KR970001476B1 - New benzimidazole derivatives with amide groups - Google Patents

Abstract

A new benoimidazole derivative of structural formula(I) is prepared by reacting M-halo amide of structural formula(II) with 2-mercapto benzimidazole of structural formula(IV). The produced benzimidazole derivative can inhibit H+/K+-ATPase enzyme 2~80 times stronger than omeprazole and it is stable as an acid. In the formula, R1, R2, R3, R4, R5 are hydrogen, halogen atom which are the same or not and low-level alkyl. alkoxyl group with carbon number 1~6. R6, R7 is low-level alkyl group with carbon number 1~4 including hydrogen atom or methyl group. R8 is alkyl, halogen, alkoxy group or like including hydrogen atom, methyl group, and n is 0 or 1.

Description

New Benzimidazole Derivatives Having Amide Groups

The present invention relates to a novel benzimidazole derivative represented by the following general formula (I) and a preparation method thereof including a pharmaceutical salt thereof.

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are the same as or different from each other, and are hydrogen atoms, halogen atoms, carbon atoms, 1 to 6 lower alkyl groups, or lower alkyl groups of 1 to 6 carbon atoms. R ₆ and R ₇ preferably have a hydrogen atom, and may include lower alkyl groups having 1 to 4 carbon atoms including a methyl group. R ₈ includes hydrogen, methyl, alkyl, halogen, alkoxy and the like. n is 0 or 1;

The cause of gastric ulcer is not clear, but the excessive secretion of gastric acid is known as an important factor, and substances that have ulcer treatment action by effectively blocking the action of H ⁺ / K ⁺ -ATRase acting at the last stage of gastric acid secretion mechanism For example, it is the focus of attention.

Among them, 1- {2- (3,5-dimethyl-4-methoxy) -pyridinemethylsulfinyl} -5-methoxybenzimidazole (omeprazole) is a substance having the above action [Am. J. of Physiol. , 245, G64-71 (1983). Sulfinylbenzimidazole having various heterocyclic compounds according to the development of omeprazole (JMC, 1989,32,1970, Chem Pharm Bull, 1990,38,534, GB2,069,492, DE3,240,248, DE3,415,971, EP167,943, JP60) , 233,070, EP178,438, EP187,977, EP174,726, EP201,094, DE3,530,342, GB2,172,285, EP234,485).

However, these conventional materials have a short advantage in treating ulcers, but have a drawback of causing side effects at too long action time.

As anti-ulcer compositions, agents that have been effective for both gastric acid secretion and gastric mucosal protection have been required. As an agent for inhibiting gastric acid secretion, antagonists for H ₂ receptors represented by cimetidine have been used, but they have not been effective for gastric mucosal protection. . The reason for this is that side effects on the central nervous system have lowered their actions in treating or preventing ulcers. Another inhibitor of gastric acid secretion, H ⁺ / K ⁺ -ATPase inhibitors, represented by omeprazole, is very effective in inhibiting gastric acid secretion but is known to cause gastric acid deficiency and is easily acid-free because it is acid-stable. It also has the disadvantage of being degraded. Therefore, it is necessary to develop antiulcer agents that have a balanced effect on both gastric acid secretion and gastric mucosal protection.

In particular, it has been required to develop a chemically stable substance that has an effect of H ⁺ / K ⁺ -ATPase inhibition such as omeprazole. Accordingly, the present inventors have tried to develop a novel H ⁺ / K ⁺ -ATP enzyme inhibitors, and the benzimidazole derivatives of the structural formula (I) make H ⁺ / K ⁺ -ATP enzymes 2 to 80 times stronger than conventional omeprazole. The present invention was completed by knowing that there is an excellent effect of inhibiting.

Hereinafter, the present invention will be described in detail.

The present invention relates to a benzimidazole derivative represented by the following structural formula (I).

In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are the same as or different from each other, and are hydrogen atoms, halogen atoms, carbon atoms, 1 to 6 lower alkyl groups, or lower alkyl groups of 1 to 6 carbon atoms. R ₆ and R ₇ preferably have a hydrogen atom, but may include a lower alkyl group having 1 to 4 carbon atoms including a methyl group. R ₈ is hydrogen, alkyl including methyl, halogen, alkoxy and the like. n is 0 or 1;

In addition, the present invention includes a method for preparing a novel benzimidazole derivative through two intermediates (II) and (III) as shown in the following structural formula.

Route 1 is a step of substitution reaction of intermediate (II) and (IV), and route 2 is a step of condensation reaction of intermediate (III) and (V).

In the above formula, the substituents are as defined above, and X and Y are semi-neutral groups which may be substituted in the total substitution reaction. X is preferably halogen such as C1, Br, but reactive groups such as sulfomate give the same result, and Y can react starting from the OH group, and includes all methods through various condensation reactions.

Among the starting materials useful in the process of the present invention, 2-mergatobenzimidazole (IV) is well known in the art, for example Org, Synth. It may be prepared according to the technique known in 30,56.

Other starting materials (including V) are commercially available and in special cases synthesized.

The above path is described in more detail as follows.

The base used in route 1 is capable of several organic bases including Et ₃ N and inorganic bases such as K ₂ CO ₃ give the same result. As the solvent used, CH ₂ CI ₂ except for the solvent of alcohols is used in the first step, and alcohols also give good results in the next step.

In route 2, the same base and solvent as in route 1 can be used, and in the second stage various condensation reagents can be used.

The last step in the above two pathways, oxidizing sulfur (n = O → n = 1), is well known in the art, although m-chloroperbenzoic acid is the most useful, but it may be hydrogen peroxide, sodium hypochlorite, or meta. Oxidizing agents such as sodium peridate are used.

The novel benzimidazole derivatives of the present invention as described above are excellent in inhibiting H ⁺ / K ⁺ -ATP enzyme and inhibiting gastric acid secretion, and thus may be usefully used as an antiulcer component.

Hereinafter, the present invention will be described in detail with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1

After dissolving 1.86 g of aniline and 2.4 g of Et ₃ N in methylene chloride, the temperature of the solution is cooled to -20 ° C. 2.3 g of chloroacetyl chloride dissolved in methylene chloride is slowly added dropwise while maintaining the temperature at -20 ° C. After 1 hour of reaction at this temperature it is further reacted for 30 minutes at room temperature.

0.1 NHCI solution was added to the above solution to adjust the pH to 2-3 and extracted with methylene chloride to obtain 2.9 g of N-phenyl α-chloroacetamide in solid form in 85% yield.

It is no longer purified and used as starting material for the next reaction.

Example 2

2.9 g of the starting material synthesized in Example 1 and 2.8 g of 2-mercapto benzimidazole 2.6 g K ₂ CO ₃ were dissolved in methanol. The solution was refluxed at 50 to 60 ° C. for 3 hours, then the solvent was removed and distilled water was added to filter the resulting solid. The obtained compound was recrystallized in acetonitrile to obtain 1.7 g of the desired compound in 71% yield.

¹ H-NMR (200 MHz, ppm, CDCI ₃ ) ^δ 4.2 (s, 2H), 6.7-7.8 (m, 9H), 10.8 (bs, 1H)

Example 3

1.7 g of the sulfide synthesized in Example 2 above was dissolved in a mixed solution of chloroform and acetone, and then cooled to -20 ° C.

A small amount of m-chloroperbenzoic acid dissolved in chloroform is slowly added dropwise. After the dropwise addition, the reaction mixture was maintained for about 1 hour while maintaining the temperature at -10 ° C. After the disappearance of the starting material, the resultant was filtered with NaHCO ₃ 5% solution to obtain 1.1 g of the inventive compound in 60% yield.

Example 4

(Invention Compound 41)

3.51 g of 3-chloro-4-methoxyaniline are dissolved in dichloromethane solvent together with 2.0 g of Et ₂ N. The solution of 2.26 g of chloroacetyl chloride in dichloromethane was slowly added dropwise while maintaining the temperature of the solution at -20 ° C.

After reacting at the above temperature for 1 hour, the mixture was further reacted for 10 minutes at room temperature, treated with 0.1N HCI, separated from dichloromethane layer, washed with saturated salt solution and concentrated to obtain an intermediate α-chloroamide as a solid. The synthesized amide derivative, 3.0 g of _2- mercapto benzimidazole and 2.0 g of Et ₂ N were dissolved together in methanol (30 ml), and stirred for 12 hours at room temperature to precipitate. The product obtained by evaporating the solvent under reduced pressure and distilled water is recrystallized from isopropyl alcohol. 1.7 g of recrystallized sulfide was dissolved in a mixture of chloroform and acetone, and then cooled to -20 ° C. A small amount of m-perchlorobenzoic acid dissolved in chloroform is slowly added dropwise. After dropping, the starting material disappeared after 1 hour while maintaining the temperature at −10 ° C., and 0.91 g of the white solid compound of the invention obtained by treatment with 5% NaHCO ₃ solution was obtained by filtration at a yield of 50%. Table 1 and Table 2 show the types and NMR spectra of the inventive compounds prepared in the same manner as in the above example.

Example 5

H / K -ATP enzyme inhibitory effect

According to the method of Forte et al. (J. Applied Physiol., 32, 714-717 (1972)), gastric secretory cells of rabbit gastric mucosa are isolated, and the cells are separated in Ficoll of discrete density gradients. Centrifugally called H / K Prepare vesicles containing the ATP enzyme. This enzyme was added to each test compound 2 × 10 After incubating for 25 minutes at room temperature in 0.5 ml of a solution containing M and imidazole buffer (pH 6) 5 mM, the mixture is heated to 37 ° C. and left at this temperature for 5 minutes. 0.5 ml of a solution containing 4 mM magnesium chloride, 80 mM imidazole buffer (pH 7.4), 20 mM potassium chloride and 4 mM ATP is added to the mixture. The resulting mixture was heated at 37 ° C. for 15 minutes and 1 ml of a 24% trichloroacetic acid solution was added to terminate the reaction. The isolated inorganic phosphorus was measured according to Fiske Subbarow method [J.Bolo, Chem, 66,375-440 (1925)] to calculate the enzyme activity. The results are shown in Table 3 below.

Claims (2)

Novel benzimidazole derivatives represented by the following structural formula (I) and their pharmaceutically acceptable salts. In the above formula, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are the same as or different from each other, and are a hydrogen atom, a halogen atom, C 1-6 lower alkyl, or C 1-6 lower alkoxy groups. R <_6> , R <_7> contains the C1-C4 lower alkyl group containing a hydrogen atom or a methyl group. R ₈ is hydrogen, including methyl, alkyl, halogen, alkoxy. n is 0 or 1; A method of preparing I (n = 1) by reacting α-haloamide of the following formula (II) and 2-mecapto benzimidazole of the following formula (IV) to form I (n = 0), followed by oxidation. X is a chlorine-substituted reactor, and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ comply with Clause 1.