JPH09176165A - Imidazo [1,2-a] pyridine derivative, process for producing the same and use thereof - Google Patents

Abstract

(57) [Summary] [Solution] General formula (I); [Wherein R ¹ and R ² are H, halogen, C _1-10 alkyl,
C _1-8 alkoxy, C _1-8 monoalkylamino, C _2-12 dialkylamino, C _1-8 haloalkyl, C _1-8 alkylthio, or R ¹ and R ² are bonded to each other to represent C _3-5 alkylene. , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are H, halogen, C
_1-10 alkyl, C _1-8 alkoxy, C _1-8 monoalkylamino, C _2-12 dialkylamino, C _1-8 haloalkyl, C
_1-8 represents alkylthio, A is -CH = CH-CH = CH- or-(CH
_{2) 4} - indicates, B is ^{_{-NH-, -CH 2 -N (R 8}} ) - (R 8 is H, C
_1-10 alkyl, C _7-10 aralkyl) is shown. ] The imidazo [1,2-a] pyridine derivative represented by these, its salt, its manufacturing method, and the ACAT inhibitor which uses this compound as an active ingredient. [Effect] The compound of the present invention has an ACAT inhibitory action, and is effective for hypercholesterolemia, atherosclerosis,
It is useful as a preventive or therapeutic agent for each disease caused by these.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an excellent acyl CoA: cholesterol O-acyltransferase (ACA).
T) An imidazo [1,2-a] pyridine derivative having an inhibitory action or a pharmacologically acceptable salt thereof, a method for producing the compound, and an ACAT inhibitor containing the compound as an active ingredient.

The compound of the present invention inhibits the absorption of cholesterol from the intestinal tract, exhibits a serum cholesterol lowering action, and suppresses the accumulation of cholesteryl ester in the arterial wall, and therefore, hypercholesterolemia and atherosclerosis. Also, it is useful as a preventive or therapeutic drug for diseases caused by these, for example, ischemic heart disease such as myocardial infarction and cerebrovascular disorder such as cerebral infarction and stroke.

[0003]

2. Description of the Related Art British Patent No. 1076089 discloses a compound such as N-((2-methylimidazo [1,2-a] pyridin-3-yl) methyl) urea as an analgesic and antipyretic agent in Journal Med.
icinal Chemistry 1987, 30, 2031-20
46 and Molcular Pharmacology
In 1990, 37 (6), 958-65, compounds such as N- (7-benzyloxy-2-methylimidazo [1,2-a] pyridin-3-yl) -N'-methylurea were used as antiulcer agents. , Tokuhei 7-10
1958 discloses N- (imidazo [1,2-a] pyridine-3-
Ile) urea is described as a partial structure of a cephem antibacterial agent, but nothing is described about its ACAT inhibitory action and serum cholesterol lowering action. Further, Japanese Patent Publication No. 3-120243 discloses imidazo [1,2-a] pyridine derivatives having an ACAT inhibitory effect, but their effects are not sufficient.

[0004]

The present invention provides a novel imidazo [1,2-a] pyridine derivative or a pharmacologically acceptable salt thereof, a method for producing the compound, and an ACAT inhibitor containing the compound as an active ingredient. Is provided.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have proposed a novel compound of general formula (I), which has not been described in the literature;

Embedded image [In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, C _1-8 haloalkyl group, C _1-8 alkylthio group, or R ¹ and R ² are bonded to each other to represent a C _3-5 alkylene group, and R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group, C _1-8 A haloalkyl group or a C _1-8 alkylthio group is shown, and A is -CH = CH-CH = CH-
Or - (CH _{2) 4} - are shown, B is -NH- or formula; -CH ₂ -N
(R ⁸ )-(R ⁸ is a hydrogen atom, a C _1-10 alkyl group or C
_{7-10 represents an} aralkyl group). ] The imidazo [1,2-a] pyridine derivative represented by the formula] has an extremely strong ACAT inhibitory action as compared with known imidazo [1,2-a] pyridine derivatives, and as an agent for lowering serum cholesterol and arteriosclerosis, The present invention was found to be useful and the present invention has been completed.

In the general formula (I), the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A C _1-10 alkyl group is a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group. Group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group Base 3,
3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl
-2-methylpropyl group, heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1,1-dimethylpentyl group, 1, 2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 2,2-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3- Dimethylpentyl group, 3,4-dimethylpentyl group, 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 2,2,3-trimethylbutyl group, 1-ethyl-1-methylbutyl group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group, 1-propyl Butyl group, 1-isopropylbutyl group, octyl group, 6-methylheptyl group, nonyl group, 7-methyloctyl group , Decyl group, 8-methylnonyl group and the like.

The C _3-5 alkylene group is a trimethylene group,
It means a tetramethylene group, a pentamethylene group or the like.
The C _1-8 haloalkyl group means a trichloromethyl group, a trifluoromethyl group, a 1,1,1-trifluoroethyl group and the like. The C _1-8 alkoxy group means a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group and the like. The C _1-8 alkylthio group means a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a sec-butylthio group, a tert-butylthio group and the like. C _1-8
Monoalkylamino group means methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-
A butylamino group is meant. The C _2-12 dialkylamino group means a dimethylamino group, a diethylamino group, a di-n-propylamino group, a diisopropylamino group, a di-n-butylamino group and the like. The aralkyl group means a benzyl group, a phenethyl group or the like, and the phenyl ring may be substituted with 1 to 2 substituents selected from a halogen atom or a C _1-10 alkyl group.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION A specific method for producing the compound represented by the general formula (I) is shown below. [Method A] (when B; -NH-)

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and A are the same as above)

The compound represented by the general formula (Ic) is obtained by reacting the compound represented by the general formula (IV) with benzene, toluene, xylene, fluorobenzene, dioxane, etc. in the presence of an organic amine such as triethylamine and diphenylphosphoryl azide. In an inert solvent of room temperature to about 150 ° C to give an isocyanate (IIa), which is then reacted with compound (IIIa) without isolation from room temperature to about 150 ° C. Can be synthesized. The molar ratio of the reaction reagents in carrying out this reaction is equimolar because they are equimolar reactions, but either may be used in excess.

The compound represented by the general formula (IVa) used in this reaction is a Journal of Organic C
The formulas (V) and (VI) according to the method described in chemistry page 2403 (1965) or a method analogous thereto.
Alternatively, it can be synthesized from the compound represented by (VII). The compound represented by the general formula (IVb) can be obtained by reducing the compound represented by the general formula (IVa).

Embedded image [Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above, R
⁹ represents COOR ¹⁰ (in the formula, R ¹⁰ represents a C _1-4 alkyl group) or a nitrile group, and Z represents a halogen atom. ]

That is, compound (V) or (VI) can be converted into imidazo [1,2-a] pyridine (VIII) by reacting with 2-aminopyridine (VII). Then, carboxylic acid (IVa) can be produced by hydrolyzing (VIII). Conversion of (V) or (VI) to (VIII) should be carried out in the range of room temperature to about 100 ° C in 2-aminopyridine (VII) and a usual solvent (eg methanol, ethanol, isopropanol, dioxane, etc.). You can The conversion of (VIII) to (IVa) can be carried out using an aqueous alkali solution such as sodium hydroxide or potassium hydroxide or an acid such as a mineral acid (eg, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.). Suitable solvents for this reaction are methanol, ethanol, isopropanol, dioxane and the like, and may be solventless. The reaction temperature is preferably in the range of room temperature to 120 ° C. The conversion of (IVa) to (IVb) is carried out at room temperature to 120 ° C. and atmospheric pressure to 5 in the presence of a metal catalyst such as platinum oxide, nickel and palladium in a solvent such as ethanol acetic acid and ethyl acetate.
It can be carried out by carrying out a hydrogenation reaction within a range of about atmospheric pressure.

[Method B]

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
A and B are the same as above. )

The compound represented by the general formula (I) is obtained by reacting the compound represented by the general formula (IIb) with an isocyanate (IIIb) and a solvent such as benzene, toluene, xylene, fluorobenzene, dioxane, tetrahydrofuran or ethyl acetate. During,
It can be synthesized by reacting within the range of room temperature to 150 ° C. The molar ratio of the reaction reagents in carrying out this reaction is equimolar because they are equimolar reactions, but either may be used in excess.

The compound represented by the general formula (IIc) used in this reaction is Journalof Medicina.
l Chemistry 19 Vol. 1352 (1976) or a method analogous thereto, it can be synthesized from a compound represented by the general formula (IVa), (VII), (IX) or (X). . The compound represented by the general formula (IId) can be obtained by reducing the compound represented by the general formula (IIc).

Embedded image [Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. Z represents a halogen atom, and R ¹¹ represents —CHO or —CH (OR ¹⁰ ) ₂
(R ¹⁰ is the same as above). ]

That is, the compound (IX) or (X) is reacted with 2-aminopyridine (VII), or the compound (IVa
) Is decarboxylated to convert it to imidazo [1,2-a] pyridine (XI). Then nitrosated to form nitroso compound (XII)
Convert to Then, by reducing (XII) (II
c) can be manufactured. (IX) or (X) to (X
The conversion to I) can be carried out in the range of room temperature to about 100 ° C. in 2-aminopyridine (VII) and an ordinary solvent (eg, methanol, ethanol, isopropanol, dioxane, etc.). The conversion of (IVa) to (XI) can be carried out in an inert solvent such as diphenyl ether or xylene or without a solvent,
Acid catalyst (eg p-toluenesulfonic acid, sulfuric acid, etc.)
It can be carried out within a range of about 150 to 250 ° C with or without. The conversion of (XI) to (XII) is carried out by using a nitrite salt such as sodium nitrite in a solvent of organic acid such as acetic acid or mineral acid (for example, hydrochloric acid, sulfuric acid) at room temperature to 120 ° C.
It can be performed within a range of about ° C. (XII) to (IIc)
Can be converted using various reducing agents,
Preferably, zinc, iron, tin, or tin chloride is used under acidic conditions in a solvent such as acetic acid, ethanol, methanol, or isopropanol at room temperature to a temperature of about 120 ° C., and a method of reducing platinum oxide, nickel, or palladium. In the presence of a metal catalyst such as, a hydrogenation reaction is carried out in a solvent such as ethanol, acetic acid, ethyl acetate or the like at room temperature to 120 ° C. and atmospheric pressure to 5 atm. Conversion from (IIc) to (IId) can be carried out in the presence of a metal catalyst such as platinum oxide, nickel or palladium in a solvent such as ethanol, acetic acid or ethyl acetate within the range of room temperature to 120 ° C and atmospheric pressure to 5 atm. Can be carried out by adding hydrogen.

The compound represented by the general formula (IIe) used in this reaction can be synthesized from the compound represented by the general formula (XI) or (VIII). The compound represented by the general formula (IIf) can be obtained by reducing the compound represented by the general formula (IIe).

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and R ⁹ are the same as above.)

That is, the compound (XI) is formylated or
Compound (VIII) is reduced to primary alcohol (XIII) and then oxidized to convert to aldehyde (XIV), followed by reductive amination reaction with primary amine (XV) (IIe)
Can be manufactured. The conversion from (XI) to (XIV) can be carried out by various formylation reactions,
Preferably, there is a method (Vilsmeier reaction) in the presence of phosphoryl chloride, phosgene, thionyl chloride or the like, using N, N-dimethylformamide or N-methylformanilide within the range of room temperature to about 100 ° C. (VIII) to (XII
For conversion to I), various metal hydrides, preferably diisobutylaluminum hydride, are used at a temperature of -60 ° C in a solvent such as anhydrous tetrahydrofuran, toluene, or dichloromethane.
To room temperature. The conversion from (XIII) to (XIV) can be carried out by using various oxidizing agents, but it is preferable to use pyridinium chlorochromate in dichloromethane in the range of 0 ° C. to room temperature, dimethyl sulfoxide. , Using oxalyl chloride and a tertiary amine (such as triethylamine or diisopropylethylamine) in dichloromethane,
Method within the range of -60 ℃ to room temperature (Swern oxidation)
There is. For conversion of (XIV) to (IIc), a primary amine (XV) and a metal hydrogen complex compound, preferably sodium cyanoborohydride, are used in a solvent such as methanol or ethanol at 0 ° C to 50 ° C. There is a method within the range of the degree. The conversion of (IIe) to (IIf) is performed with ethanol, acetic acid,
It can be carried out by hydrogenating in a solvent such as ethyl acetate in the presence of a metal catalyst such as platinum oxide, nickel and palladium at room temperature to 120 ° C. and atmospheric pressure to 5 atm.

[Method C] (A; --CH ₂ CH ₂ CH ₂ CH _2- )

Embedded image (In the formula, B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above.) The compound represented by the formula (Ia) is produced by reducing (Ib). can do. This reduction reaction is performed in the presence of a metal catalyst such as platinum oxide, nickel or palladium in a solvent such as ethanol, acetic acid or ethyl acetate from room temperature to 120 ° C.
It can be carried out by carrying out a hydrogenation reaction within the range of ℃ and atmospheric pressure to about 5 atm.

The compounds of the present invention are
It is administered orally or parenterally (intramuscularly, subcutaneously, intravenously) as a preventive or therapeutic drug for atherosclerosis. It is preferably administered to a human by oral administration. Since the compounds of the present invention may themselves be ACAT inhibitors, the active ingredient in the composition will generally be 0.01-10.
0% (by weight) is included. The dose varies depending on symptoms, age, sex, body weight, dosage form, etc., but in the case of an adult, it is usually 0.1 to 1000 mg per day.

For formulating the compound of the present invention, for example, powders, granules, tablets, dragees, capsules, pills, suspensions, solutions, emulsions, ampoules, injections,
Use isotonic solution. That is, when preparing a solid preparation for oral use, the main ingredient is an excipient and, if necessary, a binder, a wetting agent, a disintegrating agent, a surfactant, a lubricant, a dispersing agent, a flavoring agent, a flavoring agent, etc. After addition, tablets, coated tablets, granules, capsules and the like are prepared by a conventional method. Excipients used include, for example, lactose, glucose, sorbitol, corn starch, mannitol and the like, and examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc. As the disintegrant, calcium carbonate, calcium citrate, dextrin, starch, gelatin powder, etc., as the lubricant, for example, magnesium stearate, talc, polyethylene glycol, etc., as the colorant, cocoa powder, peppermint aromatic acid. , Peppermint oil and the like. These tablets,
The granules may be coated with sugar, gelatin or the like, if necessary. When preparing an injection, a pH adjusting agent, a buffering agent, a surfactant, a solubilizing agent, a solvent, a stabilizer, a preservative, etc. are added to the main drug as necessary, and subcutaneous, intramuscular, It is an intravenous injection.

Table 1 shows specific examples of the general formula (I) obtained by each production method. In the table, Me represents a methyl group and E
t is an ethyl group, i-Pr is an isopropyl group, n-hep is an n-heptyl group, and Bn is a benzyl group. Table 1

Embedded image ──────────────────────────────────── Compound number B R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ ──────────────────────────────────── 1 -NH- H 5-Me H 2- Cl H 2-iPr 6-iPr 2 -NH- H 5-Me H 2-Me H 2-iPr 6-iPr 3 -NH- H 5-Cl H 2-Cl H 2-iPr 6-iPr 4 -NH- H 5-Cl H 2-Me H 2-iPr 6-iPr 5 -NH- H 6-Me H 2-Cl H 2-iPr 6-iPr 6 -CH ₂ -N (Bn-4-Me)-HHH 4 -Cl 2-F 4-F 6-F ────────────────────────────────────

Table 2

Embedded image ──────────────────────────────────── Compound number B R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ ──────────────────────────────────── 7 -NH- HHH 2-Me H 2- iPr 6-iPr ────────────────────────────────────

Table 3

Embedded image ──────────────────────────────────── Compound number B R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ ──────────────────────────────────── 8 -NH- HHHHH 2-iPr 6-iPr 9 -NH- HHHHH 2-F 6-F 10 -NH- HHH 4-Cl H 2-iPr 6-iPr 11 -NH- HHH 2-Cl H 2-Et 6-Et 12 -NH- HHH 2-Cl H 2-iPr 6-iPr 13 -CH ₂ -N (nHep)-HHHHH 2-F 4-F 14 -CH ₂ -N (Bn-4-Me)-HHHH 2-F 4-F 6-F 15 -CH ₂ -N (Bn-4-Me)-HHH 4-Cl 2-F 4-F 6-F ─────────────────────────── ──────────

Table 4

Embedded image ──────────────────────────────────── Compound number B R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ R ⁷ ──────────────────────────────────── 16 -NH- HHHHH 2-iPr 6-iPr 17 -NH- HHHHH 2-F 6-F 18 -CH ₂ -N (nHep)-HHHHH 2-F 4-F 19 -CH ₂ -N (Bn-4-Me)-HHHH 2-F 4-F 6 -F ────────────────────────────────────

[0025]

EXAMPLES Examples, reference examples, prescription examples and test examples of the present invention are shown below, but the present invention is not limited to these. Example 1 N- [3- (2-chlorophenyl) -5-methylimidazo
[1,2-a] Pyridin-2-yl] -N '-(2,6-diisopropylphenyl) urea (Compound 1) 3- (2-chlorophenyl) -5-methyl-2-imidazo [1,2- a]
0.91 cc of triethylamine was added dropwise to a mixture of 1.00 g of pyridinecarboxylic acid hydrochloride, 0.71 cc of diphenylphosphoryl azide and 5 cc of fluorobenzene at room temperature. After stirring at the same temperature for 10 minutes, the mixture was heated at 65 to 70 ° C for 10 minutes. After cooling, 0.62 cc of 2,6-diisopropylaniline was added, and the mixture was heated at 65 to 70 ° C for 1 hour. After cooling, water was added and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain 766 mg of compound 1. Yield 53.7%, melting point 224-226 ° C, NMR
(δ, ppm; CDCl ₃ ): 1.25 (d, 12H), 2.31 (s, 3H), 3.32
(m, 2H), 6.62 (s, 1H), 7.10 (d, 1H), 7.22 (d, 2H), 7.28
(t, 1H), 7.38 (d, 1H), 7.45-7.52 (m, 4H), 7.62 (d, 1H), 1
0.63 (s, 1H)

In the same manner as in Example 1, Examples 2 to 2
The compound shown in 5 was obtained.Example 2 N- (2,6-diisopropylphenyl) -N '-[5-me
Cyl-3- (2-methylphenyl) imidazo [1,2-a] pyridine
 -2-yl] urea (Compound 2) yield 40.2%, melting point 184
~ 185 ° C, NMR (δ, ppm; CDCl_Three): 1.26 (d, 12H), 2.17
(s, 3H), 2.27 (s, 3H), 3.32 (m, 2H), 6.53 (s, 1H), 7.05
(d, 1H), 7.07 (d, 2H), 7.26 (t, 1H), 7.36-7.44 (m, 6H), 1
0.64 (s, 1H)Example 3 N- [5-chloro-3- (2-chlorophenyl) imida
Zo [1,2-a] pyridin-2-yl] -N '-(2,6-diisopropyl
Phenyl) urea (compound 3) yield 34.2%, melting point 238
~ 240 ℃, NMR (δ, ppm; CDCl_Three): 1.25 (d, 12H), 3.30
(m, 2H), 6.67 (s, 1H), 7.21-7.30 (m, 4H), 7.42-7.51 (m, 4
H), 7.64 (d, 1H), 7.74 (s, 1H), 10.46 (s, 1H) Example 4 N- [5-chloro-3- (2-methylphenyl) imida
Zo [1,2-a] pyridin-2-yl] -N '-(2,6-diisopropyl
Phenyl) urea (compound 4) yield 30.8%, melting point 224
~ 225 ℃, NMR (δ, ppm; CDCl_Three): 1.26 (d, 12H), 2.18
(s, 3H), 3.30 (m, 2H), 6.60 (s, 1H), 7.17-7.26 (m, 3H),
7.29 (t, 1H), 7.37-7.45 (m, 5H), 7.65 (s, 1H), 10.46 (s, 1
H)Example 5 N- [3- (2-chlorophenyl) -6-methylimidazo
[1,2-a] Pyridin-2-yl] -N '-(2,6-diisopropylphenyl
Phenyl) urea (Compound 5) yield 78.4%, melting point 193-1
94 ° C, NMR (δ, ppm; DMSO-d₆): 1.13 (d, 12H), 2.38
(s, 3H), 3.14 (m, 2H), 6.80 (d, 1H), 7.14 (d, 2H), 7.23
(t, 1H), 7.36 (s, 1H), 7.48-7.57 (m, 4H), 7.65 (d, 1H),
7.71 (d, 1H), 8.74 (s, 1H), 9.45 (br, 1H)

Example 6 N-[(3- (4-chlorophenyl) imidazo [1,2-a] pyridin-2-yl) methyl] -N- (4-methylbenzyl) -N '-(2,4 , 6-Trifluorophenyl) urea (Compound 6) 2,4,6-trifluoroaniline 0.17g, ethyl acetate 10cc
73 μl of trichloromethylchloroformic acid (TCF) was added dropwise to the above mixture and refluxed for 2 hours. After cooling, 3- (4-chlorophenyl) -2- (4-methylbenzylaminomethyl) imidazo [1,2
-a] Add a mixture of 400 mg of pyridine and 5 cc of ethyl acetate,
The mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogencarbonate solution was added and then extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate).
-Hexane) to obtain 475 mg of compound 6. Yield 82.8%, melting point 228-230 ° C, NMR (δ, ppm; CDCl ₃ ):
2.31 (s, 3H), 4.25 (s, 2H), 4.46 (s, 2H), 6.71-6.84 (m, 5
H), 7.00 (d, 2H), 7.27-7.32 (m, 3H), 7.55 (d, 2H), 7.63
(d, 1H), 8.00 (d, 1H), 10.14 (br, 1H) Example 7 N- (2,6-diisopropylphenyl) -N '-[4,5,
6,7-Tetrahydro-3- (2-methylphenyl) imidazo
[1,2-a] Pyridin-2-yl] urea (Compound 7) N- (2,6-diisopropylphenyl) -N '-[3- (2-methylphenyl) imidazo [1,2-a] pyridine -2-Ill] Urea
A mixture of 0.58 g, 10% palladium-carbon 50 mg and acetic acid 10 cc was stirred under a hydrogen atmosphere at 4 atm for 5 hours. After filtration through Celite, the filtrate was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was crystallized from ethyl ether to obtain 455 mg of compound 7. Yield 77.7%, melting point 188-189 ° C, NMR
(δ, ppm; CDCl ₃ ): 1.25 (d, 12H), 1.87-2.02 (m, 4H),
2.23 (s, 3H), 2.84 (m, 2H), 3.29 (m, 2H), 3.48-3.52 (m, 1
H), 3.62-3.66 (m, 1H), 6.11 (s, 1H), 7.18-7.33 (m, 7H),
10.18 (s, 1H)

Example 8 N- (2,6-diisopropylphenyl) -N '-[2-phenylimidazo [1,2-a] pyridin-3-yl]
Urea (Compound 8) 3-Amino-2-phenylimidazo [1,2-a] pyridine 200m
g, 2,6-diisopropylphenyl isocyanate 205m
g and ethyl acetate (10 cc) were refluxed for 10 hours. After cooling, the solvent was distilled off under reduced pressure, and the obtained crude crystals were collected by filtration with diethyl ether and washed to obtain 272 mg of compound 8. Yield 69.0%, melting point
263-265 ° C, NMR (δ, ppm; DMSO-d ₆ ): 1.14 (brd, 12
H), 3.25 (m, 2H), 7.04 (t, 1H), 7.12 (m, 2H), 7.21 (m, 1
H), 7.29 (t, 1H), 7.37 (t, 1H), 7.47 (t, 2H), 7.61 (d, 1H),
7.97-8.20 (m, 4H), 8.50 (s, 1H) By a method similar to that in Example 8, the compounds shown in Examples 9 to 12 were obtained. Example 9 N- (2,4-difluorophenyl) -N '-[2-phenylimidazo [1,2-a] pyridin-3-yl] urea (Compound 9) Yield 55.9%, melting point 208-209 ° C , NMR (δ, ppm; CD
Cl ₃ ): 6.81-6.90 (m, 3H), 7.20 (t, 1H), 7.32 (d, 2H),
7.44 (t, 2H), 7.60 (d, 1H), 7.99-8.07 (m, 3H), 8.23 (br, 1
H), 8.50 (br, 1H) Example 10 N- [2- (4-chlorophenyl) imidazo [1,2-
a] Pyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea (Compound 10) Yield 82.4%, melting point 300 ° C or higher, NMR (δ, ppm; DMSO-d ₆ ): 1.11 (brd , 12H), 3.10-3.
45 (br, 2H), 7.03-7.12 (m, 3H), 7.20 (d, 1H), 7.34 (t, 1
H), 7.53 (d, 2H), 7.61 (d, 1H), 8.00-8.15 (m, 4H), 8.54
(s, 1H)

Example 11 N- [2- (2-chlorophenyl) imidazo [1,2-a] pyridin-3-yl] -N '-(2,6-diethylphenyl) urea (Compound 11) Yield 73.4 %, Melting point 218
~ 220 ° C, NMR (δ, ppm; DMSO-d ₆ ): 1.09 (t, 6H), 2.52
(q, 4H), 7.02-7.14 (m, 4H), 7.34 (t, 1H), 7.39-7.48 (m, 2
H), 7.58-7.65 (m, 3H), 7.99 (br, 1H), 8.06 (br, 1H), 8.3
5 (br, 1H) Example 12 N- [2- (2-chlorophenyl) imidazo [1,2-
a] Pyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea (Compound 12) Yield 63.8%, melting point 214-21
5 ° C, NMR (δ, ppm; DMSO-d ₆ ): 1.12 (d, 12H), 3.13 (b
r, 1H), 3.30 (br, 1H), 7.05 (t, 1H), 7.11 (d, 2H), 7.20 (d,
1H), 7.34 (t, 1H), 7.41-7.47 (m, 2H), 7.58-7.64 (m, 3H),
7.95-8.08 (m, 2H), 8.34 (s, 1H)

Example 13 N- (2,4-difluorophenyl) -N '-(n-heptyl) -N'-[(2-phenylimidazo [1,2-
a] Pyridin-3-yl) methyl] urea (Compound 13) 3- (n-heptylaminomethyl) -2-phenylimidazo [1,2
-a] Pyridine 1.04g, 2,4-difluorophenyl isocyanate 0.50g, tetrahydrofuran 10cc at room temperature
Stir for 10 hours. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (elution solvent: ethyl acetate-
The product was purified by hexane) to obtain 1.35 g of Compound 13. Yield 95.0%, melting point 118-119 ° C, NMR (δ, ppm; CDCl ₃ ):
0.79-0.85 (m, 5H), 0.94-1.05 (m, 4H), 1.13-1.23 (m, 4H),
2.81 (t, 2H), 5.21 (s, 2H), 6.38 (d, 1H), 6.81-6.86 (m, 3
H), 7.23 (t, 1H), 7.39 (t, 1H), 7.46 (t, 2H), 7.46 (t, 2
H), 7.63 (d, 1H), 7.69 (d, 2H), 7.95-8.03 (m, 1H), 8.49
(d, 1H)

Example 14 N- (4-methylbenzyl) -N-
[(2-Phenylimidazo [1,2-a] pyridin-3-yl) methyl] -N '-(2,4,6-trifluorophenyl) urea (Compound 14) 2,4,6-trifluoroaniline 0.68g, ethyl acetate 20cc
73 μl of trichloromethylchloroformic acid (TCF) was added dropwise to the above mixture and refluxed for 2 hours. After cooling, 3- (4-methylbenzylaminomethyl) -2-phenylimidazo [1,2-a] pyridine
Add a mixture of 1.50g and 10cc of ethyl acetate, and add at room temperature for 12
Stirred for hours. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane).
The compound 14 was purified by the above procedure to obtain 1.73 g of Compound 14. Yield 75.4%,
Melting point 191-193 ° C, NMR (δ, ppm; CDCl ₃ ): 2.28 (s, 3
H), 4.16 (s, 2H), 5.28 (s, 2H), 6.89 (s, 1H), 6.68-6.72
(m, 4H), 6.88 (t, 1H), 6.98 (d, 2H), 7.26 (t, 2H), 7.34-
7.37 (m, 3H), 7.56-7.64 (m, 3H), 8.56 (d, 1H) By a method similar to that in Example 14, the compound shown in Example 15 was obtained. Example 15 N-[(2- (4-chlorophenyl) imidazo [1,2
-a] Pyridin-3-yl) methyl] -N- (4-methylbenzyl)
-N '-(2,4,6-trifluorophenyl) urea (Compound 1
5) Yield 88.2%, melting point 191-193 ° C, NMR (δ, ppm;
CDCl ₃ ): 2.30 (s, 3H), 4.14 (s, 2H), 5.22 (s, 2H), 6.00
(s, 1H), 6.68-6.73 (m, 4H), 6.89 (t, 1H), 6.99 (d, 2H),
7.26-7.31 (m, 3H), 7.48 (d, 2H), 7.60 (d, 1H), 8.54 (d, 1
H)

Example 16 N- (2,6-diisopropylphenyl) -N '-[4,5,6,7-tetrahydro-2-phenylimidazo [1,2-a] pyridin-3-yl] urea (Compound 16) N- (2,6-diisopropylphenyl) -N '-[2-phenylimidazo [1,2-a] pyridin-3-yl] urea 0.25g, 10% palladium-carbon 10mg, acetic acid 5cc The mixture was stirred under a hydrogen atmosphere at 4 atm for 5 hours. After filtration through Celite, the filtrate was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to obtain 222 mg of compound 16. Yield 87.9%, melting point
300 ° C or higher, NMR (δ, ppm; DMSO-d ₆ ): 1.14 (brd, 12H),
1.84 (m, 2H), 1.93 (m, 2H), 2.75 (t, 2H), 3.23 (br, 2H),
3.76 (t, 2H), 7.05-7.38 (m, 6H), 7.80-7.93 (m, 2H), 8.05
(s, 1H) By a method similar to that in Example 16, the compound shown in Example 17 was obtained. Example 17 N- (2,6-difluorophenyl) -N '-[4,5,6,
7-Tetrahydro-2-phenylimidazo [1,2-a] pyridin-3-yl] urea (Compound 17) Yield 94.3%, melting point
296-299 ° C, NMR (δ, ppm; DMSO-d ₆ ): 1.84 (m, 2H),
1.90 (m, 2H), 2.75 (t, 2H), 3.74 (t, 2H), 7.02 (t, 1H), 7.
18 (t, 1H), 7.28-7.36 (m, 3H), 7.76 (d, 1H), 8.01 (br, 1H),
8.35 (s, 1H), 8.82 (br, 1H)

Example 18 N- (2,4-difluorophenyl) -N '-(n-heptyl) -N'-[(4,5,6,7-tetrahydro-2
-Phenylimidazo [1,2-a] pyridin-3-yl) methyl] urea (Compound 18) N- (2,4-difluorophenyl) -N '-(n-heptyl) -N'-[(2
-Phenylimidazo [1,2-a] pyridin-3-yl) methyl] urea 0.42g, 10% palladium-carbon 30mg, acetic acid
The 5 cc mixture was stirred under a hydrogen atmosphere at 3 atm for 6 hours. After filtration through Celite, the filtrate was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate) to give compound 18 (320 m).
g obtained. Yield 75.4%, melting point 123-124 ° C, NMR (δ, ppm;
CDCl ₃ ): 0.85 (t, 3H), 0.92-0.95 (m, 2H), 1.06-1.11
(m, 4H), 1.19-1.28 (m, 4H), 1.93 (m, 2H), 1.99 (m, 2H),
2.88-2.95 (m, 4H), 3.91 (t, 2H), 4.88 (s, 2H), 6.40 (s, 1
H), 6.81-6.88 (m, 2H), 7.29 (t, 1H), 7.39 (t, 2H), 7.55
(d, 2H), 7.96-8.00 (m, 1H) By a method similar to that in Example 18, the compound shown in Example 19 was obtained. Example 19 N- (4-methylbenzyl) -N-[(4,5,6,7-tetrahydro-2-phenylimidazo [1,2-a] pyridine-3-
Iyl) methyl] -N '-(2,4,6-trifluorophenyl) urea (Compound 19) Yield 92.9%, melting point 208-209 ° C, NM
R (δ, ppm; CDCl ₃ ): 1.87-1.98 (m, 4H), 2.31 (s, 3H), 2.9
0 (t, 2H), 3.89 (t, 2H), 4.23 (s, 2H), 4.91 (s, 2H), 5.92
(s, 1H), 6.68 (t, 2H), 6.81 (d, 2H), 7.06 (d, 2H), 7.23-
7.29 (m, 3H), 7.44 (d, 2H)

Formulation Example 1 Compound of the present invention 10 parts Magnesium stearate 10 parts Lactose 80 parts are uniformly mixed to obtain a powder or fine powder to prepare a powder. Formulation Example 2 Compound of the present invention 50 parts Starch 10 parts Lactose 15 parts Ethylcellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts After uniformly mixing and mixing, they are crushed and granulated and sieved to obtain granules.

Formulation Example 3 99 parts of the granules obtained in Formulation Example 2 are mixed with 1 part of calcium stearate and compression-molded to give tablets having a diameter of 10 mm. Formulation Example 4 A granule is prepared in the same manner as in Formulation Example 2 using 95 parts of the compound of the present invention, 5 parts of polyvinyl alcohol, and 30 parts of water. To 90 parts of the obtained granules, 10 parts of crystalline cellulose is added and compression-molded to give tablets having a diameter of 8 mm. Further, a sugar-coated tablet is prepared by using an appropriate amount of syrup, gelatin, a mixed suspension of precipitated calcium carbonate and a coloring agent in the tablet. Formulation Example 5 Compound of the present invention 0.5 part Nonionic surfactant 2.5 parts Physiological saline 97 parts After heating and mixing, it is sterilized to obtain an injection. Formulation Example 6 The powder obtained in Formulation Example 1 is filled into a commercially available capsule container to form a capsule.

Next, test examples will be shown in order to prove the effectiveness of the present invention. Test Example 1 Acyl-CoA: Cholesterol Acyltransferase
The enzyme used in the evaluation test of ze (ACAT) inhibitory activity is the method of Heidel et al. [Journal
Oblipid Research, 24, 1127 (1983)]. That is, the white rabbit was killed by exsanguination under anesthesia, and then the mucosa of the small intestine was collected. After homogenizing this, a microsome fraction was obtained by the stepwise centrifugation method. The microsome fraction was suspended in 0.154M phosphate buffer (PH7.4), and -8
It was stored at 0 ° C. and used for the test appropriately. ACAT activity [1- ¹⁴
C] Oleyl-CoA incorporated into cholesteryl ester as an index, the method of Helgeld et al. [Journal of Lipid Research, Vol. 22, p. 271 (1
981)] was modified. For the ACAT inhibitory activity of the test compound, the inhibition rate was calculated according to the following formula. Table 5 shows the results.

[Equation 1]

[0037]

Test Example 2 Serum cholesterol in rats fed a high cholesterol diet
Lumpur reduction Evaluation of action [Experimental method] After a 6-week-old male Sprague-Dawley rats divided into groups, the ordinary feed of the normal group, high cholesterol diet in the control group and the compound-administered group (1.0% cholesterol,
1.0% K-cholic acid and 8.5% coconut hardened oil) was fed for 4 days. At the same time as the feeding of the feed,
The compound suspended in a 0.5% carboxymethylcellulose solution was administered at 30 mg / kg body weight once a day for 4 days. A 0.5% carboxymethylcellulose solution was similarly administered to the normal group and the control group. Blood was collected 24 hours after the final administration of the compound, and the cholesterol concentration in serum was measured by an enzymatic method.
From the measured values of each group, the reduction rate of the total serum cholesterol amount was calculated according to the following formula. The results are shown in Table 6.

[Equation 2] A: Serum cholesterol concentration in control group B: Serum cholesterol concentration in compound administration group C: Serum cholesterol concentration in normal group

[0039]

[0040]

INDUSTRIAL APPLICABILITY The compound of the present invention has an ACAT inhibitory activity and is useful as a preventive or therapeutic agent for hypercholesterolemia, atherosclerosis and various diseases caused by these diseases. that's all

Claims (4)

[Claims] 1. A compound of the general formula (I): [In the formula, R ¹ and R ² are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, C _1-8 haloalkyl group, C _1-8 alkylthio group, or R ¹ and R ² are bonded to each other to represent a C _3-5 alkylene group, and R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group, C _1-8 A haloalkyl group or a C _1-8 alkylthio group is shown, and A is -CH = CH-CH = CH-
Or - (CH _{2) 4} - are shown, B is -NH- or formula; -CH ₂ -N
(R ⁸ )-(R ⁸ is a hydrogen atom, a C _1-10 alkyl group or C
_{7-10 represents an} aralkyl group). ] The imidazo [1,2-a] pyridine derivative represented by these, and its pharmacologically acceptable salt. 2. A compound of the general formula (II): [Wherein R ¹ and R ² are the same or different and each is a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, a C _1-8 haloalkyl group, a C _1-8 alkylthio group, or R ¹ and R ² are bonded to each other to represent a C _3-5 alkylene group, and R ³ and R ⁴ are the same or different. Hydrogen atom, halogen atom, C _1-10 alkyl group, C _1-8 alkoxy group, C _1-8 monoalkylamino group, C _2-12 dialkylamino group, C _1-8 haloalkyl group or C _1-8 alkylthio group are shown, a is -CH = CH-CH = CH- or - (CH _{2) 4} - are shown, X is -NH _2, -NCO, -CH ₂ NCO or formula; -CH ₂ -NH-R ⁸
(R ⁸ represents a hydrogen atom, a C _1-10 alkyl group or a C _7-10 aralkyl group). ] The compound or its salt represented by the general formula (III); (R ⁵ , R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, a C _1-8 haloalkyl group or a C _1-8 alkylthio group, Y represents —N _{2 when} X is —NH ₂ or a formula; —CH ₂ —NH—R ⁸ (R ⁸ is the same as above). , X is -CH ₂ NCO or-
In the case of NCO, it shows -NH ₂ . ) A compound represented by the formula (I) or a salt thereof, represented by the general formula (I); (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
A and B are the same as above. The manufacturing method of the compound or its salt represented by these. 3. A compound represented by the general formula (Ia); [In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, C _1-8 haloalkyl group, C _1-8 alkylthio group, or R ¹ and R ² are bonded to each other to represent a C _3-5 alkylene group, and R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group, C _1-8 A haloalkyl group or a C _1-8 alkylthio group, B is —NH— or a formula; —CH ₂ —N (R ⁸ )-(R ⁸ is a hydrogen atom, a C _1-10 alkyl group or a C _7-10 aralkyl group. Is shown). ] The compound or its salt represented by the following general formula (Ib) characterized by reducing; (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and B are the same as defined above) or a method for producing a salt thereof. 4. A compound represented by the general formula (I): [In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group. Group, C _1-8 haloalkyl group, C _1-8 alkylthio group, or R ¹ and R ² are bonded to each other to represent a C _3-5 alkylene group, and R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ are the same or different and are a hydrogen atom, a halogen atom, a C _1-10 alkyl group, a C _1-8 alkoxy group, a C _1-8 monoalkylamino group, a C _2-12 dialkylamino group, C _1-8 A haloalkyl group or a C _1-8 alkylthio group is shown, and A is -CH = CH-CH = CH-
Or - (CH _{2) 4} - are shown, B is -NH- or formula; -CH ₂ -N
(R ⁸⁾ - (R ⁸ is a hydrogen atom, C _1-10 alkyl group or a C
_{7-10 represents an} aralkyl group). ] The ACAT inhibitor which uses the imidazo [1,2-a] pyridine derivative represented by these or its pharmacologically acceptable salt as an active ingredient.