JPH07196626A - New benzimidazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new benzimidazole derivative, having strong antagonistic actions on cholecystokinin(CCK) receptors and useful as a preventing and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia or acute pancreatis. CONSTITUTION:This benzimidazole derivative is expressed by formula I [R is H, a halogen or a 1-3C alkyl; R<1> is H or a 1-3C alkyl; R<2> is carboxyl or a 2-5C alkoxycarbonyl; R<3> is a 1-10C alkyl; R<4> is a 1-3C alkoxy; Y is a 3-5C alkylene; (m) is 1-2], e.g. 2-[4-carboxy-2-[N-(3-methoxypropyl)-N- pentylcarbamoyl]butyl]-5,6-dichlorobenzimidazole expressed by formula II. The compound expressed by formula III which is one of the compound expressed by formula I is obtained by reacting a carboxylic acid derivative expressed by formula IV or its reactive functional derivative with a phenylendiamine derivative expressed by formula V, providing an amide derivative expressed by formula VI (R<6> is an alkyl), then heating the resultant derivative in acetic acid, as necessary, hydrolyzing the prepared compound under alkaline conditions and, as necessary, esterifying the hydrolyzed compound with alcohols expressed by the formula R<6>OH.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzimidazole derivative useful as a medicine.

More specifically, the present invention shows a cholecystokinin (hereinafter referred to as CCK) receptor antagonism, which causes hypersensitivity colitis, biliary dyskinesia,
Useful as a preventive and therapeutic agent for diseases such as acute pancreatitis,
General formula

[0003]

[Chemical 7]

(Wherein R is a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and R ² is a carboxyl group. Or an alkoxycarbonyl group having 2 to 5 carbon atoms, R ³ is an alkyl group having 1 to 10 carbon atoms, and R ⁴
Is an alkoxy group having 1 to 3 carbon atoms, and Y is 3 to 3 carbon atoms.
5 is an alkylene group of 5 and m is an integer of 1 to 2) and a pharmaceutically acceptable salt thereof.

[0005]

CCK is a gastrin.
n) and secretin, which are typical digestive tract hormones, and are known to be particularly involved in exocrine pancreatic stimulation, gallbladder contraction, and the like.

In recent years, research on CCK has been advanced, and the involvement of CCK in various diseases has been elucidated.

As a result, the specific, competitive and reversible C
CK receptor antagonist is irritable colitis, biliary dyskinesia,
It has come to be expected as a preventive and therapeutic agent for diseases such as acute pancreatitis, and has attracted attention.

Used as a therapeutic agent for peptic ulcer,
formula

[0009]

[Chemical 8]

Proglum represented by
Since it was reported that ide) shows CCK receptor antagonistic activity, research on proglumide derivatives has been advanced,
Several compounds having CCK receptor antagonistic activity have been produced and reported so far (Japanese Patent Laid-Open No. 61-448).
55, 62-181246, 63-27468, 63-165352, 63-201156, EP-A.
1-0308885, EP-A2-0272228, W
O 87/03869, same 88/05774, same 89 /
02431).

All of these compounds are amino acid derivatives such as glutamic acid and aspartic acid, and the compounds of the present invention have completely different structures from these compounds.

[0012]

SUMMARY OF THE INVENTION The object of the present invention is CCK.
It is intended to provide a benzimidazole derivative having a receptor antagonism and useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia and acute pancreatitis.

[0013]

[Means for Solving the Problems] The present inventors have found a new compound having a CCK receptor antagonistic action and useful as a preventive and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, acute pancreatitis and the like. As a result of diligent research, it was found that certain benzimidazole derivatives have a strong CCK receptor antagonistic action, and are useful as prophylactic and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, acute pancreatitis and the like. It came to be done.

The benzimidazole derivative represented by the above general formula (I) of the present invention is CCK-8 to a CCK receptor.
Competitively antagonizing the binding of CCK-8 and having an inhibitory effect on the gallbladder contraction action and amylase secretion action by CCK-8, and a preventive and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia and acute pancreatitis Is useful as

In the compounds of general formula (I) according to the invention:
The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the lower alkyl group having 1 to 3 carbon atoms means a linear or branched lower alkyl group having 1 to 3 carbon atoms. The term "C2-C5 alkoxycarbonyl group" means a C2-C5 linear or branched alkoxycarbonyl group such as a methoxycarbonyl group. Furthermore, an alkyl group having 1 to 10 carbon atoms means a linear or branched alkyl group having 1 to 10 carbon atoms, and an alkoxy group having 1 to 3 carbon atoms has 1 to 10 carbon atoms such as a methoxy group. 3 means a linear or branched alkoxy group having 3 to 3 carbon atoms
The alkylene group of 5 means a linear or branched alkylene group having 3 to 5 carbon atoms.

The benzimidazole derivative represented by the general formula (I) of the present invention is a novel compound and can be produced as follows.

That is, among the benzimidazole derivatives represented by the general formula (I), the general formula:

[0018]

[Chemical 9]

The benzimidazole derivative represented by the formula (wherein R, R ² , R ³ , R ⁴ , Y and m have the same meanings as described above) has the general formula

[0020]

[Chemical 10]

(Wherein R ⁶ is a lower alkyl group having 1 to 3 carbon atoms, and R ³ , R ⁴ and Y have the same meanings as described above) or a carboxylic acid derivative thereof or a reactive functional group thereof. Derivatives and general formula

[0022]

[Chemical 11]

A phenylenediamine derivative represented by the formula (wherein R and m have the same meaning as described above) is reacted in the presence or absence of a basic substance and, if necessary, in the presence of a condensing agent. And general formula

[0024]

[Chemical 12]

An amide derivative represented by the formula (wherein R, R ³ , R ⁴ , R ⁶ , Y and m have the same meanings as described above),
It is then heated in acetic acid, optionally hydrolyzed under alkaline conditions such as sodium hydroxide, and if necessary,

[0026]

[Chemical 13]

It can be produced by esterification by an ordinary method with an alcohol derivative represented by (R ⁶ in the formula has the same meaning as described above).

Among the benzimidazole derivatives represented by the general formula (I) of the present invention, the general formula:

[0029]

[Chemical 14]

Benzimidazole represented by the formula (wherein R ⁷ is a lower alkyl group having 1 to 3 carbon atoms, and R, R ² , R ³ , R ⁴ , Y and m have the same meanings as described above) The derivative includes a benzimidazole derivative represented by the general formula (Ia) and a general formula

[0031]

[Chemical 15]

(Wherein X is a halogen atom or an acid residue and R ⁷ has the same meaning as described above), reacts with a compound such as sodium hydride in the presence of a base, Accordingly, it can be produced by hydrolysis under alkaline conditions such as sodium hydroxide.

In the method for producing the compound of the general formula (I) of the present invention, the above-mentioned general formula (III) used as a starting material
The compound of 1 can be produced as follows.

That is, the formula

[0035]

[Chemical 16]

Malonic acid tert-butyl ester represented by

[0037]

[Chemical 17]

[0038] It reacts in the presence of a basic substance such as Triton B, and has the general formula

[0039]

[Chemical 18]

A carboxylic acid derivative represented by the formula (wherein R ⁶ has the same meaning as described above) is prepared.

[0041]

[Chemical 19]

Benzyl bromoacetate represented by the following formula is reacted in the presence of a base such as sodium hydride to give a compound of the general formula

[0043]

[Chemical 20]

After the ester derivative represented by the formula (R ⁶ has the same meaning as described above) is prepared, it is treated with trifluoroacetic acid to give a compound of the general formula

[0045]

[Chemical 21]

A carboxylic acid derivative represented by the formula (wherein R ⁶ has the same meaning as described above) is prepared. Then, the carboxylic acid derivative or its reactive functional derivative and the general formula

[0047]

[Chemical formula 22]

(Wherein R ³ , R ⁴ and Y have the same meanings as defined above) and an amine derivative in the presence or absence of a basic substance, and optionally in the presence of a condensing agent. Reacts, general formula

[0049]

[Chemical formula 23]

After preparing the amide derivative represented by the formula (wherein R ³ , R ⁴ , R ⁶ and Y have the same meanings as described above), the benzyl group of the protecting group is replaced by the presence of a catalyst such as palladium carbon. The compound of the general formula (III) can be produced by hydrogenating and removing underneath.

In the method for producing the compound of the general formula (I) of the present invention, the other compounds represented by the general formulas (IV) and (XIV) used as starting materials are easily available as commercial products. it can.

In the present production method, the reactive functional derivative of carboxylic acid may be an acid halide, an acid anhydride, a mixed acid anhydride, an active ester or the like, and the condensing agent may be 2-chloro-1 iodide. -Methylpyridinium and the like can be mentioned.

The benzimidazole derivative represented by the general formula (I) of the present invention has an asymmetric carbon and has an optically active substance. In the present invention, any of the R isomer, the S isomer or a mixture thereof is used. Can also be used.

The benzimidazole derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method. Examples thereof include inorganic acids such as hydrochloride, hydrobromide and sulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, citrate and succinate. And acid addition salts of organic acid salts such as tartrate and fumarate. Further, as the compound in which R ² is a carboxyl group, salts with inorganic bases such as sodium salts, potassium salts, calcium salts, etc., organic amines such as morpholine, piperidine, etc., and amine salts with amino acids can be mentioned. These pharmacologically acceptable salts also have a CCK receptor antagonistic action like the free form, and are useful as prophylactic and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia and acute pancreatitis.

Among the benzimidazole derivatives represented by the general formula (I) of the present invention, preferred compounds include 2-
[4-Carboxy-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6-
Dichlorobenzimidazole, 2- [4-carboxy-
2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole, 2- [4-
Carboxy-2- [N- (3-methoxypropyl) -N
-Pentylcarbamoyl] butyl] -5,6-dimethylbenzimidazole, 5,6-dichloro-2- [4-ethoxycarbonyl-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole And more preferred examples thereof include 2- [4-carboxy-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] -5, and pharmaceutically acceptable salts thereof. 6-dichlorobenzimidazole and its pharmacologically acceptable salts can be mentioned.

When the benzimidazole derivative represented by the general formula (I) of the present invention is used as an actual therapeutic agent, it is orally used as a suitable pharmaceutical composition such as tablets, powders, granules, capsules and injections. Alternatively, it is administered parenterally. These pharmaceutical compositions are prepared by conventional pharmaceutical techniques.

The dose is appropriately determined according to the sex, age, weight, type of disease, degree of symptom, etc. of the subject patient. In the case of oral administration, the dose is generally 1 to 1000 mg per adult per day.
In the case of parenteral administration, the daily dose is generally within the range of 0.1 to 100 mg.

[0058]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 5- (Methoxycarbonyl) -3- [N- (3-methoxypropyl) -N-pentylcarbamoyl] valeric acid

4.1 ml of methyl acrylate and di-t malonate
ert-Butyl 10g to 1,2-dimethoxyethane 90m
It was dissolved in l, 20 drops of Triton B (40% methanol solution) was added, and the mixture was stirred at 60 ° C. for 24 hours. After concentrating under reduced pressure, the residue was dissolved in ether and washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 8.6 g (104 ° C / 0.35 mmHg) of di-tert-butyl (2-methoxycarbonylethyl) malonate.

NMR (CDCl ₃ ) σ: 1.46 (18H, s), 2.12 (2H, q, J = 7.5Hz), 2.39 (2H,
t, J = 7.4Hz), 3.21 (1H, t, J = 9.8Hz), 3.68 (3H, s)

0.72 g of 60% sodium hydride in oil
Suspended in 70 ml of 2-dimethoxyethane, at room temperature di-tert-butyl (2-methoxycarbonylethyl) malonate
5.0 g was added dropwise. After stirring at room temperature for 4 hours, benzyl bromoacetate (2.8 ml) was added, and the mixture was stirred overnight. Aqueous ammonium chloride solution was added, the mixture was extracted with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of methylene chloride, 20 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After concentrating under reduced pressure, the residue was dissolved in 300 ml of toluene and refluxed overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in an aqueous sodium hydrogen carbonate solution, and washed twice with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with methylene chloride, and then washed with an aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
3.6 g of benzyloxycarbonylmethyl-4-methoxycarbonylbutyric acid was obtained.

NMR (CDCl ₃ ) σ: 1.86 to 2.08 (2H, m), 2.34 to 2.59 (3H, m), 2.70 to
2.85 (1H, m), 2.88 ~ 3.00 (1H, m), 3.67 (3H, s), 5.08 ~
5.19 (2H, m), 7.29 ~ 7.40 (5H, m)

2-benzyloxycarbonylmethyl-4
3.1 g of -methoxycarbonylbutyric acid was added dropwise to a solution of 9.2 ml of oxalyl chloride heated to 50 ° C and 1 drop of N, N-dimethylformamide in 30 ml of benzene. After stirring at 60 ° C for 30 minutes, the solvent was distilled off under reduced pressure. Methylene chloride residue
Dissolve in 40 ml and add triethylamine 7.3
ml, N- (3-methoxypropyl) -N-pentylamine (2 ml), and 4-dimethylaminopyridine (0.4 g) were sequentially added. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, the precipitated crystals were filtered off, and the filtrate was diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution,
It was washed successively with aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 5-methoxycarbonyl-3- [N- (3-methoxypropyl) -N-pentylcarbamoyl] valerate benzyl 4.6.
g was obtained.

NMR (CDCl ₃ ) σ: 0.81 to 0.98 (3H, m), 1.16 to 1.39 (4H, m), 1.42 to
1.48 (2H, m), 1.71 ~ 2.01 (4H, m), 2.28 ~ 2.38 (2H, m
m), 2.39 ~ 2.49 (1H, m), 2.77 ~ 2.93 (1H, m), 3.08 ~
3.20 (2H, m), 3.22 ~ 3.51 (8H, m), 3.60 ~ 3.70 (3H, m),
5.00 ~ 5.16 (2H, m), 7.29 ~ 7.41 (5H, m)

5-methoxycarbonyl-3- [N- (3
-Methoxypropyl) -N-pentylcarbamoyl] benzyl valerate 4.0 g of 10% palladium carbon was suspended in a solution of 4.0 g of ethyl acetate in 30 ml of ethyl acetate, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in an aqueous sodium hydrogen carbonate solution. The aqueous layer was washed with diethyl ether, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and 5-methoxycarbonyl-3-
3.1 g of [N- (3-methoxypropyl) -N-pentylcarbamoyl] valeric acid was obtained.

NMR (CDCl ₃ ) σ: 0.85 to 0.96 (3H, m), 1.21 to 1.40 (4H, m), 1.49 to
1.67 (2H, m), 1.78 ~ 2.06 (4H, m), 2.41 (2H, t, J = 6.6H
z), 2.52 ~ 2.62 (1H, m), 2.68 ~ 2.81 (1H, m), 3.00 ~
3.71 (10H, m), 3.67 (3H, s)

Reference Example 2 Pancreatic CCK receptor binding test

The method of Chang et al. [Molecular Phar
volume, 30 pages, 212 pages, 1986.
Year], a pancreatic tissue membrane sample was prepared. After removing the pancreas from male Wistar rats, removing adipose tissue, and slicing in 50 times the amount of wet weight of ice-cold 50 mM Tris (Tris) HCl buffer (pH 7.4, 37 ° C.), Homogenized using an Ultra Disperser. The homogenate was centrifuged at 50,000 xg for 10 minutes, the precipitate was suspended in Tris-HCl buffer, and the suspension was centrifuged again at 50,000 xg for 10 minutes. The precipitate was resuspended in an assay buffer (50 mM Tris HCl, 5 mM MgCl ₂ , 5 mM dithiothreitol, 2 mg / ml bovine serum albumin, 0.14 mg / ml bacitracin) to give a CCK binding test material.

Pancreatic tissue membrane suspension (usually 0.5 mg original tissue weight / ml), 30 pM [ ¹²⁵ I] CCK-8 and test drug or its solvent (for total binding), 10 ^-6 M CCK-8
(For non-specific binding) is added to the assay buffer and the total volume is 1 ml.
And After incubating at 37 ° C. for 30 minutes, the sample was suction-filtered, the filter was washed with ice-cold Tris-HCl buffer, and its radioactivity was measured by a γ-counter (Packard 5650).

The specific binding amount to the CCK receptor was determined from the difference between the total binding amount and the non-specific binding amount, and the IC ₅₀ value was calculated from the inhibition rate of the specific binding amount by the test drug.

[0072]

[Table 1]

Example 1 5,6-dichloro-2- [4-methoxycarbonyl-2]
-[N- (3-Methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole (Compound 1)

5-methoxycarbonyl-3- [N- (3
-Methoxypropyl) -N-pentylcarbamoyl] valeric acid (5.4 g), 4,5-dichloro-1,2-phenylenediamine (2.8 g), and 2-chloro-1-methylpyridinium iodide (4.4 g) were suspended in 70 ml of methylene chloride. 6.8 ml of N, N-diisopropylethylamine was added at room temperature,
Stir overnight. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with an aqueous citric acid solution, an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 80 ml of acetic acid and stirred at 60 ° C for 1 hour. Acetic acid was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purified by medium pressure liquid chromatography (eluting solvent: hexane / ethyl acetate = 1/4), crystallized from diethyl ether-hexane, and 5,6-dichloro-2-
5.6 g of [4-methoxycarbonyl-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole was obtained.

Melting point: 104 to 107 ° C. IR (KBr): ν _{C = O} 1745 cm ⁻¹ , 1610 cm ⁻¹ NMR (CDCl ₃ ) σ: 0.73 to 0.92 (3H, m), 1.05 to 1.53 (6H, m ), 1.60
~ 1.90 (3H, m), 1.96 ~ 2.11 (1H, m), 2.39 ~ 2.55 (2H, m
m), 3.01 ~ 3.58 (9H, m), 3.26 (3H, s), 3.67 (3H, s),
7.44 (1H, s), 7.72 (1H, m), 11.02 ~ 11.19 (1H, m)

Example 2 The following compounds were synthesized in the same manner as in Example 1.

2- [4-methoxycarbonyl-2- [N
-(3-Methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole (Compound 2A)

[0078] _{IR (KBr): ν C =} O 1739 cm -1, 1618 cm -1 NMR (CDC1 3) σ: 0.97 (3H, t, J = 7.0Hz), 1.28~1.43 (4H, m), 1.4
9 ~ 1.62 (2H, m), 1.77 ~ 2.10 (4H, m), 2.45 (2H, t, J =
7.6Hz), 3.10 (1H, dd, J = 14.6Hz and 6.0Hz), 3.15 (1H,
dd, J = 8.0Hz), 3.28 ~ 3.55 (7H, m), 3.32 (3H, s), 3.
72 (3H, s), 7.19 ~ 7.24 (2H, m), 7.56 (2H, br-s), 11.9
(1H, m)

5,6-Dimethyl-2- [4-methoxycarbonyl-2- [N- (3-methoxypropyl) -N-
Pentylcarbamoyl] butyl] benzimidazole (Compound 2B)

IR (KBr): ν _{C = O} 1745 cm ⁻¹ , 1615 cm ⁻¹ NMR (CDC1 ₃ ) σ: 0.77 (1.5H, t, J = 7.0Hz), 0.86 (1.5H, t, J = 7.0H
z), 1.03 ~ 2.09 (10H, m), 2.33 (6H, m), 2.35 ~ 2.52 (2
H, m), 3.03 ~ 3.52 (9H, m), 3.22 (1.5H, s), 3.27 (1.5
H, s), 7.12 (1H, br-s), 7.40 (1H, br-s), 10.08 ~ 10.2
3 (1H, br)

Example 3 5,6-dichloro-2- [4-methoxycarbonyl-2]
-[N- (3-Methoxypropyl) -N-pentylcarbamoyl] butyl] -1-methylbenzimidazole
(Compound 3)

5,6-dichloro-2- [4-methoxycarbonyl-2- [N- (3-methoxypropyl) -N-
Pentylcarbamoyl] butyl] benzimidazole 10
0 mg was dissolved in 1 ml N, N-dimethylformamide and at room temperature added 9 mg of 60% sodium hydride in oil. After stirring for 1 hour, 26 μl of methyl iodide was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water, extracted with diethyl ether, the organic layer was washed with an aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by preparative thin layer chromatography (developing solvent: hexane / acetone = 3/1) to give 5,6-
Dichloro-2- [4-methoxycarbonyl-2- [N-
74 mg of (3-methoxypropyl) -N-pentylcarbamoyl] butyl] -1-methylbenzimidazole was obtained.

[0083] _{IR (KBr): ν C =} O 1740 cm -1, 1625 cm -1 NMR (CDC1 3) σ: 0.79 (1H, t, J = 7.2Hz), 0.86 (2H, t, J = 7.2Hz ),
1.01 ~ 1.48 (6H, m), 1.52 ~ 1.82 (2H, m), 1.89 ~ 2.18 (2
H, m), 2.37 ~ 2.48 (2H, m), 2.86 ~ 2.97 (1H, m), 3.06 ~
3.41 (7H, m), 3.20 (2H, s), 3.30 (1H, s), 3.45 ~ 3.59 (1
H, m), 3.68 (3H, s), 3.70 (3H, d, J = 2.6Hz), 7.36 (1H,
s), 7.86 (1H, s)

Example 4 2- [4-Carboxy-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6
-Dichlorobenzimidazole (Compound 4)

5,6-dichloro-2- [4-methoxycarbonyl-2- [N- (3-methoxypropyl) -N-
Pentylcarbamoyl] butyl] benzimidazole
2.0 g was dissolved in 14 ml of methanol, 9.0 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred for 4 hours. Methanol was distilled off under reduced pressure, and the aqueous layer was washed with diethyl ether. 9.0 ml of 1N aqueous hydrochloric acid solution was added, and the deposited precipitate was collected by filtration and dried under reduced pressure. Recrystallized from ethanol-diethyl ether to give 2- [4-carboxy-2- [N-
(3-Methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6-dichlorobenzimidazole 1.
I got 7g.

Melting point: 191-192 ° C. IR (KBr): ν _{C = O} 1715 cm ⁻¹ , 1605 cm ⁻¹ NMR (CDCl ₃ ) σ: 0.74 (1.5H, t, J = 7.2Hz), 0.80 (1.5 H, t, J = 7.2H
z), 0.93 to 1.39 (6H, m), 1.45 to 1.91 (4H, m), 2.23 (2
H, t, J = 7.3Hz), 2.86 ~ 3.42 (9H, m), 3.10 (1.5H, s),
3.19 (1.5H, s), 7.62 ~ 7.78 (2H, m), 12.11 (1H, br-
s), 12.48 (1H, br-s)

Example 5 The following compounds were synthesized in the same manner as in Example 4.

2- [4-carboxy-2- [N- (3-
Methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole (Compound 5A)

Melting point: 177 to 178 ° C. IR (KBr): ν _{C = O} 1715 cm ⁻¹ , 1625 cm ⁻¹ NMR (CDCl ₃ ) σ: 0.66 (1.4H, t, J = 6.9Hz), 0.85 (1.6 H, t, J = 6.9H
z), 1.06 ~ 1.81 (6H, m), 2.02 ~ 2.11 (1H, m), 2.44 ~
2.73 (1H, m), 3.11 (1.6H, s), 3.27 (1.4H, s), 3.06 ~
3.77 (6H, m), 7.10 ~ 7.30 (3H, m), 7.55 ~ 7.64 (2H, m)

2- [4-carboxy-2- [N- (3-
Methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6-dimethylbenzimidazole (Compound 5
B)

Melting point: 196-198 ° C IR (KBr): ν _{C = O} 1710 cm ^-1 , 1625 cm ^-1 NMR (CDCl ₃ ) σ: 0.68 (1.6H, t, J = 6.9Hz), 0.83 (1.4 H, t, J = 6.9
Hz), 1.02 ~ 1.51 (6H, m), 1.53 ~ 1.85 (3H, m), 2.00
~ 2.12 (1H, m), 2.32 (6H, s), 2.41 ~ 2.52 (1H, m), 2.60
~ 2.72 (1H, m), 3.03 ~ 3.74 (9H, m), 3.12 (1.4H, s),
3.25 (1.6H, s), 7.30 (2H, s), 9.11 ~ 9.92 (2H, br)

2- [4-carboxy-2- [N- (3-
Methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6-dichloro-1-methylbenzimidazole (Compound 5C)

Melting point: 143 to 145 ° C. IR (KBr): ν _{C = O} 1715 cm ⁻¹ , 1635 cm ⁻¹ NMR (CDCl ₃ ) σ: 0.72 to 0.85 (3H, m), 0.99 to 1.45 (6H, m ), 1.51
~ 1.77 (2H, m), 1.82 ~ 1.97 (1H, m), 2.08 ~ 2.20 (1H, m
m), 2.49 ~ 2.60 (2H, m), 3.05 ~ 3.50 (11H, m), 3.61 ~
3.71 (1H, m), 3.76 (3H, s), 7.39 (1H, s), 7.77 (1H, s)

Example 6 5,6-dichloro-2- [4-ethoxycarbonyl-2
-[N- (3-Methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole (Compound 6)

2- [4-carboxy-2- [N- (3-
Methoxypropyl) -N-pentylcarbamoyl] butyl] -5,6-dichlorobenzimidazole (633 mg) and concentrated sulfuric acid (50 μl) were dissolved in ethanol (5 ml) and the mixture was refluxed for 5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed successively with an aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. It was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Hexane was added to the residue for crystallization to obtain 500 mg of 5,6-dichloro-2- [4-ethoxycarbonyl-2- [N- (3-methoxypropyl) -N-pentylcarbamoyl] butyl] benzimidazole.

Melting point: 83 to 85 ° C. IR (KBr): ν _{C = O} 1735 cm ⁻¹ , 1610 cm ⁻¹ NMR (CDCl ₃ ) σ: 0.79 to 0.88 (3H, m), 1.09 to 1.49 (8H, m ), 1.63
~ 1.83 (4H, m), 1.86 ~ 2.06 (1H, m), 2.33 ~ 2.49 (2H, m
m), 3.08 ~ 3.56 (12H, m), 4.10 ~ 4.16 (2H, m), 7.45 (1
H, br-s), 7.73 (1H, br-s), 10.96 ~ 11.10 (1H, br-s)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Tetsuro Tamai 3868 Asamura, Higashichikuma-gun, Nagano (868) Inventor Kenji Akabane 1160-4 Toyoshina, Toyoshina-cho, Minamiazumi-gun, Nagano

Claims (6)

[Claims] 1. A general formula: (R in the formula is a hydrogen atom, a halogen atom or a carbon number of 1 to
3 is a lower alkyl group, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ² is a carboxyl group or an alkoxycarbonyl group having 2 to 5 carbon atoms, and R ³
Is an alkyl group having 1 to 10 carbon atoms, and R ⁴ is 1 to 10 carbon atoms.
3 is an alkoxy group, Y is an alkylene group having 3 to 5 carbon atoms, and m is an integer of 1 to 2), and a pharmaceutically acceptable salt thereof. 2. A general formula: (R in the formula is a hydrogen atom, a halogen atom or a carbon number of 1 to
3 is a lower alkyl group, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ² is a carboxyl group or an alkoxycarbonyl group having 2 to 5 carbon atoms, and R ⁴
Is an alkoxy group having 1 to 3 carbon atoms, and R ⁵ is 4 to 4 carbon atoms.
7 is an alkyl group, Y is an alkylene group having 3 to 5 carbon atoms, and m is an integer of 1 to 2). The benzimidazole derivative according to claim 1 or a pharmaceutically acceptable derivative thereof. Salt. 3. A general formula: (R in the formula is a hydrogen atom, a halogen atom or a carbon number of 1 to
3 is a lower alkyl group, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ² is a carboxyl group or an alkoxycarbonyl group having 2 to 5 carbon atoms, m
Is an integer of 1 to 2), and the benzimidazole derivative according to claim 2 or a pharmaceutically acceptable salt thereof. 4. A general formula: (R in the formula is a hydrogen atom, a halogen atom or a carbon number of 1 to
3 is a lower alkyl group, R ² is a carboxyl group or an alkoxycarbonyl group having 2 to 5 carbon atoms, and m is 1
The benzimidazole derivative according to claim 3 and a pharmacologically acceptable salt thereof. 5. A general formula: (R in the formula is a hydrogen atom, a halogen atom or a carbon number of 1 to
3 is a lower alkyl group and m is an integer of 1 to 2)
The benzimidazole derivative according to claim 4 represented by and a pharmacologically acceptable salt thereof. 6. The formula: The benzimidazole derivative according to claim 5 represented by and a pharmacologically acceptable salt thereof.