reaction temperature is generally about 60 ° C to 220 ° C, preferably 80 ° C to 200 ° C. The reaction time is usually about 30 minutes to 60 hours, preferably 1 hour to 24 hours. The amount of (XVI) used is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, relative to (XII). The reaction of (XII) and (XIII) is usually a solvent (eg, ethers such as ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc., aromatic hydrocarbons such as benzene, toluene, xylene, methyl acetate, ethyl acetate, etc. Ester, halogenated hydrocarbons such as dichloromethane, chloroform, pyridine, dimethylformamide) in the presence of a base (e.g., triethylamine, pyridine, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, etc.), if necessary. Done. In this reaction, a mixed solvent with water may be used if necessary.

The reaction temperature is usually about -20 ° C to 150 ° C, preferably about -10 ° C to 120 ° C. The reaction time is usually about 10 minutes to 12 hours, preferably 20 minutes to 8 hours. The amount of (XIII) used is about 1-5 molar equivalents, preferably about 1-3 molar equivalents, relative to (XII). The compound (XIV) produced by this reaction is ring-closed with a base to produce the compound (XV). This reaction is usually in a solvent (e.g., benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, etc.), a base (e.g., potassium t-butoxide, sodium methoxide, sodium ethoxide, piperidine, pyrrolidine, triethylamine, DBN, D
BU, DABCO, etc.). The reaction temperature is usually about 0 ° C to 200 ° C, preferably 20 ° C to 170 ° C.
Is. The reaction time is usually about 30 minutes to 12 hours, preferably 1 hour to 8 hours. The amount of the base used is about 0.1 to 3 molar equivalents, preferably 0.1 to 2 molar equivalents, relative to (XIV). Further, if necessary, in order to accelerate the reaction, it can be carried out while removing water generated in the reaction system by using a Dean-Stark apparatus. Compound (XV) and (X
VIII) is reacted with N-alkyl compound (XIX) and / or O
-The alkyl compound (XX) is produced. This reaction is usually a solvent
(Examples, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, ketones such as acetone and 2-butanone, dimethylformamide, dimethylsulfoxide, etc.) in a base (eg, sodium hydroxide, water) Potassium oxide,
Sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide, potassium carbonate, sodium carbonate, triethylamine, DBU, etc.). Usually in this reaction
Since a mixture of (XIX) and (XX) is produced, these can be used by separating them by recrystallization or chromatography. Also, depending on the type of (XVIII), the type of solvent, or the reaction temperature, either one may preferentially be produced. The reaction temperature is usually about -5
C. to 150.degree. C., preferably about 0.degree. C. to 100.degree. C., the reaction time is about 30 minutes to 30 hours, preferably 1 hour to 15 hours (XVIII) and the amount of the base used is 1 with respect to (XV). -5 molar equivalents, preferably 1-2 molar equivalents. Next, (XV), (XIX), and (XX) are hydrolyzed and
II), (XXI), and (XXII). This reaction is usually carried out in a solvent (for example, alcohols such as methanol, ethanol and propanol, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, or a mixed solvent thereof),
For example, it can be carried out using a hydroxide of an alkali or alkaline earth metal such as sodium hydroxide, potassium hydroxide or barium hydroxide. The reaction temperature is usually about 0 ° C to 1
20 ° C, preferably about 15 ° C to 100 ° C. The reaction time is about 30 minutes to 36 hours, preferably about 1 hour to 20 hours.
It's time. Next, the carboxylic acids (XVII), (XXI), (XXII) are converted into acid azides. Various methods are known in the literature, and any of these methods can be applied to the compounds (XVII), (XXI), and (XXII) of this method. For example, the acid azide of (XVII), (XXI) or (XXII) can be produced by using diphenylphosphoryl azide (DPPA) or the like as the azidating agent. This reaction is usually a solvent inert to the reaction (eg, ethers such as ethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, methyl acetate, ethyl acetate, etc. Ester, acetone, ketones such as 2-butanone, pyridine, N, N-dimethylformamide, etc.). In addition, the reaction may proceed in the presence of a base (eg, trimethylamine, triethylamine, N-methylmorpholine, etc.). The reaction time is usually about 5 minutes to 12 hours,
It is preferably about 10 minutes to 6 hours. The reaction temperature is usually about -10 ° C to 150 ° C, preferably about -5 ° C to 120 ° C.
Is. The amount of DPPA used is (XVII), (XXI) or (XXI
It is 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, relative to I).

The produced acid azide can be isolated and purified by a means known per se, but usually the reaction solution is heated as it is without being isolated and converted into the isocyanate compound (IX '). It is preferable to use the same solvent as that used for the azidation in this conversion reaction, and it is usually carried out by heating to about 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. The reaction time is usually about 5 minutes to 10 hours, preferably about 5 minutes to 6 hours. The obtained compound (IX ′) can be isolated by a means known per se, or can be used for the production of compound (I) without isolation or can be used as a starting material for producing (VI ′). . That is, the compound (IX ′) can be hydrolyzed to give the compound (VI ′). This hydrolysis reaction is carried out by converting the compound (XV), (XIX) or (XX) into a compound.
It can be carried out under almost the same conditions as in the case of conversion into (XVII), (XXI) and (XXII).

[Method B] The alkyl group represented by R ⁵ and R ⁶ is preferably one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. R ⁵ and R ⁶ may be linked to each other to form a ring together with a nitrogen atom, and examples thereof include a 5- to 7-membered ring such as a pyrrolidine ring, a piperidine ring and a homopiperidine ring. Further, the ring may further have another oxygen atom, and examples thereof include a morpholine ring. Compound (X
(XXV) is prepared by reacting II) with (XXIII) or (XXIV). The reaction is usually performed in a solvent (eg, esters such as methyl acetate and ethyl acetate, ketones such as acetone and 2-butanone, aromatic hydrocarbons such as benzene and toluene) in the presence of an acid. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, and the acid is in the form of an aqueous solution even when used in an anhydrous state. The reaction may be carried out in a homogeneous system or in a two-layer system of a solvent and water. Use (XXIII) or (XX
IV) is about 1-10 molar equivalents relative to (XII), preferably about 1-5 molar equivalents. The acid used is about 1-300 molar equivalents, preferably about 5-100 molar equivalents, relative to (XII). The reaction temperature is generally about 0 ° C to 120 ° C, preferably about 10 ° C to 100 ° C. The reaction time is about 30 minutes to 15 hours, preferably about 1 hour to 10 hours. Next, the compound (XXV) undergoes a ring closure reaction with a base to produce (XXVI). This ring closure reaction is based on (XIV) in [Method A]
The conditions are the same as those for producing (XV) or a method analogous thereto. Further reduction of compound (XXVI)
(VI '') is manufactured. As the reducing agent used, for example, lithium aluminum hydride, lithium borohydride, etc. are used, and the amount thereof is about 0.5 to (XXVI).
It is 10 molar equivalents, preferably about 1-5 molar equivalents. The reaction is usually performed in a solvent (eg, methanol, ethanol, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.). The reaction temperature is usually about −5 ° C.
120 ° C, preferably about 0 ° C to 100 ° C. The reaction time is usually about 15 minutes to 12 hours, preferably 30 minutes to
8 hours.

This reduction reaction can be carried out using a metal and an acid, a metal salt and an acid, or a metal and a base, in addition to using the reducing agent. Such metals include zinc, tin, iron, etc.,
Tin (II) chloride or the like is used as the metal salt, and an acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, etc.) is used as the hydrogen source. When potassium, sodium, lithium or the like is used as a metal, a base (e.g., ammonia, methylamine, dimethylamine, ethylamine, diethylamine, etc.) is mainly used as a hydrogen source, and alcohols (e.g., methanol, ethanol,
(Propanol, etc.) is also used. The amount of the metal or metal salt used in this reaction is about 1 to 20 molar equivalents, preferably about 1 to 10 molar equivalents, relative to (XXVI). The reaction is usually performed in a solvent (eg, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc.), but the acid or base used may be used as a solvent. The reaction temperature is generally about 0 ° C-150 ° C, preferably about 10 ° C-120 ° C. The reaction time is usually about 15 minutes to 12 hours, preferably about 30 minutes to 10 hours. This reduction reaction can also be performed by a catalytic reduction reaction using a catalyst. Such catalysts include palladium black, palladium carbon, platinum oxide,
Examples include platinum black, Raney nickel, and rhodium carbon. The reaction is usually performed in a solvent (eg, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dimethoxyethane, formic acid, acetic acid, N, N-dimethylformamide, etc.). The reaction temperature is about 0 ° C to 120 ° C, preferably about 10 ° C to 100 ° C. The reaction pressure is usually atmospheric pressure to 50 atm, preferably atmospheric pressure to 10 atm.

[Method C] The alkyl group represented by R ⁷ is preferably one having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl. With compound (XII)
(XXVIII) is prepared by reaction with (XXVII). The reaction is usually a solvent (for example, alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, organic solvents such as formic acid, acetic acid and propionic acid). Acid, etc.) or in the presence of an acid catalyst (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) without a solvent. The amount of (XXVII) used is (XII)
To about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents. The amount of the acid catalyst used is about 0.
01 to 2 molar equivalents, preferably about 0.05 to 1 molar equivalents. The reaction temperature is generally about 0 ° C-200 ° C, preferably about 10 ° C-150 ° C. The reaction time is generally about 15 minutes to 24 hours, preferably about 30 minutes to 15 hours.
The produced (XXVIII) is then converted into (XXIX) → (IX ″) → (VI ′ ″). These reaction conditions can be performed by the method used in [Method A] or a method analogous thereto. In addition, the raw material compound (XII) is the compound of the Journal of Medicinal Chemistry [2].
It can also be produced by the method described on page 14 (1973) or a method analogous thereto.

[0029]

The compound (I) of the present invention or a salt thereof has excellent A
Although it has a CAT inhibitory action, the results of its pharmacological tests are shown below. (1) Inhibition of acyl-CoA: cholesterol transferase (ACAT) [Experimental method] The enzyme preparation ACAT was prepared by Heider et al. [Journal of Lipit Research].
pid Research, 24, 1127 (1982) and prepared from the small intestinal mucosal microsome fraction of 6-week-old male Sprague-Dawley rats fasted for 20 hours. ACAT activity Herugeruto [Helgerud] et al. (Journal of Lippit Research, Vol. 22, page 271, 1981) according to, [1- ¹⁴ C] from oleoyl -CoA and endogenous cholesterol labeled cholesterol ester It was calculated by measuring the amount produced.

[Results] Table 1 shows the inhibition rate of labeled cholesterol ester formation when the test compound was added at 10 ⁻⁶ M.
(%) Is shown as an index of ACAT inhibitory action.

[Table 1] Table 1 shows that compound (I) or a salt thereof has an excellent ACAT inhibitory action.

[0031]

EXAMPLES Next, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention should not be limited to these Examples. Elution by column chromatography in Reference Examples and Examples was carried out by TLC (Thin Layer).
Chromatography, thin layer chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate.
A solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As the silica gel for the column, silica gel 60 (70 to 230 mesh) also manufactured by Merck was used. The abbreviations used in Examples and Reference Examples have the following meanings. mg: Milligram, g: Gram, ml: Milliliter, mp:
Melting point. The room temperature means about 15 to 25 ° C.

Example 1 A solution of 5-amino-4- (2-chlorophenyl) -2-ethylthieno [2,3-b] pyridine (288 mg) in tetrahydrofuran (3 ml) was charged with 2,4-difluorophenylisocyanate (0.13 ml). ) Was added and stirred at room temperature for 18 hours,
The solvent was distilled off. By adding isopropyl ether to the residue, N- [4- (2-chlorophenyl) -2-ethylthieno [2,3-b] pyridin-5-yl] -N '-(2,
4-difluorophenyl) urea was obtained as crystals (41
6 mg, 93.9%). A colorless prism crystal was obtained by recrystallization from acetone-hexane. mp: 217-218
° C. Elemental analysis _{C 22 H 16 ClF 2 N 3} OS Calculated: C, 59.53; H, 3.63 ; N, 9.47 Found: C, 59.57; H, 3.69 ; N, 9.44

Example 2 4-acetoxy-3,5-dimethoxycinnamic acid (638 m
g), dimethylformamide (2 drops), tetrahydrofuran
Oxalyl chloride (0.25 ml) was added dropwise to a mixture of (8 ml). After stirring at room temperature for 1 hour, the solvent was distilled off to give 4-acetoxy-3,5-dimethoxycinnamic acid chloride as crystals. This crystal dichloromethane (1
5 ml) solution, 5-amino-4- (2-chlorophenyl)
2-Ethylthieno [2,3-b] pyridine (576 mg) and N, N-dimethylaniline (0.25 ml) were added under ice cooling. Then, the mixture was returned to room temperature and stirred for 5 hours, then washed successively with water, a saturated NaHCO ₃ aqueous solution and water, and dried (MgSO ₄ ). The solvent was evaporated and the residue was crystallized from ethanol (729 mg, 67.4%). Recrystallization from acetone gave 5- (4-acetoxy-3,5-dimethoxycinnamoylamino) -4- (2-chlorophenyl) -2-ethylthieno [2,3-b] pyridine as colorless prism crystals. . mp: 133-135 ° C. Elemental analysis value C ₂₈ H ₂₅ ClN ₂ O ₅ S ・ 2/3 (CH ₃ ) ₂ C
Calculated as O: C, 62.12; H, 5.14; N, 4.83 Found: C, 62.24; H, 5.19; N, 4.71.

Example 3 4- (2-chlorophenyl) -6,7-dihydro-2-ethyl-7-methyl-6-oxothieno [2,3-b] pyridine-5-carboxylic acid (347 mg), diphenylphosphoryl Triethylamine (0.14 ml) was added dropwise to a mixture of azide (330 mg) and benzene (4 ml). After stirring for 30 minutes at room temperature and 30 minutes under reflux, 2,4-difluoroaniline (0.12 ml) was added. Reflux for 4 hours, wash with water and dry (M
After gSO ₄ ) the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with chloroform-ethyl acetate-methanol (9: 1: 0.25). By distilling off the solvent, N- [4- (2-chlorophenyl) -6,7-dihydro-2-ethyl-7-methyl-6-oxothieno [2,
3-b] Pyridin-5-yl] -N '-(2,4-difluorophenyl) urea was obtained as a colorless powder (210 mg, 4
4.4%). Elemental analysis _{C 23 H 18 ClF 2 N 3} O 2 S Calculated: C, 58.29; H, 3.83 ; N, 8.87 Found: C, 58.60; H, 4.06 ; N, 8.59

Example 4 N- (4-chlorophenyl) -N 'was prepared in the same manner as in Example 1.
-[4- (2-chlorophenyl) -2-ethylthieno [2,
3-b] Pyridin-5-yl] urea was obtained as colorless needle crystals. Yield 99.3%, mp: 230-231 ° C. Elemental analysis _{C 22 H 17 Cl 2 N 3} OS Calculated: C, 59.73; H, 3.87 ; N, 9.50 Found: C, 59.70; H, 3.86 ; N, 9.47

Example 5 N- [4- (2-chlorophenyl) was prepared in the same manner as in Example 1.
-2,3-Dimethylthieno [2,3-b] pyridin-5-yl] -N '-(2,4-difluorophenyl) urea was obtained as colorless prism crystals. Yield 91.0%, mp: 202-2
03 ° C. Elemental analysis value Calculated as C ₂₂ H ₁₆ ClF ₂ N ₃ OS: C, 59.53; H, 3.63; N, 9.47 Measured value: C, 59.72; H, 3.62; N, 9.54

Example 6 N- [4- (2-chlorophenyl) was prepared in the same manner as in Example 1.
-6,7-dihydro-5H-cyclopenta [1 ', 2': 5,
4] thieno [2,3-b] pyridin-3-yl] -N ′-(2,
4-Difluorophenyl) urea was obtained as colorless prism crystals. Yield 88.8%, mp: 223-224 ° C. Elemental analysis _{C 23 H 16 ClF 2 N 3} OS Calculated: C, 60.59; H, 3.54 ; N, 9.22 Found: C, 60.38; H, 3.47 ; N, 9.19

Example 7 3-Amino-4- (2-chlorophenyl) -6,7-dihydro-5H-cyclopenta [1 ', 2': 5,4] thieno [2,
3-b] pyridine (150 mg) and N, N-dimethylaniline
A solution of (0.065 ml) in dichloromethane (3 ml) was stirred under ice cooling while stirring with 2,4-difluorobenzoyl chloride.
(0.07 ml) was added dropwise. The mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 2 hours, washed successively with water, a saturated aqueous solution of NaHCO ₃ , and water, and dried (MgSO ₄ ). By distilling off the solvent, 4- (2-chlorophenyl) -3- (2,4-difluorobenzoylamino) -6,7-dihydro-5H-cyclopenta [1 ', 2': 5,4] thieno [2 , 3-b] Pyridine was obtained as crystals (206 mg, 93.6%). Recrystallization from acetone gave colorless prism crystals. mp: 21
9-220 ° C. Elemental analysis _{C 23 H 15 ClF 2 N 2} OS Calculated: C, 62.66; H, 3.43 ; N, 6.35 Found: C, 62.60; H, 3.58 ; N, 6.31

Example 8 4- (2-chlorophenyl) -3-as in Example 2
(2,4-difluorophenylacetylamino) -6,7-
Dihydro-5H-cyclopenta [1 ', 2': 5,4] thieno
[2,3-b] Pyridine was obtained. Yield 89.4%, mp: 127
~ 128 ° C (recrystallized from ethanol). Elemental analysis value Calculated as C ₂₄ H ₁₇ ClF ₂ N ₂ OS: C, 63.36; H, 3.77; N, 6.16 Measured value: C, 63.49; H, 4.00; N, 6.27

Example 9 In the same manner as in Example 1, N- (2,4-difluorophenyl) -N '-[4- (2-methylphenyl) thieno [2,3-]
b] Pyridin-5-yl] urea was obtained as colorless needle crystals. Yield 91.7%, mp: 223-224 ° C (recrystallized from ethanol). Elemental analysis value Calculated as C ₂₁ H ₁₅ F ₂ N ₃ OS: C, 63.79; H, 3.82; N, 10.63 Measured value: C, 63.75; H, 4.03; N, 10.60

Example 10 N- [4- (2-chlorophenyl) was prepared in the same manner as in Example 1.
-2-Methylthieno [2,3-b] pyridin-5-yl]-
N '-(2,4-difluorophenyl) urea was obtained as colorless needle crystals. Yield 88.1%, mp: 196-198 ° C. Elemental analysis value Calculated as C ₂₁ H ₁₄ ClF ₂ N ₃ OS: C, 58.68; H, 3.28; N, 9.77 Measured value: C, 58.90; H, 3.25; N, 9.74

Example 11 Triethylamine was added to a mixture of 5-amino-2-chloro-4- (2-methylphenyl) thieno [2,3-b] pyridine, hydrochloride, ethanol sorbate (160 mg) and tetrahydrofuran (3 ml). (0.07 ml) and 2,4-difluorophenylisocyanate (0.12 ml) were added dropwise. After stirring at room temperature for 5 hours, the solvent was distilled off. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎
After that, the solvent was distilled off. Isopropyl ether was added to the residual oil to give N- [2-chloro-4- (2-methylphenyl) thieno [2,3-b] pyridin-5-yl] -N '-(2,4-difluorophenyl). Urea was obtained as crystals (133 mg,
68.9%). Recrystallization from ethanol gave colorless prism crystals. mp: 225-226 ° C. Elemental analysis value Calculated as C ₂₁ H ₁₄ ClF ₂ N ₃ OS: C, 58.68; H, 3.28; N, 9.77 Measured value: C, 58.78; H, 3.41; N, 9.59

Example 12 N- [4- (2-chlorophenyl) was prepared in the same manner as in Example 1.
-5,6,7,8-Tetrahydro [1] benzothieno [2,3
-B] Pyridin-3-yl] -N '-(2,4-difluorophenyl) urea was obtained as colorless prism crystals. Yield 94.
9%, mp: 228-230 ° C (recrystallized from acetone). Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ OS: C, 61.34; H, 3.86; N, 8.94 Measured value: C, 61.62; H, 3.83; N, 8.90

Example 13 4-acetoxy-3,5-dimethylbenzoic acid (270 m
g), diphenylphosphoryl azide (DPPA, 430 m
g) and benzene (6 ml) in a mixture of triethylamine (0.1
8 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes and then for 40 minutes under reflux to prepare a 4-acetoxy-3,5-dimethylphenylisocyanate solution. 5-amino-2
-Ethyl-4- (2-methoxyphenyl) thieno [2,3-
b] Pyridine (284 mg) was added, the mixture was heated under reflux for 5 hours, washed with water,
After drying (MgSO ₄ ), the solvent was distilled off. Ethanol was added to the residue to give N- (4-acetoxy-3,5-dimethylphenyl) -N '-[2-ethyl-4- (2-methoxyphenyl).
Thieno [2,3-b] pyridin-5-yl] urea was obtained as crystals (350 mg, 71.6%). Recrystallization from ethanol gave colorless needle crystals. mp: 217-21
8 ° C. Elemental analysis value Calculated as C ₂₇ H ₂₇ N ₃ O ₄ S: C, 66.24; H, 5.56; N, 8.58 Measured value: C, 66.55; H, 5.57; N, 8.18

Example 14 In the same manner as in Example 13, N- (4-acetoxy-3,5-
Dimethoxyphenyl) -N '-[2-ethyl-4- (2-methoxyphenyl) thieno [2,3-b] pyridin-5-yl]
Urea was obtained as colorless needles. Yield 60.8%, mp: 2
44-245 ° C (recrystallized from ethanol). Elemental analysis _{C 27 H 27 N 3 O 6} S Calculated: C, 62.17; H, 5.22 ; N, 8.06 Found: C, 62.22; H, 5.31 ; N, 7.99

Example 15 In the same manner as in Example 13, N- (4-dimethylaminophenyl) -N '-[2-ethyl-4- (2-methoxyphenyl) thieno [2,3-b] pyridine- 5-yl] urea was obtained as colorless needles. Yield 74.4%, mp208-2
09 ° C. (recrystallized from acetone). Elemental analysis value Calculated as C ₂₅ H ₂₆ N ₄ O ₂ S: C, 67.24; H, 5.87; N, 12.55 Actual value: C, 67.18; H, 5.85; N, 12.44

Reference Example 1 1) 2-Amino-3- (2-chlorobenzoyl) -5-ethylthiophene (5.30 g), 1-morpholino-2-nitroethene (3.16 g), 6N HCl (5 ml), Acetone (2
5 ml) and the mixture was stirred at room temperature for 1 hour. Water was added and the mixture was extracted with ethene acetate. The extract was washed with water, dried 3 by distilling off (MgSO ₄₎ and the solvent (2-chlorobenzoyl)
2- (2-Nitroethenylamino) -5-ethylthiophene was obtained as crystals (5.65 g, 84.1%). Recrystallization from acetone gave yellow plate crystals. mp: 1
25-126 ° C. Elemental analysis value Calculated as C ₁₅ H ₁₃ ClN ₂ O ₃ S: C, 53.49; H, 3.89; N, 8.32 Found: C, 53.52; H, 3.91; N, A solution of 8.32 2) DBU (5.1 g) in benzene (50 ml) was stirred under reflux while stirring 3- (2-chlorobenzoyl) -2- (2
-Nitroethenylamino) -5-ethylthiophene (5.
1 g) of dioxane-benzene (1: 1, 30 ml) in 1
Dropwise added in time. After refluxing for another hour, wash with water and dry (Mg
SO ₄ ), the solvent was distilled off and isopropyl ether was added to the residue to give 4- (2-chlorophenyl) -2-ethyl-5-nitrothieno [2,3-b] pyridine as crystals (4.3 g). , 98.0%). Recrystallization from isopropyl ether gave pale yellow prism crystals. mp: 7
2-73 ° C. Elemental analysis value Calculated as C ₁₅ H ₁₁ ClN ₂ O ₂ S: C, 56.52; H, 3.48; N, 8.79 Measured value: C, 56.53; H, 3.48; N, 8.79 3) 4- (2-chlorophenyl) -2-ethyl-5-nitrothieno [2,3-b] pyridine (4.0 g) in dioxane (2
5 ml) and concentrated hydrochloric acid (12.5 ml) in a mixture of tin (II) chloride ・ 2
The hydrate (8.5g) was added. After stirring for 1 hour at room temperature, water was added and the mixture was made strongly alkaline with 6N NaOH and extracted with chloroform. The extract was distilled off washed with water dried (MgSO ₄₎ and the solvent. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1). The solvent was evaporated, hexane was added to the residue, and 5-amino-4- (2-
Chlorophenyl) -2-ethylthieno [2,3-b] pyridine was obtained as crystals (3.1 g, 85.6%). Recrystallization from isopropyl ether gave colorless prism crystals. mp: 87-88 ° C. Elemental analysis C ₁₅ H ₁₃ ClN ₂ S Calculated: C, 62.38; H, 4.54 ; N, 9.70 Found: C, 62.49; H, 4.57 ; N, 9. 70

Reference Example 2 1) 2-Amino-3- (2-chlorobenzoyl) -5-ethylthiophene (5.30 g), ethylmalonyl chloride
A mixture of (4.50 g) and benzene (60 ml) was heated under reflux for 1 hour, washed with water and dried (MgSO ₄ ), and the solvent was distilled off. Hexane was added to the residue to give 3- (2-chlorobenzoyl) -2-ethoxycarbonylacetylamino-5-ethylthiophene as crystals (7.1 g, 93.7%). Recrystallization from isopropyl ether gave colorless prism crystals. mp: 56-57 ° C. Elemental analysis C ₁₈ H ₁₈ ClNO ₄ S Calculated: C, 56.91; H, 4.79 ; N, 3.69 Found: C, 56.78; H, 4.73 ; N, 3. 86 2) 3- (2-chlorobenzoyl) -2-ethoxycarbonylacetylamino-5-ethylthiophene while stirring a solution of DBU (5.2 g) in toluene (50 ml) under reflux.
A solution of (6.5 g) in toluene (30 ml) was added dropwise. It was refluxed for 7 hours, washed with water and freed from the solvent dried (MgSO _4). The residue was subjected to silica gel chromatography and eluted with hexane-acetone (5: 1). Ethyl 4- (2-chlorophenyl) -6 was obtained by removing the solvent and adding hexane.
7-dihydro-2-ethyl-6-oxothieno [2,3-
b] Pyridine-5-carboxylate was obtained as crystals
(2.05 g, 33.1%). Recrystallization from ethanol gave pale yellow prism crystals. mp: 126-127
° C. Elemental analysis C ₁₈ H ₁₆ ClN ₃ OS Calculated: C, 59.75; H, 4.46 ; N, 3.87 Found: C, 59.78; H, 4.52 ; N, 3. 85

3) Ethyl 4- (2-chlorophenyl)-
6,7-dihydro-2-ethyl-6-oxothieno [2,
Methyl iodide (0.37 ml) was added dropwise to a mixture of 3-b] pyridine-5-carboxylate (1.80 g), potassium carbonate (0.7 g) and DMF (15 ml). After stirring at room temperature for 1.5 hours, water was added and the mixture was extracted with ethyl acetate. Wash the extract with water,
After drying (MgSO ₄ ), the solvent was distilled off. Ethyl 4- (2-chlorophenyl) -6,7-dihydro-2-ethyl-7-methyl-6-oxothieno [2,3-b] pyridine-5-carboxylate was added to the residue by adding isopropyl ether. Obtained as crystals (1.32 g, 70.6%).
Recrystallization from isopropyl ether gave colorless needle crystals. mp: 105-106 ° C. Elemental analysis value Calculated value as C ₁₉ H ₁₈ ClNO ₃ S: C, 60.71; H, 4.83; N, 3.73 Actual value: C, 60.53; H, 4.91; N, 3. 624) Ethyl 4- (2-chlorophenyl) -6,7-dihydro-2-ethyl-7-methyl-6-oxothieno [2,
3-b] Pyridine-5-carboxylate (1.10 g), K
A mixture of OH (0.49 g) and 80% ethanol (10 ml) was heated at 80 ° C. for 20 minutes, water was added, and the mixture was acidified with 2N HCl and extracted with ethyl acetate. The extract is washed with water and dried
After (MgSO ₄ ), the solvent was distilled off and hexane was added to give 4- (2-chlorophenyl) -6,7-dihydro-2-.
Ethyl-7-methyl-6-oxothieno [2,3-b] pyridine-5-carboxylic acid was obtained as crystals (0.91 g, 8).
9.2%). Recrystallization from ethanol gave colorless prism crystals. mp: 155-156 ° C. Elemental analysis C ₁₇ H ₁₄ ClNO ₃ S Calculated: C, 58.70; H, 4.06 ; N, 4.03 Found: C, 58.72; H, 4.06 ; N, 4. 01

In the same manner as in Reference Example 1, the following compounds of Reference Examples 3 to 9 were obtained. Reference Example 3 1) 3- (2-chlorobenzoyl) -4,5-dimethyl-
2- (2-nitroethenylamino) thiophene: mp: 17
1-173 ° C. 2) 4- (2-chlorophenyl) -2,3-dimethyl-5
-Nitrothieno [2,3-b] pyridine: mp: 136-13
7 ° C. 3) 5-amino-4- (2-chlorophenyl) -2,3-
Dimethylthieno [2,3-b] pyridine: mp: 117-11
8 ° C.

Reference Example 4 1) 3- (2-chlorobenzoyl) -5,6-dihydro-
2- (2-nitroethenylamino) -4H-cyclopenta
[b] Thiophene: mp: 118-120 ° C. 2) 4- (2-chlorophenyl) -6,7-dihydro-3
-Nitro-5H-cyclopenta [1 ', 2': 5,4] thieno
[2,3-b] Pyridine: mp: 118-119 ° C. 3) 3-amino-4- (2-chlorophenyl) -6,7-
Dihydro-5H-cyclopenta [1 ', 2': 5,4] thieno
[2,3-b] Pyridine: mp: 130-131 ° C.

Reference Example 5 1) 3- (2-Methylbenzoyl) -2- (2-nitroethenylamino) thiophene: mp: 155-156 ° C. 2) 4- (2-methylphenyl) -5-nitrothieno [2,
3-b] pyridine: mp: 111-112 ° C. 3) 5-amino-4- (2-methylphenyl) thieno [2,
3-b] pyridine: mp: 98-99 ° C.

Reference Example 6 1) 3- (2-chlorobenzoyl) -5-methyl-2-
(2-Nitroethenylamino) thiophene: mp: 160-
162 ° C. 2) 4- (2-chlorophenyl) -2-methyl-5-nitrothieno [2,3-b] pyridine: mp: 157-158 ° C. 3) 5-Amino-4- (2-chlorophenyl) -2-methylthieno [2,3-b] pyridine: mp: 114-115 ° C.

Reference Example 7 1) 5-chloro-3- (2-methylbenzoyl) -2-
(2-Nitroethenylamino) thiophene: mp: 160-
162 ° C. 2) 2-chloro-4- (2-methylphenyl) -5-nitrothieno [2,3-b] pyridine: mp: 126-127 ° C. 3) 5-amino-2-chloro-4- (2-methylphenyl) thieno [2,3-b] pyridine / hydrochloride / ethanol sorbate: mp: 114-115 ° C.

Reference Example 8 1) 3- (2-chlorobenzoyl) -2- (2-nitroethenylamino) -4,5,6,7-tetrahydrobenzo [b]
Thiophene: mp: 163-164 ° C. 2) 4- (2-chlorophenyl) -3-nitro-5,6,
7,8-Tetrahydro [1] benzothieno [2,3-b] pyridine: mp: 157-159 ° C. 3) 3-amino-4- (2-chlorophenyl) -5,6,
7,8-Tetrahydro [1] benzothieno [2,3-b] pyridine: 148-150 ° C.

Reference Example 9 1) 5-Ethyl-3- (2-methoxybenzoyl) -2-
(2-Nitroethenylamino) thiophene: mp: 140-
141 ° C. 2) 2-Ethyl-4- (2-methoxyphenyl) -5-nitrothieno [2,3-b] pyridine: mp: 116-117
° C. 3) 5-amino-2-ethyl-4- (2-methoxyphenyl) thieno [2,3-b] pyridine: mp: 91-92 ° C.

Claims (5)

[Claims] 1. A general formula: [Wherein, ring A is a benzene ring which may have a substituent, and ring B is a thiophene ring which may have a substituent,
X is the formula (In the formula, R ¹ represents hydrogen, an alkyl or alkoxy group,
Represents 0 or 1) or the formula: (Wherein R ² represents hydrogen or an alkyl group), Y is a bond, —NH—, an alkylene group having 1 or 2 carbon atoms or —CH═CH—, and R ³ is a substituent. Represents a hydrocarbon group which may have. ] The thieno pyridine derivative represented by these, or its salt. 2. A general formula: [In the formula, Q represents a carboxyl group which may be esterified or amidated, —NH ₂ or —NCO, and other symbols have the same meanings as in claim 1. ] The compound or its salt represented by these. 3. The general formula: [Chemical 5] A compound represented by or a salt thereof and a general formula: R³-Q² By reacting with a compound represented by
Characteristic general formula: [Chemical 6] Of the thienopyridine derivative represented by
Law. [In the above formula, Q¹And Q²Either one is -NH₂
And the other symbol is -NCO, and the other symbols are claims
It has the same meaning as described. ] 4. The general formula: [The symbols in the formulas have the same meaning as in claim 1. Or a salt thereof and a general formula: R ³ —Y ¹ —COOH, wherein Y ¹ is a bond, an alkylene group having 1 or 2 carbon atoms or —CH═CH—, and R ³ is It has the same meaning as the first description. ] The compound represented by the formula or a reactive derivative thereof is reacted with a general formula: [The symbols in the formulas have the same meanings as described above. ] The manufacturing method of the thieno pyridine derivative represented by these, or its salt. 5. The general formula: [The symbols in the formulas have the same meaning as in claim 1. ] An acyl CoA: cholesterol acyl transferase inhibitor comprising a thienopyridine derivative represented by the above formula or a salt thereof.