JPH01261376A - Benzimidazole derivative, its production and antiulcer agent containing said derivative - Google Patents

Abstract

NEW MATERIAL:The benzimidazole derivative of formula I (R1 and R2 are H, alkyl, cycloalkyl, aryl, aralkyl or halogenated alkyl; at least one of R1 and R2 is halogenated alkyl; R3-R7 are H, halogen, alkoxy, alkyl, alkoxycarbonyl, nitro, amino, acyl, fluorinated alkyl or fluorinated alkoxy). EXAMPLE:2-[2-[N-methyl-N-(2,2,2-trifluoroethyl)amino]benzylsulfinyl]- benzimidazole. USE:An antiulcer agent having excellent gastric inhibitory action and safety. PREPARATION:The objective benzimidazole derivative of formula I can be produced by oxidizing the compound of formula II.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel benzimidazole derivative, more specifically, the following general formula (I): (wherein R1 and R2 are hydrogen atoms, carbon atoms Numbers 1-8
an alkyl group, a cycloalkyl group having 5 to 8 carbon atoms,
An aryl group, an aralkyl group (wherein the alkyl group has 1 to 4 carbon atoms), or an alkyl group having 1 to 8 carbon atoms and having a halogen atom, in which R1 and R
At least one of 2 is a carbon atom having a halogen atom
1 to 8 alkyl groups, R3, Ra, Rs, Rh and R7 may be the same or different, and include a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group,
(a substituent selected from the group consisting of a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, and a fluorine-substituted alkoxy group); and a method for producing the same; The present invention relates to an anti-ulcer agent containing as an active ingredient.

[Prior Art] Conventionally, a benzimidazole derivative represented by the general formula (A): (wherein R8 and R9 represent a hydrogen atom or a lower alkyl group, and RIO represents a hydrogen atom or a lower alkoxy group) ten″
It is known to be useful as an anti-ulcer agent having an ATPase inhibitory effect (Japanese Patent Application Laid-Open No. 61-60660).

Further, general formula (B): (wherein, R1+ and RI2 are hydrogen atoms or lower alkyl groups, and at least one of R13 and R14 is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group) or an amino group), the benzimidazole derivative represented by
It is also known to be useful as an anti-ulcer agent having an ATPase inhibitory effect (Japanese Patent Application Laid-Open No. 61-221175).

Furthermore, general formula (C): H (wherein RI5 represents a cycloalkyl group, phenyl group or aralkyl group, RI6 represents a hydrogen atom or a lower argyl group, or R15 and R16 jointly represent an adjacent nitrogen It is also known that benzimidazole derivatives represented by (forming a ring with atoms) are useful as anti-ulcer agents that have an ATPase inhibitory effect on H.

Furthermore, it is also known that benzimidazole derivatives represented by the general formula (D) are useful as anti-ulcer agents (Japanese Patent Laid-Open No. 62-51
Publication No. 671).

[Problems to be Solved by the Invention] It is desired to provide a novel compound that has an excellent anti-ulcer effect and is also safer.

[Means for Solving the Problems] Under these circumstances, the present inventors conducted intensive research and found that the novel benzimidazole derivative represented by the above formula (I) has an excellent effect of suppressing gastric acid secretion. The present invention has been completed.

The conventionally known benzimidazole derivatives represented by the above formulas (A), (B) and (C) all have a polar group as a substituent bonded to the nitrogen atom bonded to the phenyl ring. On the other hand, in the novel benzimidazole derivative represented by formula (I) of the present invention, the substituent bonded to the nitrogen atom bonded to the phenyl ring has a polar halogen atom, It is thought that this greatly influences the properties of the compound and contributes to its safety.

Furthermore, while the benzimidazole derivative represented by the above formula (D) has an amide bond in which the substituent bonded to the nitrogen atom bonded to the phenyl ring is bonded via a carbonyl group, In the novel benzimidazole derivative of the present invention represented by the above formula (I), the substituent bonded to the nitrogen atom bonded to the phenyl ring does not have a carbonyl group but is bonded to the nitrogen atom through an alkylene group. They are different in that they are

Therefore, the present invention provides a novel benzimidazole derivative (I) useful as an anti-ulcer agent.

The present invention also provides a new method for producing benzimidazole derivatives CI).

Furthermore, the present invention provides an anti-ulcer agent containing the benzimidazole derivative (I).

The benzimidazole derivative (I) of the present invention is, for example,
According to the following reaction formula, 2-7 minobenzizoic acid ester (I
2-aminobenzyl compound (V[) produced from I)
It is produced by reacting with 2-mercaptobenzimidazole to form a compound (■), which is then oxidized.

(II) (m) (IV) (V) (■) (I) (In the formula, R1 #R7 are the same as above.) The raw material compound (II) for the production method of the present invention is a known compound. However, compounds (m), (IT), (V)
, (Vlf), (■) and (I) are new compounds.

Oxylation of compound (■) can be carried out by a conventional method, for example, using an oxidizing agent such as hydrogen peroxide, m-chloroperanate, an organic peracid such as q-fraic acid, or sodium metaperiodate.
Compound (■) may be oxidized. The reaction is carried out in an inert solvent such as chloroform, dichloromethane, methanol, ethyl acetate, etc. at -30°C to 50°C, preferably -15°C to 5°C.
It is carried out at a temperature of

As representative compounds of the benzimidazole derivatives of the present invention, the following compounds can be exemplified.

2- [2-[N-methyl-N-(2,2,2-trifluoroethyl)aminocobenzylsulfinyl 1benzimidazole, 2-(2-(N-methyl-N-)lifluoromethylamino)benzyl sulfinyl] benzimidazole.

2-[2-[N-(2-chloroethyl)-N-ethylamino)benzylsulfinyl]benzimidazole, 2-[[2-IN-(2-chloroethyl)-N-methylaminoco-5-methoxy]benzylsulfinyl finyl]benzimidazole, 2-[2-[N-ethyl-N-(2-fluoroethyl)amino]benzylsulfinyl]benzimidazole, 2-[2-[N-methyl-N-(3,3,3 -trifluoropropyl)amine]benzylsulfinyl]benzimidazole, 2- [2-[N-methyl-N-(2,2,2-trifluoroethyl)aminocobenzylsulfinyl]-5-
Methoxybenzimidazole, 2-[2-[N-methyl-N-(2,2,2-trifluoroethyl)aminocobenzylsulfinyl]-5-methylbenzimidazole, 2-[[2-[N-methyl- N-(2,2,2-
trifluoroethyl)aminoco-5-methoxy]benzylsulfinyl]benzimidazole, 2-[[2-[N-methyl-N-(2,2,2-trifluoroethyl)aminoco-5-methyl]benzimidazole 2-[[2-[N-methyl-N-(2,2,2-trifluoroethyl)amine]-5-methoxy]benzylsulf"ynyl]-5-methoxybenz Imidazole, 2-[2-[N-(2-bromoethyl)-N-methylamino]benzylsulfinyl]benzimidazole, 2-[2-[N-(3-chloropropyl)-N-methylamine]benzylsulfinyl] -5-Methoxybenzimidazole The results of a pharmacological effect test on the representative compound (I) of the present invention thus obtained are as follows.

(1) Conventional method for suppressing gastric acid secretion [Shay et al., Gastroenterology (S
Hay, H. et al., Gastroent
erology) 5.

43-61 (1945)], body weight 200-250
After fasting male Donryu rats for 24 hours (with free access to water), the abdomen was opened under ether anesthesia, the pylorus was ligated, and the test compound was administered into the duodenum. After 4 hours, the animals were sacrificed, the stomach was removed, and the gastric fluid was collected. Acidity (Ac1d output) is self! ! b Using a W4 constant apparatus.

0.0, IN sodium hydroxide to pH 7.0 and the values obtained were compared to those of control animals treated similarly but not receiving the test compound. As a result, the compound of the present invention obtained in Example 1 below was administered at a dosage of 30 mg/kg.
The compound of the present invention obtained in Example 2 also inhibited gastric acid secretion by 80.4% at a dose of 130 mg/kg.
% suppressed.

Compound (I) of the present invention can be administered either orally or parenterally. Examples of dosage forms for oral administration include single tablets, capsules, powders, granules, syrups, etc., and dosage forms for parenteral administration include injections. For their preparation, conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used. Excipients include glucose, lactose, etc. Disintegrants include starch, carboxymethyl cellulose calcium, etc. Lubricants include magnesium stearate, talc, etc. Binders include hydroxypropyl cellulose,
Gelatin, polyvinylpyrrolidone, etc. are used.

The dosage is approximately 1 ml per day for injections in normal humans.
g ~50 mg g, approximately 10 mg ~5 per day by oral administration
The dosage can be increased or decreased depending on age, symptoms, etc.

Next, the present invention will be explained with reference to Examples.

[Example 1] 2-[2-[N-methyl-N-(2,2,2-trifluoroethyl)amino]benzylsulfinyl]benzimidazole: (i) Methyl N-(2,2,2-trifluoroethyl) Fluoroethyl) anthranilate: 6.5 g (43 mmol) of methyl anthranilate and 6.5 g (23 mmol) of 2,2.2-)lifluoroethyl trichloromethane sulfonate were dissolved in 13 mJ of xylene.
The reaction mixture was refluxed for 2 hours in 100 ml of water and cooled, the precipitated crystals were filtered off, and the filtrate was distilled off under reduced pressure. Distill the residue under reduced pressure,
The residual liquid remaining at the bath temperature of 150℃ was diluted with hexane/ether (1
1.15g (21%
)'s 4#! The title compound was obtained as an oil.

IH-NMR (CDC intersection 3) δ = 3.86 (s, 3M,) 3.7
-4.2 (m, 2H,)6.5-8.0
C rin, 4H,)8.1 (
br, IM,) (ii) Methyl N-methyl-N-(2
, 2,2-trifluoroethyl) anthranilate: 2.0 g (8,58 mmol) of methyl N-(2,2,2-trifluoroethyl) anthranilate and 1.08 g (8,58 mmol) of dimethyl sulfate. ) at 3θ
After cooling the reaction mixture, stirred at 120 °C for 30 min,
After extraction with ethyl acetate and washing with 10 mJl of IN-hydrochloric acid,
Further washing with saturated NaHcO3 solution and saturated saline,
Dried mirabilite. Glauber's salt was filtered off, the solvent was distilled off under reduced pressure, and the residue was columned with hexane/ether (100/1 to 100/2) to obtain 340 mg (16.0%) of the title compound as a colorless oil.

Sen H-NMR (CDC13) δ = 3.00 (s, 3H,) 3.70
(q, 2H, J=10Hz,)3.88
(s, 3H,)6.9-7.8 (
layer, 4H,) (eye 1) 2-[N-methyl-N-(2,2
, 2-trifluoroethyl)amine] benzyl alcohol: 400 mg (1,62 mmol) of methyl
150 mg (3.9 mmol) was added under cooling,
Stir for 1 minute.

Li A I Ha by dropping saturated NHa C1 solution
The solution was filtered through Celite and the remaining solution was distilled off under reduced pressure. The residue was dissolved in chloroform/methanol (too 10-10010.
200 mg (56%) applied to a silica gel column in step 5)
The title compound was obtained as a colorless oil.

1) 1-NMRCCD0 statement 3) δ= 2.86 (s, 3H,) 3.20
(t, IH, J=7Hz,)3.56
(q, 2H, J=10Hz,)4.74
(d, 2H, J=7Hz,)6.9-7.4
(m,4H,)(ii) 2-[2-[N-methyl-N-(2,2゜2-trifluoroethyl)amine]benzylthio]benzimidazole: 2-[N-methyl-N-(2 ,2,2-)lifluoroethyl)aminocobenzyl alcohol 200 mg (0,9
1 mmol) was dissolved in Indium methylene chloride, and while cooling with water, 119 mg (1 mmol) of thionyl chloride was added and stirred for 15 minutes. The solvent was distilled off under reduced pressure, and 1 ml of ethanol was added to the residue.
and 2-mercaptobenzimidazole 137 mg (0
, 91 mmol) and stirred at room temperature for 1 hour. A saturated Na) lcO3 solution was added, the precipitated oil was extracted with methylene chloride, and the organic layer was washed with water and saturated brine. After drying Glauber's salt, the solvent was distilled off under reduced pressure, and hexane was added to the residue to crystallize it, which was collected by filtration to give 195 mg (61
%) of the title compound as pale yellow crystals.

IH-NMR (CDC cross 3) δ = 2.84 (s, 3H,) 3.50
(q, 2H, J=9Hz,)4.60
(s, 2L) 6.9-7.6
(+s, 81.) (v) 2- [2-[N-methyl-N
-(2,2゜2-trifluoroethyl)amino]benzylsulfinyl]benzimidazole: 2-[2-[N-methyl-N-(2,2,2-trifluoroethyl)amino]benzylthio]benzimidazole 195 mg (0.56 mmol) in 4 m chloroform
120 mg (purity: 80%, 0.56 mmol) of m-chloroperbenzoate was added little by little under cooling. Further, the mixture was stirred at this temperature for 30 minutes. After adding saturated NaHCO3 solution, the organic layer was separated and washed with 10% Na2S2O3 and saturated brine. After drying Glauber's salt, the solvent was distilled off under reduced pressure, and the residue was crystallized with hexane/ether to give 180 mg (87%).
Obtained a counterpart. After dissolving in methylene chloride, the residue was evaporated under reduced pressure, 3 mjL of ether was added and cooled, and the precipitated crystals were collected by filtration to obtain 130 mg (63%) of the title compound as a white powder.

mP: 115-119°C 1) 1-NMR (CDC or 3) δ = 2.80 (s, 3H,) 3.50
(q, 2H, J=10Hz,) 4.52 and 4.
88 (each d, 2H, J=13Hz,) 6.8-8.0
(Maro, 8H,) IRνW! rx: Cm-' 1420.1395, 1315, 1260°1150.
1130.1080.1050.

970.740.

[Example 2] 2-[[2-[N-(2-chloroethyl)-N-methylaminoco-5-methoxy]benzylsulfinyl]benzimidazole: (i) Methyl 4-methoxy-2-methoxycarbonylphenylamine / Acetate: 15 g of methyl 5-methoxyanthranilate (71% purity)
, 58.8 mmol) and 3.2 g of methyl chloroacetate (
29.4 mmol) was dissolved in 21 mfl of methanol and 3
The reaction mixture, which was heated for several days, was cooled and left in a refrigerator overnight, and the precipitated sweetfish product was collected by filtration and washed twice with cooled methanol. The obtained crystals were mixed with chloroform and 1N-Na.
Stirred in OH. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue to crystallize it, the residue was washed with ether, and 4.2 g (28%
) was obtained as yellow crystals.

IH-NMR (CDC statement 3) δ=3.74, 3.7G, 3.84 (each, 5.9
H, ) 3.96 (d, IH, J=6
Hz,)6.44 (d,1)1. J=10
Hz, )6.96 (d, d, IH, J=1
0Hz, 3Hz, )7.40 (d,
II, J=3Hz, )7.72 (br, I
H,)(ii) 2-[N-(2-hydroxyethyl)N-methylamine]-5-methoxybenzyl alcohol: Methyl 4-methoxy-2-methoxycarbonylphenylaminoacetate-) 4.18 g (16,5 100 mmol) and 2.7 g (21.5 mmol) of dimethyl sulfate
After cooling the reaction mixture, which was stirred at ~110°C for 1 hour, 40 ml of chloroform was added, and saturated NaHCO
x solution was added and stirred to make it slightly alkaline. The chloroform layer was washed with saturated brine and dried over sodium sulfate. By distilling off the solvent under reduced pressure, 4.44 g (100%) of the N-methyl form of the starting compound was obtained as a pale yellow oil.

IH-NMR (C00 sentence 3) δ = 2.92 (s, 3B,) 3.70,3
．． 7G, 3.86 (each s, 9H,) 3.82
(5,2H,) 6.8-7.3 (Maro, 3H,) This phase was dissolved in 15 m 41 of ether, and the ether (A1203
) 50 ml of LiAIHn 2.91 (76,
4 mmol) over approximately 20 minutes while cooling. After further stirring at 0° C. for 30 minutes, a saturated Na25Oa solution was added dropwise to form a suspension. Insoluble matter was removed by filtration through Celite, and ether was distilled off under reduced pressure to obtain 3.0 g (86%) of the title compound as a pale brown oil.

IH-NMR (C00 sentence 3) δ = 2.64 (s, 3H,) 2.9-3.
1 (shoes, 2H,) 3.4-3.7 (
Mouse, 2H,) 3.77 (s, 3H,) 4.68 (s, 2H,) 6.6-7.2 (layer, 3H,) (iii)
2- [[2-[N-(2-chloroethyl)-N-methylaminoco-5-methoxy]benzylthio]benzimidazole: 2-[N-(2-hydroxyethyl)-N-methylamino]-5-methoxybenzyl Alcohol 2.11g (
A solution of 4.76 g (40 mmol) of thionyl chloride in 20 m of methylene chloride was added.
1 solution under water cooling. After further stirring at this temperature for 30 minutes, the solvent was distilled off under reduced pressure at 40° C. or lower, 10 mJl of ethanol and 1.2 g (8 mmol) of 2-mercaptobenzimidazole were added to the residue, and the mixture was stirred at room temperature for 2 hours. 50 ml of chloroform and 20 ml of saturated NaHCD 3 solution were added for extraction, and the organic layer was washed with saturated brine. After drying Glauber's salt, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (chloroform/methanol: 10010-I
OQ/3) to produce 1.3 g (35.9%) of I
l! f! The title compound was obtained as a colorless oil. m/e
325 IH-NMR (C00 sentence 3) δ=2.68 (s, 3)1. )3, (1-
3,3C Peng, 2H,) 3.4-3.6 (layer, 2H,) 3.62
(s, 3H,) 4.52 (s, 2H,) 6.6-7.6 (ron, 78.) (i ma) 2-
[[2-[N-(2-chloroethyl)-N-methylamine]-5-methoxy]benzylsulfinyl]penzimitasole: 2- [[2-IN~(2-chloroethyl)-N-methylaminoco-5 -Methoxy]benzylthio]benzimidazole 0.74 g (2.05 mmol) was dissolved in 20 ml of chloroform, and under cooling m-chloroperbenzoic acid 48
7 mg (purity: 80%, 2.27 mmol) was added in 15 minutes. Saturated NaHCO3 solution was added and extracted with chloroform. The organic layer was diluted with 0.5N NaOHNaOH2.
The oil was extracted with 120mM of 20% NHaC and extracted with 30mJ of chloroform.

After washing with saturated brine and drying with Glauber's salt, the solvent was distilled off under reduced pressure, and 20 m of acetonitrile was added to crystallize. The crystals were collected by filtration and washed with acetonitrile to give 480 mg (6
2%) of the title compound was obtained as white crystals.

mp: 139-140°C IH-NMR (CTJCJ13) δ=2.65 (s, 3H,) 3.0-3.
6 (m, 4H,) 3.44
(s, 3H,) 4.55 and 4.95 (each a, 2H,
J=12Hz, ) 6.48-7.82 (m, 7
H,)IRylig! i: cm” 3220.1605.1495.1400.

1290.1045, 1025,740° [Example 3] Formulation example (tablet) One tablet (220mg) contains the following ingredients.

Active ingredient 50mg lactose
103 Starch 50 Magnesium stearate 2 Hydroxypropyl cellulose 15 [Example 4] Formulation example (capsule) One hard gelatin capsule contains the following ingredients (350 mg).

Active ingredient 40mg lactose
200 Starch 70 Polyvinylpyrrolidone 5 Crystalline cellulose 35 [Example 5] Formulation example (granules) 1 g of granules contains the following ingredients.

Active ingredient 200mg lactose
450 Corn starch 300 Hydroxypropyl cellulose 50 Patent applicant Nippon Chemifa Co., Ltd. Agent Patent attorney Yasuo Yanagawa

Claims (1)

[Claims] 1. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms, the number of carbon atoms is 1)
-8 alkyl group, cycloalkyl group having 5 to 8 carbon atoms, aryl group, aralkyl group (provided that the alkyl group has 1 to 4 carbon atoms), or 1 to 8 carbon atoms having a halogen atom an alkyl group, R_1
and at least one of R_2 is an alkyl group having 1 to 8 carbon atoms having a halogen atom, R_3, R_4,
R_5, R_6 and R_7 may be the same or different, and include a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, and A benzimidazole derivative represented by (a substituent selected from the group consisting of fluorine-substituted alkoxy groups). 2. The following general formula (VII): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) (In the formula, R_1 and R_2 are hydrogen atoms, the number of carbon atoms is 1)
-8 alkyl group, cycloalkyl group having 5 to 8 carbon atoms, aryl group, aralkyl group (provided that the alkyl group has 1 to 4 carbon atoms), or 1 to 8 carbon atoms having a halogen atom an alkyl group, R_1
and at least one of R_2 is an alkyl group having 1 to 8 carbon atoms having a halogen atom, R_3, R_4,
R_5, R_6 and R_7 may be the same or different, and include a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, and The following general formula (I) is characterized by oxidizing a compound represented by (a substituent selected from the group consisting of fluorine-substituted alkoxy groups): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ( In the formula, R_1, R_2, R_3, R_4, R_5, R
_6 and R_7 are the same as above) A method for producing a benzimidazole derivative represented by: 3. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are hydrogen atoms, the number of carbon atoms is 1)
-8 alkyl group, cycloalkyl group having 5 to 8 carbon atoms, aryl group, aralkyl group (provided that the alkyl group has 1 to 4 carbon atoms), or 1 to 8 carbon atoms having a halogen atom an alkyl group, R_1
and at least one of R_2 is an alkyl group having 1 to 8 carbon atoms having a halogen atom, R_3, R_4,
R_5, R_6 and R_7 may be the same or different, and include a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, and An anti-ulcer agent containing as an active ingredient a benzimidazole derivative represented by (a substituent selected from the group consisting of fluorine-substituted alkoxy groups).