JPH06340658A - Benzimidazole derivative - Google Patents

Abstract

PURPOSE:To obtain a compound having an immunosuppressive action. CONSTITUTION:A compound of formula I (R<1> is H, halogen, lower alkyl, lower alkoxy, aryl; R<2> is H, cyano, lower alkyl, lower alkanoyl, carboxy, etc.; R<1> and R<2> are combined with each other to form (CH2)m, etc.; (m) is 3-5; R<3> is H, lower alkyl, aryl, etc.; R<4>, R<5> are H, lower alkyl), e.g. 1-[4-(3- ethoxycarbonylquinoline-4-yl) benzyl]-2-propylbenzoimidazole. The compound of formula I is obtained by halogenating a compound of formula II, and subsequently condensing the produced halomethylated compound with a compound of formula III in the presence of a base (e.g. sodium carbonate) in a solvent (e.g. methanol) at room temperature to the boiling temperature of the solvent. A medicine containing the component of formula I is administered at a dose of 1-900mg/60kg/day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzimidazole derivative having an immunosuppressive action.

[0002]

2. Description of the Related Art The effectiveness of immunosuppressants has been recognized in organ transplantation and autoimmune diseases. Cyclosporin A and FK50 are among the most used immunosuppressants
6 [Journal of Antibiotics (J. Antib
iotics), 40 , 1249 (1987)] is known to have an action at a specific cell level and is used in fields such as organ transplantation. However, all of these compounds have a macrocyclic structure, and side effects have been observed. Therefore, there is a need for a drug with low toxicity, no side effects and high selectivity.

Further, it is known that a compound having a substituted biphenylmethyl at the 1-position of benzimidazole has an angiotensin receptor antagonistic action.
No. 62, JP-A-3-63264, etc., but no benzimidazole derivative having a quinoline ring is known in relation to the present invention.

[0004]

The object of the present invention is to provide a benzimidazole derivative having an immunosuppressive action.

[0005]

The present invention provides a compound of formula (I)

[0006]

[Chemical 2]

[Wherein R ¹ represents hydrogen, halogen, lower alkyl, lower alkoxy or substituted or unsubstituted aryl, R ² represents hydrogen, cyano, substituted or unsubstituted lower alkyl, lower alkanoyl, carboxy, lower] Alkoxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl, -CONR ⁶ R ⁷
(In the formula, R ⁶ and R ⁷ are the same or different and each represents hydrogen or lower alkyl, or R ⁶ and R ⁷ together represent a heterocyclic group formed by containing N.), or R ¹
And R ² together form-(CH ₂ ) _m- (wherein m
Is an integer of 3-5), or - (CH _{2) n} C
O- (in the formula, n is an integer of 2 to 4), R ³ represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl or substituted or unsubstituted aryl, and R ⁴
And R ⁵ are the same or different and each represents hydrogen or lower alkyl] and a benzimidazole derivative [abbreviated as compound (I) hereinafter] or a pharmacologically acceptable salt thereof.

In the definition of each group of the formula (I), halogen includes each atom of fluorine, chlorine, bromine and iodine. The lower alkyl, lower alkoxy and lower alkoxycarbonyl include, as the alkyl moiety, straight-chain or branched alkyl having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se.
c-butyl, tert-butyl, pentyl, isopentyl,
Hexyl, heptyl, octyl and the like can be mentioned, and examples of the substituent in lower alkyl include the same or different substituents having 1 to 3 substituents such as halogen, hydroxy, lower alkoxy, lower alkoxycarbonyl and cycloalkyl. Halogen is the same as the definition of halogen, the alkyl part of lower alkoxy and lower alkoxycarbonyl is the same as the definition of the above alkyl, and the definition of cycloalkyl is the same as the definition of cycloalkyl described later. Specific examples of the lower alkyl substituted with the above substituents include, for example, trifluoromethyl, trifluoroethyl, difluoroethyl, trichloromethyl, 2-hydroxyethyl, 1-hydroxybutyl, methoxymethyl, ethoxyethyl, methoxycarbonyl. Examples include methyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, cyclopentylmethyl and the like. Examples of cycloalkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.

Examples of the lower alkanoyl include straight-chain or branched alkanoyl having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl and the like, and the aryl moiety of aryl and aroyl is phenyl. , Naphthyl, etc. The substituents on the aryl portion of aryl and aroyl may be the same or different and have 1 to 3 substituents.
Examples thereof include halogen, lower alkyl, nitro, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, methylenedioxy, trifluoromethyl and the like. Halogen has the same definition as the above halogen, and the alkyl part of lower alkyl, lower alkoxy and lower alkoxycarbonyl has the same definition as the above alkyl.

Examples of the heterocyclic group include morpholino, piperazinyl and piperidino. Examples of the pharmacologically acceptable salt of compound (I) include hydrochloride, sulfate,
Examples thereof include inorganic acid salts such as phosphate, and organic acid salts such as maleate, fumarate and methanesulfonate.
Next, the production method of compound (I) will be described, but the production method of compound (I) is not limited to the steps described below.

The compound (I) can be obtained from the compound (II) by the method shown below.

[0012]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ is as defined above) Compound (I) is a method of halogenating compound (II) by an ordinary radical, that is, a halogenating agent such as N-bromosuccinimide in a solvent such as carbon tetrachloride or chloroform. After using it as a halomethyl compound, the compound (II
It can be obtained by condensation with I). The condensation is carried out by heating in a solvent from room temperature to around the boiling point of the solvent used in the presence of a suitable base. The base used is preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, or sodium methoxide, potassium butoxide, and the like, and the solvent used is methanol, ethanol, or the like. Lower alcohols, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, and toluene and xylene may be used alone or in combination.

Compound (I) can be prepared by the method described in the literature [Organic Reactions, 2
8 , 37 (1982)], the compound (IV) and the corresponding ketone are heated with lower alcohols such as methanol and ethanol, acetic acid, propionic acid, etc. as a solvent, and sulfuric acid, trifluoroacetic acid, etc. as a catalyst. It can be reacted and synthesized.

[0015]

[Chemical 4]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ has the same meaning as defined above. Further, in the compound (I), a compound in which R ¹ is hydrogen and R ² has various substituents can be obtained by the method shown below.

[0017]

[Chemical 5]

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R
⁷ has the same meaning as above, and R ⁸ , R ⁹ and R ¹⁰ represent lower alkyl.) The lower alkyl in R ⁸ , R ⁹ and R ¹⁰ has the same definition as the above alkyl.

Step: Compound (Ia) wherein R ² is lower alkoxycarbonyl
Is a compound (IV) in an equivalent or excess amount of methyl propynate, a propynoic acid ester such as ethyl propynoate or a 3-alkoxyacrylic acid ester such as ethyl ethoxyacrylate, methyl methoxyacrylate, sulfuric acid,
It can also be obtained by reacting under heating with an acid such as trifluoroacetic acid or acetic acid as a catalyst and a lower alcohol such as methanol or ethanol or an organic acid such as acetic acid or propionic acid as a solvent.

Step: 2 Compound (Ib) wherein R ² is carboxy is compound (Ia)
In the presence of an equivalent or excess amount of an alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, or potassium carbonate in a lower alcohol such as methanol or ethanol with water at room temperature or the boiling point of the solvent. It can be obtained by performing hydrolysis.

Step: 3 The compound (Ic) in which R ² is —CONR ⁶ R ⁷ (wherein R ⁶ and R ⁷ have the same meanings as described above) is prepared by converting the carboxy derivative (Ib) into halogen such as chloroform or dichloromethane. Oxygenated hydrocarbons, aromatic hydrocarbons such as benzene and toluene, or acid halides such as thionyl chloride and phosphorus oxychloride in an ether solvent or without solvent,
The acid halide is obtained by reacting at 1 ° C to the boiling point of the solvent for 1 to 24 hours, and using the solvent described in the acid halogenation reaction, if necessary, in the presence of a base such as triethylamine, at room temperature to the boiling point of the solvent. 1-24 with the corresponding amine, eg ammonia, ethylamine, diethylamine, etc.
It can be obtained by reacting for a time.

Step: 4 The compound (Id) in which R ² is cyano is a compound (Ic) in which R ⁶ and R ⁷ are hydrogen without solvent or in acetic acid or dimethylformamide, acetic anhydride, thionyl chloride or the like. It can be obtained by carrying out a dehydration reaction at 0 ° C to the boiling point of the solvent.

Compound (Ie) wherein R ² is hydroxy-substituted lower alkyl, Compound (If) is lower alkanoyl
Can be obtained from compound (Ia) by the method shown in steps 5-9.

Step: 5 Compound (Iea) wherein R ² is hydroxymethyl is prepared by reacting compound (Ia) with an appropriate reducing agent such as lithium aluminum hydride or lithium borohydride in an ether solvent such as diethyl ether or tetrahydrofuran. Can be used to reduce the ester.

Step: 6 The compound (Ifa) in which R ² is an aldehyde is
a) in a suitable solvent, for example, an aromatic hydrocarbon such as benzene or toluene, or a haloalkane-based solvent such as methylene chloride, using an oxidizing agent such as manganese dioxide or pyridinium chloroformate, under ice-cooling to a boiling point range of the solvent It can be obtained by oxidizing inside.

Step: 7 Compound (Ieb wherein R ² is hydroxy-substituted lower alkyl)
) Is a compound (Ifa) of 1 to 3 equivalents of a lower alkyl metal salt such as methylmagnesium bromide or methyllithium in an inert solvent such as tetrahydrofuran or diethyl ether under an inert gas atmosphere such as dry nitrogen or dry argon. With the boiling point of the solvent at 0 ° C.

Step: 8 The compound (Ifb) in which R ² is lower alkanoyl can be obtained from the compound (Ieb) according to the above-mentioned oxidation method from compound (Iea) to compound (Ifa) in step 6.

Step: 9 Compounds in which R ² is hydroxy-substituted lower alkyl (Ieb
) Is an alkanoyl compound (Ifb) according to the method for reducing a compound (Ia) to a compound (Iea) in the above step 5.
You can also get more.

Step: 10 Compound (Iec, wherein R ² is hydroxy-substituted lower alkyl)
) Is a compound (Ia) containing 2 or more equivalents of a lower alkyl metal salt such as methylmagnesium bromide or methyllithium in an inert solvent such as tetrahydrofuran or diethyl ether under an inert gas atmosphere such as dry nitrogen or dry argon. With the boiling point of the solvent at 0 ° C.

Next, a method for producing the raw material compounds (II) and (IV) will be described. Method: Compound (IIa) in which R ² is lower alkoxycarbonyl and R ¹ is hydrogen in compound (II),
Method for producing compound (IIb) which is a halogen and compound (IIc) which is a lower alkoxy

[0031]

[Chemical 6]

(Wherein R ⁸ and R ⁹ have the same meanings as defined above, R ¹¹ represents an alkyl moiety of lower alkoxy in the definition of R ¹ , X represents a leaving group, and Y represents R ¹ ). (Meaning halogen in the definition) Examples of the leaving group in X include halogen such as chlorine, bromine and iodine, methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy and the like.

Compounds (IIa), (IIb) and (IIc)
Can be obtained from compound (1) according to the above reaction step. According to the method for synthesizing compound (Ia) from compound (IV) in step 1 from 4′-methyl-2-aminobenzophenone (1) using propynoic acid ester or 3-alkoxyacrylic acid ester, compound (IIa ) Can be obtained.

From the compound (1), the synthesis (Syn
thesis), 56 (1991), using methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, diethyl ether, etc. as a solvent, an organic base such as triethylamine or pyridine, or sodium carbonate, potassium carbonate, etc. In the presence or absence of an inorganic base of -78
The compound (2) is obtained by ring-closing the anilide compound formed by reacting with a β-dicarboxylic acid monoester halide such as malonic acid monomethyl chloride at a temperature of from ° C to the boiling point of the solvent or lower. Further, when the reaction is carried out in the absence of a base, the compound (2) can be obtained by further adding the above-mentioned base. Further, the compound (IIb) can be obtained by heating the compound (2) in a halogenating agent such as thionyl chloride or phosphorus oxychloride without a solvent. In addition, the compound (IIc) is prepared by reacting the compound (2) with 1 to 2 equivalents of a base in an inert solvent to give 1
Obtained by reacting ˜2 equivalents of alkylating agent. The base is preferably sodium hydride, potassium carbonate, cesium carbonate and the like, and the inert solvent is preferably tetrahydrofuran, dimethylformamide, acetone, methyl ethyl ketone and the like. The reaction is carried out under ice cooling or under heating, and the reaction time is preferably about 10 minutes to 24 hours. Method: 2 Method for producing compound (IV)

[0035]

[Chemical 7]

(Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above) The compound (IV) can be obtained from the compound (3) according to the above reaction step. Compound (III) was prepared according to the method of synthesizing compound (I) from compound (II) described above.
) And then further reducing nitro to amino to obtain the compound (IV). The reduction can be carried out, for example, by catalytic reduction or a conventional method using a metal. Catalytic reduction is usually performed at room temperature and atmospheric pressure with Raney nickel,
This can be carried out by using a catalyst such as palladium carbon or platinum oxide as a catalyst and ventilating hydrogen gas in a solvent such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran or acetic acid. Examples of the reduction using a metal include, for example, in the presence of a catalyst such as zinc-acetic acid, iron-acetic acid, iron-ferric chloride-ethanol-water, iron-hydrochloric acid, tin-hydrochloric acid, usually from room temperature to the boiling point of the solvent. It is performed at a temperature near.

In the above production method, the reaction time is preferably 1 to 24 hours unless otherwise specified. The intermediates and target compounds in the above production methods are purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, drying, concentration,
It can be isolated and purified by subjecting it to recrystallization, various kinds of chromatography and the like. In addition, the intermediate can be subjected to the next reaction without further purification.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is, and when it is obtained in a free form, a usual and suitable compound is used. The salt may be formed by dissolving or suspending in an organic solvent and adding an acid. The compound (I) and the pharmacologically acceptable salt thereof shown here may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

Compound (I) obtained by the above production method
Specific examples of are shown in Tables 1-1 to 1-4.

[0040]

[Table 1]

[0041]

[Table 2]

[0042]

[Table 3]

[0043]

[Table 4]

Next, the pharmacological action of the representative compound (I) will be shown in Test Examples. Test Example 1. T Cell Proliferation Inhibition Test in Mouse Lymphocyte Mixed Reaction (MLR) Spleen was aseptically removed from C3H / He mice to obtain a single cell suspension. Mitomycin C (MMC) (manufactured by Kyowa Hakko Kogyo Co., Ltd.) was added to this suspension (final concentration 50 μg / ml), and the mixture was incubated at 37 ° C. for 30 minutes. After culturing, washing was carried out 3 times to obtain 8 × 10 ⁶ cells.
Adjusted to / ml. Ba in each well of a 96-well microplate
50 μl of lymph node cell suspension of lb / c mouse (5 × 10 ⁵
cells), 50 μl of MMC-treated C3H / He mouse splenocytes suspension (containing 5 × 10 ⁵ cells), and 50 μl of the test compound solution at the test concentration were added, and the mixture was incubated in a CO ₂ incubator at 37 ℃ for 72 hours. Cultured. 8 hours before the end of culture
[ ³ H] -thymidine 0.5 μCi was added. After completion of the culture, the cells were collected on a filter paper with a cell harvester, dried and a toluene scintillator was added, and the radioactivity of [ ³ H] -thymidine incorporated into the cells was measured with a liquid scintillation counter. The results are shown in Table 2. The T cell proliferation inhibition rate was calculated according to the following equation.

[0045]

[Equation 1]

[0046]

[Table 5]

Compound (I) or a pharmacologically acceptable salt thereof is orally prepared by preparing into a commonly applied dosage form such as tablets, capsules, syrups, or intramuscular injection or intravenous injection. , Parenteral administration such as intraarterial injection, infusion, and rectal administration by suppository.
Conventionally known methods are applied to formulate such dosage forms for oral or parenteral administration, and examples include various excipients, lubricants, binders, disintegrants, suspending agents. , Tonicity agents,
You may contain an emulsifier etc.

Examples of the pharmaceutical carrier used include:
Water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate. , Magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glycerin fatty acid ester and the like.

The dose is 1 to 900 mg / 60 for both oral and parenteral
kg / day is appropriate. The following examples and reference examples
1 illustrates an aspect of the present invention.

[0050]

【Example】

Example 1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 1) 1-[(2-aminobenzophenone-obtained in Reference Example 1 4'-yl) methyl] -2-propylbenzimidazole (Compound A) 0.59 g (1.6 mmol) was dissolved in 1.4 ml of ethyl 3-ethoxyacrylate, a catalytic amount of trifluoroacetic acid was added, and the mixture was heated at 120 ° C for 4 hours. did. Water was added to the reaction mixture, the mixture was extracted with dichloromethane and then evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform).
And purified by diethyl ether to give 0.47 g (63%) of white crystals. ¹ H-NMR (CDCl ₃ ) δ: 9.41 (s, 1H), 8.23 (d, 1H, J = 9Hz),
7.9-7.7 (m, 3H), 7.52 (m, 2H), 7.3-7.2 (br-s, 6H),
5.48 (s, 2H), 4.13 (q, 2H, J = 7Hz), 2.88 (t, 2H, J = 7H
z), 1.98 (sext, 2H, J = 7Hz), 1.07 (t, 3H, J = 7Hz), 1.0
0 (t, 3H, J = 7Hz). IR (KBr lock): 2958, 1704, 1461, 1321, 1253, 772, 736
cm ^-1 .Melting point (diethyl ether): 126-128 ℃

Example 2. 1- [4- (3-Ethoxycarbonyl-2-methylquinolin-4-yl) benzyl]-
2-Propylbenzimidazole (Compound 2) 2.21 g (6 mmol) of the compound (A) was dissolved in 30 ml of acetic acid, 0.765 ml (6 mmol) of ethyl acetoacetate and a catalytic amount of sulfuric acid were added, and the mixture was heated under reflux for 2 hours. 50 ml of water and 10 ml of concentrated ammonia water in the reaction product.
Was added, and the mixture was extracted with chloroform, washed with saturated brine, dried, and the organic layer was concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (chloroform: methanol = 100: 1) and recrystallized from diethyl ether to give 1.46 g (52.4%) of white crystals.
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, 1H, J = 8.4Hz), 7.81 (dd,
1H, J = 6.9, 2.0Hz), 7.72-7.70 (m, 1H), 7.50-7.39 (m, 2
H), 7.34-7.17 (m, 7H), 5.45 (s, 2H), 4.03 (q, 2H, J =
7.4Hz), 2.90 (t, 2H, J = 7.4Hz), 2.77 (s, 3H), 1.94 (se
xt, 2H, J = 7.4Hz), 1.07 (t, 3H, J = 7.4Hz), 0.91 (t, 3H,
J = 7.4Hz). IR (KBr tablets): 1717, 1410, 1233, 1068, 764, 744 cm ^-1 Melting point (diethyl ether): 110-112 ℃

Example 3.1 1- [4- (3-ethoxycarbonyl-2-propylquinolin-4-yl) benzyl]
2-Propylbenzimidazole (Compound 3) Compound 3 was prepared according to the method of Example 2 except that ethyl 3-oxohexanoate was used instead of ethyl acetoacetate.
Obtained in a yield of 2%. ¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, 1H, J = 8.4Hz), 7.80 (m, 1
H,), 7.71 (m, 1H), 7.49-7.40 (m, 2H), 7.32 (d, 2H, J =
8.0Hz), 7.28-7.22 (m, 2H), 7.18 (d, 2H, J = 8.0Hz), 5.
44 (s, 2H), 4.01 (q, 2H, J = 7.0Hz), 2.98 (t, 2H, J = 8.0
Hz), 2.90 (t, 2H, J = 8.0Hz), 1.99-1.82 (m, 4H), 1.06
(t, 3H, J = 7.5Hz), 1.03 (t, 3H, J = 7.5Hz), 0.91 (t, 3H,
J = 7.5Hz). IR (KBr tablets): 2968, 1723, 1462, 1235, 750, cm ^-1 . Melting point (diethyl ether): 97-98 ℃

Example 4.1 1- [4- (3-Ethoxycarbonyl-2-isopropylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 4) 4-Methyl-3 in place of ethyl acetoacetate Compound 4 was obtained in a yield of 89% according to the method of Example 2 except that ethyl oxopentanoate was used and the solvent was changed from acetic acid to ethanol. ¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, 1H, J = 8.4Hz), 7.80 (d, 1
H, J = 6.9Hz), 7.67 (m, 1H), 7.47-7.15 (m, 9H), 5.41
(s, 2H), 4.01 (q, 2H, J = 7.0Hz), 3.27 (m, 1H), 2.87
(t, 2H, J = 7.4Hz), 1.93 (sext, 2H, J = 7.0Hz), 1.42 (d,
6H, J = 6.4Hz), 1.06 (t, 3H, J = 7.4Hz), 0.91 (t, 3H, J
= 7.0Hz). IR (KBr tablets): 2964, 1724, 1461, 1403, 1232, 1046, 76
6, 742 cm ^-1 .Melting point (diethyl ether): 139-140 ℃

Example 5.1 1- [4- (3-Ethoxycarbonyl-2-phenylquinolin-4-yl) benzyl]
2-Propylbenzimidazole (Compound 5) Compound 5 was prepared according to the method of Example 2 except that ethyl 3-oxo-3-phenylpropanoate was used instead of ethyl acetoacetate and the solvent was changed from acetic acid to ethanol. 92%
It was obtained in a yield of. ¹ H-NMR (CDCl ₃ ) δ: 8.23 (d, 1H, J = 8.0Hz), 7.88-7.60
(m, 3H), 7.55-7.40 (m, 4H), 7.35-7.10 (m, 9H), 5.44
(s, 2H), 3.85 (q, 2H, J = 7.0Hz), 2.89 (t, 2H, J = 6.9H
z), 1.95 (sext, 2H, J = 6.9Hz), 1.13 (t, 3H, J = 6.9Hz),
0.76 (t, 3H, J = 7.0Hz). IR (KBr tablets): 2958, 1729, 1460, 1231, 766, 743 cm ^-1 . Melting point (diethyl ether): 78-80 ° C

Example 6.1 1- [4- (3-acetyl-2
-Methylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 6) Compound 6 was obtained in a yield of 78% according to the method of Example 2 except that acetylacetone was used instead of ethyl acetoacetate. It was ¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, 1H, J = 8.4Hz), 7.82-7.78
(m, 1H), 7.73 (dd, 1H, J = 8.4,1.5Hz), 7.51 (d, 1H, J =
7.0Hz), 7.43 (br-t, 1H, J = 7.0Hz), 7.33-7.08 (m, 7H),
5.45 (s, 2H), 2.88 (t, 2H, J = 7.5Hz), 2.68 (s, 3H), 1.
99 (s, 3H), 1.88 (sext, 2H, J = 7.5Hz), 1.05 (t, 3H, J =
7.5Hz), 0.76 (t, 3H, J = 7.0Hz). IR (KBr tablets): 2956, 1691, 1406, 777, 745 cm ^-1 . Melting point (diethyl ether): 183-185 ℃

Example 7.1 1- [4- (3-phenylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 7) Example except that phenylpyruvic acid was used instead of ethyl acetoacetate. Compound 7 was obtained according to the method of 2 in a yield of 92%. ¹ H-NMR (CDCl ₃ ) δ: 8.97 (s, 1H), 8.19 (d, 1H, J = 8.1H
z), 7.85-7.40 (m, 4H), 7.29-7.05 (m, 12H), 5.35 (s, 2
H), 2.82 (t, 2H, J = 7.0Hz), 1.90 (sext, 2H, J = 7.0Hz),
1.02 (t, 3H, J = 7.0Hz). IR (KBr tablets): 1460, 1408, 768, 737, 700 cm ^-1 . Melting point (diethyl ether): 148-149 ℃

Example 8 1- [4- (2-phenylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 8) The same as in Example 2 except that acetophenone was used instead of ethyl acetoacetate. Compound 8 was obtained according to a method in a yield of 79%. ¹ H-NMR (CDCl ₃ ) δ: 8.25-8.15 (m, 3H), 7.84-7.70 (m, 3
H), 7.77 (s, 1H), 7.55-7.43 (m, 6H), 7.32-7.21 (m, 5
H), 5.47 (s, 2H), 2.91 (t, 2H, J = 7.5Hz), 1.95 (sext,
2H, J = 7.5Hz), 1.07 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1592, 1460, 771, 745 cm ^-1 Melting point (diethyl ether): 184-185 ℃

Example 9.1- [4- (2,3-Dihydro-1H-cyclopenta [b] quinolin-9-yl) benzyl] -2-propylbenzimidazole (Compound 9) Cyclo instead of ethyl acetoacetate Compound 9 was obtained in a yield of 79% according to the method of Example 2 except that pentanone was used. ¹ H-NMR (CDCl ₃ ) δ: 8.05 (d, 1H, J = 7.9Hz), 7.80 (d, 1
H, J = 6.4Hz), 7.64-7.54 (m, 2H), 7.39-7.20 (m, 8H),
5.46 (s, 2H), 3.22 (t, 2H, J = 7.5Hz), 2.93-2.83 (m, 4
H), 2.15 (t, 2H, J = 7.5Hz), 1.91 (sext, 2H, J = 7.2Hz),
1.05 (t, 3H, J = 7.2Hz). IR (KBr tablets): 2956, 1459, 774, 744 cm ^-1 . Melting point (diethyl ether): 185-186 ℃

Example 10- [4- (2,3-dihydro-1-oxo-1H-cyclopenta [b] quinoline-
9-yl) benzyl] -2-propylbenzimidazole (Compound 10) Compound 10 was prepared according to the method of Example 2 except that 1,3-cyclopentanedione was used instead of ethyl acetoacetate.
Was obtained in a yield of 60%. ¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, 1H, J = 7.9Hz), 7.85-7.78
(m, 2H), 7.68 (d, 1H, J = 7.9), 7.54-7.44 (m, 2H), 7.3
5-7.21 (m, 6H), 5.49 (s, 2H), 3.43 (m, 2H), 2.91 (t, 2
H, J = 7.4Hz), 2.82 (m, 2H), 1.94 (sext, 2H, J = 7.4Hz),
1.07 (t, 3H, J = 7.4Hz). IR (KBr tablets): 1715, 1592, 1459, 758 cm ^-1 . Melting point (diethyl ether): 172-173 ℃

Example 11.1- [4- (1-oxo-
1,2,3,4-tetrahydroacridin-9-yl)
Benzyl] -2-propylbenzimidazole (Compound 11) Compound 11 was prepared according to the method of Example 2 except that 1,3-cyclohexanedione was used instead of ethyl acetoacetate.
Was obtained in a yield of 66%. ¹ H-NMR (CDCl ₃ ) δ: 8.14 (d, 1H, J = 7.9Hz), 7.95-7.80
(m, 2H), 7.50-7.21 (m, 9H), 5.59 (s, 2H), 3.45 (t, 2
H, J = 6.0Hz), 3.07 (br-t, 2H), 2.78 (t, 2H, J = 6.9Hz),
2.37-2.30 (m, 2H), 2.06-2.04 (m, 2H), 1.29 (t, 3H, J
IR (KBr tablets): 2960, 1690, 1550, 1460, 750 cm ^-1 Melting point (diethyl ether): 194-196 ℃

Example 12- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] benzimidazole (Compound 12) Reference was made using 440 mg (1.61 mmol) of the compound (B) obtained in Reference Example 2. Bromination and condensation reaction were performed according to the method of Example 1. The compound (B) was brominated to obtain 462.4 mg of a crude product of 4- (4-bromomethylphenyl) -3-ethoxycarbonylquinoline, and 140 mg of this crude product was used to obtain benzimidazole (56 mg). To give the title compound as white crystals (recrystallized from diethyl ether).
43.3 mg (22% in 2 steps) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.36 (s, 1H), 8.19 (d, 1H, J = 8.4H
z), 8.06 (s, 1H), 7.89-7.77 (m, 2H), 7.55-7.13 (m, 9
H), 5.50 (s, 2H), 4.10 (q, 2H, J = 7.0Hz), 0.97 (t, 3H,
J = 7.0Hz) .IR (KBr tablets): 1718, 1498, 1224, 777, 748 cm ^-1 . Melting point (diethyl ether): 131-132 ℃

Example 13. 1- [4- (3-ethoxycarboxyl]
Rubonylquinolin-4-yl) benzyl] -5,6-di
Methylbenzimidazole (Compound 13) 5,6-Dimethylbenzoi instead of benzimidazole
According to the method of Example 12 except that imidazole was used.
The title compound was obtained as white crystals in 24.5% in 2 steps. ¹ H-NMR (CDCl₃) δ: 9.36 (s, 1H), 8.18 (d, 1H, J = 8.4H
z), 7.94 (s, 1H), 7.62 (s, 1H), 7.49 (m, 2H), 7.35-7.
20 (m, 5H), 7.15 (s, 1H), 5.45 (s, 2H), 4.11 (q, 2H, J =
7.0Hz), 2.39 (s, 6H), 0.99 (t, 3H, J = 7Hz) .IR (KBr tablets): 1721, 1576, 1497, 1370, 1335, 1165, 774
 cm ^-1. Melting point (diethyl ether): 205-207 ° C

Example 14. 1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-methylbenzimidazole (Compound 14) Except that 2-methylbenzimidazole is used instead of benzimidazole. According to the method of Example 12, the title compound as white crystals was obtained in 2 steps of 14.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.33 (s, 1H), 8.18 (d, 1H, J = 8.0H
z), 7.90-7.63 (m, 2H), 7.55-7.42 (m, 2H), 7.38-7.20
(m, 7H), 5.44 (s, 2H), 4.11 (q, 2H, J = 7.0Hz), 2.66
(s, 3H), 0.99 (t, 3H, J = 7.0Hz). IR (KBr tablets): 1721, 1399, 1224, 767, 744 cm ^-1 . Melting point (diisopropyl ether): 128-129 ℃

Example 15. 1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -4-methyl-2-propylbenzimidazole (Compound 15) 4-methyl-2-in place of benzimidazole The title compound as white crystals was obtained in two steps of 11.6% according to the method of Example 12 except that propylbenzimidazole was used. ¹ H-NMR (CDCl ₃ ) δ: 9.45 (s, 1H), 8.27 (d, 1H, J = 8.4H
z), 7.91-7.86 (m, 1H), 7.59-7.54 (m, 2H), 7.36-7.17
(m, 7H), 5.57 (s, 2H), 4.21 (q, 2H, J = 6.9Hz), 3.07
(t, 2H, J = 7.4Hz), 2.82 (s, 3H), 1.98 (sext, 2H, J = 7.
4Hz), 1.17 (t, 3H, J = 7.4Hz), 1.12 (t, 3H, J = 6.9Hz). IR (KBr tablets): 1725, 1221, 756 cm ^-1 . Melting point (diethyl ether): 165- 167 ° C

Example 16. 2-Butyl-1- [4- (3
-Ethoxycarbonylquinolin-4-yl) benzyl]
Benzimidazole (Compound 16) A white crystalline title compound was obtained in 2 steps of 28.0% according to the method of Example 12 except that 2-butylbenzimidazole was used in place of benzimidazole. ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.18 (d, 1H, J = 8.4H
z), 7.80-7.75 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.19
(m, 7H), 5.47 (s, 2H), 4.12 (q, 2H, J = 7.0Hz), 2.93
(t, 2H, J = 7.5Hz), 1.90 (quint, 2H, J = 7.5Hz), 1.47 (s
ext, 2H, J = 7.5Hz), 1.01 (t, 3H, J = 7.0Hz), 0.97 (t, 3
H, J = 7.5Hz). IR (KBr tablets): 1727, 1221, 1460, 775, 756 cm ^-1 . Melting point (diethyl ether): 121-122 ℃

Example 1 1- [4- (3-Carboxyquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 17) 150 mg of the compound (1) was dissolved in 3 ml of ethanol, and lithium hydroxide 1 water was added. 28 mg of Japanese products and 0.5 ml of water were added, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in water, and 2N
Hydrochloric acid was added and the mixture was filtered off to obtain 123 mg of white crystals (yield 88%). ¹ H-NMR (DMSO-d ₆ ): 9.21 (s, 1H), 8.12 (d, 1H, J = 7.5H
z), 7.85 (t, 1H, J = 7.5Hz), 7.59 (m, 2H), 7.42 (d, 1H,
J = 7.5Hz), 7.3-7.15 (m, 6H), 5.62 (s, 2H), 2.86 (t,
2H, J = 7.0Hz), 1.78 (sext, 2H, J = 7.0Hz), 0.97 (t, 3H,
J = 7.0Hz).

Example 1 1- [4- (3-carbamoylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 18) Compound (17) 300 mg (0.711 mmol) was added to thionyl chloride 4.5 ml.
Was added and the mixture was heated under reflux for 1.5 hours. The reaction solution was returned to room temperature and the solvent was distilled off under reduced pressure to obtain a crude product of 1- [4- (3-chloroformylquinolin-4-yl) benzyl] -2-propylbenzimidazole as crystals. This compound was unstable in air and was not isolated and purified but used in the next reaction.

To this crude product was added an excess amount of 30% aqueous ammonia solution at 0 ° C. Immediately, the reaction solution was neutralized with 4N hydrochloric acid, extracted with chloroform, and the organic layer was washed and dried. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol: triethylamine = 50: 1: 0.1), and the obtained crude product was recrystallized from diethyl ether to give the title compound as white crystals. (167 mg, 56% yield in two steps) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.24 (s, 1H), 8.17 (d, 1H, J = 8.6H
z), 7.85-7.74 (m, 2H), 7.50-7.48 (m, 2H), 7.39 (d, 1
H, J = 7.9Hz), 7.33-7.26 (m, 5H), 5.49 (s, 2H), 2.95
(t, 2H, J = 7.3Hz), 1.96 (sext, 2H, J = 7.3Hz), 1.07 (t,
IR (KBr tablets): 2960, 1461, 1409, 759, 744 cm ^-1 . Melting point (diethyl ether): 184-186 ℃

Example 1 1- [4- (3-Cyanoquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 19) Compound (18) 100 mg (0.24 mmol) was added to dimethylformamide (DMF) 2 ml. The resulting solution was dissolved in water and 0.5 ml of thionyl chloride was added dropwise under ice cooling. After stirring for 30 minutes, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate, and the organic layer was washed and dried. After distilling off the solvent, the residue was subjected to silica gel column chromatography (chloroform: methanol: triethylamine = 5).
(0: 1: 0.1) and the obtained crystals were recrystallized from diethyl ether. White crystalline title compound (85.
2 mg, 88%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.09 (s, 1H), 8.21 (d, 1H, J = 7.9H
z), 7.91-7.80 (m, 2H), 7.69 (d, 1H, J = 7.4Hz), 7.62-
7.56 (m, 1H), 7.45 (d, 1H, J = 8.4Hz), 7.35-7.22 (m, 5
H), 5.50 (s, 2H), 2.92 (t, 2H, J = 7.4Hz), 1.93 (sext,
2H, J = 7.4Hz), 1.07 (t, 3H, J = 7.4Hz). IR (KBr tablets): 2224, 1409, 752 cm ^-1 Melting point (diethyl ether): 183-185 ℃

Example 20 0.1- [4- (3-Ethylaminocarbonylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 20) Compound (17) 160 mg (0.377 mmol) was used. Example 18
The acid chloride obtained according to the synthetic method shown in was dissolved in 5 ml of dichloromethane, and 0.53 ml of triethylamine (3.77 mmo
l) and ethylamine hydrochloride 92.3 mg (1.13 mmol) were added,
Stir for 20 minutes at room temperature. Water was added to the reaction solution for liquid separation, the organic layer was washed with saturated saline and then dried, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (chloroform: methanol 50: 1), and the obtained crystals were recrystallized from diethyl ether to give the title compound (65.4 mg, two-step yield 38.5%) as white crystals. It was ¹ H-NMR (CDCl ₃ ) δ: 9.13 (s, 1H), 8.15 (d, 1H, J = 8.4H
z), 7.85 (d, 1H, J = 7.4Hz), 7.77-7.71 (m, 1H), 7.53-
7.22 (m, 9H), 5.49 (s, 2H), 3.18-3.11 (m, 2H), 2.98
(t, 2H, J = 7.4Hz), 1.96 (sext, 2H, J = 7.4Hz), 1.07 (t,
3H, J = 7.4Hz), 0.76 (t, 3H, J = 7.4Hz). IR (KBr tablets): 3300 (br), 1656, 1531, 1462, 742 cm ^-1 . Melting point (diethyl ether): 226- 227 ° C

Example 21- [4- (3-Diethylaminocarbonylquinolin-4-yl) benzyl] -2-
Propylbenzimidazole (Compound 21) Compound (17) was prepared according to the synthetic method of Example 20 except that diethylamine was used instead of ethylamine / hydrochloride.
200 mg (0.474 mmol) to 191.3 mg (2 step 87%) of the title compound were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 8.85 (s, 1H), 8.17 (d, 1H, J = 8.4H
z), 7.79-7.73 (br-t, 2H), 7.67 (d, 1H, J = 8.4Hz), 7.5
5-7.49 (m, 2H), 7.32-7.19 (m, 6H), 5.45 (s, 2H), 3.36-
2.73 (m, 4H), 2.88 (t, 2H, J = 7.5Hz), 1.92 (sext, 2H,
J = 7.5Hz), 1.06 (t, 3H, J = 7.5Hz), 0.88 (t, 3H, J = 7.5H
z), 0.74 (t, 3H, J = 7.5Hz). IR (KBr tablets): 2968, 1627, 1459, 1429, 778, 747 cm ^-1 Melting point (diisopropyl ether): 141-143 ℃

Example 22- [4- (3-Hydroxymethylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 22) 21 mg (0.56 mmol) of lithium aluminum hydride was added to 3 ml of tetrahydrofuran (THF). Dissolved in a solution of 250 mg (0.56 mmol) of compound (1) in THF (2 m) at 0 ° C. under an argon gas atmosphere.
l solution was added dropwise. After stirring at 0 ° C. for 20 minutes, 2 ml of ethyl acetate was added, a saturated aqueous ammonium chloride solution was further added, and this was extracted with ethyl acetate. The organic layer is washed, dried and the solvent is distilled off, and the residue is subjected to silica gel column chromatography (chloroform: methanol:
It was purified by triethylamine = 30: 1: 0.1), and the obtained oil was dried under reduced pressure to give the title compound (215.6 mg, 94%) as an amorphous solid. ¹ H-NMR (CDCl ₃ ) δ: 9.06 (s, 1H), 8.05 (d, 1H, J = 8.0H
z), 7.70-7.40 (m, 2H), 7.35-7.10 (m, 9H), 5.36 (s, 2
H), 4.59 (s, 2H), 2.82 (t, 2H, J = 7.5Hz), 1.83 (sext,
2H, J = 7.5Hz), 0.98 (t, 3H, J = 7.5Hz). IR (KBr tablets): 3200 (br), 1498, 1465, 1409, 1082, 759 c
m ^-1 .Melting point (diethyl ether): 160-162 ℃

Example 2 3.1- [4- (3-Formylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 23) 590 mg (1.45 mmol) of compound (22) was dissolved in 10 ml of toluene. Then, 0.63 g (7.25 mmol) of manganese dioxide was added and the mixture was heated under reflux for 1 hour. The reaction solution was filtered while hot using a filter aid, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from diethyl ether. The title compound (360.9
mg, 61%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.80 (s, 1H), 9.39 (s, 1H), 8.19
(d, 1H, J = 8.3Hz), 7.86-7.77 (m, 2H), 7.68-7.52 (m, 2
H), 7.38 (d, 2H, J = 8.3Hz), 7.30-7.24 (m, 5H), 5.49
(s, 2H), 2.89 (t, 2H, J = 7.3Hz), 1.92 (sext, 2H, J = 7.
3Hz), 1.06 (t, 3H, J = 7.3Hz). IR (KBr tablets): 1692, 1409, 764, 749 cm ^-1 Melting point (diethyl ether): 155-156 ℃

Example 24.1- {4- [3- (1-hydroxy-1-methylethyl) quinolin-4-yl] benzyl} -2-propylbenzimidazole (Compound 2
4) Dissolve 300 mg (0.667 mmol) of compound (1) in 12 ml of THF,
0.55 ml (1.67 mmol) of methyl magnesium bromide (3 M, ether solution) was added dropwise at 0 ° C. under an argon gas atmosphere. After stirring at room temperature for 1.5 hours, a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed and dried, then the solvent was distilled off and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) and recrystallized from diethyl ether to give the title compound. Obtained as 145 mg (50%) of white crystals. ¹ H-NMR (CDCl ₃ ) δ: 9.30 (s, 1H), 8.08 (d, 1H, J = 8.4H
z), 7.79-7.75 (m, 1H), 7.65-7.59 (m, 1H), 7.37-7.05
(m, 9H), 5.44 (s, 2H), 2.87 (t, 2H, J = 7.4Hz), 1.87 (s
ext, 2H, J = 7.5Hz), 1.47 (s, 6H), 1.03 (t, 3H, J = 7.4H
z). IR (KBr tablets): 3200 (br), 1495, 1458, 1401, 1208, 1143,
767, 744 cm ^-1 .Melting point (diethyl ether): 199-202 ℃

Example 25.1- [4- (3-Hydroxymethyl-2-methylquinolin-4-yl) benzyl]-
2-Propylbenzimidazole (Compound 25) Using compound (2) (463 mg, 1 mmol), the title compound (156.7 mg, 37.5%) was obtained as white crystals according to the method of Example 22. ¹ H-NMR (CDCl ₃ ) δ: 7.96 (d, 1H, J = 8.4Hz), 7.65-7.52
(m, 2H), 7.27-7.08 (m, 9H), 5.36 (s, 2H), 4.56 (s, 2
H), 2.83 (s, 3H), 2.77 (t, 2H, J = 7.4Hz), 1.79 (sext,
2H, J = 7.4Hz), 0.94 (t, 3H, J = 7.4Hz). IR (KBr tablets): 3200 (br), 1459, 767 cm ^-1 Melting point (diethyl ether): 173-174 ℃

Example 26.1- [4- (3-formyl-
2-Methylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 26) Using Compound (25) 115 mg (0.276 mmol), Example 23
According to the method described in (1), 50.2 mg (43%) of the title compound was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 10.06 (s, 1H), 8.10 (d, 1H, J = 8.4H
z), 7.96-7.88 (m, 2H), 7.55 (d, 2H, J = 3.5Hz), 7.45-7.
33 (m, 7H), 5.61 (s, 2H), 3.10 (s, 3H), 3.05 (t, 2H, J
= 7.5Hz), 2.06 (sext, 2H, J = 7.5Hz), 1.18 (t, 3H, J = 7.
IR (KBr tablets): 1699, 1561, 1558, 1396, 747 cm ^-1 Melting point (diethyl ether): 197-198 ℃

Example 27.1- {4- [3- (1-hydroxyethyl) quinolin-4-yl] benzyl} -2-
Propylbenzimidazole (Compound 27) Compound (23) 300 mg (0.74 mmol) and 1.2 equivalents of methylmagnesium bromide were used according to the method of Example 24 to obtain 148.0 mg (49.2%) of the title compound as white crystals. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.23 (s, 1H), 8.11 (d, 1H, J = 8.4H
z), 7.76-7.62 (m, 2H), 7.42-7.14 (m, 9H), 5.45 (s, 2
H), 4.82 (q, 1H, J = 6.4Hz), 2.88 (t, 2H, J = 7.4Hz), 1.
89 (sext, 2H, J = 7.4Hz), 1.46 (d, 3H, J = 6.4Hz), 1.03
(t, 3H, J = 7.4Hz) .IR (KBr lock): 3200 (br), 2964, 1459, 1409, 1106, 1072,
759 cm ^-1 .Melting point (diethyl ether): 172-175 ℃

Example 28.1- {4- [3- (1-hydroxybutyl) quinolin-4-yl] benzyl} -2-
Propylbenzimidazole (Compound 28) According to the method of Example 24, except that 300 mg (0.74 mmol) of Compound (23) and 1.5 equivalents of propylmagnesium bromide were used together with 124 mg (41%) of Compound (22), the title compound 158.2 mg (48%) of white crystals were obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.17 (s, 1H), 8.13 (d, 1H, J = 8.4H
z), 7.78-7.74 (m, 1H), 7.66 (t, 1H, J = 7.5Hz), 7.40
(t, 1H, J = 7.5Hz), 7.30-7.08 (m, 8H), 5.46 (s, 2H),
4.64 (dd, 1H, J = 7.9,4.9Hz), 2.89 (t, 2H, J = 7.5Hz),
1.97-1.79 (m, 4H), 1.65-1.58 (m, 1H), 1.37-1.29 (m, 1
H), 1.04 (t, 3H, J = 7.5Hz), 0.76 (t, 3H, J = 7.5Hz) .IR (KBr tablets): 3200 (br), 2964, 1458, 768 cm ^-1 . Melting point (diethyl Ether): 160-162 ℃

Example 2 1- [4- (3-butyrylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 29) Compound (28) 86 mg (0.185 mmol) was used in the Example. 23
26 mg (31%) of the title compound was obtained as white crystals according to the method described in. ¹ H-NMR (CDCl ₃ ) δ: 8.99 (s, 1H), 8.18 (d, 1H, J = 8.4H
z), 7.82-7.74 (m, 2H), 7.61 (dd, 1H, J = 8.4,1.0Hz),
7.54-7.50 (m, 1H), 7.34-7.22 (m, 7H), 5.48 (s, 2H),
2.89 (t, 2H, J = 7.5Hz), 2.23 (t, 2H, J = 7.5Hz), 1.93 (s
ext, 2H, J = 7.5Hz), 1.45 (sext, 2H, J = 7.5Hz), 1.06 (t,
3H, J = 7.5Hz), 0.70 (t, 3H, J = 7.5Hz). IR (KBr tablets): 2960, 1673, 1460, 1405, 763, 735 cm ^-1 . Melting point (diethyl ether): 157-159 ℃

Example 3 0.1- {4- [3- (1-hydroxyethyl) -2-methylquinolin-4-yl] benzyl} -2-propylbenzimidazole (Compound 3
0) 110 mg (0.255 mmol) of compound (6) was dissolved in 2 ml of ethanol, an excess amount of sodium borohydride was added, and the mixture was heated at 60 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with 1N hydrochloric acid, extracted with chloroform, and the organic layer was washed and dried. The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and the obtained crude crystals were recrystallized from diethyl ether to obtain 80.2 mg (73%) of the title compound as a white crystal. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.92 (d, 1H, J = 8.6Hz), 7.51-7.46
(m, 2H), 7.23-7.06 (m, 7H), 6.97 (d, 1H, J = 8.3Hz),
6.79 (d, 1H, J = 7.9Hz), 6.70 (d, 1H, J = 7.9Hz), 5.32
(s, 2H), 4.97 (q, 1H, J = 6.6Hz), 3.00 (s, 3H), 2.71
(t, 2H, J = 7.6Hz), 1.72 (sext, 2H, J = 7.6Hz), 1.47 (d,
3H, J = 6.6Hz), 0.92 (t, 3H, J = 7.6Hz). IR (KBr tablets): 3200 (br), 2962, 1462, 1409, 766, 755 cm
^-1 . Melting point (diethyl ether): 219-220 ℃

Example 31 1 .- [4- (2-chloro-3
-Ethoxycarbonylquinolin-4-yl) benzyl]
2-Propylbenzimidazole (Compound 31) Using 1.98 g (6.40 mmol) of the compound (D) obtained in Reference Example 4, bromination and condensation reactions were performed according to the method of Reference Example 1. The compound (D) was subjected to bromination to obtain 482 mg (18%) of a crude product of bromide, and 400 mg of this crude product was used for condensation with 2-propylbenzimidazole to give the title white crystal. 210.7 mg (44%) of the compound (recrystallized from diethyl ether) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, 1H, J = 8.4Hz), 7.82-7.74
(m, 2H), 7.53-7.49 (m, 2H), 7.34 (d, 2H, J = 8.4Hz),
7.29-7.19 (m, 5H), 5.46 (s, 2H), 4.10 (q, 2H, J = 7.4H
z), 2.89 (t, 2H, J = 7.4Hz), 1.93 (sext, 2H, J = 7.4Hz),
1.06 (t, 3H, J = 7.4Hz), 1.00 (t, 3H, J = 7.4Hz). IR (KBr tablets): 1722, 1233, 768, 743 cm ^-1 . Melting point (diethyl ether): 117-119 ℃

Example 32. 1- [4- (2-butoxy-
3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-propylbenzimidazole (Compound 32) Using the compound (E) 200 mg (0.55 mmol) obtained in Reference Example 5, bromine was prepared according to the method of Reference Example 1. The condensation and condensation reactions were carried out. The compound (E) was brominated to obtain 221.3 mg of a crude product of bromide, and 221.3 mg of the crude product was condensed with 2-propylbenzimidazole to give the title compound as a colorless oil. 129.6 mg (25.6 steps, 45.6%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.93-7.84 (m, 2H), 7.71-7.65 (m, 1
H), 7.48-7.29 (m, 7H), 7.22 (d, 2H, J = 8.4Hz), 5.50 (s,
2H), 4.59 (t, 2H, J = 6.4Hz), 4.12 (q, 2H, J = 7.0Hz),
2.98 (t, 2H, J = 7.9Hz), 2.05-1.80 (m, 4H), 1.56 (sext,
2H, J = 7.0Hz), 1.11 (t, 3H, J = 7.0Hz), 1.04 (t, 3H, J =
7.0Hz), 1.03 (t, 3H, J = 7.4Hz) .IR (NaCl neat): 2960, 1728, 1459, 1327, 1230 cm ^-1 .

Example 33.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-phenylbenzimidazole (Compound 33) Except that 2-phenylbenzimidazole is used instead of benzimidazole. According to the method of Example 12, the title compound as white crystals was obtained in 2 steps of 40.5%. ¹ H-NMR (CDCl ₃ ) δ: 9.34 (s, 1H), 8.18 (d, 1H, J = 8.4H
z), 7.91 (m, 1H), 7.84-7.76 (m, 3H), 7.54-7.49 (m, 5
H), 7.39-7.25 (m, 7H), 5.60 (s, 2H), 4.10 (q, 2H, J = 7.
5Hz), 1.00 (t, 2H, J = 7.5Hz) .IR (KBr tablets): 1724, 1461, 1445, 1390, 1218, 1156, 111
0, 739 cm ^-1 .Melting point (diethyl ether): 189-191 ° C

Example 34.1- {4- [3- (4-morpholinocarbonyl) quinolin-4-yl] benzyl}-
2-Propylbenzimidazole (Compound 34) According to the synthetic method of Example 20, morpholine was used in place of ammonia, and Compound (17) 200 mg (0.474 mmol) to 16
4.0 mg (70% for 2 steps) of the title compound were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 8.87 (s, 1H), 8.17 (d, 1H, J = 8.3H
z), 7.80-7.70 (m, 2H), 7.55-7.49 (m, 2H), 7.31-7.18
(m, 6H), 5.47 (s, 2H), 3.38-3.06 (m, 6H), 2.89 (t, 2H,
J = 7.3Hz), 2.86-2.77 (m, 2H), 1.92 (sext, 2H, J = 7.3H
z), 1.07 (t, 3H, J = 7.3Hz). IR (KBr tablets): 1640, 1462, 1434, 1117, 771, 744 cm
^-1 . Melting point (diisopropyl ether-diethyl ether):
190-196 ℃

Example 35.2 2-Butyl-1- [4- (3
-Ethoxycarbonyl-2-methylquinolin-4-yl) benzyl] benzimidazole (Compound 35) Compound (F) obtained in Reference Example 6 instead of Compound (A).
Compound 35 was obtained in a yield of 33% according to the method of Example 2 except that was used. ¹ H-NMR (CDCl ₃ ) δ: 8.07 (d, 1H, J = 8.4Hz), 7.81-7.68
(m, 2H), 7.49-7.41 (m, 2H), 7.34-7.17 (m, 7H), 5.44
(s, 2H), 4.03 (q, 2H, J = 7.5Hz), 2.91 (t, 2H, J = 7.8H
z), 2.77 (s, 3H), 1.93-1.81 (m, 2H), 1.51-1.43 (m, 2
H), 0.96 (t, 3H, J = 7.5Hz), 0.91 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1710, 1410, 1234, 1068, 771, 742 cm
^-1 . Melting point (diisopropyl ether-hexane): 81-83 ° C

Example 36.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-pentylbenzimidazole (Compound 36), except that 2-pentylbenzimidazole is used instead of benzimidazole. White crystalline title compound (recrystallized from isopropyl ether) according to the method of Example 12.
Was obtained in two steps of 40.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.18 (d, 1H, J = 8.6H
z), 7.80-7.76 (m, 2H), 7.49-7.47 (m, 2H), 7.33-7.19
(m, 7H), 5.47 (s, 2H), 4.12 (q, 2H, J = 7.0Hz), 2.92
(t, 2H, J = 7.8Hz), 1.94-1.85 (m, 2H), 1.48-1.35 (m, 4
H), 1.01 (t, 3H, J = 7.5Hz), 0.90 (t, 3H, J = 6.9Hz). IR (KBr tablets): 1720, 1226, 745 cm ^-1 . Melting point (diisopropyl ether): 124- 126 ° C

Example 37.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-hexylbenzimidazole (Compound 37), except that 2-hexylbenzimidazole is used instead of benzimidazole. According to the method of Example 12, a white crystal of the title compound (recrystallized from isopropyl ether-hexane mixed solution) was obtained in 2 steps of 47.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.18 (d, 1H, J = 8.6H
z), 7.80-7.74 (m, 2H), 7.49-7.48 (m, 2H), 7.32-7.19
(m, 7H), 5.47 (s, 2H), 4.11 (q, 2H, J = 7.5Hz), 2.92
(t, 2H, J = 7.8Hz), 1.92-1.84 (m, 2H), 1.45-1.24 (m, 6
H), 1.01 (t, 3H, J = 7.5Hz), 0.87 (dist.-t, 3H) .IR (KBr tablets): 2920, 1721, 1226, 769, 744 cm ^-1 . Melting point (diisopropyl ether-hexane) ): 91-93 ℃

Example 38.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-heptylbenzimidazole (Compound 38), except that 2-heptylbenzimidazole is used instead of benzimidazole. White crystalline title compound (recrystallized from isopropyl ether) according to the method of Example 12.
Was obtained in 2 steps of 22.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.18 (d, 1H, J = 8.6H
z), 7.81-7.74 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.19
(m, 7H), 5.47 (s, 2H), 4.11 (q, 2H, J = 7.5Hz), 2.93
(t, 2H, J = 7.8Hz), 1.96-1.86 (m, 2H), 1.48-1.22 (m, 8
H), 1.01 (t, 3H, J = 7.5Hz), 0.86 (t, 3H, J = 6.3Hz) .IR (KBr tablets): 2950, 1721, 1223, 764, 744 cm ^-1 . Melting point (diisopropyl ether ): 76-77 ℃

Example 39.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-isopropylbenzimidazole (Compound 39) Except for using 2-isopropylbenzimidazole instead of benzimidazole. According to the method of Example 12, the title compound as white crystals (recrystallized from isopropyl ether) was obtained in 2 steps of 20.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.34 (s, 1H), 8.18 (d, 1H, J = 8.5H
z), 7.82-7.74 (m, 2H), 7.55-7.44 (m, 2H), 7.32-7.15
(m, 7H), 5.50 (s, 2H), 4.11 (q, 2H, J = 7.5Hz), 3.32-
3.21 (m, 1H), 1.45 (d, 6H, J = 6.6Hz), 1.01 (t, 3H, J =
IR (KBr tablets): 1728, 1225, 781, 746 cm ^-1 . Melting point (diisopropyl ether): 139-140 ℃

Example 4 0.2-Cyclopropyl-1-
[4- (3-ethoxycarbonylquinolin-4-yl)
Benzyl] benzimidazole (Compound 40) 2% of the title compound (recrystallized from isopropyl ether-hexane mixed solvent) as white crystals according to the method of Example 12 except that 2-cyclopropylbenzimidazole is used instead of benzimidazole. Obtained in step 68.6%. ¹ H-NMR (CDCl ₃ ) δ: 9.34 (s, 1H), 8.18 (d, 1H, J = 8.8H
z), 7.81-7.73 (m, 2H), 7.52-7.44 (m, 2H), 7.34-7.21
(m, 7H), 5.60 (s, 2H), 4.10 (q, 2H, J = 7.5Hz), 2.09-
1.95 (m, 1H), 1.37-1.31 (m, 2H), 1.17-1.10 (m, 2H),
0.99 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1723, 1218, 766, 743 cm ^-1 . Melting point (diisopropyl ether-hexane): 148-150
℃

Example 41 2-Cyclopentyl-1-
[4- (3-ethoxycarbonylquinolin-4-yl)
Benzyl] benzimidazole (Compound 41) A white crystalline title compound (recrystallized from isopropyl ether) was obtained in 2 steps of 30.0% according to the method of Example 12 except that 2-cyclopentylbenzimidazole was used instead of benzimidazole. It was ¹ H-NMR (CDCl ₃ ) δ: 9.34 (s, 1H), 8.18 (d, 1H, J = 8.3H
z), 7.86-7.75 (m, 2H), 7.49-7.47 (m, 2H), 7.32-7.19
(m, 7H), 5.52 (s, 2H), 4.11 (q, 2H, J = 7.5Hz), 3.33 (q
uint, 1H, J = 8.5Hz), 2.19-1.68 (m, 8H), 1.02 (t, 3H,
J (7.5Hz). IR (KBr tablets): 2950, 1698, 1323, 773, 754 cm ^-1 . Melting point (diisopropyl ether): 154-156 ℃

Example 42.2-Cyclopentylmethyl-
1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] benzimidazole (Compound 42) White crystals were obtained according to the method of Example 12 except that 2-cyclopentylmethylbenzimidazole was used instead of benzimidazole. The title compound (recrystallized from isopropyl ether) was obtained in two steps of 12.0%. ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.17 (d, 1H, J = 8.3H
z), 7.82-7.74 (m, 2H), 7.50-7.46 (m, 2H), 7.31-7.18
(m, 7H), 5.47 (s, 2H), 4.11 (q, 2H, J = 7.5Hz), 2.94
(d, 2H, J = 7.3Hz), 2.56-2.44 (m, 1H), 1.89-1.70 (m, 2
H), 1.68-1.55 (m, 4H), 1.34-1.25 (m, 2H), 1.01 (t, 3
H, J = 7.5Hz). IR (KBr tablets): 2950, 1708, 1320, 771, 740 cm ^-1 . Melting point (diisopropyl ether): 127-128 ℃

Example 43.2-Cyclohexyl-1-
[4- (3-ethoxycarbonylquinolin-4-yl)
Benzyl] benzimidazole (Compound 43) A white crystalline title compound (recrystallized from isopropyl ether) was obtained in 2 steps of 49.0% according to the method of Example 12 except that 2-cyclohexylbenzimidazole was used instead of benzimidazole. It was ¹ H-NMR (CDCl ₃ ) δ: 9.35 (s, 1H), 8.18 (d, 1H, J = 8.4H
z), 7.82-7.74 (m, 2H), 7.48-7.47 (m, 2H), 7.31-7.19
(m, 7H), 5.49 (s, 2H), 4.12 (q, 2H, J = 7.5Hz), 3.00-
2.85 (m, 1H), 1.91-1.68 (m, 6H), 1.37-1.23 (m, 4H),
1.03 (t, 3H, J = 7.5Hz). IR (KBr tablets): 2930, 1219, 739 cm ^-1 . Melting point (diisopropyl ether): 159-161 ℃

Example 44.1- [4- (3-Ethoxycarbonylquinolin-4-yl) benzyl] -2-phenylbenzimidazole (Compound 44) Except that 2-phenylbenzimidazole is used instead of benzimidazole. According to the method of Example 12, the title compound as white crystals (recrystallized from ether) was used in 2 steps 40.5.
Earned in%. ¹ H-NMR (CDCl ₃ ) δ: 9.34 (s, 1H), 8.18 (d, 1H, J = 8.5H
z), 7.91 (dd, 1H, J = 8.5,1.3Hz), 7.85-7.75 (m, 3H),
7.53-7.49 (m, 5H), 7.39-7.20 (m, 7H), 5.60 (s, 2H),
4.10 (q, 2H, J = 7.5Hz), 1.00 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1724, 1219, 739 cm ^-1 . Melting point (diethyl ether): 195-196 ℃

Example 45.2-Hexyl-1- [4-
(3-Hydroxymethylquinolin-4-yl) benzyl] benzimidazole (Compound 45) Compound (37) (735 mg, 1.5 mmol) was used to give 571.3 mg (85.8%) of the title compound in white according to the method of Example 22. Obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 9.08 (s, 1H), 8.13 (d, 1H, J = 8.2H
z), 7.82-7.79 (m, 1H), 7.71-7.65 (m, 1H), 7.42-7.20
(m, 9H), 5.48 (s, 2H), 4.60 (s, 2H), 2.98-2.92 (dist.
-t, 2H), 1.91-1.80 (m, 2H), 1.45-1.29 (m, 6H), 0.88-
0.84 (dist.-t, 3H). IR (KBr tablets): 3200 (br), 1461, 1413, 1033, 742 cm ^-1 . Melting point (diethyl ether): 134-136 ℃

Example 46.1- [4- (3-formylquinolin-4-yl) benzyl] -2-hexylbenzimidazole (compound 46) Compound (45) 551.5 mg (1.24 mmol) was used in the Example. Two
According to the method of 3, 345.5 mg (63.0%) of the title compound was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 9.92 (s, 1H), 9.43 (s, 1H), 8.22
(d, 1H, J = 8.2Hz), 7.88-7.79 (m, 2H), 7.60-7.53 (m, 2
H), 7.40-7.23 (m, 7H), 5.50 (s, 2H), 2.95-2.89 (dist.
-t, 2H), 1.92-1.87 (m, 2H), 1.45-1.29 (m, 6H), 0.89-
0.85 (dist.-t, 3H). IR (KBr tablets): 2950, 1675, 1251, 752 cm ^-1 Melting point (diethyl ether): 136-138 ℃

Example 47.2-Hexyl-1- {4-
[3- (1-hydroxybutyl) quinolin-4-yl]
Benzyl} benzimidazole (Compound 47) According to the method of Example 24, except that 309.4 mg (0.7 mmol) of compound (46) and 1.1 equivalents of propylmagnesium bromide were used, the title compound 172.9 m was prepared along with Compound (45).
g (50.9%) of white amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.18 (s, 1H), 8.12 (d, 1H, J = 8.3H
z), 7.75-7.63 (m, 2H), 7.41-7.11 (m, 9H), 5.45 (s, 2
H), 4.68-4.63 (m, 1H), 2.90-2.84 (dist.-t, 2H), 1.87-
1.18 (m, 12H), 0.90-0.86 (dist.-t, 3H), 0.77 (dist.-
IR (KBr tablets): 3200 (br), 2858, 1463, 1410 cm ^-1 .

Example 48.1- [4- (3-butyrylquinolin-4-yl) benzyl] -2-hexylbenzimidazole (Compound 48) Compound (47) 460.0 mg (0.95 mmol) was used. Example 2
The free base of the title compound was obtained as a yellow oil according to the method of 3, and was then added to a saturated hydrogen chloride-ether solution to give 20
Obtained as 4.4 mg (41.4%) of the title compound hydrochloride salt (pale yellow crystals). ¹ H-NMR (CDCl ₃ ) δ: 9.16 (s, 1H), 8.58 (d, 1H, J = 8.3H
z), 8.03-7.97 (m, 2H), 7.70-7.27 (m, 9H), 5.77 (s, 2
H), 3.45-3.35 (dist.-t, 2H), 2.46-2.21 (dist.-t, 2H),
2.05-1.95 (m, 2H), 1.56-1.30 (m, 8H), 0.87-0.82 (dis
t.-t, 3H), 0.75 (t, 3H, J = 7.5Hz). IR (KBr tablets): 3400, 2950, 1700, 1460 cm ^-1 . Melting point (diethyl ether): 135 ℃

Example 49.2-Hexyl-1- {4-
[3- (1-Hydroxy-2-methylpropyl) quinolin-4-yl] benzyl} benzimidazole (Compound 49) Compound (46) 442.0 mg (1.0 mmol) and 1.2 equivalents of isopropyl magnesium bromide were used. Example 2
According to the method of 4 above, the title compound 25 together with the compound (45)
7.2 mg (53.0%) of white amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.13 (s, 1H), 8.12 (d, 1H, J = 8.3H
z), 7.77-7.76 (m, 2H), 7.41-7.15 (m, 9H), 5.45 (s, 2
H), 4.28 (d, 1H, J = 8.3Hz), 2.91-2.86 (dist.-t, 2H),
2.06-2.01 (m, 1H), 1.87-1.82 (m, 2H), 1.42-1.28 (m, 6
H), 0.99 (d, 3H, J = 6.6Hz), 0.89-0.84 (dist.-t, 3H),
0.64 (d, 3H, J = 6.6Hz). IR (KBr lock): 3200 (br), 2928, 1464, 765, 743 cm ^-1 .

Example 5 0.2-Hexyl-1- [4-
(3-Isobutyrylquinolin-4-yl) benzyl] benzimidazole (Compound 50) Using compound (47) 177.2 mg (0.37 mmol), Example 2
The free base of the title compound was obtained as a yellow oil according to the method of 3, and was then added to a saturated hydrogen chloride-ether solution to give 5
Obtained as 1.0 mg (26.5%) of the hydrochloride salt of the title compound (pale yellow crystals). ¹ H-NMR (CDCl ₃ ) δ: 9.05 (s, 1H), 8.59 (d, 1H, J = 8.3H
z), 8.06-7.94 (m, 2H), 7.70-7.24 (m, 9H), 5.71 (s, 2
H), 3.42-3.32 (dist.-t, 2H), 2.68-2.63 (m, 1H), 2.02-
1.97 (m, 2H), 1.48-1.31 (m, 6H), 0.96 (d, 6H, J = 6.9H
z), 0.88-0.83 (dist.t, 3H). IR (KBr tablets): 1700, 1483, 1380, 750 cm ^-1 .Melting point (diethyl ether): 127 ℃

Example 51 2-Hexyl-1- {4-
[3- (1-Hydroxypentyl) quinolin-4-yl] benzyl} benzimidazole (Compound 51) Example 24 except that 442.0 mg (1.0 mmol) of compound (46) and 1.05 equivalent of butylmagnesium chloride are used. 214.7 m of the title compound with compound (45) according to the method of
g (43.0%) of white amorphous solid was obtained. ¹ H-NMR (CDCl ₃ ) δ: 9.18 (s, 1H), 8.12 (d, 1H, J = 8.3H
z), 7.77-7.63 (m, 2H), 7.42-7.15 (m, 9H), 5.46 (s, 2
H), 4.70-4.60 (m, 1H), 2.92-2.86 (dist.-t, 2H), 1.92-
1.15 (m, 14H), 0.90-0.84 (dist.-t, 3H), 0.81-0.76 (di
st.-t, 3H) .IR (KBr tablets): 2918, 1460, 764, 740 cm ^-1 .

Example 52.2-Hexyl-1- [4-
(3-valerylquinolin-4-yl) benzyl] benzimidazole (Compound 52) Using Compound (47) 164.0 mg (0.33 mmol), Example 2
The free base of the title compound was obtained as a yellow oil according to the method of 3, and was then added to a saturated hydrogen chloride-ether solution to give 8
Obtained as 0.1 mg (45.5%) of the title compound as a hydrochloride salt (pale yellow crystals). ¹ H-NMR (CDCl ₃ ) δ: 9.20 (s, 1H), 8.68 (d, 1H, J = 8.3H
z), 8.05-7.90 (m, 2H), 7.80-7.28 (m, 9H), 5.81 (s, 2
H), 3.46-3.36 (dist.-t, 2H), 2.41-2.31 (dist.-t, 2H),
2.03-1.92 (m, 2H), 1.60-1.15 (m, 10H), 0.90-0.84 (di
st.-t, 3H), 0.81-0.78 (dist.-t, 3H). IR (KBr tablets): 2950, 1700, 1466, 1367, 747 cm ^-1 . Melting point (diethyl ether): 132 ℃

Reference Example 1. 1-[(2-Aminobenzophenone-4'-yl) methyl] -2-propylbenzimidazole (Compound A) 4'-Methyl-2-nitrobenzophenone 8.0 g (33 mmol)
Dissolved in 70 ml of carbon tetrachloride, N-bromosuccinimide
6.2 g (34.8 mmol) and a catalytic amount of azoisobutyronitrile were added and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was washed, dried and the solvent was distilled off, and the obtained crystals were recrystallized from diethyl ether to obtain 3.4 g (32%) of 4'-bromomethyl-2-nitrobenzophenone as light brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 8.20 (dd, 1H, J = 7.0,2.0Hz), 7.8-
7.2 (m, 7H), 4.48 (s, 2H).

6.4 g (20 mmol) of 4'-bromomethyl-2-nitrobenzophenone and 2-propylbenzimidazole
3.5 g (22 mmol) was dissolved in 12 ml of dimethylformamide, 2.3 g of sodium carbonate was added and heated at 80 ° C. for 14 hours.
The solvent was distilled off, water was added, and the mixture was extracted with chloroform,
Washed. The crude product obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane: ethyl acetate:
Triethylamine = 50: 10: 1) and 3.
84 g (48%) of pale yellow crystals were obtained as 1-[(2-nitrobenzophenone-4′-yl) methyl] -2-propylbenzimidazole. ¹ H-NMR (CDCl ₃ ) δ: 8.22 (br-d, 1H), 7.7-7.0 (m, 11H),
5.42 (s, 2H), 2.80 (t, 2H, J = 7.5Hz), 1.86 (sext, 2H,
J = 7.5Hz), 1.00 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1676, 1531, 1349, 745 cm ^-1 . Melting point (diethyl ether): 94-96 ℃

1-[(2-nitrobenzophenone-4 '
-Yl) methyl] -2-propylbenzimidazole 3.
78 g (9.5 mmol) was dissolved in 150 ml of ethanol and 15 ml of water, 3.8 g of iron and a catalytic amount of anhydrous ferric chloride were added, and the mixture was heated under reflux for 2 hours. The reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure, and the obtained crystals were recrystallized from ethanol to obtain 2.6 g (74%) of yellow crystals of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.9-7.2 (m, 10H), 6.8-6.5 (m, 2H),
5.42 (s, 2H), 2.85 (t, 2H, J = 7.5Hz), 1.92 (sext, 2H,
J = 7.5Hz), 1.02 (t, 3H, J = 7.5Hz). IR (KBr tablets): 1620, 1461, 1248, 748 cm ^-1 . Melting point (ethanol): 159-161 ℃

Reference Example 2.3-Ethoxycarbonyl-4-
(4-Toluyl) quinoline (Compound B) 4'-methyl-2-aminobenzophenone 200 mg (0.947m
mol) in 3 ml of ethanol and add ethyl propynate (0.52
ml, 5 mmol) and a catalytic amount of sulfuric acid were added, and the mixture was heated under reflux for 8 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform to wash and dry the organic layer. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and recrystallized from diethyl ether to give the title compound as white crystals (182.7 mg, 66%). ¹ H-NMR (CDCl ₃ ) δ: 9.33 (s, 1H), 8.17 (d, 1H, J = 7.9H
z), 7.76 (ddd, 1H, J = 8.4,7.9,1.5Hz), 7.65 (d, 1H, J =
7.0Hz), 7.47 (ddd, 1H, J = 8.4,7.0,1.5Hz), 7.31 (d, 2
H, J = 7.9Hz), 7.19 (d, 2H, J = 7.9Hz), 4.15 (q, 2H, J =
6.9Hz), 2.46 (s, 3H), 1.05 (t, 3H, J = 6.9Hz). IR (KBr tablets): 1720, 1573, 1498, 1372, 1224, 1165, 778
cm ^-1 .Melting point (diethyl ether): 110-112 ℃

Reference Example 3.3-Ethoxycarbonyl-2-
Oxo-4- (4-toluyl) -1,2-dihydroquinoline (Compound C) 4'-methyl-2-aminobenzophenone 5.28 g (25 mmo
l) is dissolved in 50 ml of dichloromethane, and 1 equivalent of malonic acid monoethyl chloride (purity 90%, 3.55 ml, 25 mmo under ice cooling)
A solution of l) in dichloromethane (10 ml) was added dropwise. After stirring with ice cooling for 10 minutes, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (4.5 ml, 3
A solution of 0 mmol) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature for 20 minutes.
Stir for minutes. Water was added to the reaction solution and extracted with dichloromethane, and the organic layer was washed and dried. The solvent was distilled off under reduced pressure and the obtained residue was recrystallized from diethyl ether to obtain 4.68 g (64%) of the title compound as a white crystal. ¹ H-NMR (CDCl ₃ ) δ: 12.40 (br-s, 1H), 7.67-7.56 (m, 2
H), 7.46-7.37 (m, 5H), 7.27-7.21 (m, 1H), 4.25 (q, 2
H, J = 6.9Hz), 2.55 (s, 1H), 1.13 (t, 3H, J = 6.9Hz) .IR (KBr tablets): 2864, 1730, 1660, 1634, 1242, 1088, 755
cm ^-1 .Melting point (diethyl ether): 219-222 ℃

Reference Example 4. 2-Chloro-3-ethoxycarbonyl-4- (4-toluyl) quinoline (Compound D) To 2.0 g (6.87 mmol) of compound (C) was added 10 ml of phosphorus oxychloride at 100 ° C. Heated for 1 hour. Phosphorus oxychloride was distilled off under reduced pressure, ethyl acetate was added to the residue, washed with saturated aqueous sodium hydrogen carbonate, and dried. The solvent was distilled off and the obtained crystal was triturated with diethyl ether to obtain 1.98 g (yield 93%) of the title compound as a white crystal. ¹ H-NMR (CDCl ₃ ) δ: 8.08 (d, 1H, J = 8.9Hz), 7.76 (m, 1
H), 7.63 (d, 1H, J = 8.4Hz), 7.50 (m, 1H), 7.32-7.25
(m, 4H), 4.15 (q, 2H, J = 7.4Hz), 2.45 (s, 3H), 1.07
(t, 3H, J = 7.4Hz). IR (KBr tablets): 1719, 1552, 1492, 1400, 1236, 1131, 103
3, 769 cm ^-1 .Melting point (diethyl ether): 139-141 ℃

Reference Example 5. 2-Butoxy-3-ethoxycarbonyl-4- (4-toluyl) quinoline (Compound E) 582 mg (2 mmol) of compound (C) was dissolved in 3 ml of DMF to obtain 60%.
To a solution of sodium hydride (88 mg, 2.2 mmol) in DMF (2 ml) was added under ice cooling. After 10 minutes, 0.228 ml (2 mmol) of iodobutane
Was added and reacted at room temperature for 2 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, extracted with ethyl acetate and washed,
Dried. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and the title compound was obtained as a colorless oil (239.6 mg, 33%) as a first eluting component. Also, 1-butyl-3-ethoxycarbonyl-2-oxo-4- (4-toluyl) -1,2-dihydroquinoline was obtained as white crystals (290.0 mg, 40%) as the second component. ¹ H-NMR (CDCl ₃ ) δ: 7.90 (d, 1H, J = 8.0Hz), 7.75-7.32
(m, 3H), 7.30 (s, 4H), 4.58 (t, 2H, J = 6.2Hz), 4.16
(q, 2H, J = 7.0Hz), 2.46 (s, 3H), 2.00-1.30 (m, 4H),
1.09 (t, 3H, J = 7.0Hz) .IR (NaCl neat): 2950, 1735, 1590, 1320, 1230, 1090,
760 cm ^-1 .

Reference Example 6.1 1-[(2-Aminobenzophenone-4'-yl) methyl] -2-butylbenzimidazole (Compound F) Except that 2-butylbenzimidazole is used instead of 2-propylbenzimidazole. According to the method of Reference Example 1, the title compound as white crystals was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.9-7.1 (m, 10H), 6.8-6.5 (m, 2H),
5.41 (s, 2H), 2.86 (t, 2H, J = 7.5Hz), 1.90-1.81 (m, 2
H), 1.47-1.39 (m, 2H), 0.93 (t, 3H, J = 7.5Hz).

[0112]

INDUSTRIAL APPLICABILITY The present invention provides a benzimidazole derivative having an immunosuppressive action.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Soichiro Sato 564-5 Nakachikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Takemori Omori 2-14-3 Fuyodai, Mishima-shi, Shizuoka Inventor Etsuko Nakai 1198-1 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture

Claims (1)

[Claims] 1. Formula (I): [Wherein R ¹ represents hydrogen, halogen, lower alkyl, lower alkoxy or substituted or unsubstituted aryl,
R ² is hydrogen, cyano, substituted or unsubstituted lower alkyl, lower alkanoyl, carboxy, lower alkoxycarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted aroyl, —CONR ⁶ R ⁷ (wherein R ⁶ and R ⁷ is the same or different and represents hydrogen or lower alkyl, or a heterocyclic group formed by combining R ⁶ and R ⁷ together with N), or R ¹ and R ² together. turned by - (CH _{2) m} - (wherein, m is an integer of 3-5), or - (CH _{2) n} CO- (in wherein, n
Is an integer of 2 to 4), R ³ represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl or substituted or unsubstituted aryl, R ⁴ and R ⁵ are the same or different and are hydrogen or Represents a lower alkyl] or a pharmaceutically acceptable salt thereof.