JPH01207277A - Quaternary salt of benzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:The quaternary salt of a benzimidazole derivative of formula I (R<1>, R<2> and R<3> are linear or cyclic alkyl, aryl or aralkyl, or R<1> and R<2> form 5-7 membered ring together; R<4a>, R<4b>, R<5a>, R<5b> and R<5c> are H, halogen, alkoxy, alkyl, trifluoromethyl, alkoxycarbonyl, nitro, amino, acyl or fluorine-substituted alkoxy; X<-> is anion). EXAMPLE:2-[(Benzimidazol-2-ylsulfinyl)methyl]phenyltrimethyl ammonium hydroxide. USE:The salt exhibits an ulcer-resistant action, a gastrointestinal cell-protecting action, etc., and is useful as a drug. PREPARATION:The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III (Y is reactive group), oxidizing the obtained compound of formula IV (Z<-> is anion) and, if necessary, subjecting the product to a cation exchange reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides quaternary salts of benzimidazole derivatives, in which R1, R2 and R3 represent linear or cyclic alkyl, aryl or aralkyl, or R1 and R2 jointly represent 5 ~ forms a 7-membered ring, R4-5R4b, R5-,
R5b and R5Cq hydrogen, halogen, alkoxy, alkyl, trifluoromethyl, alkoxycarbonyl, nitro, amino, acyl or fluorine-substituted alkoxy; Concerning quaternary salt.

Examples of benzimidazole derivatives having antiulcer effects include omebrazole (Japanese Patent Publication No. 6O-34956), 2-(
2-dimethylaminobenzylsulfinyl)benzimidazole (Japanese Unexamined Patent Publication No. 61-60660) and the like are known.

However, the benzimidazole derivative represented by the above general formula (I) is completely unknown and is a new compound.

The present inventors conducted research on a new compound represented by the above general formula (I), and found that it has different physicochemical properties from known benzimidazole derivatives, and is particularly stable against gastric juice. The present invention has been completed based on the discovery that the compound of general formula (I) has anti-ulcer effects and gastrointestinal cell protective effects that are suitable for use as pharmaceuticals.

Therefore, the object of the present invention is to provide a quaternary salt of a benzimidazole derivative represented by the above general formula (I), in which R's R2 and R3 have 1 to 1 carbon atoms;
6 lower alkyl, cyclic alkyl having 5 to 7 carbon atoms, phenyl, pencil, etc., preferably methyl, ethyl, isobutyl, cyclohexyl, etc., and R
It is also preferred that 1 and R2 jointly form a piperidino ring with the adjacent nitrogen atom.

R", R4b, R", R5b, R5e and Lr are hydrogen, halogen, lower alkoxy having 1 to 6 carbon atoms, carbon tB
, 1-6 alkyl, trifluoromethyl, carbon number 1-6
6 lower alkoxycarbonyl, nitro, amino, a-, sil, or fluorine-substituted lower alkoxy having 1 to 6 carbon atoms, and preferably hydrogen, chlorine,
Examples include methoxy, ethyl, methyl, and ethyl.

Examples of the anion represented by X- include anions such as a hydroxyl group, a halogen, and a sulfonyloxy group such as methanesulfonyloxy and toluenesulfonyloxy, preferably a hydroxyl ion.

Next, representative compounds of the quaternary salt of the benzimidazole derivative (the compound of the present invention) represented by the above formula (I) of the present invention are shown below.

Compound 1: 2-[(benzimidazol-2-ylsulfinyl)methyl]phenyltrimethylammonium hydroxide Compound 2: 2-[(benzimidazol-2-ylsulfinyl)methyl 1 phenyltriethylammonium hydroxide Compound 3: 2-[(5-methoxybenzimidazole-
2-ylsulfinyl)methyl1phenyltriethylammonium hydroxide compound 4:2-[(benzimidazol-2-ylsulfinyl)methyl2-3-methylphenyltrimethylammonium hydroxide compound 5:2-ECbenzimidazole-2- ylsulfinyl)methyl]-4-methoxyphenyltrimedelammonium hydroxide compound 6:2-[(benzimidazol-2-ylsulfinyl)methyl]-4-methoxycarbonylphenyltrimethylammonium hydroxide compound 7:2
-[(5-methylbenzimidazol-2-ylsulfinyl)methyl]phenyltrimethylammonium hydroxide compound 8:2-[(5-chlorobenzimidazole-2
-ylsulfinyl)methyl]phenyltrimethylammonium hydroxide compound 9 2-[(benzimidazol-2-ylsulfinyl)methyl]-4-methylphenyltrimethylammonium hydroxide compound 10: N-2-[(benzimidazole) -2
-ylsulfinyl)methyl]phenyl-N-benzyl-N-dimethylammonium hydroxide compound 11: N-2-[(benzimidazole-2
-ylsulfinyl)methyl]phenyl-H-cyclohexyl-H-dimethylammonium hydroxide Compound 12: 1-[2-((benzimidazo-2-ylsulfinyl)methyl)phenyl]-1-methylpiperidi Compound 13: 2-[(benzimidazol-2-ylsulfinyl)methyl]phenyltrimethylammonium chloride Compound 14: 2-[(benzimidazol-2-ylsulfinyl)methyl 1-4-methoxyphenyltrimethylammonium chloride Compound 15: 2-[(benzimidazol-2-ylsulfinyl)methyl 1 phenyltriethylammonium bromide Compound 16: 2-[(benzimidazol-2-ylsulfinyl)methyl]phenyltrimethylammonium methanesulfonate Compound 17: N,N -dimethylto-2-[(benzimidazol-2-ylsulfinyl)methylcophenyroto(3-methylprobyl)ammonium hydroxide compound 18: N-2-[(5-trifluoromethylbenzimidazol-2-ylsulfinyl) ) Methyl 1 phenyltriethylammonium hydroxide - The compound of the present invention represented by the formula (I) can be obtained, for example, by the method shown in the following reaction formula (+71
) (wherein, Y represents a reactive group, Z- represents an anion,
So L Te'R', R2, R3, R4m,, R4b,
R5aR5b, R5C and X″″ are the same as above) The reaction between compound (II) and compound (+1 [)
This is carried out by stirring in an inert solvent such as benzene, ethanol, acetone, etc. at room temperature to reflux for 30 minutes to 24 hours. At this time, NaOH1KOH1
Preferably, an alkaline agent such as 2CO3 or NaHCO3 is present in the reactor to receive the acid produced. Compound (II
In [), examples of the reactive group represented by Y include halogens such as chlorine and bromine, and sulfonyloxy groups such as methylsulfonyloxy and toluenesulfonyloxy groups. Examples of 2- include anions of reactive groups represented by Y.

Compound (rV) can be oxidized by a conventional method, for example, by using hydrogen peroxide, an organic peracid such as m-chloroperbenzoic acid, or an oxidizing agent such as sodium metaperiodate, compound (rV) is ) can be oxidized. The reaction is carried out in an inert solvent such as 1-form, dichloromethane, methanol, ethyl acetate, etc. at -30 to 50°C, preferably -15 to 5°C.
carried out at a temperature of

The anion conversion reaction may be caused by the reaction treatment process in the above-mentioned oxation, or may be carried out by a normal salt exchange reaction.

Note that the raw material (Ilt) for the method of the present invention can be obtained, for example, by the method shown below.

(In the formula, Roll, R5b and R''c are the same as above) Regarding the representative compounds of the compounds of the present invention obtained in this way,
The results of pharmacological effects testing are as follows.

<Experiment 1> Effect on suppressing gastric acid secretion After fasting rats for 24 hours, the abdomen was opened under ether anesthesia, and the pylorus was ligated. After 3 hours, the gastric juice accumulated in the stomach was collected, and the gastric juice volume (m!; l/rat) and gastric acidity (mEq.
/ and ) was determined as '&11, and the amount of acid discharged (μEq/h) was calculated. Gastric acid acidity is determined by Autoburett (Radiom
eter) and 0. lN-1 (a pH 7 with OH,
It was titrated to 0. The investigational drug is pyloric ligation py16r.
It was administered orally 0.5 hours before US ligation.

The results are shown in Table 1.

Table 1 Inventive compound 1: 2-[(benzimidazol-2-ylsulfinyl)methylcophenyltrimethylammonium hydroxide Inventive compound II: 2-[(benzimidazole-2-
[Ilsulfinyl)methyl]-4-methoxyphenyltrimethylammonium hydroxide Experiment 2> After fasting rats with hydrochloric acid-ethanol ulcers for 24 hours, hydrochloric acid-ethanol (150 mM hydrochloric acid in 60X ethanol) was added to 1 m or 200
g body weight was administered orally. After 1.5 hours, the animals were sacrificed with ether, and the stomachs were removed and treated with 8 mp of 2% formalin solution.
was injected into the stomach, and further immersed in the same solution for 10 minutes to slightly fix it. Make an incision along the front and under a dissecting microscope (10x magnification)
The length (mm) of the damage occurring in the glandular stomach at a1]
The total amount per animal was taken as the damage coefficient. The test drug was orally administered 0.5 hours before the administration of hydrochloric acid-ethanol. In addition, only the solvent was administered to the control group.

The results are shown in Table 2.

Table 2 (Compounds of the present invention and II are the same as those in Experiment 1) Next, the stability of the compounds of the present invention in gastric fluid means that omebrazole has a half-life of 4 minutes in simulated gastric fluid (pharmacopoeial fluid 1). It was found that Compound II of the present invention (same as in Experiment 1) remained stable even after 1 hour had elapsed.

The compounds of the present invention can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, powders, granules, and syrups, and examples of 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, carboxymethylcellulose calcium, etc., lubricants include magnesium stearate, talc, etc., and binders include hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc. used b'.

The dosage is usually about 1 mg per day for adults as an injection.
The dose is 100 mg, or about 10 mg to 1 g per day when administered orally, but the dose can be increased or decreased depending on age, symptoms, etc.

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

Reference Example 1 (,1)-1 Under nitrogen, 50 g of 2-dimethylamino-5-methoxybenzyl alcohol was added to 80 m of methyl iodide, and 12
Refluxed for an hour. After cooling, the precipitated crystals were collected by filtration, washed with ether, dissolved under heating in 150 ml of methanol, and 150 ml of ether was added. After stirring and cooling, the precipitated crystals were collected by filtration and washed with methanol/ether (1/10) to obtain 52 g (yield 58%) of (2-hydroxymethyl-4-methoxy)phenyltrimethylammonium iodide. Obtained as crystals.

'HNMR (CD30D) δ=3.80 (s, 9H) 3.87 (s, 3H) 4.92 (s, 2H) 7.04 (dd, IH, J: 9Hz, 3Hz) 7.20
(d, IH, J: 3 Hz) 7.85 (d, IH, J = 9 Hz) 3.23 g (10 m
Silver chloride (1.44g) was dissolved in 15ml of water, and silver chloride (1.44g
0 mmo) was added thereto, and the mixture was stirred at room temperature for 2 hours in the dark. Insoluble matters were removed by Celite filtration, water was distilled off under reduced pressure at 60 to 80°C, and the precipitated crystals were suspended in acetone and collected by filtration.2.
27 g (98% yield) of (2-hydroxymethyl-4
-methoxy)phenyltrimethylammonium chloride was obtained as white crystals.

'HNMR(CD30D'CDCMata3)δ=3.80(
s, 9H) 3.96 (s, 3H) 4,88 (s, 2H) 6.9-7.2 (m, 2) 1) 7.74 (d, IH, J=9Hz) Reference example (1 )-2 A solution of 2.2 g of the quaternary salt obtained in 2.
7 g (12.4 mmol) of methylene chloride solution was added dropwise.

After stirring at room temperature for 30 minutes, add thionyl chloride 1, 47 g.
was added dropwise, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was distilled off under reduced pressure, a small amount of acetone was added to the residue, and ether was further added to crystallize it, which was collected by filtration and dried under reduced pressure to obtain 1.7 g (yield: 72%) of the title compound as a light brown powder.

'HNMR (CD30D+CDC3) δ=3.86(
s, 3) 1) 3.88 (s, 9H) 5.00 (s, 2H) 6.9-7.2 (m, 2H) 7.80 (d, if (, J: 9Hz) Example 1 1-(a) Dissolve 292 mg (6,8 mm) of 93% sodium hydroxide in 0.5 mm of water, add 5 mm of ethanol,
2-Mercaptobenzimidazole 1.02g (6,8
mmof) was added and dissolved. Next, 1.7 g (6.8 mmol) of (2-chloromethyl-4-methoxy)phenyltrimethylammonium chloride was added and
Stirred for 0 minutes. After the solvent was distilled off under reduced pressure, 25 mL of ethanol was added to the residue, and insoluble matter was filtered off. The obtained crystals were suspended in 40 ml of methanol, insoluble matters were removed by filtration through Celite, and the liquid was concentrated under reduced pressure to obtain a solid. This solid was suspended in ether and collected by filtration to obtain 1.56 g (yield 63χ) of white crystals of 2-[(benzimidazol-2-ylthio)methyl]-4-methoxyphenyltrimethylammonium chloride. .

'HNMR (CD30D) δ=3.68 (s, 3H) 3.84 (s, 9H) 4.90 (s, 2H) 6.98 (dd, LH, J: 10Hz, 3Hz) 7.0
6-7.60 (m, 5H) 7.78 (d, 1) 1. J: 10 Hz) 1-(b) 1.5 g (4
, 1 mm), 15 m of chloroform, and 3 m of methanol.
884 m of m-chloroperbenzoic acid dissolved in mfi and cooled on ice.
g (purity: 80χ.

4.1 mmof) was added in about 5 minutes. Furthermore, at this temperature 3
After stirring for 0 minutes, the solvent was distilled off under reduced pressure at a temperature below 40°C. 20 m of water and 50 m of ether were added to the residue to dissolve it.

The aqueous layer was further washed with ether, and water was distilled off under reduced pressure at below 40°C. The residue was dissolved in 10 methanol of methanol and
Separated using tman PLKC-18F (Developing solvent:
MeOH/H20/1IH40H=70/3010.5
). The target fraction was eluted twice with 300 ml of methanol. Methanol was distilled off under reduced pressure, 20 ml of methanol was added to the residue, and insoluble matter was filtered. ii was distilled off under reduced pressure, and the precipitated solid was suspended in ether and collected by filtration to obtain 720 mg (yield: 49χ) of the title compound as a pale yellow powder. 'HNMR indicates that the purity is approximately 90% (MeO
(contains 3% H and 7% ether).

'H) IMR (DMSO-d6) δ=3.67 (s, 3H) 3,75 (s, 9H) 4.76 (d, 2H, J=14) 1z) 5.27 (d,
2H, J = 14Hz) 6.7-7.6 (m, 6H) 7.82 (d, LH, J: 9Hz) IR Shi2X. m −1 3410, 1605, 1495, 1370, 1270,
1030,750 Reference Example 2 White crystals of 2-hydroxymethylphenyltrimethylammonium iodide were obtained in the same manner as in Reference Example (2)-1.

'HN A R (CD30D) δ = 3.84 (s, 9H) 4.94 (s, 3H) 7.4 to 8.0 (m, 4H) In the same manner as Reference Example (1)-2, 2 -Hydroxymethylphenylammonium chloride was obtained as white crystals.

' HNMR (CD30D) δ = 3.83 (s, 9H) 4.98 (s, 2H) 7.4-8.0 (m, 4H) In the same manner as in Reference Example (1)-3, the title compound was Obtained.

Example 2 Oxide 2-(a) 2-[(benzimidazol-2-ylthio) Methyl 1-phenyltrimethylammonium chloride was obtained as a light brown powder in a yield of 88χ.

'H) iMR (CD30D) δ=3.86 (s, 9H) 4.98 (s, 2H) 7.06-8. OO('m, 8H) 2-(b) 2.7 g of sulfide obtained in 2-(a) (purity 92
% = 7.45 mm) was dissolved in 20 m of chloroform and 3 m of methanol, and m-chloroperbenzoic acid (purity: 80%, 1.51 g, 7.45 mm) was dissolved under cooling.
) was added little by little. The mixture was further stirred at room temperature for 15 minutes, and the solvent was distilled off under reduced pressure. 30ml of water was added to the residue, the precipitated m-chlorobenzoic acid was filtered off, and the filtrate was distilled off under reduced pressure at 40°C or below. 2.5 g of the obtained residue was
n PLCK-18F (developing solvent: MeO
)1/H20/NH40H-70/3010.5). The target fraction was eluted with 300ml methanol and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol, the insoluble matter was filtered, and the 'a solution was distilled off under reduced pressure to obtain 1.21 g (yield: 49%) of the title compound as a light brown powder.

' According to HN HR, the purity is approximately 91% (methanol 8%
, containing 1% ether).

'HNMR (DMSO-ds) δ=3.79 (s, 9H) 4.74 (d, 2H,, C14Hz) 5.38 (d, 2) 1. J=14tlz)6.7~8.
0 (m, 8H) IRνma: Cm-' 1375 , 1265 , 1060 , 1045 , 1
035, 750 patent applicant Nippon Chemifa Co., Ltd.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R^2 and R^3 represent chain or cyclic alkyl, aryl or aralkyl, or R^1 and ^2 jointly form a 5- to 7-membered ring, R^4^
a, R^4^b, R^5^a, R^5^b and R^5^
c is hydrogen, halogen, alkoxy, alkyl, trifluoromethyl, alkoxycarbonyl, nitro, amino,
represents acyl or fluorine-substituted alkoxy, and
- indicates an anion) A quaternary salt of a benzimidazole derivative represented by: (2) R^1, R^2 and R^3 are lower alkyl, and R
^4^a and R^4^b are hydrogen, R^5^a, R^5
The quaternary salt of a benzimidazole derivative according to claim 1, wherein ^b and R^5^c are hydrogen or lower alkoxy. (3) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^4^a and R^4^b are hydrogen, halogen,
alkoxy, alkyl, trifluoromethyl, alkoxycarbonyl, nitro, amino, acyl, or fluorine-substituted alkoxy) and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1, R ^2 and R^3 represent a chain or cyclic alkyl, aryl or aralkyl, or R^1 and R^2 together form a 5- to 7-membered ring, and R^5^
a, R^5^b and R^5^c represent hydrogen, halogen, alkoxy, alkyl, trifluoromethyl, alkoxycarbonyl, nitro, amino, acyl or fluorine-substituted alkoxy, Y represents a reactive group, and Z^- indicates an anion) are reacted, and the general formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3, R^4^a, R^4
^b, R^5^a, R^5^b, R^5^c and Z^-
There are general formulas, ▲mathematical formulas, chemical formulas, tables, etc., which are characterized by obtaining a compound represented by indicates anion, R^1, R^2, R^3
, R^4^a, R^4^b, R^5^a, R^5^b and R^5^c are the same as above). (4) An anti-ulcer agent containing the quaternary salt according to claim 1 as an active ingredient.