JPS63159383A - Benzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula A (a represents formula II; R represents H, lower alkoxyl or haloalkoxyl; n is 0 or 1). EXAMPLE:2-2(-Pyridylmethyl)thio-5,6-(3,6,9-thioxaundecane-1,11-dioxy)b enzimida zole. USE:A remedial and prophylactic drug for gastritis, gastric ulcer, etc., having anti-ulcer action, protecting action for gasteric mucous membrane and controlling action on secretion of acid in the stomach, and superior drug-efficiency and safety. PREPARATION:A 4'-amino-5'-nitrobenzo-15-crown-5 expressed by formula III is initially reduced by, for example, such as catalytic reduction using Pd-carbon as a catalyst, etc., to form a 4',5'-diamino derivative expressed by formula IV. Then the resultant compound is condensed with a potassium ethylxanthogenate expressed by formula V to form a compound expressed by formula VI, which is then reacted with a compound expressed by formula VII in a solvent such as THF, etc., in the presence of an alkali at 0 deg.C - boiling point of the solvent to afford the compound expressed by formula I wherein n is 0.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to benzimidazole derivatives having a crown ether ring at the 5.6-position and exhibiting antiulcer activity.

1 (7) 1 Substances that inhibit the activity of the enzyme involved in the production of hydrochloric acid in the gastric juice, that is, potassium ion-dependent adenosine triphosphatase [hereinafter abbreviated as (H"+K") ATPase]. Many studies have revealed the usefulness of Gastroenterology as an anti-ulcer agent.
Astroen Mt.〇-1ogy), Volume 1, No. 420
Page (1943), vol. 73.

No. 921 (1977)]. Among them, 5-methoxy-2-[2-(4-methoxy-3,5-dimethyl)
Pyridylmethylsulfinyl]benzimidazole is
It has been found that it is a substance with a strong (H"+K">ATPase inhibitory effect), and its development as an anti-ulcer agent is currently underway [Japanese Patent Application Laid-open No. 141783/1983, British Medical Journal
Medical Journal), Vol. 87, p. 12 (1983).

Problems to be Solved by the Invention However, the above-mentioned benzimidazole derivatives cannot be said to be sufficient in terms of safety.

The purpose of the present invention is to obtain a drug that has stronger efficacy and safety that can withstand long-term administration.

Means for Solving Problem 11 It is well known that 15-crown-5 or 18-crown-6 has the property of incorporating alkali metal ions such as sodium ions and potassium ions.

The present inventor has discovered that (H"+K")ATP due to the interaction
The present invention was completed by examining the effect on enzyme activity.

The present invention is based on the general formula [wherein A is a group represented by the formula -(OCHzCH4-0-], R represents a hydrogen atom, a lower alkoxy group, or a haloalkoxy group, and n represents 0 or 1. It is a benzimidazole derivative represented by

In the present invention, a lower alkoxy group has 1 to 1 carbon atoms.
These are four alkoxy groups, such as a methoxy group, an ethoxy group, and a propoxy group. A haloalkoxy group is an alkoxy group having 1 to 3 carbon atoms substituted with a fluorine atom or a chlorine atom.

The compound of the present invention can be used, for example, as shown in the reaction formula below, using the known 4'-amino-5'-nitrobenzo-15-
Crown-5 [Acta Hemica Power Demia Scientific Power Hungary (Acta.

Chem, Acad, Sci, Hung, ), 1st
Vol. 10, p. 24 (1982), Vol. 110, No. 2
9 (1982)] (In the following reaction formula, A and R have the same meanings as above, and
represents a leaving group such as a tonohalogen atom such as chlorine, bromine, or iodine, a P-toluenesulfonyloxy group, or a methanesulfonyloxy group).

Iris ■ That is, first 4゛-amino-5゛-nitrobenzo-1
5-Crown-Reducing 5 to 4° of 2■.

5'-diamino form. The reduction method may be a normal nitro group reduction method, for example, catalytic reduction using palladium-carbon as a catalyst.

The obtained 4',5'-diamino compound of formula (1) is condensed with potassium ethylxanthate to form the benzimidazole ring (2). This reaction can be carried out following the previous catalytic reduction. That is, after catalytic reduction, the reaction solution is filtered to remove the catalyst, potassium ethylxanthate is added, and the reaction time is 1 to 4.
time, usually 2 to 3 hours.

Next, the compound of the present invention can be obtained by reacting this with a compound of formula V. The reaction between the compound 2) and the compound of formula V is usually carried out in the presence of an alkali. The alkali is a hydroxide, hydride, alkoxide, carbonate or bicarbonate of an alkali metal or an alkaline earth metal, and is used in an amount of 1 to 5 equivalents relative to the compound (2). Examples of solvents include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane, N,N-dimethylformamide, 1-
A suitable one can be selected from amides such as formylpiperidine, and water can be further added depending on the case. The reaction temperature can be appropriately selected from O'C to the boiling point of the solvent. For example, when potassium carbonate in N,N-dimethylformamide is used, a temperature between room temperature and the boiling point of the solvent is preferred, and when an aqueous sodium hydroxide solution in ethanol is used, the boiling point of ethanol is preferred. The reaction ends immediately, but for 30 minutes to 2
It is recommended to stir for a long time. Also, in order to accelerate the reaction, iodine, inorganic iodide, quaternary ammonium bromide,
It is also possible to add quaternary ammonium iodide, quaternary phosphonium bromide, quaternary phosphonium iodide, crown ether, or the like.

For the reaction of obtaining the present compound of formula (2) by oxidizing the present compound of formula (1), a known technique for oxidizing a sulfide compound to form a sulfoxide compound can be used. Therefore, any reagent commonly used for the oxidation of sulfide compounds can be used as the oxidizing agent in this reaction, especially performic acid, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc. Reaction solvents are preferably acids, such as chloroform, dichloromethane, toluene,
This can be carried out using a single or mixed solvent system such as benzene, methanol, ethanol, isopropanol or water. The reaction temperature is -70°C to the boiling point of the solvent, preferably -30 to 10°C. halogen,
Hypohalides, halides, etc. are also available at 0 to 40°
C can be used in the oxidation of the sulfide of formula (2).

The compound of the present invention has an anti-ulcer effect, a gastric mucosal protective effect, and an inhibitory effect on gastric acid secretion in the treatment of peptic ulcers, and is effective in treating gastrointestinal inflammatory diseases such as gastritis, gastric ulcer, duodenal ulcer, and upper digestive tract. It can be used for the treatment and prevention of ductal bleeding, Seelinger-Ellison syndrome, etc.

The method for producing the compound of the present invention will be explained in further detail in Examples below.

Example 1 4'-amino-5'-nitrobenzo-15-crown-
514.6g was suspended in 300mQ of methanol, 10%
Add 1.5 g of palladium return element and heat under hydrogen stream for 40~
Stir vigorously at 50°C.

After completion of the reduction, the palladium element was filtered off using Celite, 8.5 g of potassium ethylxanthate was added to the filtrate, and the mixture was heated to reflux. After 3 hours, cool to room temperature and add acetic acid 5
ml, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 5.6-(3,6°9-trioxaundecane-
6.22 g of 1,11-dioxy)-2-mercaptobenzimidazole was obtained. m, p, 300°C or higher Example 2 5.6-(3,6,9-)rioxaundecane-1,1
1-dioxy)-2-mercaptobenzimidazole 2
．． 00 g was suspended in a mixture of 40 mQ of ethanol and 10 TIIQ of water, 0.78 g of sodium hydroxide was added, and the suspension was stirred and refluxed to dissolve. To this, add 0.96 g of 2-pyridylmethyl chloride hydrochloride to 20 mQ of ethanol and 10 mQ of water.
The solution was dissolved in a mixed solution of mQ and added dropwise, and after completion of the addition, the solution was heated under reflux for 30 minutes. After cooling, the mixture was extracted with dichloromethane, washed with water and then with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-(2-pyridylmethyl)thio-5,6-(3,6,9-trioxaundecane-1) as a pale brown oil. 1.12 g of 11-dioxy)benzimidazole was obtained.

'H-NMR (CDC13): S (ppm) = 8.65 (11, d, J: 4
Hz >7, 73 (IH, ddd, J+=8Hz, Jt
=8Hz.

J*”2Hz) 6.9-7.4 (4H) 4.38 (2H, s) 4, 1-4.2 (411, m) 3, 9-4.0 (4H, m> 3, 78 (8H, s) Example 3 In the same manner as in Example 2, 2.00 g of 5.6-(3,6,9-trioxaundecane-1,11-dioxy)-2-mercaptobenzimidazole and 4 -Methoxy 2
-1.14 g of pyridylmethyl chloride hydrochloride was condensed in the presence of 0.71 g of sodium hydroxide to give an oily 2-(
4-methoxy-2-pyridylmethyl)thio-5,6-(
1.30 g of 3,6,9-dioxaundecane-1,11-dioxy)benzimidazole was obtained.

' H-NMR (CDCR3):S (ppm)
= 8.47 (IH, d, J = 6Hz) 7, 18 (I
H, bs) 6.99 (IH, bs) 6, 86 (IH, d, J=2Hz) 6, 80 (IH
, dd, J+”2H2, J*=6H2)4, 28(2H
, S) 4, 1-4.2 (4) 1. m) 3,9-4.0(4H,m) 3,86(3H,S) 3,78(8H,s) Example 4 In the same manner as Example 2, 5°6-(3,6, 2.00 g of 9-trioxaundecane-1,11-dioxy)-2-mercaptobenzimidazole and 4-(2,2,2
-trifluoroethoxy)-2-pyridylmethyl chloride hydrochloride (1.54 g) was condensed in the presence of 0.71 g of sodium hydroxide to obtain an oily 2-[4-(2,2,2-trifluoroethoxy)- 2-pyridylmethylthio-5,6
1.37 g of -(3,6,9-trioxaundecane-1,11-dioxy)benzimidazole was obtained.

'H-NMR(CD(J)3): δ(ppn) -8,55(IH,d, J=5Hz)
7.17 (IH, bs) 6,98 (IH, bs) 6,95 (IH, dd, J1=3H2, J*=5Hz)
6.85(LH, dd, J+=31(z, Jg=51(
z) 4, 42 (2H, q, Ju-p=8Hz) 4.31
(2H,s) 4.1-4.2 (4H) 3,9-4.0 (4H,m) 3,78 (8H,s) Example 5 2-(2-pyridylmethyl)thio-5 ,6(3゜6.9
1.10 g of -trioxaundecane-1,11-dioxy)benzimidazole was dissolved in 30 ml of dichloromethane, cooled to below -30°C, and stirred.

A solution of 572 mg of metachloroperbenzoic acid dissolved in a mixed solution of 15 mQ of dichloromethane and 5 ml of methanol was added dropwise to this. After the reaction was completed, the mixture was washed successively with a saturated aqueous sodium bicarbonate solution, a 5% aqueous sodium thiosulfate solution, water, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography, and recrystallized from methanol-diethyl ether to give 2-(2-pyridylmethyl)sulfinyl-5,6-(3,6,9-) as a colorless powder. Trioxaundecane-1
538 ug of 11-dioxy)benzimidazole was obtained.

m, p, 165-166°C IR (KBr): V (am-') = 103
0(S-"0)'H-NMR (CD(J)3): δ(ppm) -7,55(LH, ddd, J r
=8Hz, J*=8Hz.

Ji=2Hz>6,9~7.3(4H,m>4.75(IH,d,J=12H2) 4.60(IH,d,J=12Hz>4.1~4.2(4H, m> 3,9~4.0 (4H, m) 3,79 (8H, s) Elemental analysis value (as C□H,, N, O, S -H, O)
Theoretical value (%): c; s4. ts, H; 5.84.
N; 9.03 Actual value (%”): C; 54.64.H
;5.54. Ni9.11 Example 6 In the same manner as in Example 5, 2-(4-methoxy-2-pyridylmethyl)thio-5,6-(3,6,9-trioxaundecane-1,11-dioxy)benz 1.28 g of imidazole was oxidized using 622 mg of metachloroperbenzoic acid, and 2-(4-methoxy-2-pyrdylmethyl)sulfinyl-5,6-(3,6,9trioxaundecane-1,11-dioxy ) Benzimidazole 665m
I got g.

m, Ri, 174-176°C (decomposed) (recrystallized from methanol) I R (KBr); ν (am-')-10
12(S→O)'H-NMR(CDCR3):
6 (ppm) = 8.31 (IH, d, J = 5Hz)
7, 24 (IH, bs) 6, 94 (LH, bs) 6, 69 (LH, dd, J+=5Hz, Jt=2Hz)
6, 56 (LH, d, J = 2Hz> 4.71 (LH, d,, C13Hz) 4, 55 (LH, d, J = 13Hz) 4, 1-4.2 (4H, m) 3, llJ ~4.0 (4H, m) 3,88 (8H, s) 3.57 (3H, s) Example 7 2-[4-(2,2,2-trifluoroethyl) ) pyridylmethylcothio-5,6-(3,
6,9-trioxaundecane-1゜11-dioxy)
1.35 g of benzimidazole was oxidized using 572 mg of metachloroperbenzoic acid to form 2-[4-(2,2,2
-trifluoroethyl)pyridylmethyl]sulfinyl-5,6-(3,6,9-trioxaundecane-1,
922 mg of 11-dioxy)benzimidazole was obtained.

m, p, 99-100°C (recrystallized from methanol) I R (KBr): ν (cm-') = 1040
(S-"O)'H-NMR (CDCR3): S (ppm> = 8.35 (IH, d, J: 6Hz
>6, 9~7.2 (2H, br) 6.76 (LH, dd, J+=6Hz, Jt=2Hz)
6, 61 (LH, d, J = 2Hz) 4, 71 (LH, d, J = 12H2) 4, 55 (LH, d, J = 12Hz) 4, 0 to 4.2 (4H, m) 3, ! J~4.0 (4H, m) 3,79 (8H, s)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A is a group represented by the formula -(OCH_2CH_2), -O-, R is a hydrogen atom, a lower alkoxy group, or a haloalkoxy group, n represents 0 or 1. ] A benzimidazole derivative represented by.