JPH0533950B2 - - Google Patents

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention exhibits a remarkable anti-ulcer effect in experimental ulcers, particularly in water immersion restraint stress ulcer experiments using rats, and has been shown to have a significant anti-ulcer effect on the stomach and duodenum of mammals including humans. The present invention relates to benzimidazoline derivatives useful as ulcer therapeutic agents and their pharmacologically acceptable acid addition salts.

[Prior Art] Traditionally, as therapeutic agents for gastric and duodenal ulcers, (1) antacids and antipepsin agents that neutralize and deactivate gastric acid or digestive juices in the stomach, (2) chemicals involved in the secretion of gastric acid, etc. Histamine is an anticholinergic drug that suppresses the secretion of gastric acid by antagonizing the transmitters acetylcholine and histamine.
H ₂ -Receptor Antagonist (3) Many drugs have been developed and used to protect and repair damaged gastric mucosa, such as gastric mucosal fluid secretion enhancers, local circulation improvers, and tissue repair agents.

Furthermore, the application of prostaglandin derivatives, which have gastric acid secretion suppressing and cell protective effects, to ulcer therapeutic agents has recently been studied.

However, few ulcer therapeutic agents have been developed that are effective for stomach and duodenal ulcers caused by stress, which have been on the rise in recent years.

[Problem that the invention seeks to solve]

Currently, the drugs used to treat gastric and duodenal ulcers are mainly antacids, antipepsin drugs,
These include anticholinergic agents and histamine H ₂ -receptor antagonists. All of these treat ulcers by neutralizing, inactivating, or suppressing secretion.

On the other hand, clinical findings suggest that patients with gastric and duodenal ulcers do not necessarily exhibit hyperacidity;
In fact, there are many reports of cases showing hypoacidity.

It is said that there are many cases of gastric and duodenal ulcers caused by stress, which has been on the rise in recent years, but among the conventional ulcer treatments, there are none that are effective for stomach and duodenal ulcers caused by stress. rare. Therefore, in actual treatment, a method is commonly used in which ordinary ulcer treatment agents are used in combination with anxiolytics or tranquilizers.

However, these drugs have a strong central depressing effect and often cause side effects such as hypnosis and motor inhibition.

The purpose of the present invention is to treat the stomach caused by such stress,
An object of the present invention is to provide a novel benzimidazoline derivative that is effective against duodenal ulcer.

[Means for solving problems]

The present inventors have conducted extensive research to find a compound effective in treating gastric and duodenal ulcers caused by stress, and have discovered that the objective can be achieved with a certain benzimidazoline derivative, and have thus achieved the present invention. Ivy.

That is, the present invention provides a general formula that exhibits remarkable anti-ulcer effects in experimental ulcers, particularly water immersion stress ulcer experiments using rats, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans. (R ¹ and R ² in the formula may be the same or different and are each a linear or branched alkyl group having 3 to 5 carbon atoms, and Y is a linear or branched alkyl group having 2 to 4 carbon atoms. or a branched alkylene chain) and pharmacologically acceptable acid addition salts thereof.

This benzimidazoline derivative represented by the general formula () is a new compound, and the general formula (in the formula, Y, R ¹ and R ² have the same meanings as above) and an equimolar to excess molar amount of phosgene, urea, ethyl carbamate, diethyl chlorocarbonate, or 1,
It can be produced by reacting a carbonylation reagent such as 1'-carbonyldiimidazole in the presence or absence of a base such as triethylamine.

The compound of the general formula () used as a starting material in this production method has the general formula Equimolar to slightly excess molar amount of the nitrobenzene derivative represented by the general formula (X in the formula is a halogen atom or a nitro group) (In the formula, Y, R ¹ and R ² have the same meanings as above) are reacted with an amine derivative represented by the formula A nitroaniline derivative represented by the formula (Y, R ¹ and R ² have the same meanings as above) is prepared, and then this is hydrogenated in the presence of a catalyst such as palladium carbon or platinum oxide, or , zinc, tin, or stannous chloride, and an acid such as hydrochloric acid.

In this production method, the compounds of general formulas () and () used as starting materials are all known compounds and can be obtained as commercially available products or can be easily produced by known methods. .

The compound of the general formula () produced in this way is a crystal or oily substance, and although it can be purified by recrystallization or column chromatography of itself or an acid addition salt, it becomes colored by undergoing air oxidation. Since it is a simple compound, it is preferable to use it immediately without any particular purification in this production method.

In order to suitably carry out the present invention, the compound of general formula () produced by the above method is dissolved in an inert solvent such as benzene, toluene, dioxane, etc., and an equimolar to slightly excess molar amount of 1 ，
Add 1′-carbonyldiimidazole and adjust from 0 to 100
React for 3 to 20 hours at °C. If necessary, the reaction solution is concentrated under reduced pressure, then dissolved in an organic solvent such as benzene or methylene chloride, washed with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by an appropriate method or converted into an acid addition salt such as a hydrochloride, and then recrystallized from an appropriate solvent to obtain the desired product.

The benzimidazoline derivative represented by the general formula () of the present invention can be converted into an acid addition salt by a conventional method. For example, a hydrochloride salt can be obtained by adding 1N hydrochloric acid in an equivalent molar amount to a slight excess molar amount of ethanol, distilling off the solvent under reduced pressure, and recrystallizing the remaining crystals from an appropriate solvent. In addition to hydrochloride, acid addition salts include hydrobromide, hydrogen iodide, sulfate, acetate, oxalate, malate, tartrate, citrate, mandelate, fumarate, maleate, benzenesulfonate,
Examples include p-toluenesulfonate.

The benzimidazoline derivatives represented by the general formula () or their pharmacologically acceptable acid addition salts of the present invention can be used in ordinary preparations either as they are or after being mixed with appropriate pharmaceutical excipients. Depending on the method, it can be made into various dosage forms, such as oral preparations such as powders, granules, fine granules, capsules, syrups, liquids, etc., and parenteral preparations such as injections.

When the benzimidazoline derivatives of the present invention represented by the general formula () or their pharmacologically acceptable acid addition salts are used for treatment, the dosage thereof is as follows:
Although it is determined appropriately depending on the patient's age, sex, weight, degree of symptoms, etc., in the case of oral administration, adults
In the case of parenteral administration, the dose is administered within the range of 1 mg to 1000 mg per day for adults.

〔Effect of the invention〕

The benzimidazoline derivatives of the present invention represented by the general formula () or their pharmacologically acceptable acid addition salts exhibit remarkable suppressive effects on experimental ulcers. For example, in a water immersion restraint stress ulcer experiment using male Wistar rats (8 weeks old), oral administration of 100 mg/kg body weight resulted in approximately 40% to 95%
shows a suppressive effect.

Thus, the benzimidazoline derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention have strong antiulcer effects,
Moreover, since it has few side effects, it is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans.

〔Example〕

The content of the present invention will be explained in further detail using the following reference examples and examples.

Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference example 1 2-(2-diisopropylaminoethylamino)
Aniline A mixture of 7.85 g of 2-chloronitrobenzene, 7.20 g of 2-diisopropylaminoethylamine, and 7.59 g of anhydrous potassium carbonate was stirred at 100° C. for 71 hours. After cooling, water was added to the reaction mixture, followed by extraction with methylene chloride, washing with water, and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from benzene-hexane to obtain 9.70 g of N-(2-diisopropylaminoethyl)-2-nitroaniline with a melting point of 107-109°C.

Elemental analysis value (as C ₁₄ H ₂₃ N ₃ O ₂ ) C% H% N% Calculated value 63.37 8.74 15.84 Actual value 63.31 8.90 15.67 IR (KBr): ν _NH 3325cm ^-1 ν _NO2 1555cm ^-1 NMR (CDCl ₃ ) δ: 1.07 (12H, d, J = 6.6Hz), 2.83 (2H, t,
J=6.1Hz), 3.08 (2H, sept, J=6.6Hz), 3.26
(2H, q, J = 6.1Hz), 6.60 (1H, ddd, J =
1.6, 7.1, and8.8Hz), 6.82 (1H, dd, J=
1.6and8.8Hz), 7.41 (1H, ddd, J=1.6, 7.1,
and8.8Hz), 8.17 (1H, dd, J=1.6and8.8Hz),
8.47 (1H, br-s) N-(2-diisopropylaminoethyl)-2-
7.00 g of nitroaniline was suspended in 200 ml of ethanol, 300 mg of 10% palladium on carbon was added, and the mixture was hydrogenated at room temperature under normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 6.06 g of 2-(2-diisopropylaminoethylamino)aniline having a melting point of 62 to 66°C.

IR (KBr): ν _NH 3325, 3310 cm ^-1 NMR (CDCl ₃ ) δ: 1.04 (12H, d, J = 6.6Hz), 2.80 (2H, t,
J=6.1Hz), 2.95-3.15 (4H, m), 3.31 (3H,
br-s), 6.6-6.85 (4H, m) Reference Example 2 2-(2-Dibutylaminoethylamino)aniline A mixture of 7.85 g of 2-chloronitrobenzene, 9.00 g of 2-dibutylaminoethylamine and 7.59 g of anhydrous potassium carbonate was Stir at 100°C for 51 hours.
After cooling, water was added to the reaction mixture, followed by extraction with methylene chloride, washing with water, and drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: benzene/chloroform = 1/1) to obtain oily N-(2-dibutylaminoethyl)-2.
- 10.20 g of nitroaniline were obtained.

IR (neat): ν _NH 3350cm ^-1 ν _NO2 1565cm ^-1 NMR (CDCl ₃ ) δ: 0.89 (6H, t, J = 7.1Hz), 1.2 to 1.55 (8H,
m), 2.46 (4H, t, J=7.1Hz), 2.75 (2H,
t, J = 6.0Hz), 3.30 (2H, q, J = 6.0Hz),
6.61 (1H, t, J = 8.2Hz), 6.83 (1H, d, J
= 8.2Hz), 7.42 (1H, dt, J = 1.7and8.2Hz),
8.17 (1H, dd, J=1.7and8.2Hz), 8.40 (1H,
br-s) Dissolve 10.15 g of N-(2-dibutylaminoethyl)-2-nitroaniline in 150 ml of ethanol,
% palladium on carbon was added thereto, and hydrogenation was carried out at room temperature under normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain 8.70 g of oily 2-(2-dibutylaminoethylamino)aniline.

IR (neat): ν _NH 3300cm ^-1 NMR (CDCl ₃ ) δ: 0.91 (6H, t, J = 7.1Hz), 1.15-1.6 (8H,
m), 2.54 (4H, t, J=7.1Hz), 2.81 (2H,
t, J = 6.0Hz), 3.17 (2H, t, J = 6.0Hz),
3.45 (3H, br), 6.55-6.85 (4H, m) Example 1 1-(2-diisopropylaminoethyl)benzimidazolin-2-one 2-(2-diisopropylaminoethylamino)
Dissolve 2.08g of aniline in 100mg of dry benzene,
After adding 1.44 g of 1,1'-carbonyldiimidazole and stirring at room temperature for 14 hours, the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was washed, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from diethyl ether-hexane to obtain 1.52 g of 1-(2-diisopropylaminoethyl)benzimidazolin-2-one having a melting point of 112-114°C.

Elemental analysis value (as C ₁₅ H ₂₃ N ₃ O) C% H% N% Calculated value 68.93 8.87 16.08 Actual value 68.90 9.10 15.79 IR (KBr): ν _NH 3175cm ^-1 ν _CO 1705, 1655cm ^-1 NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6Hz), 2.75 (2H, t,
J=7.1Hz), 3.05 (2H, sept, J=6.6Hz), 3.85
(2H, t, J=7.1Hz), 6.95-7.15 (4H, m),
9.97 (1H, s) Example 2 1-(2-dibutylaminoethyl)benzimidazolin-2-one Dissolve 4.30 g of 2-(2-dibutylaminoethylamino)aniline in 200 ml of dry dioxane and add 1,
After adding 3.00 g of 1'-carbonyldiimidazole and stirring at room temperature for 14 hours, the mixture was heated under reflux for 5 hours. After concentrating the reaction solution under reduced pressure, water was added to the residue, extracted with benzene, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform/ethanol = 10/1) to obtain oily 1-(2-dibutylaminoethyl)benzimidazolin-2-one. 3.32g was obtained.

Elemental analysis value (as C ₁₇ H ₂₇ N ₃ O) C% H% N% Calculated value 70.55 9.40 14.52 Actual value 70.50 9.65 14.47 IR (neat): ν _NH 3150cm ^-1 ν _CO 1685cm ^-1 NMR (CDCI ₃ ) δ : 0.88 (6H, t, J=7.1Hz), 1.15~1.5 (8H,
m), 2.50 (4H, t, J=7.1Hz), 2.78 (2H,
t, J=7.7Hz), 3.96 (2H, t, J=7.7Hz),
6.95-7.15 (4H, m), 9.80 (1H, s)

Claims (1)

[Claims] 1. General formula (R ¹ and R ² in the formula may be the same or different and are each a linear or branched alkyl group having 3 to 5 carbon atoms, and Y is a linear or branched alkyl group having 2 to 4 carbon atoms. (alkylene chain)
The represented benzimidazoline derivatives and their pharmacologically acceptable acid addition salts.