KR0139977B1 - Beuzimidazole derivatives having pyrazole group - Google Patents

Abstract

The present invention relates to a benzimidazole derivative containing pyrazole represented by the following structural formula (I), which has the ability to inhibit gastric acid secretion of a mammal and is very useful as an active ingredient of an anti-ulcer agent.

In the above formula,

R ¹ is a hydrogen atom, a halogen atom or an alkoxy group having 1 to 3 carbon atoms,

R ² is a hydrogen atom, an alkoxy group or benzyloxy group having 1 to 3 carbon atoms,

R ³ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkynyl group having 1 to 3 carbon atoms, a benzyl group or a substituted benzyl group wherein the substituent is a halogen atom or an alkoxy group having 1 to 3 carbon atoms,

R ⁴ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a benzyl group,

R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a carboalkoxy group having 1 to 3 carbon atoms,

n is 0 or 1;

Description

Benzimidazole Derivatives Containing Parasols

The present invention relates to a benzimidazole derivative containing a parasol represented by the following structural formula (I), which has a gastric acid secretion ability of a mammal and is very useful as an active ingredient of an anti-ulcer agent.

In the above formula,

R ¹ is a hydrogen atom, a halogen atom or an alkoxy group having 1 to 3 carbon atoms,

R ² is a hydrogen atom, an alkoxy group or benzyloxy group having 1 to 3 carbon atoms,

R ³ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkynyl group having 1 to 3 carbon atoms, a benzyl group or a substituted benzyl group, wherein the substituent is a halogen atom or an alkoxy group having 1 to 3 carbon atoms,

R ⁴ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a benzyl group,

R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a carboalkoxy group having 1 to 3 carbon atoms,

n is 0 or 1;

Benzimidazole derivatives containing pyridine are well known for their ability to inhibit gastric acid secretion and have also been developed and commercialized as gastric acid secretion inhibitors. The manufacturing method thereof is described in US Pat. No. 4,182,766, EP 208,422, UK Pat. No. 1,525,958, and the like. However, benzimidazole derivatives containing pyridine, commercialized as omeprazole, have an excellent effect on suppressing gastric acid secretion, but they accumulate in the body after prolonged administration. The problem is included. This is because the pyridine group itself in the benzimidazole derivatives containing pyridine has a strong basicity, and therefore, it was determined that rearrangement occurs easily and converts into a highly active compound even under weakly acidic conditions.

Therefore, to partially solve this problem, gastric acid secretion similar to omeprazole is achieved by converting a pyrazole group, which is believed to form a more stable compound under weakly acidic conditions, instead of a pyridine group in a benzimidazole derivative containing pyridine. New benzimidazole derivatives containing pyrazoles exhibiting inhibitory effects have been developed.

The present invention shows a novel structure in which benzimidazole is bonded to a substituted pyrazole having various substituents, its manufacturing process is simple, its raw material is inexpensive, and the above structural formula has a gastric acid secretion inhibitory effect similar to that of omeprazole. It is an object to provide a benzimidazole derivative represented by I).

Hereinafter, the present invention will be described in detail.

The present invention is characterized by a benzimidazole derivative represented by the following structural formula (I) having a gastric acid secretion inhibitory effect.

In the above formula,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are each as defined above.

Referring to the present invention in more detail as follows.

The present invention relates to a benzimidazole derivative containing parasol represented by Structural Formula (I), which is useful as an active ingredient of gastric ulcer therapeutic agent because of excellent gastric acid secretion inhibitory effect, and the preparation thereof may be represented as in the following scheme.

Scheme

In the above formula,

R ¹ , R ² , R ³ , R ⁴ and n are as defined in the above formula (I),

R ⁶ is an alkyl group having 1 to 3 carbon atoms,

X is a halogen atom.

First, the ethyl 3-pyrazole carboxylate represented by the above formula (II) is continuously subjected to conventional alkylation, reduction and chlorination to prepare a substituted pyrazole derivative represented by the above formula (III). Since the compound of the formula (II) used as a starting material in the present invention is a known compound and has the following resonance structure, it is represented by the following formula (III-a) or (III-b) by an alkylation reaction. Compounds can be produced, and R ³ or R ⁴ substituted compounds can be selectively obtained if the reaction conditions are properly adjusted.

At this time, the alkylation reaction is dissolved in ethyl 3-pyrazole carboxylate represented by the formula (II) in a reaction solvent selected from tetrahydrofuran, dichloromethane, dimethylformamide and ethyl ether at room temperature, and then potassium carbonate, A base selected from sodium hydroxide and sodium carbonate is reacted with an alkyl halide (R ³ X or R ⁴ X).

The reduction reaction is carried out using lithium aluminum hydride (LiAIH ₄ ) as a reducing agent in an ether solvent, and the chlorination reaction is performed by dissolving the compound prepared above in the solvent used in the alkylation reaction, followed by a general chlorinating agent, that is, thionyl chloride (SOCl _2). To be implemented.

Then, the compound represented by the above formula (III) is reacted with 2-mercaptobenzimidazole represented by the above formula (IV) in the presence of sodium hydroxide to the above formula (Ia) where R ⁵ = H and n = 0. To prepare the benzimidazole derivative indicated.

In addition, in order to prepare the benzimidazole derivative represented by the above formula (Ib) having R ⁵ = H and n = 1, the compound of the above formula (IV) is oxidized with a general oxidizing agent such as metachloroperbenzoic acid or hydrogen peroxide. .

In addition, the benzimidazole derivative represented by the above formula (Ib) having R ⁵ = H may introduce an alkyl group or a carboxyalkoxy group by a general alkylation reaction.

In addition, a benzimidazole derivative represented by Structural Formula (I-c) having n = 0 may be prepared by directly alkylating the compound represented by Structural Formula (I-a) without oxidation.

Representative examples of the benzimidazole derivatives containing pyrazole represented by the structural formula (I) according to the present invention are shown in Table 1 below.

Table 1

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

Example 1

2- (1-Methyl-pyrazol-3-yl) -methylthiobenzimidazole (Compound No. 1)

To ethanol (40 mL) was added 1-methyl-3-chloromethylpyrazole (700 mg, 5.3 mmol), 2-mercaptobenzimidazole (805 mg, 5.36 mmol) and sodium hydroxide (428.8 mg, 6.72 mmol). It is made to react at 50 degreeC for 3 hours. The reaction solvent was removed under reduced pressure, ethyl acetate (100 mL) and 10% NaOH (50 mL) were added, extracted into an organic layer, dried over MgSO ₄ and concentrated under reduced pressure. Recrystallization from ethyl ether gave 0.758 g (yield 58%) of the title compound as a solid.

¹ H NMR (CDCl ₃ ): δ 3.93 (s, 3H), 4.53 (s, 2H), 6.30 (d, 1H), 7.06 to 7.60 (m, 5H).

Example 2

2- (1-Methyl-pyrazol-3-yl) -methylthio-5-methoxybenzimidazole (Compound No. 15)

In ethanol (40 mL) 1-methyl-3-chloropyrazole (261.3 mg, 2 mmol), 2-mercapto-5-methoxybenzimidazole (360.4 mg, 2 mmol) and sodium hydroxide (120 mg, 3 mmol) is added and reacted at 50 ° C for 3 hours. The reaction solvent was removed under reduced pressure and chromatography (ethyl acetate: hexane = 6: 1) afforded 0.169 g (yield 31%) of the title compound as a liquid.

¹ H NMR (acetone-d ₆ ): δ 3.80 (s, 3H), 3.85 (s, 3H), 4.65 (s, 2H), 6.15 (d, 1H), 6.75 to 7.85 (m, 4H).

Example 3

2- (1-benzyl-pyrazol-3-yl) -methylthiobenzimidazole (Compound No. 19)

To ethanol (40 mL) was added 1-benzyl-3-chloropyrazole (1 g, 48 mmol), 2-mercaptomethoxybenzimidazole (0.8 g, 50 mmol) and sodium hydroxide (0.2 g, 48 mmol) and 50 It is made to react at 3 degreeC. The reaction solvent was removed under reduced pressure and chromatographed (ethyl acetate: hexane = 1: 2) gave 0.9 g (yield 64%) of the title compound as a solid.

Melting Point (℃): 135 ~ 140

¹ H NMR (CDCl ₃ ): δ 4.46 (s, 2H), 5.25 (s, 2H), 6.26 (d, 1H), 7.05 to 7.5 (m, 10H).

Example 4

2- (1-Benzyl-pyrazol-3-yl) -methylthio-5-methoxybenzimidazole (Compound No. 23)

In ethanol (60 mL) 1-benzyl-3-chloromethylpyrazole (700 mg, 3.4 mmol), 5-methoxy-2-mercaptobenzimidazole (525 mg, 3.4 mmol) and sodium hydroxide (205.9 mg, 515 mmol) is added and reacted at 50 ° C for 3 hours. The reaction solvent was removed under reduced pressure, and chromatography (ethyl acetate: hexane = 1: 1) afforded 1.02 g (yield 93.1%) of the target compound as a liquid.

¹ H NMR (acetone-d ₆ ): δ 3.76 (s, 3H), 4.53 (s, 2H), 5.29 (s, 2H), 6.26 (d, 1H), 6.66 to 7.53 (m, 9H).

Example 5

2- (1-Methyl-methoxy-pyrazol-3-yl) -methylthiobenzimidazole (Compound No. 26)

1-Methyl-3-chloromethyl-5-methoxy-pyrazole (500 mg, 283 mmol), 2-mercaptobenzimidazole (425 mg, 2.83 mmol) and sodium hydroxide (124 mg) in ethanol (30 mL) , 3 mmol) is added and reacted at 50 ° C. for 3 hours. The reaction solvent was removed under reduced pressure and chromatograph (chloroform: methanol = 20: 1) gave 0.66 g (yield 80.3%) of the title compound as a liquid.

¹ H NMR (CDCl ₃ ): δ 3.60 (s, 3H), 3.76 (s, 3H), 5.33 (s, 2H), 5.50 (s, 1H), 7.06 to 7.70 (m, 4H).

Example 6

2- (2-Methyl-pyrazol-3-yl) -methylthio-1-methyl-5-methoxybenzimidazole (Compound No. 29)

In tetrahydrofuran (100 mL) 1- (2-methyl-pyrazol-3-yl) -methylthio-5-methoxybenzimidazole (800 mg, 2.9 mmol) and iodine methane (0.18 mg, 2.9 mmol) Was added and reacted at 0 ° C for 5 hours. The reaction solvent was removed under reduced pressure and chromatographed (ethyl acetate: hexane = 5: 1) gave 0.6 g (yield 74.3%) of the title compound as a liquid.

¹ H NMR (CDCl ₃ ): δ 3.46 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 4.60 (s, 1H), 6.20 (d, 1H), 6.63 to 7.63 (m, 4H).

Example 7

2- (1-Benzyl-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazole (Compound No. 32)

To dichloromethane (30 mL) was added 2- (1-benzyl-3-yl) -methylthio-5-methoxybenzimidazole (400 mg, 1.24 mmol) and metachloroperbenzoic acid (385.5 mg, 2.04 mmol). React for 3 hours. The reaction solvent was evaporated under reduced pressure to afford 0.31 g (yield 72.7%) of the title compound as a liquid by chromatography (chloroform: methanol = 20: 1).

¹ H NMR (Methanol-d ₄ ): δ 3.78 (s, 3H), 4.56 (d, 2H), 4.95 (s, 1H), 5.12 (s, 2H), 6.05 (d, 1H), 6.92 to 7.82 ( m, 9H).

Example 8

2- (2-Methyl-pyrazol-3-yl) -methylsulfonyl-5-methoxybenzimidazole (Compound No. 35)

2- (1-methyl-pyrazol-3-yl) -methylthio-5-methoxybenzimidazole (380 mg, 1.39 mmol) and metachloroperbenzoic acid (330 mg, 1.53 mmol) in dichloromethane (30 mL). ) For 30 minutes. The reaction solvent was evaporated under reduced pressure to remove 0.274 g (yield 72%) of the title compound as a liquid by chromatography (ethyl acetate: hexane = 6: 1).

¹ H NMR (CDCl ₃ ): δ 3.78 (s, 3H), 3.86 (s, 3H), 4.59 (m, 2H), 6.02 (d, 1H), 6.89 to 7.69 (m, 4H).

Example 9

2- (1-Methyl-5-methoxy-pyrazol-3-yl) -methylsulfinylbenzimidazole (Compound No. 38)

2- (1-methyl-5-methoxy-pyrazol-3-yl) -methylthiobenzimidazole (450 mg, 1.55 mmol) in dichloromethane (30 mL), metachloroperbenzoic acid (368.9 mg, 1.71 mmol) ) For 30 minutes. The reaction solvent was removed under reduced pressure and chromatography (ethyl acetate: hexane = 6: 1) yielded 0.181 g (yield 42.8%) of the title compound as a solid.

Melting Point: 170 ~ 175 ℃

¹ H NMR (CDCl ₃ ): δ 3.60 (s, 3H), 3.76 (s, 3H), 4.34 (s, 2H), 5.5 (s, 1H), 7.05 to 7.70 (m, 4H).

Example 10

2- (1-Methyl-5-methoxy-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazole (Compound No. 42)

In dichloromethane (30 mL) 2- (1-methyl-5-methoxy-3-yl) -methylthio-5-methoxybenzimidazole (420 mg, 1.31 mmol) and metachloroperbenzoic acid (282.6 mg, 1.31 mmol) is added and reacted for 30 minutes. The reaction solvent was removed under reduced pressure and chromatography (chloroform: methanol = 20: 1) afforded 0.35 g (yield 79.4%) of the title compound as a solid.

¹ H NMR (Methanol-d ₄ ): δ 3.50 (s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 3.43 (s, 2H), 5.33 (s, 1H), 6.90 to 7.74 ( m, 3H).

Example 11

2- (1-benzyl-pyrazol-3-yl) -methylthio-1-methyl-5-methoxybenzimidazole (Compound No. 45)

In tetrahydrofuran (50 mL) 2- (1-benzyl-3-yl) -methylsulfinyl-5-methoxybenzimidazole (560 mg, 1.74 mmol), potassium hydroxide (143 mg, 2.61 mmol) and iodine Methane (0.11 mL, 1.74 mmol) is added and reacted for 1 hour. The reaction solvent was removed under reduced pressure and chromatography (chloroform: methanol = 20: 1) afforded 0.54 g (yield 92%) of the title compound as a liquid.

¹ H NMR (CDCl ₃ ): δ 3.46 (s, 3H), 3.80 (s, 3H), 3.60 (d, 2H), 5.20 (s, 2H), 6.23 (m, 1H), 6.63 to 7.62 (m, 4H).

Example 12

2- (1-ethyl-pyrazol-3-yl) -methylsulfinyl-1-acetyl-5-methoxybenzimidazole (Compound No. 47)

2- (1-ethyl-pyrazol-3-yl) -methylthio-1-acetyl-5-methoxybenzimidazole (400 mg, 1.2 mmol) and metachloroperbenzoic acid (258.5 mg, 1.2 mmol) It is added to methane (50 mL) and reacted for 30 minutes. The reaction solvent was removed after distillation under reduced pressure to obtain 0.35 g (yield 82.3%) of the title compound by chromatography (chloroform: methanol = 20: 1).

¹ H NMR (CDCl ₃ ): δ 1.50 (t, 3H), 3.90 (s, 3H), 4.16 (s, 3H), 4.03 (q, 2H), 4.53 (s, 2H), 6.33 (d, 2H) , 6.90 to 7.73 (m, 4H).

Example 13

2- (1-Benzyl-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazole (Compound No. 50)

2- (2-methyl-pyrazol-3-yl) -methylthio-5-methoxybenzimidazole (240 mg, 0.88 mmol), and metaperchlorobenzoic acid (189 mg, 0.88 mmol) in dichloromethane (10 mL ) And react for 30 minutes. The reaction solvent was removed under reduced pressure and chromatograph (chloroform: methanol = 20: 1) yielded 0.24 g of the target compound (yield 92.5%).

¹ H NMR (acetone-d ₆ ): δ 3.80 (s, 3H), 3.85 (s, 3H), 4.76 (d, 2H), 5.90 (d, 1H), 6.86-77.7 (m, 4H).

Example 14

2- (1-Methyl-5-methoxy-pyrazol-3-yl) -methylsulfinyl-5-chlorobenzimidazole (Compound No. 53)

2- (1-methyl-5-methoxy-pyrazol-3-yl) -methylthio-5-chlorobenzimidazole (400 mg, 1.36 mmol) and metachloroperbenzoic acid (293.4 mg, 1.36 mmol) It is added to methane (10 ml) and reacted for 30 minutes. The reaction solvent was removed under reduced pressure and chromatography (chloroform: methanol = 20: 1) yielded 0.29 g (yield 69%) of the title compound as a solid.

¹ H NMR (CDCl ₃ ): δ 3.46 (s, 3H), 3.80 (s, 3H), 4.46 (d, 2H), 5.36 (s, 1H), 7.20 to 7.80 (m, 3H).

Benzimidazole derivatives containing pyrazole represented by the above formula (I) and acid addition salts thereof according to the present invention have a gastric acid secretion inhibitory ability and are very useful as a therapeutic agent for gastric ulcer.

Therefore, the present invention comprises a pharmaceutical composition comprising the novel benzimidazole derivative as an active ingredient, these pharmaceutical compositions are added to the compound of formula (I), a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient It can be administered orally or parenterally.

Pharmaceutical compositions comprising the compound represented by the above formula (I) as an active ingredient are oral dosage forms, for example, tablets, troches, lozenges, water-soluble or oily suspensions, prepared powders or granules, emulsions, Formulated in hard or soft capsules, syrups or elixirs. Binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin for preparation in formulations such as tablets and capsules; Excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch; Lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax. In the case of capsule formulation, in addition to the above-mentioned substances, it contains a liquid carrier such as fatty oil.

In addition, the compound represented by the formula (I) can be administered parenterally as an active ingredient, parenteral administration is by the injection method of subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection. To formulate into a parenteral formulation, the compound of formula (I) is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is formulated in unit dosage form of ampoules or vials.

The dosage of the compound represented by Structural Formula (I) may vary depending on the patient's age, weight, sex, dosage form, health condition, and degree of disease. In general, the daily dosage is 15∼ based on an adult male. 25 mg is preferred.

Syrup

A syrup containing 2% of active ingredient (weight / volume) was prepared by the following ingredients.

2- (2-Methyl-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazole-HCl2g

Saccharin0.8g

25.4g per sugar

Glycerin8.0g

Spice0.04g

Ethanol4.0g

Sorbate 0.4g

Distilled water

Sugars, saccharin and addition salts were dissolved in 80 g of warm water. After cooling the solution, a solution consisting of glycerin, saccharin, spices, ethanol, sorbic acid and water was prepared and placed in a bottle. Water was added to this mixture to 100 ml. The addition salt can be replaced with another salt.

refine

A tablet containing 15 mg of active ingredient was prepared by the following method.

250 g of 2- (2-methyl-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazoleHCl salt were mixed with 175.9 g lactose, 180 g potato starch and 32 g colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground to pass 14 meshes. It was dried and the mixture obtained by adding 160 g potato starch, 50 g active and 5 g magnesium stearate to this was purified.

Injection

1 g of 2- (2-methyl-pyrazol-3-yl) -methylsulfinyl-5-methoxybenzimidazole.HCl, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to obtain 100 ml. This solution contains 10 mg of the active ingredient, which is placed in a bottle and sterilized by heating at 20 ° C. for 30 minutes.

(Biopharmacological activity search)

Intraperitoneal section of Sprague Dawley male rats (150-200 g) was injured and ligated into the pyloric region, and the amount of 20 mg / kg of the solution suspended or dissolved in 30% polyethylene glycol (PEG) 400 aqueous solution was measured. It was injected into the duodenum. The abdominal cavity was sewn again and allowed to stand for 5 hours, and then killed by cervical dislocation to detect the stomach and collected gastric juice. After removing the precipitate by centrifugation, the amount and pH of gastric juice were measured, and acidity was titrated using an Orion 960 automatic analyzer to compare and analyze the effect of gastric juice secretion between the control, comparative (Omeprazole) and test substance. The H ⁺ / K ⁺ -ATPase in vitro enzyme reaction experiment the H ⁺ / K ⁺ -ATPase activity stimulated by Mg ²⁺ in the negative control, and stimulated by Mg ²⁺ and K ⁺ H ⁺ / K ⁺ - ATPase activity was taken as a positive control.

The test results (in vivo test) are shown in Table 2 below.

TABLE 2

Claims (7)

Benzimidazole derivatives represented by the following structural formula (I), In the above formula, R ¹ is a hydrogen atom, a halogen atom or an alkoxy group having 1 to 3 carbon atoms, R ² is a hydrogen atom, an alkoxy group having 1 to 3 carbon atoms or a benzyloxy group, R ³ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkynyl group having 1 to 3 carbon atoms, a benzyl group or a substituted benzyl group wherein the substituent is a halogen atom or an alkoxy group having 1 to 3 carbon atoms, R ⁴ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a benzyl group, R ⁵ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a carboalkoxy group having 1 to 3 carbon atoms, n is 0 or 1; The benzimidazole derivative according to claim 1, wherein R ¹ is a hydrogen atom, a halogen atom or a methoxy group. The benzimidazole derivative according to claim 1, wherein R ² is a hydrogen atom or a methoxy group. The benzimidazole derivative according to claim 1, wherein R ³ is a methyl group, a propargyl group or a benzyl group. The benzimidazole derivative according to claim 1, wherein R ⁴ is a hydrogen atom, a methyl group or a benzyl group. The benzimidazole derivative according to claim 1, wherein R ⁵ is a hydrogen atom or a methoxy group. A gastric ulcer therapeutic composition comprising a benzimidazole derivative represented by the following structural formula (I) and acid addition salts thereof as an active ingredient. In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are each as defined in claim 1 above.