JPH01121274A - 2-substituted cycloheptimidazole derivative, antiulcer agent and production thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel 2-substituted cyclohebutoimidazole derivative useful as an anti-ulcer agent and a method for producing the same.

(Prior Art and Problems) Conventional anti-ulcer agents have been mainly used to suppress gastric juice secretion based on anticholinergic effects or to suppress gastric juice secretion due to antihistamine effects. However, in recent years, H.
CP- acts on H+ secreted by [H'''', K''] ATPase, which carries out membrane transport of l, and converts it into gastric acid (HCj2>
In the process of generating this [H'', K'']ATP
There is a desire for a substance that inhibits gastric juice secretion by inhibiting ase.

(Solution Means) With this background in mind, the present invention is based on proton botanium A.
This was discovered after searching for a useful substance as a TPase inhibitor.

The compound according to the present invention is - killing (I):...
(1) [wherein A is a pyrrolidyl group, dioxopyrrolidinyl group, piperidyl group, morpholinyl group, piperazinyl group, N-lower alkyl-substituted piperazinyl group, or N-aralkyl-substituted piperazinyl group, and n is O or 1, respectively. same as below. ] and pharmaceutically acceptable acid addition salts of this derivative.

Some of the compounds belonging to the above general formula (I) are illustrated below.

(1) 2-[2-(1-pyrrolidinyl)benzylthiococyclohebutoimidazole (2) 2-[2-(1-piperidyl)benzylthiococyclohebutoimidazole (3) 2-(2-morpholinobenzyl thio)cyclohebutoimidazole (4) 2-[2-(1-piperazinyl)benzylthiococyclohebutoimidazole (5) 2-[3-(1-piperazinyl)benzylthiococyclohebutoimidazole (6) 2 -[2-(4-methylpiperazin-1-yl)
Benzylthiococyclohebutoimidazole (7) 2-[3-(4-methylpiperazin-1-yl)
Benzylthiococycloheptoimidazole (8) 2-[2-(4-benzylpiperazin-1-yl)Benzylthiococycloheptoimidazole (9) 2-[3-(4-benzylpiperazin-1-yl) benzi, ruthio]cyclohebutoimidazole (10) 2-[2-(2,5-dioxopyrrolidine-
1-yl)benzylthiococyclohebutoimidazole (11) 2-[2-(1-pyrrolidinyl)benzylsulfinyl J-cyclohebutoimidazole (12> 2-
[2-(1-piperidyl)benzylsulfinylcyclohebutoimidazole (13) 2-(2-morpholinobenzylsulfinyl)-cyclohebutoimidazole (14) 2-[2-(1-piperazinyl)penzylsulfinylcocyclo Hebutoimidazole (15) 2-
[3-(1-piperazinyl)penzylsulfinylcocyclohebutoimidazole (16) 2-[2-(4-methylpiperazin-1-yl)benzylsulfinylcocyclohebutoimidazole (17) 2-[3- (4-methylbiperazin-1-yl)benzylsulfinyl]-cyclohebutoimidazole (18) 2-[2-(4-benzylpiperazine-1
-yl)penzylsulfinylcocyclohebutoimidazole (!9) 2-[3-(4-benzylpiperazin-1-yl)benzylsulfinyl]-cycloheptoimidazole (20) 2-[2-(2, 5-dioxopyrrolidine-
1-yl)benzylsulfinyl]-cyclohebutoimidazole The compounds (1), (2), to (20) above are referred to below as compound 1, compound 2, to compound 20.

The present compound represented by the general formula (I>) comprises 2-mercaptocyclohebutoimidazole represented by the formula (I) near- and the general formula (■): [wherein, X represents a halogen group, and A represents Same as above.It can be obtained by reacting with the compound represented by .

The compound of formula (If) can be obtained by condensing a compound represented by formula (IV) below with thiourea by a known method. That is, furthermore, the compounds of -Sakatsu (I [ It was first synthesized by

For example, (1-pyrrolidyl)benzyl alcohol can be converted to the corresponding pyrrolidyl-2,5-
It can be obtained by reducing dione with LiAj2H4.

110- Route a: In the case of a piperazine derivative, it can be obtained by reacting the corresponding bromide with a Li salt of the piperazine derivative and deprotecting it by the following route b.

Route b: [However, THP: represents a 2-tetrahydropyranyl group, and R represents a substituent such as a lower alkyl group or a benzyl group, respectively.

] By halogenating the alcohol obtained by route a or b, such as chlorination, a compound of -killing (I[) can be obtained.

The reaction between the compound of general formula (IF) and the compound of -killing (1M) is generally carried out in the presence of a base. The base used in this case is preferably pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium R acid, sodium ethylate, or the like. Ethanol, acetone, tetrahydrofuran or water is used as the solvent. The reaction proceeds at room temperature or by heating. The reaction product is purified by conventional methods such as recrystallization and column chromatography.

In the general formula (I), the compound where n=1 is obtained by oxidizing the sulfide obtained by the above method to form a sulfoxide, and this reaction can be carried out by a known method. As the oxidizing agent, commonly used reagents such as peracetic acid, m-chloroperbenzoic acid, 3.
Peracids such as 5-dinitroperbenzoic acid, hyperhalogenides such as sodium hypochlorite, and the like can be used.

This oxidation reaction is preferably carried out under cooling (-306C to 0C). As the solvent, benzene, toluene, dichloroethane, acetic acid ethyl ester, etc. are used.

The compound (I) obtained in this manner exhibits remarkable gastric acid secretion suppressing action and mucosal protective effect as described later. Although it can be used as an anti-ulcer agent in the form of
It is also possible to react this with a pharmaceutically acceptable acid, for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as succinic acid or fumaric acid, and administer it in the form of an acid addition salt thereof. The dosage form for administration can be either oral or parenteral. The dosage varies depending on the patient's age, symptoms, etc., but is generally 10 mg to 5 mg per day for adults.
Sufficient effects can be expected by using it in the range of 00 mg. Examples of formulations of the antiulcer agent of the present application are shown below.

[Formulation Example 1 Production of granules Compound 6 50 mg lactose
40 mg cornstarch
57 mg.

Methyl cellulose 3 m Total 150 mg The mixture of the above composition is made into granules by a conventional method.

[Formulation Example 2] Preparation of tablets Compound 20 30 mg Lactose 30 mg.

Cornstarch 45 mg Methyl cellulose 3 mg Elle ``Beonda to Tadasugote 1'' Unihy 2na Total 110 mg
.

A mixture having the above composition is made into tablets by a conventional method.

Examples of pharmacological tests and manufacturing examples of the compound of the present invention are listed below.

[Pharmacological test example 1 (gastric acid secretion suppressing effect) The gastric acid secretion suppressing effect of the compound of the present invention was evaluated using a 5-hay method (Ga
According to Stro-Enterology 26.906), using rats that had been fasted for 24 hours, the test drug was administered into the duodenum, and 4 hours later, gastric juice was taken and acidity was measured.

The results are shown in Table 1.

Production of (compound 1) (1) 2-(1-pyrrolidinyl)benzyl alcohol L
iAj2H, 2.5g in ether 20ml, THF50
2-(1-pyrrolidinyl-2,5-
Dione) 0-acetate of benzyl alcohol 8.0g
15 ml of THF solution was added dropwise, and after 1 hour, the mixture was heated at 40"C for 2 hours.
Stir for 0 minutes and leave to cool. 10% sodium hydroxide 2.5
ml and then 3 ml of water, stirred for 10 minutes, then added 1 g of Glauber's Salt, stirred for 10 minutes, and then filtered through Celite. Extract with ether, concentrate, and purify by silica gel column chromatography.

Yield: 1.15 g (y, 20.0%) 8.0 g of 0-(1-pyrrolidinyl)benzyl alcohol was dissolved in benzene, reacted with thionyl chloride, and dried under reduced pressure to give 0.
-(1-pyrrolidinyl)benzyl chloride hydrochloride is obtained. Sodium hydride with dimethylformamide
Add 9.17 g of 2-mercapto-cyclohebutoimidazole at OoC, and stir at room temperature for 30 minutes. The above chloride hydrochloride was added to this, and the mixture was stirred at room temperature for 2 hours. Pour into 200ml of water, extract twice with 300ml of ethyl acetate:hexane (4:1), and dilute with water.
Excluding MF.

Purify by column chromatography to obtain the desired product as a yellow solid.

Yield 12.6 g (83.1%) Recrystallize from ethyl acetate to obtain reddish brown needle crystals.

m, p, 105-107°C [Example 2 Preparation of (Compound 6) and (Compound 7) 2.95 g of N-methylbiperazine was added to If (F40 ml
g equivalent of n-BuLio was added at -50°C, stirred for 30 minutes, and then stirred at o'c for 30 minutes, a solution of 4.0 g of 0-bromobenzyl alcohol protected with THP in fHF was added dropwise, and the mixture was heated at 0°C. The reaction mixture is stirred for 1.5 hours at room temperature, and then stirred for 1 hour at room temperature. The mixture is poured into saturated ammonium chloride and extracted with 30 ml of ethyl acetate. After washing and drying, the mixture is concentrated under reduced EE to obtain a brownish oily substance.

This oil was made into I) IF solution, 10% HCf was added,
React for 15 minutes at room temperature and slowly pour into 10% NaOH. After extraction with ethyl acetate, washing, drying, and concentration, separation and purification with silica gel column chromatography yielded 0.3 g of 2-(4-methylbiperazin-1-yl)benzyl alcohol (
yield 9.8%) and 3-(4-methylbiperazine-1-
1.5 g (yield 49.3%)
and get.

(Compound 6) The reaction was carried out according to the method shown in Example 1 (2), and the target compound (6) and compound (7) were obtained in yields of 87.7% and 87.0%, respectively. Both compounds are oily substances.

[Example 3] Corresponding substituted benzyl alcohols were produced according to the method of Example 1 or Example 2, and then a reaction was carried out using the halogenated compounds to produce the compounds listed in Table 2. Obtained.

Table 2 Preparation of Example 4 (Compound 12) 2-[2-(1-Piperidyl)benzylthiococyclohebutoimidazole (Compound 2) 0.5 g is dissolved in 30 ml of dichloroethane and cooled to -25°C. . There m-
0.36 g of chloroperbenzoic acid in 10 m of dichloroethane
1 was gradually added dropwise, and the mixture was stirred and reacted at -25°C for 2 hours. Add 2 ml of triethylamine and 5 ml of 10% sodium hypochlorite solution, separate and wash with water. The resulting crude product is purified by column chromatography. Raw material recovery 0
．． 15 g of the desired product was recrystallized from ethyl acetate to obtain yellow crystals.

Yield 0.2 g (yield 54.5%) m, L 141-142' / d [Example 5] Same as Example 4 for each of Compound 1, Compound 3, Compound 4, ..., Compound 10 By performing the treatment, compound 11, compound 13, compound 14, ... compound 20
were obtained respectively.

Claims (3)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, A is a pyrrolidyl group, dioxopyrrolidinyl group, piperidyl group, morpholinyl group, piperazinyl group, N-lower alkyl-substituted piperazinyl group , or an N-aralkyl-substituted piperazinyl group, and n represents 0 or 1, respectively. ] A 2-substituted cycloheptoimidazole derivative represented by
Or a pharmaceutically acceptable acid addition salt of the derivative. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, in the formula, A is a pyrrolidyl group, dioxopyrrolidinyl group, piperidyl group, morpholinyl group, piperazinyl group, N-lower alkyl-substituted piperazinyl group , or an N-aralkyl-substituted piperazinyl group, and n represents 0 or 1, respectively. ] A 2-substituted cycloheptoimidazole derivative represented by
or an anti-ulcer agent containing an acid addition salt thereof as an active ingredient. (3) General formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ 2-mercapto-cycloheptoimidazole and General formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, in the formula, X is a halogen group, A is a pyrrolidyl group,
Each represents a dioxopyrrolidinyl group, a piperidyl group, a morpholinyl group, a piperazinyl group, an N-lower alkyl-substituted piperazinyl group, or an N-aralkyl-substituted piperazinyl group. The same applies to this section below. ] By reacting with the compound shown by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [However, A is the same as above. ] A 2-substituted cycloheptoimidazole derivative represented by the following formula, which is characterized by further oxidizing the derivative according to the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [n is 1 or 0, A is the same as above. ] A method for producing a 2-substituted cycloheptoimidazole derivative.