JPH0753714B2 - ACAT inhibitor, quinoline derivative and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a quinoline derivative having excellent acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory activity. INDUSTRIAL APPLICABILITY The compound of the present invention inhibits absorption of cholesterol from the intestinal tract in mammals and suppresses the accumulation of cholesterol ester in the arterial wall. , Ischemic heart disease such as myocardial infarction, and cerebrovascular disorder such as cerebral infarction and stroke).

2. Description of the Related Art Japanese Patent Publication No. 55-5502, British Patent 1387477 has 6-chloro-
4-phenyl-3- (3-phenylureido) quinoline (Compound A), 6-chloro-3- [3 (4-chlorophenyl) ureido] -4-phenylquinoline (Compound B)
And 3- (3-benzylureido) -6,7-dimethoxy-4-phenylquinoline (Compound C) are specifically described and described as having an anti-ulcer effect.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention However, there has been no report or description of any pharmacological action useful as an arteriosclerotic agent such as ACAT inhibitory action and blood cholesterol lowering action of these compounds, and no studies have been made thereafter. Therefore, whether or not these compounds A, B, C and their related compounds are useful as agents for arteriosclerosis has not been studied at all.

Means for Solving the Problems As a result of various studies on the above-mentioned compounds A, B, C and their related compounds, the present inventors have not specifically described the known compounds such as the compound B and the above-mentioned publications and patents. It was found that various novel compounds exhibit a strong ACAT inhibitory effect and are useful as agents for arteriosclerosis, and based on this, the present invention was completed.

That is, the present invention [In the formula, R represents hydrogen, C _1-8 alkyl or C _7-9 aralkyl group, m and n represent 0 or 1, and ring A, ring B and ring C each may have a substituent. Good. ] An ACAT inhibitor comprising a quinoline derivative represented by the following or a salt thereof: (2) In the quinoline derivative represented by the general formula (I), m is 1, or m is 0 and the ring B is The present invention relates to a novel quinoline derivative or a salt thereof, which is substituted or, if the B ring is unsubstituted, a C ring is substituted with fluorine, and (3) a method for producing the novel quinoline derivative or salt thereof according to (2) above. is there.

The alkyl group represented by R in the general formula (I) is preferably, for example, a linear or branched one having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like are used.

Examples of the alkyl group represented by R include benzyl, 1
A phenylalkyl group having 7 to 9 carbon atoms such as -phenylethyl, 2-phenylethyl, 2-phenylpropyl, and 3-phenylpropyl is preferable, and the ring A, ring B and ring C described below are further present on these benzene rings. It may have a substituent similar to. Further, R may be a heteroarylalkyl group having 5 to 8 carbon atoms in which a heterocycle such as thiophene, furan or pyridine ring is substituted instead of the benzene ring in the above-mentioned phenylalkyl group. A preferred example of R is, for example, hydrogen or the like.

Although n represents 0 or 1, it is more preferable that n is 0. Ring A, Ring B and Ring C may have a substituent,
Examples of such a substituent include halogen, an optionally halogenated lower alkyl group, an optionally halogenated lower alkoxy group, an optionally halogenated lower alkylthio group, a nitro group and an esterified group. Optionally carboxyl group, hydroxyl group, C _1-4 acyloxy group (eg formyloxy, acetoxy, propionyloxy, butyryloxy, 2-methylpropionyloxy etc.), C _1-3 acyl group (eg formyl, acetyl,
Propionyl etc.) and the like are used. Examples of halogen as such a substituent include fluorine, chlorine, bromine and iodine. Examples of the optionally halogenated lower alkyl group include linear or branched lower alkyl having 1 to 6 carbon atoms and halogen atoms of 2 to 5
And the like, such as 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-trifluoromethyl Pentyl is often used. The lower alkoxy which may be halogenated and the lower alkylthio which may be halogenated may be formed, for example, by combining the above lower alkyl group or the halogenated lower alkyl group with an oxygen atom and a sulfur atom, respectively. A lower alkoxy which may be halogenated, a lower alkylthio group which may be halogenated and the like are used. The carboxyl group which may be esterified includes, for example, methyl,
Carboxyl groups esterified with alkyl having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl are used.

The A ring, B ring, and C ring substituents may be substituted at any position of the respective rings, and may be the same or different and each may be substituted with 1 to 4 substituents. Preferred positions are the 6-position and / or the 8-position of the quinoline skeleton in the case of the A ring, the 2-position in the case of the B ring, and the 2-position and / or the 4-position in the case of the C ring. As the substituent on the C ring, chlorine or fluorine is particularly preferable, and especially 2,
The 4-difluoro substituent is preferred.

Examples of salts of the quinoline derivative (I) include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, maleic acid, citric acid, tartaric acid, etc. When an acidic group such as a carboxyl group is present in the molecule, a salt with an alkali metal such as sodium, potassium or calcium or an alkaline earth metal is used.

Typical examples of the quinoline derivative represented by the general formula (I) include the following compounds.

(I) General formula [In the formula, R ² and R ³ are the same or different and are halogen or
A C _1-4 alkyl group is shown. ] The quinoline derivative represented by these, or its salt. As the halogen represented by R ² and R ³ , Cl, Br, F and the like are used. C represented by R ² and R ³
Examples of _1-4 alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl and the like. Preferred examples of R ² are, for example, Cl, methyl, ethyl, i-propyl and the like. Preferred examples of R ³ are, for example, Cl, methyl and the like.

(Ii) General formula [In the formula, R ⁴ and R ⁵ are the same or different and each represents a C _1-4 alkyl group, and R ³ has the same meaning as described above. ] The quinoline derivative represented by these, or its salt. As C _1-4 alkyl represented by R ⁴ and R ⁵ , for example, those described for R ³ above are used.
It is preferable that both R ⁴ and R ⁵ are, for example, methyl and the like.

The quinoline derivative represented by the general formula (I) or a salt thereof is, for example, a compound represented by the general formula: Or a salt thereof and a general formula A compound represented by or the formula reacting the salt thereof (II ^a), in (III ^b), Q ¹ is , Q ² is -NCO, Q ¹ is -NCO or In this case, Q ² is —NH ₂ , R ¹ is a C _1-8 alkyl or C _7-9 aralkyl group, X is a halogen, and other symbols are as defined above. ] And the like. As the C _1-8 alkyl represented by R ¹ or the C _7-9 aralkyl group,
For example, those described in R above are used. As the halogen represented by X, for example, Cl, Br, etc. are used. The specific method for producing the compound (I) is shown below.

[Method A] [The symbols in the formulas have the same meanings as described above. ] [Method B] (when R = H) [The symbols in the formulas have the same meanings as described above. ] [C method] (when R ≠ H) [The symbols in the formulas have the same meanings as described above. ] [D method] [The symbols in the formulas have the same meanings as described above. ] The compound ^{(II a), (III b} ), (II) ~ (VIII)
May be used in the form of a salt, and as such a salt, for example, those described in the above compound (I) and the like can be used.

[Method A] A compound (I) or a salt thereof is produced by reacting a 3-aminoquinoline derivative (II) or a salt thereof with an isocyanate ester (III). This reaction is usually performed in an appropriate solvent. Any solvent may be used as long as it is inert to the reaction, for example, ethers such as ethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, Esters such as methyl acetate and ethyl acetate, ketones such as acetone and methyl ethyl ketone, pyridine, N, N-dimethylformamide and the like are used. The reaction is usually about 0 ° C
It is carried out at 150 ° C, preferably about 15 ° C to 120 ° C. (III)
The amount used is usually about 1 to 5 equivalents, preferably about 1 to 3 equivalents, relative to (II). The reaction time varies depending on the raw materials used, solvent, reaction temperature and the like, but is usually 5 to 70 hours, preferably 10 to 30 hours.

[Method B] In this method, first, quinoline-3-carboxylic acid (IV) is azidated to prepare (V), which is then heated to 3-isocyanatoquinoline (VI), which is then treated with amine (VII Compound (I) represented by R = H is produced by reacting Various methods for converting a carboxylic acid into an acid azide are known in the literature, and any of these methods can be applied in this method. For example, by using diphenylphosphoryl azide (DPPA) or the like as an azidating agent (IV ) Can be converted to (V). This azidation reaction can be carried out in the same inert solvent as that usually used in Method A. The reaction may be allowed to proceed in the presence of a base (eg, triethylamine, tributylamine, N-methylmorpholine, etc.). The reaction temperature is usually about 0 ° C to 50 ° C, preferably about 10 ° C to 40 ° C. The amount of DPPA used is usually about 1 to 2 equivalents, preferably about 1 to 1 with respect to (IV).
It is 1.5 equivalents. The produced (V) can be isolated and purified by a means known per se, but it is usually heated without being isolated and the reaction mixture is heated to convert it to isocyanatoquinoline (VI). For this conversion reaction, it is preferable to use the same solvent as that used for the azidation. This conversion reaction is usually carried out by heating to about 60 ° C to 150 ° C, preferably about 80 ° C to 120 ° C. The (VI) obtained may be isolated by a means known per se or immediately (VI
The desired product (I) with R = H can be produced by reacting with I). The reaction with (VII) can be carried out, for example, in the same solvent as used in Method A. Usually about 20 ℃ ~ 130
C., preferably about 60 to 120.degree. C., at a reaction temperature.
The amount of (VII) used is usually about 1 to 3 equivalents, preferably about 1 to 2 equivalents, relative to (VI). The reaction time is not particularly limited as long as the purpose of the reaction is achieved.

[Method C] The target compound (I) with R ≠ H can also be produced by Method C. In this method, first, a raw material compound (II) with R ≠ H and a compound represented by the formula COX ₂ or CX ₃ OCOX (the symbols in the formula have the same meanings as described above) [eg, phosgene, trichloromethyl chlorocarbonate (phosgene dimer)] Etc.] to produce (VIII). This reaction can be carried out, for example, in the same inert solvent as that used in Method A. If necessary, the reaction can proceed in the presence of a base (eg, triethylamine, tributylamine, N-methylmorpholine, pyridine, quinoline, etc.). Usually, it can be carried out at a reaction temperature of about 0 ° C to 60 ° C, preferably about 10 ° C to 40 ° C. When phosgene or trichloromethyl chlorocarbonate is used, the amount of phosgene used is usually about 1 to 6 equivalents, preferably about 2 to 5 equivalents, relative to (II) (R ≠ H). The resulting (VIII) can be isolated by a means known per se, or can be reacted with the reaction mixture as it is (VII) without isolation to produce (I) (R ≠ H). This reaction can also be carried out, for example, in the same inert solvent as that used in the above Method A. If necessary, the reaction may be promoted in the presence of the same base as described in the above (VIII) production. Usually about 20 ℃ -150 ℃, preferably about 60 ℃ -1
It can be carried out at a reaction temperature of 20 ° C. Also, for example, 4-dimethylaminopyridine or the like may be added to accelerate the reaction.

[Method D] The target compound (I) having m = 1, that is, the compound (I ^d ) is
It is carried out by oxidizing the target compound (I) having m = 0, that is, the compound (I ^c ). This reaction can be carried out using hydrogen peroxide or organic peracid, and as such organic peracid, formic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc. are used. . The reaction conditions vary depending on the type of oxidizing agent used, but are usually in the range of about 10 ° C to 100 ° C in formic acid, acetic acid, trifluoroacetic acid and their water-containing solvents, chloroform, dichloromethane, etc.
C., preferably about 20.degree. C. to 80.degree. C., and the amount of the oxidizing agent used is about 1-10 mol, preferably about 1-5 mol, per 1 mol of ( ^I.sub.c ).

When a lower alkoxy group is contained in the ring A, B or C in the compound (I) produced by the above methods A to D, it may be converted into a hydroxyl group by reacting it with boron tribromide or the like, if necessary. You can also This reaction is usually carried out with a solvent (eg, dichloromethane, chloroform, carbon tetrachloride, benzene,
About -20 ° C to 80 ° C, preferably about 0 ° C to
It is carried out at 30 ° C., and the amount of boron tribromide used is about 1-10 equivalents, preferably about 1-5 equivalents, relative to one lower alkoxy group.

When the compound (I) produced by the above method contains a carboxyl group or an acyloxy group esterified on the A, B or C ring, it is converted to a carboxyl group or a hydroxyl group by hydrolyzing them if necessary. be able to. This hydrolysis reaction is usually carried out in the presence of a solvent (eg, alcohols such as methanol, ethanol, propanol, etc.) with an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide. Can be done using. The reaction temperature is about 0 ° C to 100 ° C, preferably about 20 ° C to 80 ° C.

The target compound (I) obtained by the above method is purified by using a separation and purification means known per se (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.),
Can be collected.

Further, the compound (I) has a basic nitrogen atom,
When this is obtained in a free form, or (and) an acidic group such as a carboxyl group is present in the molecule in a free form, a salt may be formed according to a conventional method. When it is obtained in step 1, it may be in free form according to a conventional method.

Compound (I) has an excellent inhibitory effect on acyl-CoA: cholesterol acyltransferase (ACAT), and is weak in both acute toxicity and toxicity by continuous administration. ACAT is an enzyme involved in higher fatty acid esterification of cholesterol in cells, and is known to play an important role in cholesterol absorption in the small intestine and cholesterol ester accumulation in cells. Therefore, ACAT inhibitors inhibit the absorption of dietary cholesterol from the intestinal tract, suppress the increase in blood cholesterol level, suppress the accumulation of intracellular cholesterol ester in arteriosclerotic lesions, and prevent the progression of atherosclerosis. it can. Inventive Compound (I)
Is therefore a mammal (eg mouse, rat, hamster,
Rabbits, cats, dogs, horses, cows, sheep, monkeys, humans, etc.) hypercholesterolemia, atherosclerosis, and diseases caused by these (eg, ischemic heart disease such as myocardial infarction and cerebral infarction) It is useful as a safe prophylactic / therapeutic agent for cerebrovascular disorders such as stroke.

When the compound represented by the general formula (I) is used as the above-mentioned pharmaceutical, it is mixed with an appropriate pharmacologically acceptable carrier, excipient and diluent to give powder, granules, tablets, capsules,
Although it can be administered orally or parenterally in the form of an injection, etc., when it is used for the purpose of inhibiting absorption of cholesterol, it is more preferably administered orally. Although the dose varies depending on the type of compound, administration route, symptoms, age of the patient, etc., for example, when administered orally to an adult patient with hypercholesterolemia, the daily dose is about 0.005 to 50 mg / kg body weight. The dose is preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, and this amount is preferably divided into 1 to 3 times a day.

The starting compound for producing the compound (I) of the present invention can be produced, for example, as follows.

[E method] [In the formula, X ¹ represents a leaving group, and other symbols have the same meanings as above].

[F method] [G method] [Wherein each symbol has the same meaning as described above] [Method E] Using 2-aminobenzophenone (IX) as a starting material,
3-aminoquinoline (II ') via (X) and (XI)
The method of manufacturing is already in the Journal of Chemical
Society [Journal of Chemical Society], page 3914 (1953) or Japanese Patent Publication No. 48-6474,
(II ′) can be produced by these methods or methods analogous thereto. The acetylation of (II ′) can also be carried out by the method described in JP-B-48-6474 or the pharmaceutical journal, 93, 1263 (1973) or a method analogous thereto, and the compound (XII) can be obtained. Can be manufactured. Then, (XII) can be produced by reacting (XII) with (XIII) to give (XIV), which is then hydrolyzed to produce (II ″).
The reaction with II) can be performed usually in a solvent (eg, tetrahydrofuran, dimethoxoxyethane, N, N-dimethylformamide, etc.). The reaction may be promoted in the presence of a base (eg, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, sodium amide, potassium t-butoxide, etc.). Usually about -10 ℃
It is carried out by reacting at -120 ° C, preferably about 0 ° C-100 ° C. At this time, the leaving group X ¹ is halogen (eg,
Chlorine, bromine, iodine), C _1-4 alkanesulfonyloxy group (eg, methanesulfonyloxy group, ethanesulfonyloxy group), C _1-4 alkoxysulfonyloxy (eg, methoxysulfonyloxy group, ethoxysulfonyloxy group) , C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group) and the like are used. The amount of the base and (X III) used is usually 1 to 3 equivalents relative to (X II). The obtained (X IV) can be hydrolyzed to produce (II ″). This hydrolysis reaction can be usually performed in the presence of a solvent (eg, alcohol such as methanol, ethanol, propanol, acetic acid, etc.). Mineral acids (eg, chlorine, hydrobromic acid, sulfuric acid, etc.) are usually about 2-20 per mole of (X IV).
Mol, preferably about 3 to 15 mol. About 60 ℃ ~ 12
It can be carried out at a reaction temperature of 0 ° C, preferably about 70 ° C to 100 ° C.

(II ″) can also be produced by directly reacting the compound (I ′) with the compound (X III). In this case, a solvent (eg, carbon tetrachloride, chloroform, methylene chloride, acetone, tetrahydrofuran, dimethoxy) is used. Ethane, N, N-dimethylformamide, etc.), if necessary, in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine, etc. The reaction temperature is usually about -20 ° C to 10 ° C.
0 ° C, preferably about 0 ° C to 60 ° C. The amount of (XIII) used is about 1-5 mol, preferably about 1-2 mol, per 1 mol of (II ').

[Method F] This method is already in Japanese Examined Patent Publication No. Sho 48-6474 or Pharmaceutical Journal, 93, 126.
It can be performed by the method described on page 3 (1973) or a method analogous thereto.

[Method G] The reaction between 2-aminobenzophenones (IX) and alkoxymethylenemalonic acid diester is described in the Canadian Journal of Chemistry.
emistry], Vol. 47, p. 489 (1969), or according to it. Then you get (X
VII) is reacted with sodium chloride or lithium chloride under heating to produce quinoline-3-carboxylic acid ester (X IX). This reaction is usually performed with dimethyl sulfoxide, sulfolane,
It is preferably carried out in a solvent such as N, N-dimethylformamide. It is carried out by heating to about 120 ° C to 220 ° C, preferably about 150 ° C to 200 ° C. The amount of sodium chloride or lithium chloride used is usually about 1-20 equivalents, preferably about 2-10 equivalents, relative to (XVII). In this reaction, a compound (X VIII) is first produced as an intermediate, which undergoes dehydration ring closure (X IX).
Is believed to give. Finally, (IV) can be produced by subjecting (XIX) obtained to alkaline hydrolysis. This hydrolysis reaction is usually performed with a solvent (eg, methanol, ethanol,
Propanol etc.) in the presence of. The reaction can be promoted in the presence of an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide. About 20 to 100 ° C, preferably about 30
It can be carried out at reaction temperatures of ~ 90 ° C.

Compounds (II ′), (II ″), (I
V) can be used as a starting material for the method of the present invention after isolation by a means known per se or without isolation as it is as a reaction mixture.

The 3-nitro compound (XI) having a substituted thio group on the ring A or the ring B can also be produced, for example, according to the following reaction formula.

[H method] [In the formula Is a substituent CH ₃ O—, HO—, on the A ring or (and) B ring,
_{(CH 3) 2 NCSO-, HS-} , indicates that there is R ^2a -S-, R ^2a
Is an optionally halogenated lower alkyl group, and X ¹ has the same meaning as described above.] [Method H] First, (XX) having a methoxy group on the A ring or (and) B ring is hydrobromic acid. To demethylate to produce (X XI). This reaction is usually performed under reflux with heating using an aqueous solution of hydrobromic acid as a solvent. If necessary, acetic acid may be added to aid dissolution. The resulting phenol (X XI) is then reacted with N, N-dimethylthiocarbamoyl chloride to produce (X XII). This reaction is usually an inert solvent (eg, diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, N, N
-Dimethylformamide). Usually about −
It can be carried out at a reaction temperature of 10 ° C to 80 ° C, preferably about 0 ° C to 60 ° C. The amount of N, N-dimethylthiocarbamoyl chloride used is usually about 1 to 2 equivalents, preferably about 1 to 1.5 equivalents, relative to (X XI). (X XII) is about 150 ℃ ~ 250
It can be converted to (XX III) by heating to 0 ° C, preferably about 170 ° C to 230 ° C. This conversion reaction is usually performed without a solvent by heating above the melting point of (XXII). The hydrolysis reaction of (XX III) can be usually performed under alkaline conditions. For example, it proceeds advantageously by using sodium hydroxide, potassium hydroxide, barium hydroxide or the like in the presence of a solvent (eg, methanol, ethanol, propanol, 2-methoxyethanol, dioxane, dimethoxyethane, etc.). Reaction temperature is usually about 10 ℃ ~ 10
The temperature is 0 ° C, preferably about 20 ° C to 90 ° C. The alkylation reaction of (XX IV) is carried out using a solvent (eg, methanol, ethanol,
R, in the presence of a base (eg, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.) in propanol, dimethoxyethane, dioxane, tetrahydrofuran, acetone, N, N-dimethylformamide, etc.).
It is carried out by reacting ^2a- X ¹ . The reaction temperature is generally -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C, and R ^2a
The amount of -X ¹ used is about 1 to 2 equivalents, preferably about 1 to 1.5 equivalents, relative to (XX IV). When R ^2a -X ¹ is in a gaseous state, it can be carried out by introducing an excess amount into the reaction solution. The thus-obtained (XI ′) can be isolated by a method known per se, or can be used as a raw material for the next step as it is as a reaction mixture without isolation.

The 3-nitro compound (XI) having a substituted oxy group on ring A or ring B can also be produced, for example, according to the following reaction scheme.

[Method I] [In the formula Has a substituent R ^2a —O— on the A ring or (and) B ring, and other symbols have the same meanings as above] [Method I] Intermediate (X XI) obtained by Method H producing (XI ') by reacting R ^2a -X ^1. Intermediate (X XI) and R ^2a-
This reaction with X ¹ can be carried out in the same manner as the reaction between (XX IV) and R ^2a -X ¹ in the above Method H. The thus-obtained (XI ′) can be isolated by a method known per se, or can be used as a raw material for the next step as it is as a reaction mixture without isolation.

Nitroenamine (XX
(XI) can also be produced all at once by the following method using V).

[J method] [Wherein R ⁶ and R ⁷ are the same or different and represent a lower alkyl group, a phenyl group or a benzyl group, or R ⁶ and R ⁷ are groups which are linked to each other to form a ring with an adjacent nitrogen atom] [Method J] Examples of the lower alkyl group represented by R ⁶ and R ⁷ include 1 to 1 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl.
4 is preferable. When R ⁶ and R ⁷ are linked to each other to form a ring with a nitrogen atom, the ring may further have another oxygen atom, and examples thereof include a pyrrolidine ring, a piperidine ring and a homopiperidine ring. , 5- to 7-membered ring such as morpholine ring.

The reaction between compounds (IX) and (XXV) is usually carried out in a solvent in the presence of an acid. As the solvent, for example, ethyl acetate, acetone, benzene, toluene, etc., and as the acid, hydrochloric acid,
Hydrobromic acid, sulfuric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. are used. Such acids may be used in an anhydrous state or as an aqueous solution, and the reaction is carried out in a homogeneous system. Alternatively, a two-layer system of a solvent and water may be used. The amount of (XXV) used is about 1-10 mol, preferably about 2-6 mol, per 1 mol of (IX). The amount of acid used is about 1 to 20 mol per 1 mol of (IX),
It is preferably about 2 to 10 mol. Reaction temperature is usually about 20 ℃
-100 ° C, preferably about 50-80 ° C.

Compound (X IX) can also be produced all at once by the following method using compound (XX VI) instead of (X VI) in Method G.

[K method] [Symbols in the Formulas Have the Same Meaning as Above] [Method K] This reaction is usually carried out in a solvent such as benzene, toluene, xylene or the like in the presence of an acid catalyst such as benzenesulfonic acid or p-toluenesulfonic acid. . The amount of the compound (XX VI) used is usually 1 to 5 mol, preferably about 1 to 3 mol, relative to 1 mol of (IX), and the amount of the acid used is about 1 mol to (IX).
0.01 to 1 mol, preferably about 0.05 to 0.5 mol. The reaction is usually performed near the boiling point of the solvent, and it is preferable to perform the reaction while separating water produced during the reaction.

When compound (XX VII) is used instead of (XX VI) in Method K, compound (XX VIII) can be produced,
(XX VIII) can also be led to compound (II) via (XX IX) (method L).

[L method] [The symbols in the formulas have the same meanings as above].

[Method L] The reaction between compound (IX) and (XX VII) is (I) in method J.
It can be carried out in the same manner as the reaction between (X) and (XX VI). Then (XX VIII) is partially hydrolyzed to give compound (X
X IX) is manufactured. This hydrolysis reaction can be carried out with an acid or an alkali. As the acid, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are used, and as the alkali, sodium hydroxide, potassium hydroxide, etc. are used. It is carried out in the presence or absence of methanol, ethanol, propanol, dioxane, dimethoxyethane, etc.). The reaction temperature is about 0 ° C to 100 ° C, preferably about 20 ° C to 80 ° C.

Further, (XX VIII) can also be introduced into (XX IX) by oxidizing with hydrogen peroxide in the presence of alkali. This reaction is usually carried out in the same solvent as used for hydrolysis in the presence of an alkali such as sodium hydroxide or potassium hydroxide. The amount of alkali and hydrogen peroxide used is about 1-10 mol, preferably about 1.5-5 mol, per 1 mol of (XX VIII), and the reaction temperature is about 10 ° C-100 ° C.
C, preferably about 20-80C.

Next, (XX IX) is reacted with bromine or chlorine in the presence of an alkali to produce (II) by a so-called Hofmann reaction. In this reaction, first, (XX IX) is reacted with bromine or chlorine in the presence of an alkali in a solvent. Dioxane, dimethoxyethane, methanol, ethanol, etc. are used as the solvent, and sodium hydroxide, potassium hydroxide, etc. are used as the alkali. This reaction can be carried out by adding bromine or chlorine to a mixture of (XX IX) and alkali, or by first reacting alkali with bromine or chlorine to produce hypobromous acid or hypochlorous acid. The reaction temperature may be usually about -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C. At lower temperatures, the isocyanato compound (VI) is first formed and then hydrolyzed to form (II). Therefore, it is generally preferable to carry out the reaction stepwise. It is preferable to raise the reaction temperature. The amount of alkali used in this reaction is about 2-8 mol, preferably about 4 mol, per 1 mol of (XX IX).
~ 6 mol, the amount of bromine or chlorine used is (XX IX)
It is about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol.

Preferred examples of the compound (II) are, for example, compounds of the formula [In the formula, R ³ has the same meaning as described above, and A'ring is halogen and C
It is substituted with two selected from _1-4 alkyl groups. ]
And a salt thereof or the like. Formula (II ^b )
The substituents on the R ³ and A ′ rings and the substitution positions thereof are as described for R ² , R ³ , R ⁴ and R ⁵ in the compounds (I ^a ) and (I ^b ).

The following method of hydrolyzing the intermediate (XX VIII) of Method L to produce (IV) can also be used.

[M method] [Method M] This hydrolysis reaction is carried out using an acid or an alkali in a solvent, but it is preferable to use an alkali. Methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol and the like are used as the solvent, and sodium hydroxide, potassium hydroxide and the like are used as the alkali. The amount of alkali used is usually about 2-20 mol, preferably about 3-10 mol, per 1 mol of (XX VIII).
The reaction is usually performed at about 60 ° C to 150 ° C, preferably about 80 ° C to 130 ° C.

The raw material (IX) of the method E is, for example, a journal
Of Organic Chemistry [Journal of Organ
ic Chemistry], 26, 4488 (1961), ibid, 27, 37
By the method described on page 81 (1962) or the like or a method similar thereto, the raw material (XV) of the method F is, for example, JP-B-48-64
74, Pharmaceutical Journal, 93, 1263 (1973), or the like, or a method analogous thereto.

Further, the raw material (XXV) in the J method is, for example, synthesis [S
Synthesis], page 260 (1982) or a method analogous thereto.

Actions The results of the pharmacological tests showing the excellent usefulness of the quinoline derivative (I) of the present invention or a salt thereof are shown below.

1. Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory action.

[Experimental method] Enzyme preparation ACAT is a journal of Heidel [Heider] et al. [Journal of Lipid Researc]
h], 24, 1127 (1982).
6-week-old male Sprague-Dawley [Spra
gue-Dawley] rat small intestinal mucosa microsome fraction.

ACAT activity is the method of Helgerud et al. (Journal of Lippit Research, 22: 271, 1981)
Accordingly it was calculated by measuring the production amount of labeled cholesterol ester from [1- ¹⁴ C] oleoyl -CoA and endogenous cholesterol.

[Results] Table 1 shows the labeled cholesterol ester production inhibition rate (%) when the test compound was added at 10 ^-6 M to 10 ^-8 M by ACAT.
Shown as an index of inhibitory action.

This Table 1 clearly demonstrates that the quinoline derivative (I) containing the compound B or a salt thereof has an excellent ACAT inhibitory action.

2. Plasma cholesterol lowering effect in cholesterol-loaded rats [Experimental method] 7-week-old male Sprague Dawley
Rats received a 1% cholesterol diet (0.5% cholic acid and 5%
% Olive oil) was given for 3 days, grouped by plasma cholesterol level, and then fed with the same feed containing 0.0005% of the test compound for another 4 days. 8:30 am in satiety
Blood was collected between ~ 10: 00 and plasma cholesterol levels were measured enzymatically. The compound intake was calculated from the food intake.

[Results] As shown in Table 2, the test compound significantly reduced plasma cholesterol during cholesterol loading.

This Table 2 clearly demonstrates that the quinoline derivative (I) or its salt has an excellent plasma cholesterol-lowering effect.

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 performed under observation by TLC (Thin Layer Chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as the TLC plate, and the solvent used as the elution solvent in column chromatography was used as the developing solvent as the detection method.
UV detector is adopted. As the silica gel for the column, silica gel 60 (70 to 230 mesh, also manufactured by Merck & Co., Inc.) was used.

The abbreviations used in Examples and Reference Examples have the following meanings.

mg: milligram, g: gram, ml: millimeter, mp: melting point.

The room temperature means about 15 to 25 ° C.

Example 1 3-amino-6-chloro-4-phenylquinoline (509m
2,4-Difluorophenylisocyanate (0.24 ml) was added to a solution of g) in anhydrous tetrahydrofuran (8 ml), and the mixture was allowed to stand at room temperature for 20 hours. The precipitated crystals were collected by filtration. Further crystals were obtained by concentrating the filtrate, and the crystals were combined and recrystallized from ethanol to give 6-chloro-3- [3- (2,4-
Difluorophenyl) ureido] -4-phenylquinoline (638 mg, 77.8%) was obtained as colorless crystals.

mp206-207 ° C. Elemental analysis _{C 22 H 14 ClF 2 N 3} O Calculated: C, 64.48; H, 3.44 ; N, 10.25 Found: C, 64.23; H, 3.55 ; N, 10.04 Similarly the following, the corresponding 3-amino The following Examples 2-39 by reacting a quinoline derivative with an isocyanate
Was obtained.

Example 2 6-Chloro-3- [3- (4-fluorophenyl) ureido] -4-phenylquinoline: mp 205-207 ° C (recrystallized from ethanol). Yield 66.5%. Elemental analysis C ₂₂ H ₁₅ ClFN ₃ O Calculated: C, 67.44; H, 3.86 ; N, 10.72 Found: C, 67.63; H, 3.87 ; N, 10.76 Example 3 6-Chloro-3- [3 -(3-Fluorophenyl) ureido] -4-phenylquinoline: mp213-214 ° C (recrystallized from acetone). Yield 84.1%. Elemental analysis C ₂₂ H ₁₅ ClFN ₃ O Calculated: C, 67.44; H, 3.86 ; N, 10.72 Found: C, 67.51; H, 3.86 ; N, 10.64 Example 4 6-Chloro-3- [3 -(2-Fluorophenyl) ureido] -4-phenylquinoline: mp 197-198 ° C (recrystallized from acetone-hexane). Yield 77.3%. Elemental analysis C ₂₂ H ₁₅ ClFN ₃ O Calculated: C, 67.44; H, 3.86 ; N, 10.72 Found: C, 67.32; H, 3.86 ; N, 10.70 Example 5 6-Chloro-3- [3 -(3-Methylphenyl) ureido] -4-phenylquinoline: mp204-206 ° C (acetone-
Recrystallized from ethanol). Yield 78.2%. Elemental analysis C ₂₃ H ₁₈ ClN ₃ O Calculated: C, 71.22; H, 4.68 ; N, 10.83 Found: C, 71.16; H, 4.67 ; N, 10.89 Example 6 6-Chloro-4-phenyl - 3- [3- (3-trifluoromethylphenyl) ureido] quinoline: mp203-204 ° C
(Recrystallized from acetone-isopropyl ether). yield
80.5%. Elemental analysis _{C 23 H 15 ClF 3 N 3} O Calculated: C, 62.52; H, 3.42 ; N, 9.51 Found: C, 62.73; H, 3.71 ; N, 9.23 Example 7 6-chloro-3- [3- (2,4-dimethoxyphenyl)
Ureido] -4-phenylquinoline: mp 210-211 ° C (recrystallized from acetone-ethanol). Yield 41.5%. Calculated elemental analysis _{C 24 H 20 ClN 3 O 3} : C, 66.44; H, 4.65; N, 9.68 Found: C, 66.38; H, 4.55 ; N, 9.63 Example 8 6-Chloro-3- [ 3- (3,4-Dichlorophenyl) ureido] -4-phenylquinoline: mp226-227 ° C (recrystallized from acetone). Yield 79.3%. Elemental analysis _{C 22 H 14 Cl 3 N 3} O Calculated: C, 59.68; H, 3.19 ; N, 9.49 Found: C, 59.63; H, 3.07 ; N, 9.55 Example 9 6-Chloro-3- [3- (2,5-Dichlorophenyl) ureido] -4-phenylquinoline (acetone sorbate): mp 191-192 ° C (recrystallized from acetone-isopropyl ether). Yield 82.8%. Elemental analysis value Calculated as C ₂₂ H ₁₄ Cl ₃ N ₃ O ・ C ₃ H ₆ O: C, 59.96; H, 4.03; N, 8.39 Measured value: C, 60.04; H, 4.04; N, 8.42 Example 10 6-chloro-3- [3- (2,4-dichlorophenyl) ureido] -4-phenylquinoline: mp 214-215 ° C (recrystallized from acetone). Yield 74.2%. Elemental analysis value Calculated as C ₂₂ H ₁₄ Cl ₃ N ₃ O: C, 59.68; H, 3.19; N, 9.49 Found: C, 59.53; H, 3.10; N, 9.45 Example 11 6-Brom-3- [3- (2,4-difluorophenyl)
Ureido] -4-phenylquinoline: mp 195-197 ° C (recrystallized from acetone-isopropyl ether). Yield 82.1
%. Elemental analysis _{C 22 H 14 BrF 2 N 3} O Calculated: C, 58.17; H, 3.11 ; N, 9.25 Found: C, 57.96; H, 3.06 ; N, 9.11 Example 12 3- [3- ( 2,4-Difluorophenyl) ureido]-
4-phenylquinoline (1/2 ethanol sorbate): mp
193-195 ° C (recrystallized from ethanol). Yield 74.3%. Elemental analysis value Calculated as C ₂₂ H ₁₅ F ₂ N ₃ O ・ 1 / 2C ₂ H ₆ O: C, 69.34; H, 4.55; N, 10.55 Measured value: C, 69.48; H, 4.55; N, 10.57 Example 13 3- [3- (2,4-difluorophenyl) ureido]-
6-Methyl-4-phenylquinoline: mp 189-191 ° C (recrystallized from acetone-isopropyl ether). Yield 72.0
%. Elemental analysis _{C 23 H 17 F 2 N 3} O Calculated: C, 70.94; H, 4.40 ; N, 10.79 Found: C, 70.88; H, 4.39 ; N, 10.80 Example 14 3- [3- ( 2,4-Difluorophenyl) ureido]-
6-Ethyl-4-phenylquinoline: mp189-190 ° C (recrystallized from ethanol). Yield 70.5%. Elemental analysis value Calculated as C ₂₄ H ₁₉ F ₂ N ₃ O: C, 71.45; H, 4.75; N, 10.42 Actual value: C, 71.28; H, 4.78; N, 10.29 Example 15 3- [3- (3- ( 2,4-Difluorophenyl) ureido]-
6-isopropyl-4-phenylquinoline: mp211-212 ° C
(Recrystallized from ethanol). Yield 74.5%. Elemental analysis value Calculated as C ₂₅ H ₂₁ F ₂ N ₃ O: C, 71.93; H, 5.07; N, 10.07 Measured value: C, 71.92; H, 5.04; N, 9.99 Example 16 3- [3- (3- ( 2,4-Difluorophenyl) ureido]-
7-Methyl-4-phenylquinoline: mp 195-197 ° C. (recrystallized from acetone). Yield 76.2%. Elemental analysis _{C 23 H 17 F 2 N 3} O Calculated: C, 70.94; H, 4.40 ; N, 10.79 Found: C, 70.99; H, 4.38 ; N, 10.67 Example 17 3- [3- ( 2,4-Difluorophenyl) ureido]-
4-phenyl-6-trifluoromethylquinoline: mp203
-204 ° C (recrystallized from ethanol). Yield 65.3%. Elemental analysis _{C 23 H 14 F 5 N 3} O Calculated: C, 62.31; H, 3.19 ; N, 9.48 Found: C, 62.39; H, 3.12 ; N, 9.52 EXAMPLE 18 3- [3- ( 2,4-Difluorophenyl) ureido]-
6-Methoxy-4-phenylquinoline: mp 126-130 ° C. (recrystallized from acetone-isopropyl ether). Yield 87.7
%. Elemental analysis _{C 23 H 17 F 2 N 3} O 2 Calculated: C, 68.14; H, 4.23 ; N, 10.37 Found: C, 68.20; H, 4.18 ; N, 10.19 Example 19 3- [3- (2,4-Difluorophenyl) ureido]-
6,7-Dimethoxy-4-phenylquinoline: mp202-203 ° C
(Recrystallized from methanol). Yield 77.2%. Elemental analysis value Calculated as C ₂₄ H ₁₉ F ₂ N ₃ O ₃ : C, 66.20; H, 4.40; N, 9.65 Actual value: C, 65.92; H, 4.35; N, 9.49 Example 20 3- [3- (2,4-Difluorophenyl) ureido]-
6-Nitro-4-phenylquinoline (2/3 acetone sorbate): mp 193-194 ° C (recrystallized from acetone). Yield 7
6.3%. Elemental analysis _{C 22 H 14 F 2 N 4} O 3 · 3 / 2C 3 H 6 O Calculated: C, 62.79; H, 3.95 ; N, 12.20 Found: C, 62.84; H, 4.05 ; N, 12.09 Example 21 4- (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] quinoline (1/2 ethanol sorbate): mp 198-200 ° C (recrystallized from ethanol).
Yield 85.5%. Elemental analysis value Calculated as C ₂₂ H ₁₄ ClF ₂ N ₃ O ・ 1 / 2C ₂ H ₆ O: C, 63.82; H, 3.96; N, 9.71 Actual value: C, 63.57; H, 4.02; N, 9.64 Implemented Example 22 6-chloro-3- [3- (2,4-difluorophenyl)
Ureido] -4- (2-fluorophenyl) quinoline: m
p218-220 ° C (recrystallized from ethanol). Yield 78.3%. Elemental analysis _{C 22 H 13 ClF 3 N 3} O Calculated: C, 61.77; H, 3.06 ; N, 9.82 Found: C, 61.51; H, 3.03 ; N, 9.64 Example 23 6-Chloro-4- (2-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] quinoline: mp21
0-212 ° C (recrystallized from acetone-water). Yield 86.7%. Elemental analysis value Calculated as C ₂₂ H ₁₃ Cl ₂ F ₂ N ₃ O: C, 59.48; H, 2.95; N, 9.46 Found: C, 59.28; H, 2.88; N, 9.37 Example 24 6-chloro- 4- (3-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] quinoline: mp20
7-208 ° C (recrystallized from acetone-water). Yield 68.1%. Elemental analysis value Calculated value as C ₂₂ H ₁₃ Cl ₂ F ₂ N ₃ O: C, 59.48; H, 2.95; N, 9.46 Actual value: C, 59.31; H, 2.96; N, 9.59 Example 25 6-chloro- 4- (4-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] quinoline: mp21
5-217 ° C (recrystallized from ethanol). Yield 74.1%. Elemental analysis value Calculated as C ₂₂ H ₁₃ Cl ₂ F ₂ N ₃ O: C, 59.48; H, 2.95; N, 9.46 Found: C, 59.31; H, 2.96; N, 9.59 Example 26 6-chloro- 3- [3- (2,4-difluorophenyl)
Ureido] -4- (4-methylphenyl) quinoline: mp1
88-189 ° C (recrystallized from ethanol). Yield 79.7%. Elemental analysis _{C 23 H 16 ClF 2 N 3} O Calculated: C, 65.18; H, 3.80 ; N, 9.91 Found: C, 65.19; H, 3.78 ; N, 9.79 Example 27 6-chloro-3- [3- (2,4-difluorophenyl)
Ureido] -4- (2-methylphenyl) quinoline: mp2
19-220 ° C (recrystallized from acetone-hexane). Yield 72.6
%. Elemental analysis _{C 23 H 16 ClF 2 N 3} O Calculated: C, 65.18; H, 3.80 ; N, 9.91 Found: C, 65.34; H, 3.79 ; N, 10.04 Example 28 6-chloro-3- [3- (2,4-difluorophenyl)
Ureido] -4- (4-methoxyphenyl) quinoline: m
p208-209 ° C (recrystallized from ethanol). Yield 82.7%. Elemental analysis _{C 23 H 16 ClF 2 N 3} O 2 Calculated: C, 62.81; H, 3.67 ; N, 9.55 Found: C, 62.86; H, 3.70 ; N, 9.50 Example 29 6-chloro-3 -[3- (2,4-difluorophenyl)
Ureido] -4- (2-methoxyphenyl) quinoline: m
p221-222 ° C (recrystallized from ethanol). Yield 65.9%. Elemental analysis _{C 23 H 16 ClF 2 N 3} O 2 Calculated: C, 62.81; H, 3.67 ; N, 9.55 Found: C, 62.81; H, 3.71 ; N, 9.81 Example 30 4- (2- Chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] -6-methylquinoline: mp2
25-226 ° C (recrystallized from acetone). Yield 64.7%. Elemental analysis _{C 23 H 16 ClF 2 N 3} O Calculated: C, 65.18; H, 3.80 ; N, 9.91 Found: C, 65.12; H, 3.77 ; N, 9.87 Example 31 3- [3- ( 2,4-Difluorophenyl) ureido]-
6-methyl-4- (2-methylphenyl) quinoline: mp2
18-220 ° C (recrystallized from acetone-benzene). Yield 65.7
%. Elemental analysis value Calculated as C ₂₄ H ₁₉ F ₂ N ₃ O: C, 71.45; H, 4.75; N, 10.42 Actual value: C, 71.26; H, 4.65; N, 10.30 Example 32 4- (2-chlorophenyl ) -3- [3- (2,4-Difluorophenyl) ureido] -6,8-dimethylquinoline:
mp198-200 ° C (recrystallized from acetone-benzene). Yield 6
1.4%. Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ O: C, 65.83; H, 4.14; N, 9.60 Found: C, 65.67; H, 4.13; N, 9.71 Example 33 4- (2-chlorophenyl ) -3- [3- (2,4-Difluorophenyl) ureido] -6-ethylquinoline: mp2
28-229 ° C (recrystallized from acetone). Yield 75.4%. Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ O: C, 65.83; H, 4.14; N, 9.60 Found: C, 65.80; H, 4.14; N, 9.61 Example 34 4- (2-chlorophenyl ) -3- [3- (2,4-Difluorophenyl) ureido] -6-isopropylquinoline: mp232-233 ° C (recrystallized from acetone). Yield 79.3%. Elemental analysis value Calculated as C ₂₅ H ₂₀ ClF ₂ N ₃ O: C, 66.45; H, 4.46; N, 9.30 Found: C, 66.34; H, 4.45; N, 9.30 Example 35 6-Butyl-4- (2-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] quinoline: mp20
2-203 ° C (recrystallized from acetone-hexane). Yield 72.7
%. Elemental analysis _{C 26 H 22 ClF 2 N 3} O Calculated: C, 67.02; H, 4.76 ; N, 9.02 Found: C, 66.98; H, 4.72 ; N, 8.78 Example 36 4- (2-Chlorophenyl ) -3- [3- (2,4-Difluorophenyl) ureido] -6-fluoroquinoline: m
p212-213 ° C (recrystallized from acetone-hexane). Yield 6
8.3%. Elemental analysis _{C 22 H 13 ClF 3 N 3} O Calculated: C, 61.77; H, 3.06 ; N, 9.82 Found: C, 61.74; H, 3.06 ; N, 9.68 Example 37 3- [3- ( 2,4-Difluorophenyl) ureido]-
6-methylthio-4-phenylquinoline: mp117-120 ° C
(Recrystallized from methanol). Yield 89.4%. Elemental analysis _{C 23 H 17 F 2 N 3} OS Calculated: C, 65.55; H, 4.07 ; N, 9.97 Found: C, 65.43; H, 4.02 ; N, 9.91 Example 38 6-Chloro-4- (2-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] -8-methylquinoline: mp 199-201 ° C (recrystallized from acetone-benzene). Yield 67.8%. Elemental analysis _{C 23 H 15 Cl 2 F 2} N 3 O Calculated: C, 60.28; H, 3.30 ; N, 9.17 Found: C, 60.25; H, 3.30 ; N, 9.04 Example 39 3- [3 -(2,4-Difluorophenyl) ureido]-
6,8-Dimethyl-4- (2-methylphenyl) quinoline (1/2 ethanol sorbate): mp 200-201 ° C (recrystallized from ethanol). Yield 66.0%. Elemental analysis value Calculated as C ₂₅ H ₂₁ F ₂ N ₃ O ・ 1 / 2C ₂ H ₆ O: C, 70.89; H, 5.49; N, 9.54 Actual value: C, 70.63; H, 5.41; N, 9.46 Implemented Example 40 A mixture of 6-chloro-3-methylamino-4-phenylquinoline (0.54 g), 2,4-difluorophenylisocyanate (0.48 ml) and anhydrous toluene (10 ml) was heated under reflux for 22 hours and then concentrated. The residue was purified by silica gel chromatography and recrystallized from ethyl acetate-ethanol to give 6-chloro-3- [3- (2,4-difluorophenyl) -1-methylureido] -4-phenylquinoline as colorless crystals. Got as. Yield 0.56g (66%). Mp200-201
° C. Elemental analysis _{C 23 H 16 ClF 2 N 3} O Calculated: C, 65.18; H, 3.80 ; N, 9.91 Found: C, 65.24; H, 3.70 ; N, the following in the same manner as 9.81 Example 40 The compounds of Examples 41-44 were obtained.

Example 41 6-chloro-3- [3- (2,4-difluorophenyl)
-1-Ethylureido] -4-phenylquinoline: mp141
-142 ° C (recrystallized from ethanol). Yield 53.7%. Elemental analysis _{C 24 H 18 ClF 2 N 3} O Calculated: C, 65.83; H, 4.14 ; N, 9.60 Found: C, 65.73; H, 4.22 ; N, 9.68 Example 42 3- [1-butyl -3- (2,4-difluorophenyl)
Ureido] -6-chloro-4-phenylquinoline (recrystallized from ethyl ether-hexane): mp 66-69 ° C. Yield 5
9.5%. Elemental analysis _{C 26 H 22 ClF 2 N 3} O Calculated: C, 67.02; H, 4.76 ; N, 9.02 Found: C, 67.06; H, 4.85 ; N, 8.99 Example 43 3- [1- benzine -3- (2,4-Difluorophenyl) ureido] -6-chloro-4-phenylquinoline: m
p150-152 ℃ (recrystallized from ethanol). Yield 47%. Elemental analysis value Calculated as C ₂₉ H ₂₀ ClF ₂ N ₃ O: C, 69.67; H, 4.03; N, 8.40 Actual value: C, 69.66; H, 4.10; N, 8.25 Example 44 6-chloro-3- [3- (2,4-difluorophenyl)
-1-Heptylureido] -4-phenylquinoline: mp1
09-110 ℃ (recrystallized from ethanol). Yield 29.7%. Elemental analysis _{C 29 H 28 ClF 2 N 3} O Calculated: C, 68.57; H, 5.56 ; N, 8.27 Found: C, 68.67; H, 5.55 ; N, 8.05 Example 45 6-chloro-3- Heptylamino-4-phenylquinoline (353mg), activated carbon (8mg), triethylamine (0.14
ml) and anhydrous tetrahydrofuran (6 ml) with stirring while stirring 10% of trichloromethyl chloroformate.
1.5 ml of a toluene solution was added dropwise. The mixture was further stirred overnight at room temperature, nitrogen gas was blown into the mixture to remove excess phosgene, and p-chloroaniline (126 mg) in anhydrous tetrahydrofuran (6 ml), triethylamine (0.28 ml) and 4-dimethylaminopyridine were then added. (24 mg) was added and the mixture was reacted under heating under reflux for 12 hours. After removing the sediment,
The filtrate was concentrated, and the residue was crystallized from ethanol to give 6-chloro-3- [3- (4-chlorophenyl) -1-heptylureido] -4-phenylquinoline as colorless crystals. Yield 207mg (40.9%). Mp180-18
2 ° C. Elemental analysis value Calculated as C ₂₉ H ₂₉ Cl ₂ N ₃ O: C, 68.77; H, 5.77; N, 8.30 Actual value: C, 69.00; H, 5.80; N, 8.01 Example 46 6-chloro-4- Triethylamine (0.34 mg) was added to a mixture of phenyl-3-quinolinecarboxylic acid (566 mg), diphenylphosphoryl azide (660 mg) and dioxane (10 ml).
ml) was added, the mixture was stirred at room temperature for 15 minutes and then at reflux for 20 minutes. After cooling 2,6-difluoroaniline (3
10 mg) and the mixture was stirred at room temperature for 15 minutes and at reflux for 30 minutes. After diluting with water and extracting with ethyl acetate, the organic layer was water, 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with water. After drying over anhydrous MgSO ₄ , the solvent was distilled off,
6-chloro-3- [3- (2,6-difluorophenyl) ureido] was obtained by recrystallizing the residue from acetone.
-4-Phenylquinoline was obtained as colorless needle crystals. Yield 562 mg (68.7%). Mp 228-229 ° C. Elemental analysis _{C 22 H 14 ClF 2 N 3} O Calculated: C, 64.48; H, 3.44 ; N, 10.25 Found: C, 64.64; H, 3.40 ; N, in the same manner as 10.01 Example 47 Example 46 6-chloro-3- [3- (2,4-
Dimethylphenyl) ureido] -4-phenylquinoline was obtained. mp 230-231 ° C (recrystallized from acetone). Yield 42.
9%. Elemental analysis value Calculated as C ₂₄ H ₂₀ ClN ₃ O: C, 71.73; H, 5.02; N, 10.46 Measured value: C, 71.75; H, 4.96; N, 10.46 Example 48 Same as Example 46 6 -Chloro-3- [3- (2,4-
Difluorobenzyl) ureido] -4-phenylquinoline was obtained. mp 243-244 ° C (recrystallized from acetone). Yield 2
2.0%. Elemental analysis value Calculated as C ₂₃ H ₁₆ ClF ₂ N ₃ O: C, 65.18; H, 3.80; N, 9.91 Actual value: C, 64.91; H, 3.72; N, 9.71 Example 49 (1) 4- ( 2-chlorophenyl) -3- [3- (2,4
-Difluorophenyl) ureido] -6,8-dimethylquinoline 10g (2) Lactose 50g (3) Corn starch 15g (4) Carboxymethylcellulose calcium 44g (5) Magnesium stearate 1g 1000 tablets 120g (1), (2), The whole amount of (3) and 30 g of (4) were kneaded with water, vacuum dried and granulated. 14 in this granulated powder
Tablets containing 10 mg of (1) per tablet by mixing 1 g of g (4) and (5) and tableting with a tableting machine.
Made 00 pieces.

The compounds of Examples 50 to 55 below were obtained in the same manner as in Example 1.

Example 50 6-chloro-4- (2-chlorophenyl) -3- [3-
(4-Chlorophenyl) ureido] quinoline: mp217-219
C (recrystallized from acetone-benzene). Yield 56.8%. Elemental analysis value Calculated as C ₂₂ H ₁₄ Cl ₃ N ₃ O: C, 59.68; H, 3.19; N, 9.49 Found: C, 59.47; H, 3.12; N, 9.43 Example 51 4- (2-chlorophenyl ) -3- [3- (4-Chlorophenyl) ureido] -6,8-dimethylquinoline: mp219-
221 ° C (recrystallized from acetone-benzene). Yield 61.3
%. Elemental analysis value Calculated as C ₂₄ H ₁₉ Cl ₂ N ₃ O: C, 66.06; H, 4.39; N, 9.63 Actual value: C, 65.96; H, 4.42; N, 9.50 Example 52 6-chloro-3- [3- (2,4-difluorophenyl)
Ureido] -4- (2-methylthiophenyl) quinoline: mp 219-221 ° C (recrystallized from acetone). Yield 69.1%. Elemental analysis _{C 23 H 16 ClF 2 N 3} OS Calculated: C, 60.59; H, 3.54 ; N, 9.22 Found: C, 60.75; H, 3.46 ; N, 9.29 Example 53 6-difluoromethylthio -3 -[3- (2,4-Difluorophenyl) ureido] -4-phenylquinoline: mp1
10-112 ℃ (recrystallized from methanol). Yield 20.6%. Elemental analysis _{C 23 H 15 F 4 N 3} OS Calculated: C, 60.39; H, 3.31 ; N, 9.19 Found: C, 60.44; H, 3.28 ; N, 9.08 Example 54 6-difluoromethoxy -3 -[3- (2,4-difluorophenyl) ureido] -4-phenylquinoline: mp102
-104 ° C (recrystallized from methanol). Yield 58.5%. Elemental analysis _{C 23 H 15 F 4 N 3} O 2 Calculated: C, 62.59; H, 3.43 ; N, 9.52 Found: C, 62.50; H, 3.31 ; N, 9.44 Example 55 8-Chloro-4 -(2-chlorophenyl) -3- [3-
(2,4-Difluorophenyl) ureido] -6-methylquinoline: mp 220-222 ° C (recrystallized from acetone-benzene). Yield 63.0%. Elemental analysis value Calculated as C ₂₃ H ₁₅ Cl ₂ F ₂ N ₃ O: C, 60.28; H, 3.30; N, 9.17 Actual value: C, 59.98; H, 3.20; N, 9.13 Example 56 Example 40 and Similarly, 3- [1-butyl-3- (2,4-
Difluorophenyl) ureido] -6-chloro-4-
(2-chlorophenyl) quinoline was obtained. mp63-66 ℃
(Recrystallized from ethyl acetate-hexane). Yield 72.0%. Elemental analysis value Calculated as C ₂₆ H ₂₁ Cl ₂ F ₂ N ₃ O: C, 62.41; H, 4.23; N, 8.40 Actual value: C, 62.37; H, 4.16; N, 8.33 Example 57 In Example 32 Obtained 4- (2-chlorophenyl) -3- [3
-(2,4-Difluorophenyl) ureido] -6,8-dimethylquinoline (0.2 g) was dissolved in a mixed solution of acetone (10 ml) and 2N-hydrochloric acid (0.5 ml) by heating at 80 ° C and then concentrated.
The precipitated crystals were collected by filtration to give 4- (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] -6,8-dimethylquinoline hydrochloride as pale yellow needle crystals. . Yield 0.19g.mp 227-228 ° C. Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ O.HCl: C, 60.77; H, 4.04; N, 8.86 Measured value: C, 60.92; H, 4.01; N, 8.78 As in Example 1. The following compounds of Examples 58-60 were obtained.

Example 58 6-Chloro-3- [3- (4-fluoro-3-nitrophenyl) ureido] -4- (2-methylphenyl) quinoline: mp 229-232 ° C (recrystallized from acetone). Yield 58%. Calculated elemental analysis _{C 23 H 16 ClFN 4 O 3} : C, 61.27; H, 3.58; N, 12.43 Found: C, 60.99; H, 3.56 ; N, 12.34 Example 59 3- [3- (2 , 4-Difluorophenyl) ureido]-
6-Methyl-4- (2-methylthiophenyl) quinoline (methanol sorbate): mp213-215 ° C (recrystallized from methanol). Yield 87.0% Elemental analysis value Calculated as C ₂₄ H ₁₉ F ₂ N ₃ OS ・ CH ₄ O: C, 64.22; H, 4.96; N, 8.99 Actual value: C, 64.27; H, 4.94; N, 9.03 Implemented Example 60 6-chloro-3- [3- (2,4-difluorophenyl)
Ureido] -4- (3,4-dimethoxyphenyl) quinoline: mp 252-254 ° C (recrystallized from acetone). Yield 85.4%. Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ O ₃ : C, 61.35; H, 3.86; N, 8.94 Measured value: C, 61.33; H, 3.85; N, 8.87 Example 61 Same as Example 46 4- (2-chlorophenyl) -6,
By reacting 8-dimethyl-3-quinolinecarboxylic acid with diphenylphosphoryl azide and then with 2,4-difluoroaniline, 4- (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ) Ureido] -6,8-dimethylquinoline was obtained. Yield 35.9% .mp
198-200 ° C. This product is the same as that obtained in Example 32.

Example 62 4- (2-chlorophenyl) -6, as in Example 46
By reacting 8-dimethyl-3-quinolinecarboxylic acid with diphenylphosphoryl azide and then with 2,4,6-trifluoroaniline, 4- (2-chlorophenyl) -6,8-dimethyl-3- [ 3- (2,4,6-Trifluorophenyl) ureido] quinoline was obtained. mp219-
220 ° C (recrystallized from ethanol). 73.0% Elemental analysis yields _{C 24 H 17 ClF 3 N 3} O Calculated: C, 63.23; H, 3.76 ; N, 9.22 Found: C, 63.14; H, 3.67 ; N, 9.08 Example 63 4- A mixture of (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] -6,8-dimethylquinoline (1.1 g), m-chloroperbenzoic acid (1.08 g) and dichloromethane (15 ml). Was heated to reflux for 20 hours. The reaction solution was washed with a sodium sulfite aqueous solution, a sodium hydrogen carbonate aqueous solution and water in this order, dried over anhydrous MgSO ₄ , and the solvent was distilled off. The residue was recrystallized from ethyl acetate and then methanol-chloroform to give 4- (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] -6,8-dimethylquinoline 1-oxide. Was obtained as pale yellow prism crystals. Yield 0.72g (63.2%). Mp230-23
2 ° C. Elemental analysis _{C 24 H 18 ClF 2 N 3} O 2 Calculated: C, 63.51; H, 4.00 ; N, 9.26 Found: C, 63.89; H, 3.91 ; N, 9.09 Example 64 3,4,5 Triethylamine (0.37 ml) was added dropwise to a mixture of -trimethoxybenzoic acid (563 mg), diphenylphosphoryl azide (730 mg) and dioxane (10 ml). This was further stirred at room temperature for 30 minutes and under reflux for 40 minutes to prepare a 3,4,5-trimethoxyphenylisocyanate solution. After cooling, 3-amino-4- (2-chlorophenyl) -6,
8-Dimethylquinoline (500 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, the residue was purified by silica gel chromatography, and recrystallized from dichloromethane.
-(2-chlorophenyl) -6,8-dimethyl-3- [3
-(3,4,5-Trimethoxyphenyl) ureido] quinoline was obtained as colorless needles. Yield 490mg (56.3%). Mp20
4-206 ° C. Elemental analysis C ₂₇ H ₂₆ ClN ₃ O ₄ Calculated: C, 65.92; H, 5.33 ; N, 8.54 Found: C, 65.81; H, 5.29 ; N, the following carried out in the same manner as 8.47 Example 64 The compounds of Examples 65 and 66 were obtained.

Example 65 3- [3- (3,5-Di-tert-butyl-4-hydroxyphenyl) ureido] -4- (2-chlorophenyl)-
6,8-Dimethylquinoline: mp 262-264 ° C (recrystallized from acetone). Yield 20.6%. Elemental analysis value Calculated as C ₃₂ H ₃₆ ClN ₃ O ₂ : C, 72.50; H, 6.84; N, 7.93 Actual value: C, 72.22; H, 6.83; N, 7.77 Example 66 3- [3- (3 , 5-Di-tert-butyl-4-hydroxyphenyl) ureido] -6-chloro-4-phenylquinoline: mp 277-280 ° C (recrystallized from acetone). Yield 13.2
%. Elemental analysis value Calculated as C ₃₀ H ₃₂ ClN ₃ O ₂ : C, 71.77; H, 6.42; N, 8.37 Actual value: C, 71.88; H, 6.39; N, 8.36 Example 67 In the same manner as Example 40. 3- [1- (3,5-di-tert-butyl-4-hydroxybenzyl) -3- (2,4-difluorophenyl) ureido] -4- (2-chlorophenyl) -6,8-dimethylquinoline Obtained. mp124-126 ° C (recrystallized from methanol). Yield 66.2%. Elemental analysis value Calculated as C ₃₉ H ₄₀ ClF ₂ N ₃ O ₂ : C, 71.38; H, 6.14; N, 6.40 Actual value: C, 71.27; H, 6.43; N, 6.30 Example 68 Same as Example 1 6-chloro-3- [3- (2,4-
Difluorophenyl) ureido] -4- (2,3,4-trimethoxyphenyl) quinoline was obtained. mp 120-122 ℃ (recrystallized from methanol). Yield 94.9%. Elemental analysis _{C 25 H 20 ClF 2 N 3} O 4 Calculated: C, 60.07; H, 4.03 ; N, 8.41 Found: C, 59.68; H, 4.05 ; N, similarly to 8.30 Example 69 Example 1 6-chloro-3- [3- (2,4-
Difluorophenyl) ureido] -4- (2-hydroxy-3,4-dimethoxyphenyl) quinoline (recrystallized from methanol) was obtained. mp218-220 ° C. Yield 82.0%. Elemental analysis _{C 24 H 18 ClF 2 N 3} O 4 Calculated: C, 59.33; H, 3.73 ; N, 8.65 Found: C, 59.53; H, 3.67 ; N, in the same manner as 8.50 Example 46 following The compounds of Examples 70 and 71 were obtained.

Example 70 4- (2-chlorophenyl) -6,8-dimethyl-3-
[3- (2,6-Dimethylphenyl) ureido] quinoline:
mp 237-238 ℃ (recrystallized from ethanol). Yield 56.5%. Elemental analysis C ₂₆ H ₂₄ ClN ₃ O Calculated: C, 72.63; H, 5.63 ; N, 9.77 Found: C, 72.85; H, 5.64 ; N, 9.78 Example 71 4- (2-chlorophenyl) - 3- [3- (2,6-diisopropylphenyl) ureido] -6,8-dimethylquinoline: mp257-258 ° C (recrystallized from ethanol). Yield 63.3
%. Elemental analysis value Calculated value as C ₃₀ H ₃₂ ClN ₃ O: C, 74.13; H, 6.64; N, 8.65 Measured value: C, 74.32; H, 6.64; N, 8.62 72-75 compounds were obtained.

Example 72 4- (2-chlorophenyl) -3- [3- (4-nitrophenyl) ureido] -6,8-dimethylquinoline: mp228
C (decomposition) (recrystallized from acetone-hexane). Yield 5
1.5%. Calculated elemental analysis _{C 24 H 19 ClN 4 O 3} : C, 64.50; H, 4.29; N, 12.54 Found: C, 64.29; H, 4.18 ; N, 12.27 Example 73 4- (2-chlorophenyl) -3- [3- (2,4-difluorophenyl) ureido] -6,7-dimethylquinoline:
mp 220-222 ° C (recrystallized from acetone). Yield 73.8%. Elemental analysis value Calculated as C ₂₄ H ₁₈ ClF ₂ N ₃ O: C, 65.83; H, 4.14; N, 9.60 Actual value: C, 65.65; H, 4.08; N, 9.52 Example 74 4- (2-chlorophenyl ) -3- [3- [2,4-Difluorophenyl) ureido] -6,7,8-trimethylquinoline: mp 197-199 ° C. (recrystallized from ether-hexane).
Yield 65.6%. Elemental analysis value Calculated as C ₂₅ H ₂₀ ClF ₂ N ₃ O: C, 66.45; H, 4.46; N, 9.30 Found: C, 66.41; H, 4.41; N, 9.27 Example 75 6-Chloro-3- [3- (2,4-difluorophenyl)
To a solution of ureido] -4- (3,4-dimethoxyphenyl) quinoline (250 mg) in dichloromethane (20 ml) was added 1.0 ml of a mixture of boron tribromide and dichloromethane 1: 2 (v / v).
Added at ° C. The mixture was further stirred at 0 ° C. for 30 minutes, diluted with water and extracted with ethyl acetate. The extract was washed with water and dried (anhydrous MgSO ₄ ) and the solvent was distilled off. By recrystallizing the residue from methanol, 6-chloro-3- [3- (2,4
-Difluorophenyl) ureido] -4- (3,4-dihydroxyphenyl) quinoline hemihydrate crystals were obtained (1
. 67mg, 70.8%) mp> 300 ℃ Elemental analysis _{C 22 H 14 ClF 2 N 3} O 3 · 1 / 2H 2 O Calculated: C, 58.61; H, 3.35 ; N, 9.32 Found: C, 58.48 H, 3.18; N, 9.21 Example 76 4-acetoxy-3,5-diisopropylbenzoic acid (238 m
g), diphenylphosphoryl azide (300 mg), benzene (10 ml) was added dropwise with stirring triethylamine (0.15 ml). This was further stirred at room temperature for 30 minutes and under reflux for 40 minutes to prepare a 4-acetoxy-3,5-diisopropylphenylisocyanate solution. After cooling, a solution of 3-amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (255 mg) in benzene (255 mg) and triethylamine (0.15 ml) were added, and the mixture was stirred at room temperature for 2 hours and under reflux for 3 hours. Stir it. Ethyl acetate was added, the organic layer was separated, washed successively with 2N-hydrochloric acid and water, and dried (anhydrous MgSO ₄ ).
After that, the solvent was distilled off. The residue was recrystallized from acetone-isopropyl ether to give 3- [3- (4-acetoxy-3,5-diisopropylphenyl) ureido].
-4- (2-Chlorophenyl) -6,8-dimethylquinoline was obtained as colorless needles. Yield 367 mg (74.9%). mp2
48-249 ° C Elemental analysis value Calculated as C ₃₂ H ₃₄ ClN ₃ O ₃ : C, 70.64; H, 6.30; N, 7.72 Actual value: C, 70.73; H, 6.57; N, 7.48 Same as Example 76 The following compounds of Examples 77 and 78 were obtained.

Example 77 3- [3- (4-acetoxy-3,5-dimethylphenyl) ureido] -4- (2-chlorophenyl) -6,8-
Dimethyl quinoline: mp179-181 ℃ (acetone - recrystallized from isopropyl ether) Yield 69.9% Elemental analysis C ₂₈ H ₂₆ ClN ₃ O ₃ Calculated: C, 68.92; H, 5.37 ; N, 8.61 Found: C , 68.90; H, 5.49; N, 8.48 Example 78 3- [3- (4-acetoxy-2,3,5-trimethylphenyl) ureido] -4- (2-chlorophenyl) -6,8
-Dimethylquinoline: mp222-224 ° C (recrystallized from acetone-isopropyl ether). Yield 61.1% Elemental analysis value C ₂₉ H ₂₈ ClN ₃ O ₃ Calculated value: C, 69.38; H, 5.62; N, 8.37 Measured value: C, 69.24; H, 5.62; N, 8.34 Example 79 3- [3 -(4-acetoxy-3,5-diisopropylphenyl) ureido] -4- (2-chlorophenyl) -6,
8-dimethylquinoline (300 mg), methanol (20 ml), 1
A mixture of N-sodium hydroxide (2 ml) was stirred at room temperature for 1.5 hours. After concentration, the mixture was diluted with water, acidified with 2N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (anhydrous MgSO ₄ ), the solvent was distilled off, and the residue was recrystallized from acetone-isopropyl ether to give 4- (2).
-Chlorophenyl) -3- [3- (4-hydroxy-3,
5-Diisopropylphenyl) ureido] -6,8-dimethylquinoline was obtained as colorless prism crystals. Yield 116 mg (4
1.9%). Mp94-196 ° C. Elemental analysis C ₃₀ H ₃₂ ClN ₃ O ₂ Calculated: C, 71.77; H, 6.42 ; N, 8.37 Found: C, 71.39; H, 6.22 ; N, in the same manner as 8.28 Example 79 The following compounds of Examples 80 and 81 were obtained.

Example 80 4- (2-chlorophenyl) -3- [3- (4-hydroxy-3,5-dimethylphenyl) ureido] -6,8-dimethylquinoline: mp 229-231 ° C (recrystallized from acetone-isopropyl ether ). Yield 54.8% Elemental analysis C ₂₆ H ₂₄ ClN ₃ O ₂ Calculated: C, 70.03; H, 5.42 ; N, 9.42 Found: C, 69.96; H, 5.60 ; N, 9.29 Example 81 4- ( 2-chlorophenyl) -3- [3- (4-hydroxy-2,3,5-trimethylphenyl) ureido] -6,8-
Dimethylquinoline: mp 244-245 ° C (recrystallized from acetone-isopropyl ether). 43.0% Elemental analysis yields C ₂₇ H ₂₆ ClN ₃ O ₂ Calculated: C, 70.50; H, 5.70 ; N, 9.14 Found: C, 70.51; H, 5.66 ; N, 9.14 Example 82 Example 75 And 6-chloro-3- [3- (2,4-
Difluorophenyl) ureido] -4- (2,3,4-trihydroxyphenyl) quinoline hemihydrate was obtained. mp
> 300 ° C. (recrystallized from acetone-isopropyl ether). Yield 83.0% Elemental analysis value Calculated as C ₂₂ H ₁₄ ClF ₂ N ₃ O ₄ 1 / 2H ₂ O: C, 56.60; H, 3.24; N, 9.00 Actual value: C, 56.90; H, 3.02; N , 8.71 Example 83 4- (2-chlorophenyl) -3 in the same manner as in Example 1.
-[3- (2,4-difluorophenyl) ureido] -5
-Methylquinoline was obtained. mp218-220 ° C (recrystallized from ethanol). 64.3% Elemental analysis yields _{C 23 H 16 ClF 2 N 3} O Calculated: C, 65.18; H, 3.80 ; N, 9.91 Found: C, 65.39; H, 3.72 ; N, 9.85 Reference Example 1 (1 ) 2-Amino-5-trifluoromethylbenzophenone (5.3 g) in acetone (100 ml) in 20% hydrochloric acid (40 m
l) and metazonic acid (5.0 g, wet) were added, and the mixture was left at room temperature overnight. After diluting with water, the precipitated yellow crystals were collected by filtration to obtain 6.4 g (95.2%) of 2- (2-nitrovinylamino) -5-trifluoromethylbenzophenone. A part of it was recrystallized from acetone to obtain yellow needle crystals showing mp 196-198 ° C.

Calculated elemental analysis _{C 16 H 11 F 3 N 2} O 3: C, 57.15; H, 3.30; N, 8.33 Found: C, 57.16; H, 3.27 ; N, 8.21 (2) 2- (2- Nitrovinylamino) -5-trifluoromethylbenzophenone (6.0g) and methanol (60m
2N-NaOH (9.0 ml) was added dropwise to the mixture of (1) with stirring. After stirring at room temperature for 30 minutes, dilute with water,
3-Nitro-4-phenyl-6-trifluoromethylquinoline was obtained as crystals (4.88 g, 84.5%). Recrystallized from chloroform-methanol to give pale yellow needles (4.50g, 79.2g).
%) Was obtained.

mp192-193 ° C. Elemental analysis _{C 16 H 9 F 3 N 2} O 2 Calculated: C, 60.38; H, 2.85 ; N, 8.80 Found: C, 60.16; H, 2.82 ; N, 8.68 (3) 3- nitro-4 -Phenyl-6-trifluoromethylquinoline (2.0 g), stannous chloride dihydrate (5.0
A mixture of g) and concentrated hydrochloric acid (20 ml) was stirred at 100 ° C. for 1 hour. After neutralizing with 6N-NaOH, extract with chloroform,
The chloroform layer was washed with water and dried over anhydrous MgSO ₄ . The solvent was distilled off and the residue was recrystallized from isopropyl ether-hexane to give 3-amino-4-phenyl-6-trifluoromethylquinoline (1.46 g, 80.7%). mp
107-108 ° C. Elemental analysis value Calculated value as C ₁₆ H ₁₁ F ₃ N ₂ : C, 66.66; H, 3.85; N, 9.72 Actual value: C, 66.67; H, 3.79; N, 9.49 Seventeen compounds were prepared.

Reference Example 2 (1) 5-Ethyl-2- (2-nitrovinylamino) benzophenone: Not isolated.

(2) 6-Ethyl-3-nitro-4-phenylquinoline: mp139-140 ° C. (3) 3-Amino-6-ethyl-4-phenylquinoline: mp206-209 ° C. Reference Example 3 (1) 5-Isopropyl-2- (2-nitrovinylamino) benzophenone: mp166-167 ° C. (2) 6-isopropyl-3-nitro-4-phenylquinoline: mp115-116 ° C. (3) 3-amino-6-isopropyl-4-phenylquinoline: mp128-129 ° C. Reference Example 4 (1) 4-Methyl-2- (2-nitrovinylamino) benzophenone: mp163-164 ° C. (2) 7-methyl-3-nitro-4-phenylquinoline: mp176-177 ° C. (3) 3-Amino-7-methyl-4-phenylquinoline: mp167-168 ° C. Reference Example 5 (1) 2'-chloro-2- (2-nitrovinylamino)
Benzophenone: mp140-144 ° C. (2) 4- (2-chlorophenyl) -3-nitroquinoline: mp124-125 ° C. (3) 3-amino-4- (2-chlorophenyl) quinoline: mp155-156 ° C. Reference Example 6 (1) 5-chloro-2'-fluoro-2- (2-nitrovinylamino) benzophenone: mp219-221 ° C. (2) 6-chloro-4- (2-fluorophenyl) -3
-Nitroquinoline: mp150-151 ° C. (3) 3-Amino-6-chloro-4- (2-fluorophenyl) quinoline: mp 150-151 ° C. Reference Example 7 (1) 5,3′-dichloro-2- (2-nitrovinylamino) benzophenone: mp 195-197 ° C. (2) 6-chloro-4- (3-chlorophenyl) -3-
Nitroquinoline: mp135-136 ° C. (3) 3-Amino-6-chloro-4- (3-chlorophenyl) quinoline: mp 154-155 ° C. Reference Example 8 (1) 5,4′-dichloro-2- (2-nitrovinylamino) benzophenone: mp218-220 ° C. (2) 6-chloro-4- (4-chlorophenyl) -3-
Nitroquinoline: mp148-149 ° C. (3) 3-Amino-6-chloro-4- (4-chlorophenyl) quinoline: mp 190-191 ° C. Reference Example 9 (1) 5-chloro-4′-methyl-2- (2-nitrovinylamino) benzophenone: mp227-228 ° C. (2) 6-chloro-4- (4-methylphenyl) -3-
Nitroquinoline: mp127-128 ° C. (3) 3-Amino-6-chloro-4- (4-methylphenyl) quinoline: mp 144-145 ° C. Reference Example 10 (1) 5-chloro-2′-methyl-2- (2-nitrovinylamino) benzophenone: mp184-186 ° C. (2) 6-chloro-4- (2-methylphenyl) -3-
Nitroquinoline: mp176-177 ° C. (3) 3-amino-6-chloro-4- (2-methylphenyl) quinoline: mp 132-133 ° C. Reference Example 11 (1) 5-chloro-2′-methoxy-2- (2-nitrovinylamino) benzophenone: mp217-218 ° C. (2) 6-chloro-4- (2-methoxyphenyl) -3
-Nitroquinoline: mp213-214 ° C. (3) 3-Amino-6-chloro-4- (2-methoxyphenyl) quinoline: mp 137-138 ° C. Reference Example 12 (1) 2'-chloro-5-methyl-2- (2-nitrovinylamino) benzophenone: mp136-137 ° C. (2) 4- (2-chlorophenyl) -6-methyl-3-
Nitroquinoline: mp168-169 ° C. (3) 3-amino-4- (2-chlorophenyl) -6-
Methylquinoline: mp121-123 ° C. Reference Example 13 (1) 5,2'-Dimethyl-2- (2-nitrovinylamino) benzophenone: mp 148-149 ° C. (2) 6-methyl-4- (2-methylphenyl) -3-
Nitroquinoline: mp112-113 ° C. (3) 3-Amino-6-methyl-4- (2-methylphenyl) quinoline: oil. Reference Example 14 (1) 2'-chloro-5-ethyl-2- (2-nitrovinylamino) benzophenone: mp 180-181 ° C. (2) 4- (2-chlorophenyl) -6-ethyl-3-
Nitroquinoline: mp 151-152 ° C. (3) 3-amino-4- (2-chlorophenyl) -6-
Ethylquinoline: mp 91-92 ° C. Reference Example 15 (1) 2'-chloro-5-isopropyl-2- (2-nitrovinylamino) benzophenone: mp 166-167 ° C. (2) 4- (2-chlorophenyl) -6-isopropyl-3-nitroquinoline: mp116-117 ° C. (3) 3-amino-4- (2-chlorophenyl) -6-
Isopropylquinoline: mp101-102 ° C. Reference Example 16 (1) 5-Butyl-2'-chloro-2- (2-nitrovinylamino) benzophenone: mp143-144 ° C. (2) 6-butyl-4- (2-chlorophenyl) -3-
Nitroquinoline: mp96-97 ° C. (3) 3-Amino-6-butyl-4- (2-chlorophenyl) quinoline: oil. Reference Example 17 (1) 2'-chloro-5-fluoro-2- (2-nitrovinylamino) benzophenone: mp 118-119 ° C. (2) 4- (2-chlorophenyl) -6-fluoro-3
-Nitroquinoline: mp185-186 ° C. (3) 3-amino-4- (2-chlorophenyl) -6-
Fluoroquinoline: mp131-133 ° C. Reference Example 18 (1) 2-Amino-2′-chloro-3,5-dimethylbenzophenone (1 g), acetone (50 ml), 20% hydrochloric acid (20 m
The mixture of l) and methasonic acid (4.5 g, wet) was stirred at room temperature for 2 hours and then heated under reflux for 4 hours. After diluting with water and extracting with chloroform, the organic layer was washed with water and dried (anhydrous MgSO ₄ ). The solvent was distilled off, and the residue was purified by silica gel chromatography to give 4- (2-chlorophenyl) -6,8-
Dimethyl-3-nitroquinoline was obtained as crystals. Recrystallized from methanol-chloroform. mp130-131 ° C. yield
1.95g (54.2%). (2) 4- (2-chlorophenyl) -6,8-dimethyl-
3-Amino-4- (2-chlorophenyl) was obtained by reducing 3-nitroquinoline in the same manner as in Reference Example 1- (3).
-6,8-Dimethylquinoline was obtained. mp152-154 ° C. Yield 8
0.1%. Reference Example 19 In the same manner as in Reference Example 18, the following compound was obtained.

(1) 6-chloro-4- (2-chlorophenyl) -8-
Methyl-3-nitroquinoline: mp138-139 ° C. (2) 3-Amino-6-chloro-4- (2-chlorophenyl) -8-methylquinoline: mp 138-139 ° C. Reference Example 20 The following compound was obtained in the same manner as in Reference Example 18.

(1) 6,8-Dimethyl-4- (2-methylphenyl)-
3-nitroquinoline: mp101-102 ° C. (2) 3-Amino-6,8-dimethyl-4- (2-methylphenyl) quinoline hydrochloride: mp204-206 ° C. Reference Example 21 (1) A mixture of 6-methoxy-3-nitro-4-phenylquinoline (3.50 g) and 47% hydrobromic acid (50 ml) was heated under reflux for 7 hours. The crystals precipitated after cooling were collected by filtration and recrystallized from acetone to obtain 6-hydroxy-3-nitro-4-phenylquinoline as yellow needle crystals.

Yield 3.01g (90.7%). Mp 282-284 ° C. Calculated elemental analysis _{C 15 H 10 N 2 O 3} : C, 67.67; H, 3.79; N, 10.52 Found: C, 67.68; H, 3.79 ; N, 10.42 (2) 6- hydroxy-3-nitro N, N-dimethylthiocarbamoyl chloride (1.28) was added to a solution of 4-phenylquinoline (2.50 g) in N, N-dimethylformamide (30 ml).
g) and 1,4-diazabicyclo [2,2,2] octane (1.05
g) was added, and the mixture was stirred overnight at room temperature. By pouring the mixture into ice water and filtering the precipitate and recrystallizing from acetone, 6-
(N, N-Dimethylthiocarbamoyloxy) -3-nitro-4-phenylquinoline was obtained as yellow prism crystals. Yield 1.70g (51.2%). Mp 205-208 ° C. Elemental analysis _{C 18 H 15 N 3 O 3} S Calculated: C, 61.18; H, 4.28 ; N, 11.89 Found: C, 61.40; H, 4.28 ; N, 11.74 (3) 6- (N, N -Dimethylthiocarbamoyloxy)
215-2 with -3-nitro-4-phenylquinoline (1.50 g)
Heated at 20 ° C. for 3 hours. After cooling, it was recrystallized from acetone to give 6- (N, N-dimethylcarbamoylthio) -3.
-Nitro-4-phenylquinoline was obtained as pale yellow needles. Yield 1.30g (86.7%). Mp 171-173 ° C. Elemental analysis _{C 18 H 15 N 3 O 3} S Calculated: C, 61.18; H, 4.28 ; N, 11.89 Found: C, 61.40; H, 4.28 ; N, 11.74 (4) 6- (N, N -Dimethylcarbamoylthio) -3-
2N-NaOH (50 ml) and methanol (20 ml) in a solution of nitro-4-phenylquinoline (2.50 g) in dioxane (100 ml).
ml) was added and the mixture was stirred at room temperature for 7 hours. After diluting with water, acidify with hydrochloric acid and filter the precipitated crystals. By recrystallizing from acetone, 6-mercapto-3-nitro-4-phenylquinoline was obtained as yellow needle crystals. Yield 1.68g (84.0
%). Mp 160-163 ° C. Elemental analysis value Calculated as C ₁₅ H ₁₀ N ₂ O ₂ S: C, 63.82; H, 3.57; N, 9.92 Actual value: C, 63.80; H, 3.49; N, 9.68 (5) 6-mercapto-3- Nitro-4-phenylquinoline (1.55 g) in dioxane (30 ml) in potassium carbonate (1.14 g) in water (10 ml) and methyl iodide (1.1 ml).
7g) was added, and the mixture was stirred at room temperature for 2.5 hours. After diluting with water, acidify with hydrochloric acid and collect crystals by filtration. Recrystallization from acetone gave 6-methylthio-3-nitro-4-phenylquinoline as yellow needle crystals. Yield 1.39g (85.3%).
mp131-133 ° C. Elemental analysis value Calculated as C ₁₆ H ₁₂ N ₂ O ₂ S: C, 64.85; H, 4.08; N, 9.45 Actual value: C, 64.77; H, 4.07; N, 9.42 (5) 6-methylthio-3- Nitro-4-phenylquinoline (1.20 g) was reduced in the same manner as in Reference Example 1- (3) to obtain 3-amino-6-methylthio-4-phenylquinoline as colorless rod-shaped crystals. Yield 0.77g (71.3%). Mp135-13
7 ° C. Elemental analysis value Calculated value as C ₁₆ H ₁₄ N ₂ S: C, 72.15; H, 5.30; N, 10.52 Actual value: C, 72.00; H, 5.31; N, 10.52 Reference example 22 (1) 3-acetamido-6 To a solution of -chloro-4-phenylquinoline (1 g) in N, N-dimethylformamide (10 ml) was added 60% oily sodium hydride (0.15 g), and the mixture was stirred at room temperature for 30 minutes, and then methyl iodide (0.25 ml)
Was added dropwise, and the mixture was further stirred at room temperature for 1 hr. Dilute with water and collect the precipitated crystals by filtration. By recrystallizing from methanol-chloroform, 6-chloro-3- (N-methylacetamido) -4-phenylquinoline was obtained as colorless crystals. Yield 0.96g (91.4%). Mp 268-270 ° C. Elemental analysis C ₁₈ H ₁₅ ClN ₂ O Calculated: C, 69.57; H, 4.86 ; N, 9.01 Found: C, 69.52; H, 4.85 ; N, 8.89 (2) 6- chloro-3-(N -Methylacetamide)-
4-phenylquinoline (0.9 g), methanol (5 ml),
A mixture of concentrated hydrochloric acid (5 ml) was refluxed for 5 hours. The mixture was diluted with water, neutralized with an aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. 6-chloro-by recrystallization from methanol
3-Methylamino-4-phenylquinoline was obtained as pale yellow crystals. Yield 0.65g (83.5%). Mp 139-140 ° C. Elemental analysis value Calculated value as C ₁₆ H ₁₃ ClN ₂ : C, 71.51; H, 4.88; N, 10.42 Actual value: C, 71.71; H, 4.87; N, 10.45 ~ 26 compounds were obtained.

Reference Example 23 (1) 6-chloro-3- (N-ethylacetamide)-
4-phenylquinoline: mp227-228 ° C. (2) 6-chloro-3-ethylamino-4-phenylquinoline: mp 106-107 ° C. Reference Example 24 (1) 3- (N-butylacetamide) -6-chloro-
4-phenylquinoline: mp108-110 ° C. (2) 3-Butylamino-6-chloro-4-phenylquinoline: mp 71-73 ° C. Reference Example 25 (1) 6-chloro-3- (N-heptylacetamide)
-4-Phenylquinoline: oil (2) 6-chloro-3-heptylamino-4-phenylquinoline: mp62-63 ° C. Reference Example 26 (1) 3- (N-benzylacetamido) -6-chloro-4-phenylquinoline: mp 57-61 ° C. (2) 3-benzylamino-6-chloro-4-phenylquinoline: mp 140-141 ° C. Reference Example 27 The following compound was obtained in the same manner as in Reference Example 1.

(1) 5-chloro-2- (2-nitrovinylamino)-
2'-methylthiobenzophenone: mp188-190 ° C. (2) 6-chloro-4- (2-methylthiophenyl)-
3-nitroquinoline: mp 180-182 ° C. (3) 3-Amino-6-chloro-4- (2-methylthiophenyl) quinoline: mp 153-155 ° C. Reference Example 28 6-mercapto-3-nitro-4-phenylquinoline (1.00 g) was dissolved in a mixture of 2N-NaOH (20 ml) and dioxane (20 ml), and chlorodifluoromethane gas was conducted at 75-80 ° C for 2 hours. did. It was diluted with water and extracted with chloroform. The chloroform layer was washed with 2N-NaOH aqueous solution and water and then anhydrous M
It was dried over gSO ₄ and the solvent was distilled off. By recrystallizing the residue from isopropyl ether, 6-difluoromethylthio-3-nitro-4-phenylquinoline was obtained as yellow prism crystals. Yield 948mg (80.5%). Mp101-103
° C. Elemental analysis value Calculated as C ₁₆ H ₁₀ F ₂ N ₂ O ₂ S: C, 57.83; H, 3.03; N, 8.43 Actual value: C, 57.92; H, 3.13; N, 8.37 (2) Obtained above 6-Difluoromethylthio-3-nitro-4-phenylquinoline was reduced in the same manner as in Reference Example 1- (3) to give 3-amino-6-difluoromethylthio-4-phenylquinoline as an oil.
This product was used as a raw material without purification.

Reference Example 29 (1) 6-Hydroxy-3-nitrophenylquinoline (1.00 g) was dissolved in a mixture of 2N-NaOH (20 ml) and dioxane (20 ml), and chlorodifluoromethane gas was conducted at 75-80 ° C for 8 hours. did. By treating this in the same manner as in Reference Example 28- (1), 6-difluoromethoxy-3-nitro-4-phenylquinoline was obtained as light brown prism crystals. Yield 794mg, 66.8% .mp 112-114 ° C. Calculated elemental analysis _{C 16 H 10 F 2 N 2} O 3: C, 60.76; H, 3.19; N, 8.86 Found: C, 61.04; H, 3.24 ; N, was obtained in 8.80 (2) above 6 -Difluoromethoxy-3-nitro-4-phenylquinoline was reduced in the same manner as in Reference Example 1- (3) to obtain 3-amino-6-difluoromethoxy-4-phenylquinoline as an oil. This product was used as a raw material without purification.

Reference Example 30 In the same manner as in Reference Example 18, the following compound was obtained.

(1) 8-chloro-4- (2-chlorophenyl) -6-
Methyl-3-nitroquinoline: mp152-154 ° C. (2) 3-Amino-8-chloro-4- (2-chlorophenyl) -6-methylquinoline: mp 148-149 ° C. Reference Example 31 The following compound was obtained as in Reference Example 22.

(1) 3- (N-butylacetamide) -6-chloro-
4- (2-chlorophenyl) quinoline: mp 108-109 ° C. (2) 3-Butylamino-6-chloro-4- (2-chlorophenyl) quinoline: mp 90-91 ° C. Reference Example 32 (1) Diethyl (2-benzoyl-4-chlorophenyl) aminomethylenemalonate (7.0 g), lithium chloride (3.
A mixture of 7g) and dimethyl sulfoxide (70ml) at 180 ℃
Heated at 1.5 hours. It was diluted with water to obtain ethyl 6-chloro-4-phenyl-3-quinolinecarboxylate as crystals (3.8 g, 70.0%). Recrystallization from ethanol gave needle crystals. mp123-124 ° C. Elemental analysis C ₁₈ H ₁₄ ClNO ₂ Calculated: C, 69.35; H, 4.53 ; N, 4.49 Found: C, 69.32; H, 4.48 ; N, 4.31 (2) 6- chloro-4- phenyl-3 A mixture of ethyl quinolinecarboxylate (2.5 g), potassium hydroxide (2.24 g) and ethanol (25 ml) was heated at 80 ° C for 10 minutes. 6-chloro-4 by diluting with water and acidifying with hydrochloric acid
-Phenyl-3-quinolinecarboxylic acid was obtained as crystals (2.20 g, 96.9%). Recrystallization from methanol-chloroform gave pale yellow prism crystals. mp269-270 ° C. Elemental analysis C ₁₆ H ₁₀ ClNO ₂ Calculated: C, 67.74; H, 3.55 ; N, 4.94 Found: C, 67.77; H, 3.52 ; N, 4.94 Reference Example 33 (1) 2-amino-2 ' -Chloro-3,5-dimethylbenzophenone (2.59g), methyl 3,3-dimethoxypropionate (3.7g), p-toluenesulfonic acid hydrate (0.19g)
A mixture of g) and benzene (30 ml) was heated under reflux for 16 hours while decomposing water using a Dean-Stark apparatus. The solvent was distilled off, and the residue was purified by silica gel chromatography to give 4- (2-chlorophenyl) -6,8-dimethyl-3.
-Methyl quinolinecarboxylate was obtained as crystals (1.90 g,
58.5%). Recrystallization from isopropyl ether gave colorless prism crystals. mp117-118 ° C. Elemental analysis C ₁₉ H ₁₆ ClNO ₂ Calculated: C, 70.50; H, 4.95 ; N, 4.30 Found: C, 70.14; H, 4.97 ; N, 4.27 (2) 4- (2- chlorophenyl) -6 , 8-dimethyl-
A mixture of methyl 3-quinolinecarboxylate (0.98 g), potassium hydroxide (0.5 g) and 80% ethanol (10 ml) was heated under reflux for 15 minutes. 4 by adding water and acidifying with hydrochloric acid
-(2-Chlorophenyl) -6,8-dimethyl-3-quinolinecarboxylic acid was obtained as crystals (0.90 g, 96.8%). Recrystallization from ethanol gave colorless prism crystals. mp234-23
5 ° C. Elemental analysis C ₁₈ H ₁₄ ClNO ₂ Calculated: C, 69.35; H, 4.53 ; N, 4.49 Found: C, 69.10; H, 4.53 ; N, 4.41 Reference Example 34 2-Amino-2'-chloro - 3,5-Dimethylbenzophenone (15.54g), 6N hydrochloric acid (60ml), ethyl acetate (180ml)
1-morpholino-2-nitroethene (9.48
g) was added, and the mixture was stirred at 60 to 70 ° C. After 2 hours and 4 hours, 9.48 g of 1-morpholino-2-nitroethene was added, and the mixture was further stirred for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and water, and dried (anhydrous MgSO ₄ ). Evaporate the solvent,
By recrystallizing the residue from ethanol, 4-
(2-Chlorophenyl) -6,8-dimethyl-3-nitroquinoline was obtained as yellow crystals (15.75g, 84.1%). mp1
31-132 ° C. This product is the same as that obtained in Reference Example 18- (1).

Reference Example 35 (1) In the same manner as in Reference Example 34, 6-chloro-4- (3,4-
Dimethoxyphenyl) -3-nitroquinoline was obtained. mp
188-190 ° C. Yield 83.5%. (2) 6-chloro-4- (3,4-dimethoxyphenyl)
-3-Nitroquinoline was reduced in the same manner as in Reference Example 1- (2) to give 3-amino-6-chloro-4- (3,4-dimethoxyphenyl) quinoline. mp187-190 ° C. Yield 92.9
%. The compounds of the following Reference Examples 36 to 37 were obtained in the same manner as in Reference Example 35.

Reference Example 36 (1) 4- (2-chlorophenyl) -6,7-dimethyl-
3-Nitroquinoline: mp156-157 ° C. Yield 50.9%. (2) 3-amino-4- (2-chlorophenyl) -6,7
-Dimethylquinoline: mp 194-195 ° C. Yield 68.9%. Reference Example 37 (1) 4- (2-chlorophenyl) -6,7,8-trimethyl-3-nitroquinoline: mp 190-191 ° C. Yield 53.3%. (2) 3-amino-4- (2-chlorophenyl) -6,7,
8-Trimethylquinoline: mp116-118 ° C. Yield 79.8%. Reference Example 38 2,6-di-tert-butyl-4-methylphenol (2.34
g), N-bromosuccinimide (1.88 g) and carbon tetrachloride (25 ml) were heated under reflux for 2 hours, and the insoluble precipitate was removed by filtration to give 4-bromomethyl-2,6-di-ter.
A solution of t-butylphenol was obtained. 3-Amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (2.0 g) was added thereto, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with chloroform, washed with water, dried (anhydrous MgSO ₄ ), and the solvent was evaporated. The residue was purified by silica gel chromatography and then acetone-
By recrystallizing from isopropyl ether, 4-
(2-Chlorophenyl) -3- (2,6-di-tert-butyl-4-hydroxyphenyl) amino-6,8-dimethylquinoline was obtained as colorless prism crystals (1.59g, 44.9).
%). mp183-185 ° C. Elemental analysis value Calculated as C ₃₂ H ₃₇ ClNO ₂ : C, 76.70; H, 7.44; N, 5.59 Actual value: C, 76.70; H, 7.53; N, 5.52 Reference Example 39 (1) 2-amino-2 ′ -Chloro-3,5-dimethylbenzophenone (20.0g), 2,2-dimethoxypropionitrile (11.5g), p-toluenesulfonic acid hydrate (1.46g),
A mixture of toluene (200 ml) was heated under reflux for 3 hours while separating water using a Dean-Stark apparatus. The extract was washed with aqueous sodium hydrogen carbonate solution and water, dried over anhydrous MgSO ₄ , and the solvent was evaporated. The residual crystals were collected by filtration and washed with hexane to give 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarbonitrile (20.7 g, 92.0%). Recrystallization from ethanol gave pale yellow plate crystals. mp153-154 ° C. Elemental analysis C ₁₈ H ₁₃ ClN ₂ Calculated: C, 73.85; H, 4.48 ; N, 9.57 Found: C, 73.66; H, 4.42 ; N, 9.54 (2) 4- (2- chlorophenyl) -6 , 8-dimethyl-
A mixture of 3-quinolinecarbonitrile (0.5 g), 6N-sodium hydroxide (1.5 ml) and 2-methoxyethanol (3 ml) was stirred and heated under reflux for 8 hours. 4- (2-Chlorophenyl) -6,8-dimethyl-3-quinolinecarboxylic acid was obtained by filtering the precipitated crystals by adding water to acidify the hydrochloric acid (0.46 g, 86.8%). Recrystallization from ethanol gave colorless prism crystals. mp234-235 ° C. This product is Reference Example 33
Is the same as that obtained in.

Reference Example 40 (1) 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarbonitrile (1 obtained in Reference Example 39- (1)
A mixture of 7.6 g) and 97% sulfuric acid (120 ml) was stirred at room temperature for 24 hours. The mixture was added to ice water, made alkaline with aqueous ammonia, and extracted with ethyl acetate. The extract was washed with water and anhydrous MgSO ₄
After drying with, the solvent was distilled off, and methanol was added to the residue to obtain 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarboxamide / methanol sorbate as crystals (18.5 g, 90.2%). ). Recrystallization from methanol gave colorless prism crystals. mp163-164 ° C. Elemental analysis value Calculated as C ₁₈ H ₁₅ ClN ₂ O ・ CH ₄ O: C, 66.57; H, 5.59; N, 8.17 Found: C, 66.75; H, 5.52; N, 8.19 (2) Sodium hydroxide ( Bromine (3.2 ml) was added dropwise to a solution of 10.4 g) in water (100 ml) with stirring under ice cooling. Then 4- (2-chlorophenyl) -6,8-dimethyl-3-
Quinolinecarboxamide / methanol sorbate (18.5
g) in dioxane (100 ml) was added dropwise at room temperature for 30 minutes, 9
Stir for 40 minutes at 0 ° C. The pH was adjusted to 1 with 6N-hydrochloric acid, the mixture was stirred at room temperature for 30 minutes, a small amount of red precipitate was removed by filtration, and the filtrate was made alkaline with 6N-sodium hydroxide. After further diluting with water and extracting with ethyl acetate, the extract was washed with water and anhydrous MgSO 4.
After drying at ₄ , the solvent was distilled off. Hexane was added to the residue for crystallization to give 3-amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (14.0 g, 9
1.7%). Recrystallization from ethanol gave colorless prism crystals. mp151-152 ° C. This product is the same as that obtained in Reference Example 18.

Reference Example 41 (1) 5-chloro-2-tosylaminobenzoic acid (14.0
A mixture of g), thionyl chloride (30 ml) and N, N-dimethylformamide (0.5 ml) was heated under reflux for 40 minutes and then concentrated to dryness under reduced pressure. The residue was dissolved in 1,2-dichloroethane (100 ml), anhydrous aluminum chloride (6.88 g) was added, and the mixture was stirred at room temperature for 10 min and then 1,2,3-trimethoxybenzene (8.6
7g) was added. The mixture was stirred at room temperature for 10 minutes and heated under reflux for 45 minutes. After cooling, 2N hydrochloric acid was added, and the mixture was stirred at room temperature for 30 min, the organic layer was separated, and extracted with a dilute aqueous sodium hydroxide solution. The alkaline layer was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and dried (anhydrous MgSO ₄ ).
The solvent was distilled off. By recrystallizing the residue from acetone, 2-tosylamino-5-chloro-2'-hydroxy-3 ', 4'-dimethoxybenzophenone was obtained as prism crystals (5.89 g, 29.6%). mp185-187 ° C. Elemental analysis C ₂₂ H ₂₀ ClNO ₆ S Calculated: C, 57.21; H, 4.36 ; N, 3.03 Found: C, 57.16; H, 4.24 ; N, 3.17 (2) 2- tosylamino-5-chloro - 2'-hydroxy-3 ', 4'-dimethoxybenzophenone (5.89g) and 7
A mixture with 0% sulfuric acid (50 ml) was heated at 90 ° C. for 1 hour, diluted with water, and extracted with chloroform. The chloroform layer was washed with water, dried (anhydrous MgSO ₄ ), concentrated, and the residue was purified by silica gel chromatography. By recrystallizing from ether-hexane, 2-amino-5-chloro-2′-hydroxy-3 ′, 4′-dimethoxybenzophenone was obtained as colorless prism crystals (3.01 g, 76.8%).

mp112-115 ° C. Elemental analysis C ₁₅ H ₁₄ ClNO ₄ Calculated: C, 58.55; H, 4.59 ; N, 4.55 Found: C, 58.65; H, 4.61 ; N, 2- amino obtained in 4.51 Reference Example 42 Reference Example 41 Reference example from -5-chloro-2'-hydroxy-3 ', 4'-dimethoxybenzophenone
The following compound was obtained in the same manner as in 35.

(1) 6-chloro-4- (2-hydroxy-3,4-dimethoxyphenyl) -3-nitroquinoline: mp156-158 ° C.
Yield 91.8%. (2) 3-Amino-6-chloro-4- (2-hydroxy-3,4-dimethoxyphenyl) quinoline: mp 198-201 ° C.
Yield 60.5%. Reference Example 43 (1) 6-chloro-4- (2-hydroxy-3,4-dimethoxyphenyl) -3-nitroquinoline (1.20 g), N, N
A mixture of dimethylformamide (20 ml), powdered potassium carbonate (0.92 g) and methyl iodide (0.41 ml) at 0 ° C.
Stir for 0 minutes at room temperature for 2 hours. It was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried (anhydrous MgSO ₄ ).
The solvent was evaporated, and the residue was recrystallized from methanol to give 6-chloro-4- (2,3,4-trimethoxyphenyl) -3-nitroquinoline as yellow prism crystals (1.12 g, 89.6%).

mp114-116 ° C. (2) 6-Chloro-4- (2,3,4-trimethoxyphenyl) -3-nitroquinoline was reduced in the same manner as in Reference Example 1- (2) to give 3-amino-6-chloro-4- ( 2,3,4-trimethoxyphenyl) quinoline was obtained. mp180-181 ℃. Yield 95.9%. Reference Example 44 In the same manner as in Reference Example 35, the following compound was obtained.

(1) 4- (2-chlorophenyl) -5-methyl-3-
Nitroquinoline: mp147-148 ° C. Yield 69.8%. (2) 3-amino-4- (2-chlorophenyl) -5-
Methylquinoline: mp152-153 ° C. Yield 97.8%. Effect of the Invention Since the quinoline derivative (I) or a salt thereof has an excellent ACAT inhibitory action and high safety, the present invention provides a novel arteriosclerotic agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 31/47 AED 9454-4C C07D 215/60 C12N 9/99

Claims (4)

[Claims] 1. A general formula [In the formula, R represents hydrogen, C _1-8 alkyl or C _7-9 aralkyl group, m and n represent 0 or 1, and ring A, ring B and ring C each may have a substituent. Good. ] An acyl-CoA: cholesterol acyltransferase inhibitor comprising a quinoline derivative represented by the above or a salt thereof. 2. General formula [In the formula, R represents hydrogen, C _1-8 alkyl or C _7-9 aralkyl group, m and n represent 0 or 1, and when m = 1, ring A,
Rings B and C may each have a substituent, m
When = 0, ring A and ring C may each have a substituent, and ring B is substituted, or when ring B is unsubstituted, ring C is substituted with fluorine. Substituents on ring A, ring B and ring C are each halogen, optionally halogenated lower alkyl group, optionally halogenated lower alkoxy group, optionally halogenated lower alkylthio group, nitro group , Optionally esterified carboxyl group, hydroxyl group, C _1-4 acyloxy group and
It is selected from C _1-3 acyl groups. ] The quinoline derivative or its salt represented by these. 3. General formula Or a salt thereof and a general formula A compound represented by the following formula or a salt thereof: A method for producing a quinoline derivative represented by or a salt thereof [wherein Q ¹ is , Q ² is -NCO, Q ¹ is -NCO or In this case, Q ² represents —NH ₂ , R ¹ represents a C _1-8 alkyl or C _7-9 aralkyl group, X represents a halogen, and other symbols have the same meanings as in claim (2). 4. A general formula [In the formula, each symbol has the meaning described in claim (1). ] The compound represented by the general formula characterized by oxidizing [In the formula, each symbol has the same meaning as described above. ] The manufacturing method of the compound represented by these.