JPH0533699B2 - - Google Patents

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention exhibits a mild central depressant effect and a remarkable anti-ulcer effect against experimental ulcers, especially stress ulcers, and is useful for the treatment of gastric and duodenal ulcers in mammals including humans. The present invention provides benzimidazolin-2-one derivatives useful as agents and pharmacologically acceptable acid addition salts thereof.

[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 mucus secretion enhancers, local circulation improvers, and tissue repair agents.

Recently, prostaglandins, which are physiologically active substances widely distributed in the body, have attracted attention for their suppressive effects on gastric acid secretion and cell protective effects, especially their cell protective effects.
Application as an ulcer treatment agent is being considered.

However, few ulcer therapeutic agents have been developed that have a mild central depressant effect and are effective in treating gastric and duodenal ulcers caused by stress, etc., which have been on the rise in recent years.

[Problem that the invention seeks to solve]

Currently, the drugs mainly used to treat gastric and duodenal ulcers include antacids, antipepsin agents, anticholinergic agents, and histamine H ₂ -receptor antagonists, all of which reduce the secretion of gastric acid, etc. This is considered to be the main factor in the development of ulcers, and attempts are made to 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 have been many reports of cases showing hypoacidity.

Stomach problems due to stress, which has been increasing in recent years,
It is said that there are many cases of duodenal ulcers, but among the conventional ulcer treatment agents, there are almost none that exhibit central depressant effects that are effective in treating gastric and duodenal ulcers caused by stress, etc. In actual treatment, conventional ulcer treatment agents are used in combination with anti-anxiety agents or tranquilizers.

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

[Means for solving problems]

The present inventors conducted an investigation to develop a therapeutic agent for ulcers that has a mild central action and is effective in treating gastric and duodenal ulcers caused by stress, etc., and found that a certain benzimidazolin-2-one derivative was used to treat ulcers. The inventors have discovered that the object can be achieved, and have completed the present invention.

That is, the present inventor has found that a mild central depressant effect,
A general formula that has a remarkable anti-ulcer effect on experimental ulcers, especially stress ulcers, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans. (In the formula, R ¹ is a hydrogen atom, a halogen atom, or a lower alkyl group, R ₂ is a lower alkyl group or an aralkyl group, Y is an alkylene chain having 2 to 4 carbon atoms that may be branched, and Z is The present invention provides benzimidazolin-2-one derivatives represented by (which is a secondary amino group) and pharmacologically acceptable acid addition salts thereof.

The benzimidazolin-2-one derivatives of the present invention represented by the general formula () show almost no inhibitory effect on acid secretion induced by histamine, carbachol, etc.; shows a remarkable inhibitory effect on acid secretion. This indicates that the present compound has an inhibitory effect on acid secretion caused by central stimulation.

The compound of general formula () of the present invention exhibits a remarkable suppressive effect on experimental ulcers, such as water immersion restraint stress ulcers in rats, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans.

The compound of general formula () of the present invention is a novel compound that has not been described in any literature, and can be produced as follows.

That is, the general formula (R ¹ and R ² in the formula have the same meanings as above)
A compound represented by the following, and an amine derivative represented by the general formula It can be produced by reacting an acid addition salt with an inert solvent in the presence of a base.

Examples of inert solvents used in this reaction include benzene, toluene, xylene, dioxane,
1,2-dimethoxyethane, tetrahydrofuran, N,N-dimethylformamide, or a mixed solvent thereof can be used. Also,
Bases include, for example, potassium carbonate, sodium hydride, sodium amide or potassium tert.
-butoxide etc. can be used.

Most of the compounds of general formula () used as starting materials in this production method are known compounds, and J.
H. Cooley et al.'s method [J.Org.Chem., 40 . ,552
(1975)] or the method of J. Perronnet et al. [Gazz.
Chim.Ital., 112 , 507 (1982)] or a method similar thereto.

Further, the amine derivative represented by the general formula () used as the other starting material is also a known compound and can be obtained as a commercial product or easily produced by a known method.

In order to suitably carry out the method for producing a compound of the general formula () of the present invention, the compound represented by the general formula () and the compound represented by the general formula () in an equimolar to slightly excess molar amount The amine derivative or its acid addition salt is added to an inert solvent such as N,N-dimethylformamide, and after adding the required amount of base such as sodium hydride at 0 to 30°C,
The reaction is carried out at ~150°C, preferably 70-120°C for 1-20 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and a suitable solvent such as diethyl ether or methylene chloride is added to the residue, washed with an aqueous sodium hydroxide solution and water, and then treated with activated carbon if necessary. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, or the residue is purified by column chromatography, recrystallization, etc., or it is converted into an appropriate acid addition salt and then recrystallized. The desired product is obtained by purification etc.

The benzimidazolin-2-one derivative represented by the general formula () of the present invention can be converted into an acid addition salt by a conventional method. For example, after adding 1N hydrochloric acid in an equivalent molar amount to a slightly excess molar amount of ethanol,
The hydrochloride salt can be obtained by 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, hydroiodide, sulfate, acetate, oxalate, malate, tartrate, citrate, mandate, and fumarate. , maleate, benzene sulfonate, p-toluenesulfonate, and the like.

The benzimidazolin-2-one derivatives represented by the general formula () or their pharmacologically acceptable acid addition salts of the present invention are usually used alone or after being mixed with appropriate pharmaceutical excipients. Depending on the method used for preparation, various dosage forms are available, such as oral preparations such as powders, granules, fine granules, tablets, capsules, syrups, liquids, etc., and parenteral preparations such as injections. can do.

When the benzimidazolin-2-one derivatives represented by the general formula () or their pharmacologically acceptable acid addition salts of the present invention are used for treatment, the dosage should be determined based on the patient's age, sex, body weight, Although appropriately determined depending on the severity of symptoms, etc., it is generally administered within the range of 10 mg to 5000 mg per day for adults in the case of oral administration, and 1 mg to 1000 mg per day for adults in the case of parenteral administration.

〔Effect of the invention〕

The benzimidazolin-2-one derivatives represented by the general formula () or their pharmacologically acceptable acid addition salts of the present invention exhibit a remarkable inhibitory effect on experimental ulcers in animals. For example, in a water immersion restraint stress ulcer experiment using male Wistar rats (8 weeks old), oral administration of 100 mg/kg of body weight shows an inhibitory effect of about 30% to 95%. In particular, 1-
Benzyloxy-3-(2-diisopropylaminoethyl)benzimidazolin-2-one showed an inhibitory effect of about 70% even when administered orally at a dose of 50 mg/kg body weight.

The compound of general formula () of the present invention shows almost no inhibitory effect on histamine- or carbachol-induced acid secretion, but shows a significant inhibitory effect on 2-deoxy-D-glucose-induced acid secretion. show. Therefore, it can be said that the compound of general formula () of the present invention has an inhibitory effect on acid secretion caused by central stimulation.

The compound of the general formula () of the present invention hardly exhibits the sleep prolonging effect seen in ordinary tranquilizers and the like.

As described above, the benzimidazolin-2-one derivative represented by the general formula () of the present invention has a strong anti-ulcer effect, has few side effects, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans. It is.

〔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 each compound in Reference Examples and Examples are all uncorrected.

Reference Example 6-Fluoro-1-methoxybenzimidazolin-2-one 60% in 100ml of dry N,N-dimethylformamide
Suspended 3.74 g of sodium hydride (oil-based), added 7.80 g of 0-methylhydroxylamine hydrochloride while stirring under ice-cooling, and reacted for 1 hour.
- 10.67 g of fluorophenyl isocyanate was added and reacted at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure, water and methylene chloride were added to the residue and stirred. Insoluble matter was filtered off, and the methylene chloride layer was treated with activated carbon and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane.
-(4-fluorophenyl)-3-methoxyurea
6.47g was obtained.

Elemental analysis value (as C ₈ H ₉ FN ₂ O ₂ ) C% H% N% Calculated value 52.17 4.93 15.21 Actual value 52.51 4.93 14.91 IR (KBr): ν _NH 3340, 3250cm ^-1 νco 1665cm ^-1 NMR (CDCl ₃ ) δ: 3.80 (3H, s), 7.03 (2H, t, J = 8.8
Hz), 7.11 (1H, br-s), 7.4-7.55 (3H,
m) Dissolve 6.41 g of this urea in 100 ml of dry chloroform and add 16.24 g of lead tetraacetate while stirring at room temperature.
After dropping 105 ml of dry chloroform/acetic acid (20/1) solution of
The mixture was heated to reflux for an hour. After cooling, add 10% hydrochloric acid to the reaction solution.
After adding 100ml and stirring, filter out the precipitate.
The chloroform layer was washed with an aqueous sodium bicarbonate solution and water, treated with activated carbon, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from chloroform-hexane and the melting point
4.52 g of 6-fluoro-1-methoxybenzimidazolin-2-one was obtained at 181-184°C.

Elemental analysis value (as C ₈ H ₇ FN ₂ O ₂ ) C% H% N% Calculated value 52.75 3.87 15.38 Actual value 52.87 3.85 15.38 IR (KBr): νco 1700cm ^-1 NMR (CDCl ₃ ) δ: 4.12 (3H, s), 6.82 (1H, ddd, J=
2.2, 7.7and8.2Hz), 6.90 (1H, dd, J=
2.2and7.7Hz), 7.03(1H, dd, J=
4.4and8.2Hz), 9.51 (1H, s) Example 1 1-benzyloxy-3-(2-diisopropylaminoethyl)benzimidazoline-2-one 1-benzyloxybenzimidazoline-2-
Dissolve 12.01 g of 2-diisopropylaminoethyl chloride hydrochloride and 12.01 g of 2-diisopropylaminoethyl chloride hydrochloride in 200 ml of dry N,N-dimethylformamide, and while stirring under ice cooling, add 4.00 g of 60% sodium hydride (oil-based) after washing with dry benzene. After reacting for 40 minutes, the mixture was reacted at room temperature for 1 hour and then at 80°C for 16 hours. After concentrating the reaction solution under reduced pressure, water was added to the residue, extracted with diethyl ether, treated with activated carbon, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was dissolved in hexane and treated with activated carbon, and then the solvent was distilled off under reduced pressure. The residue was further dissolved in diethyl ether and treated with activated carbon, and the solvent was distilled off under reduced pressure to give an oily 1-benzyloxy-3-
16.02 g of (2-diisopropylaminoethyl)benzimidazolin-2-one was obtained.

Elemental analysis value (as C ₂₂ H ₂₉ N ₃ O ₂ ) C% H% N% Calculated value 71.90 7.95 11.43 Actual value 71.98 8.08 11.36 IR (neat): νco 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.00 (12H, d, J=6.6Hz), 2.73(2H,
t, J = 7.2Hz), 3.04 (2H, sept, J = 6.6
Hz), 3.82 (2H, t, J=7.2Hz), 5.24
(2H, s), 6.82 (1H, d, J=7.1Hz),
6.9~7.1 (3H, m), 7.3~7.4 (3H, m),
7.45-7.55 (2H, m) Example 2 1-benzyloxybenzimidazoline-2-
The following compound was produced in substantially the same manner as in Example 1 using 2-dibutylaminoethyl chloride and 2-dibutylaminoethyl chloride hydrochloride.

1-Benzyloxy-3-(2-dibutylaminoethyl)benzimidazolin-2-one Properties: Oil Yield: 27.9% Elemental analysis (as C ₂₄ H ₃₃ N ₃ O ₂ ) C% H% N% Calculation Value 72.88 8.41 10.62 Actual value 72.80 8.66 10.38 IR (neat): νco 1705cm ^-1 NMR (CDCl ₃ ) δ: 0.87 (6H, t, J = 7.1Hz), 1.15 to 1.5
(8H, m), 2.48 (4H, t, J=7.1Hz),
2.75 (2H, t, J = 7.1Hz), 3.93 (2H, t,
J=7.1Hz), 5.24 (2H, s), 6.82 (1H,
d, J=8.8Hz), 6.9-7.15 (3H, m), 7.3
~7.4 (3H, m), 7.45 ~ 7.55 (2H, m) Example 3 The following procedure was carried out in the same manner as in Example 1 using 1-methoxybenzimidazolin-2-one and 2-dibutylaminoethyl chloride hydrochloride. A compound was prepared.

3-(2-dibutylaminoethyl)-1-methoxybenzimidazolin-2-one Properties: Oil Yield: 60.1% Elemental analysis value (as C ₁₈ H ₂₉ N ₃ O ₂ ) C% H% N% Calculated value 67.68 9.15 13.15 Actual value 67.60 9.44 12.86 IR (neat): νco 1715cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, t, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.47 (4H, t, J=7.1Hz),
2.75 (2H, t, J = 7.1Hz), 3.92 (2H, t,
J=7.1Hz), 4.08 (3H, s), 6.95~7.2
(4H, m) Example 4 The following compound was produced in substantially the same manner as in Example 1 using 1-methoxybenzimidazolin-2-one and 3-dimethylamino-2-methylpropyl chloride hydrochloride.

3-(3-dimethylamino-2-methylpropyl)-1-methoxybenzimidazoline-2-
On Properties: Oil Yield: 16.8% Elemental analysis value (as C ₁₄ H ₂₁ N ₃ O ₂ ) C% H% N% Calculated value 63.85 8.04 15.96 Actual value 64.19 8.27 15.85 IR (neat): νco 1710cm ^-1 NMR ( _CDCl3 ) δ: 0.94 (3H, d, J = 6.0Hz), 2.05 to 2.3
(9H, m), 3.67 (1H, dd, J=7.7and14.3
Hz), 3.97 (1H, dd, J=4.4and14.3Hz),
4.09 (3H, s), 7.0 to 7.2 (4H, m) Example 5 In almost the same manner as in Example 1, using 1-methoxy-6-methylbenzimidazolin-2-one and 2-diisopropylaminoethyl chloride hydrochloride. The following compound was produced.

1-(2-diisopropylaminoethyl)-3-
Methoxy-5-methylbenzimidazoline-2
-On Properties: Crystal (melting point 59-61℃) Yield: 80.5% Elemental analysis value (as C ₁₇ H ₂₇ N ₃ O ₂ ) C% H% N% Calculated value 66.85 8.91 13.76 Actual value 66.67 9.17 13.71 IR ( KBr): νco 1715, 1695 cm ^-1 NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6Hz), 2.41 (3H,
s), 2.71 (2H, t, J = 7.1Hz), 3.02
(2H, sept, J = 6.6Hz), 3.79 (2H, t,
J=7.1Hz), 4.07 (3H, s), 6.85~7.0
(3H, m) Example 6 The following compound was produced in substantially the same manner as in Example 1 using 6-chloro-1-methoxybenzimidazolin-2-one and 2-diisopropylaminoethyl chloride hydrochloride. .

5-chloro-1-(2-diisopropylaminoethyl)-3-methoxybenzimidazoline-
2-one Properties: Crystal (melting point 85-87℃) Yield: 86.6% Elemental analysis value (as C ₁₆ H ₂₄ ClN ₃ O ₂ ) C% H% N% Calculated value 58.98 7.42 12.90 Actual value 59.28 7.64 12.97 IR (KBr): νco 1720, 1700cm ^-1 NMR (CDCl ₃ ) δ: 0.96 (12H, d, J = 6.6Hz), 2.71 (2H,
t, J = 7.1Hz), 3.01 (2H, sept, J = 6.6
Hz), 3.79 (2H, t, J=7.1Hz), 4.07
(3H, s), 6.92 (1H, d, J=8.2Hz),
7.0 to 7.15 (2H, m) Example 7 The following compound was prepared in substantially the same manner as in Example 1 using 6-fluoro-1-methoxybenzimidazolin-2-one and 2-diisopropylaminoethyl chloride hydrochloride. was manufactured.

1-(2-diisopropylaminoethyl)-5-
Fluoro-3-methoxybenzimidazoline-
2-one Properties: Crystal (melting point 40-42℃) Yield: 87.7% Elemental analysis value (as C ₁₆ H ₂₄ FN ₃ O ₂ ) C% H% N% Calculated value 62.12 7.82 13.58 Actual value 62.09 8.16 13.50 IR (KBr): νco 1715, 1700cm ^-1 NMR (CDCl ₃ ) δ: 0.97 (12H, d, J = 6.6Hz), 2.71 (2H,
t, J = 7.1Hz), 3.70 (2H, sept, J = 6.6
Hz), 3.79 (2H, t, J = 7.1Hz), 4.08
(3H, s), 6.75-7.0 (3H, m) Example 8 3-(3-dimethylaminopropyl)-1-methoxybenzimidazolin-2-one 50% in 80 ml of dry N,N-dimethylformamide
After washing 0.67 g of sodium hydride (oil-based) with dry benzene, add 1-methoxybenzimidazolin-2-one while stirring under ice-cooling.
After adding 1.15 g and reacting for 30 minutes, 1.11 g of 3-dimethylaminopropyl chloride hydrochloride was added and reacted at 100°C for 16 hours. After concentrating the reaction solution under reduced pressure, a 10% aqueous sodium hydroxide solution was added to the residue, extracted with diethyl ether, washed with water, treated with activated carbon, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.69 g of oily 3-(3-dimethylaminopropyl)-1-methoxybenzimidazolin-2-one.

Elemental analysis value (as C ₁₃ H ₁₉ N ₃ O ₂ ) C% H% N% Calculated value 62.62 7.68 16.86 Actual value 62.63 7.97 16.73 IR (neat): νco 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.92 (2H, quint, J=7.1Hz), 2.23(6H,
s), 2.34 (2H, t, J=7.1Hz), 3.93
(2H, t, J=7.1Hz), 4.10 (3H, s),
7.05-7.2 (4H, m) Example 9 The following compound was produced in substantially the same manner as in Example 8 using 1-methoxybenzimidazolin-2-one and 2-dimethylaminoethyl chloride hydrochloride.

3-(2-dimethylaminoethyl)-1-methoxybenzimidazolin-2-one Properties: Oil Yield: 22.5% Elemental analysis (as C ₁₂ H ₁₇ N ₃ O ₂ ) C% H% N% Calculated value 61.25 7.28 17.86 Actual value 60.99 7.38 17.53 IR (neat): νco 1705cm ^-1 NMR (CDCl ₃ ) δ: 2.33 (6H, s), 2.65 (2H, t, J = 7.1
Hz), 3.98 (2H, t, J=7.1Hz), 4.09
(3H, s), 7.0 to 7.2 (4H, m) Example 10 The following procedure was carried out in the same manner as in Example 8 using 1-methoxybenzimidazolin-2-one and 2-(1-pyrrolidinyl)ethyl chloride hydrochloride. The compound was prepared.

1-Methoxy-3-[2-(1-pyrrolidinyl)
Ethyl]benzimidazolin-2-one Properties: Oil Yield: 29.9% Elemental analysis value (as C ₁₄ H ₁₉ N ₃ O ₂ ) C% H% N% Calculated value 64.35 7.33 16.08 Actual value 64.07 7.44 15.73 IR (neat ): νco 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.7 to 1.85 (4H, m), 2.55 to 2.7 (4H,
m), 2.82 (2H, t, J = 7.7Hz), 4.03
(2H, t, J=7.7Hz), 4.09 (3H, s),
7.0-7.2 (4H, m) Example 11 3(2-diisopropylaminoethyl)-1-methoxybenzimidazolin-2-one 50% in 80 ml of dry N,N-dimethylformamide
After washing 0.67 g of sodium hydride (oil-based) with dry benzene, add 1-methoxybenzimidazolin-2-one while stirring under ice-cooling.
Add 1.15g and react for 30 minutes, then add 1.40g of 2-diisopropylaminoethyl chloride hydrochloride and heat at 100℃.
The reaction was allowed to proceed for 16 hours. After concentrating the reaction solution under reduced pressure, a 10% aqueous sodium hydroxide solution was added to the residue, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, water containing 6.5 ml of 1N hydrochloric acid was added to the residue and dissolved.
After treatment with activated carbon, the mixture was neutralized with 6.5 ml of 1N aqueous sodium hydroxide solution and extracted with diethyl ether.
The diethyl ether layer was washed with water, treated with activated carbon, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.36 g of oily 3-(2-diisopropylaminoethyl)-1-methoxybenzimidazolin-2-one.

Elemental analysis value (as C ₁₆ H ₂₅ N ₃ O ₂ ) C% H% N% Calculated value 65.95 8.65 14.42 Actual value 65.90 8.85 14.24 IR (neat): νco 1715cm ^-1 NMR (CDCl ₃ ) δ: 0.99 (12H, d, J = 6.6Hz), 2.72 (2H,
t, J = 7.1Hz), 3.03 (2H, sept, J = 6.6
Hz), 3.81 (2H, t, J = 7.1Hz), 4.08
(3H, s), 6.95-7.15 (4H, m) Example 12 The following compound was prepared in substantially the same manner as in Example 11 using 1-methoxybenzimidazolin-2-one and 2-piperidinoethyl chloride hydrochloride. was manufactured.

1-methoxy-3-(2-piperidinoethyl)
Benzimidazolin-2-one Properties: Oil Yield: 41.1% Elemental analysis value (as C ₁₅ H ₂₁ N ₃ O ₂ ) C% H% N% Calculated value 65.43 7.69 15.26 Actual value 65.58 7.82 15.28 IR (neat): νco 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.35 to 1.65 (6H, m), 2.4 to 2.55 (4H,
m), 2.64 (2H, t, J = 7.1Hz), 4.00
(2H, t, J=7.1Hz), 4.09 (3H, s),
7.0 to 7.2 (4H, m) Example 13 The following compound was produced in substantially the same manner as in Example 11 using 1-methoxybenzimidazolin-2-one and 2-diethylaminoethyl chloride hydrochloride.

3-(2-diethylaminoethyl)-1-methoxybenzimidazolin-2-one Properties: Oil Yield: 47.9% Elemental analysis (as C ₁₄ H ₂₁ N ₃ O ₂ ) C% H% N% Calculated value 63.85 8.04 15.96 Actual value 63.88 8.12 15.93 IR (neat): νco 1715cm ^-1 NMR (CDCl ₃ ) δ: 1.01 (6H, t, J = 7.1Hz), 2.60 (4H,
q, J = 7.1Hz), 2.76 (2H, t, J = 7.1
Hz), 3.94 (2H, t, J = 7.1Hz), 4.08
(3H, s), 7.0-7.15 (4H, m) Example 14 1-benzyloxy-3-(2-diethylaminoethyl)benzimidazolin-2-one 1-benzyloxybenzimidazoline-2-
2.40 g of 1.72 g of 2-diethylaminoethyl chloride hydrochloride and 3.04 g of potassium carbonate were stirred in 80 ml of dry N,N-dimethylformamide at 80 DEG C. for 5 hours. After concentrating the reaction solution under reduced pressure, the residue
A 10% aqueous sodium hydroxide solution was added, extracted with diethyl ether, washed with water, treated with activated carbon, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in hexane, treated with activated carbon, and then the solvent was distilled off under reduced pressure. Further, the residue was dissolved in diethyl ether and treated with activated carbon.
The solvent was distilled off under reduced pressure to obtain 0.20 g of oily 1-benzyloxy-3-(2-diethylaminoethyl)benzimidazolin-2-one.

Elemental analysis value (as C ₂₀ H ₂₅ N ₃ O ₂ ) C% H% N% Calculated value 70.76 7.42 12.38 Actual value 70.88 7.26 12.01 IR (neat): νco 1715cm ^-1 NMR (CDCl ₃ ) δ: 1.02 (6H, t, J=7.1Hz), 2.2~2.85
(6H, m), 3.85-4.05 (2H, m), 5.24
(2H, s), 6.82 (1H, d, J=7.1Hz),
6.9-7.1 (3H, m), 7.3-7.6 (5H, m) Example 15 1-benzyloxy-3-[2-(2,2,6,
6-Tetramethylpiperidino)ethyl]benzimidazolin-2-one 1-benzyloxybenzimidazoline-2-
1.50 g of 2-(2,2,6,6-tetramethylpiperidino)methyl chloride hydrochloride were dissolved in 80 ml of dry N,N-dimethylformamide.
While stirring under ice-cooling, 0.50 g of 60% sodium hydride (oil-based) was added, and after reacting for 50 minutes, the reaction was continued for 1 hour at room temperature and further for 14 hours at 80°C. After concentrating the reaction solution under reduced pressure, water was added to the residue, extracted with methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: benzene/chloroform = 4/1), and then recrystallized from diethyl ether-hexane.
1-Benzyloxy-3-[2-
0.98 g of (2,2,6,6-tetramethylpiperidino)ethyl]benzimidazolin-2-one was obtained.

Elemental analysis value (as C ₂₅ H ₃₃ N ₃ O ₂ ) C% H% N% Calculated value 73.68 8.16 10.31 Actual value 73.74 8.26 10.36 IR (KBr): νco 1710cm ^-1 NMR (CDCl ₃ ) δ: 1.13 (12H, s), 1.4-1.65 (6H, m),
2.65-2.8 (2H, m), 3.75-3.85 (2H, m),
5.25 (2H, s), 685 (1H, dd, J=7.1
and7.1Hz), 6.9~7.1 (3H, m), 7.35~7.55
(5H, m) Example 16 The following compound was produced in substantially the same manner as in Example 15 using 1-methoxybenzimidazolin-2-one and 2-morpholinoethyl chloride hydrochloride.

1-Methoxy-3-(2-morpholinoethyl)
Benzimidazolin-2-one Elution solvent: methylene chloride/ethanol = 100/
1 Properties: Oil Yield: 22.1% Elemental analysis value (as C ₁₄ H ₁₉ N ₃ O ₃・0.1CH ₂ Cl ₂ ) C% H% N% Calculated value 59.25 6.77 14.70 Actual value 59.45 6.86 14.81 IR (neat) :νco 1705cm ^-1 NMR (CDCl ₃ ) δ: 2.5 to 2.6 (4H, m), 2.69 (2H, t, J=
7.1Hz), 3.65-3.75 (4H, m), 4.01 (2H,
t, J=7.1Hz), 4.09 (3H, s), 7.0~7.2
(4H, m) Example 17 1-benzyloxybenzimidazoline-2-
The following compound was produced in substantially the same manner as in Example 15 using 1.1 and 2-morpholinoethyl chloride hydrochloride.

1-benzyloxy-3-(2-morpholinoethyl)benzimidazolin-2-one Elution solvent: methylene chloride/ethanol = 100/
1 Properties: Oil Yield: 11.3% Elemental _analysis value (as _C20H23N3O3・_0.05CH2Cl2 ) C% H% _N % Calculated _value 67.33 6.51 _11.75 Actual value 67.34 6.63 11.76 IR (neat) :νco 1710cm ^-1 NMR (CDCl ₃ ) δ: 2.5 to 2.6 (4H, m), 2.69 (2H, t, J=
7.1Hz), 3.65-3.75 (4H, m), 4.01 (2H,
t, J=7.1Hz), 5.24 (2H, s), 6.83
(1H, dd, J=1.6and7.7Hz), 6.65~7.1
(3H, m), 7.3-7.55 (5H, m) Example 18 1-benzyloxy-3-(2-diisopropylaminoethyl)benzimidazolin-2-one hydrochloride 1-benzyloxy-3-(2-diisopropyl aminoethyl)benzimidazolin-2-one
Dissolve 8.12g in 100ml of ethanol and add 1N hydrochloric acid.
After adding 22.1 ml, the solvent was distilled off under reduced pressure.
After dissolving the residue in water and treating it with activated carbon,
After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue to crystallize it, the residue was collected by filtration, and recrystallized from methylene chloride-diethyl ether to give 1-
Benzyloxy-3-(2-diisopropylaminoethyl)benzimidazolin-2-one hydrochloride
7.36g was obtained.

Elemental analysis value (as C ₂₂ H ₃₀ ClN ₃ O ₂・0.1H ₂ O) C% H% N% Calculated value 65.12 7.50 10.36 Actual value 64.94 7.54 10.40 IR (KBr): νco 1735, 1720 cm ^-1 NMR (CDCl ₃ ) δ: 1.52 (6H, d, J = 6.6Hz), 1.61 (6H,
d, J=6.6Hz), 3.15-3.3 (2H, m), 3.6
~3.8 (2H, m), 4.6 ~ 4.75 (2H, m), 5.24
(2H, s), 6.86 (1H, d, J=7.1Hz),
7.04 (1H, t, J = 7.1Hz), 7.12 (1H, t,
J=7.7Hz), 7.3~7.55 (6H, m), 12.06
(1H, s)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a halogen atom, or a lower alkyl group, R ² is a lower alkyl group or an aralkyl group, Y is an alkylene chain having 2 to 4 carbon atoms that may be branched, and Z is a secondary amino group) and pharmacologically acceptable acid addition salts thereof. Benzimidazolin-2-one derivatives and pharmacologically acceptable acid addition salts thereof according to claim 1, wherein 2Z is a dialkylamino group. 3 Claim 1 in which Z is a cyclic amino group
Benzimidazolin-2-one derivatives and pharmacologically acceptable acid addition salts thereof as described in 1. 4 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 5 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 6 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 7 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 8 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 9 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 10 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 11 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 12 formula The benzimidazolin-2-one derivative according to claim 2, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 13 formula The benzimidazolin-2-one derivative according to claim 3, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 14 formula The benzimidazolin-2-one derivative according to claim 3, which is represented by: and a pharmacologically acceptable acid addition salt thereof. 15 formula The benzimidazolin-2-one derivative according to claim 3, which is represented by: and a pharmacologically acceptable acid addition salt thereof.