Imidazole derivative

Abstract: Novel imidazole derivatives and their acid adducts are disclosed. The imidazole derivatives are represented by formula: wherein R₁ represents an alkyl group, R₂ represents a hydrogen atom, an alkyl group which may have a substituent, or an aralkyl group which may have a substituent, provided that R₁ and R₂ are not both methyl groups at the same time. They have strong antimicrobial activity, especially against those fungi belonging to the genera Candida, Trichophyton, Microsporum, and Epidermorphyton, as well as against Gram-­ positive bacteria, and thus is useful as a antimicrobial agent.

Description: This invention relates to novel imidazole derivatives, and, more particularly, to novel imidazole derivatives having antimicrobial activities against Gram-positive bacteria, fungi, and the like. A number of imidazole derivatives having antimicrobial activities are conventionally known. Their antimicrobial activities, especially antifungal activities, are not necessarily satisfactory. Development of compounds having more effective activities are, therefore, required. In view of this situation, the present inventors have undertaken extensive studies for the synthesis of various imidazole derivatives and for the detection of their pharmacological activities. As a result, the inventors have found that novel compounds represented by the following formula (I) exhibited strong antimicrobial activities, especially against Gram-positive bacteria, and fungi. This finding has led to the development and completion of this invention. Accordingly, an object of this invention is to provide an imidazole derivative represented by formula (I): wherein R₁ represents an alkyl group, R₂ represents a hydrogen atom, an alkyl group which may have a substituent, selected from a halogen atom, a lower alkoxy group, a lower alkanoyl group, and a cyano group, or an aralkyl group, in which the aryl moiety may be substituted by a member selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group and a cyano group, provided that R₁ and R₂ are not both methyl groups at the same time; or an acid adduct thereof. Examples of alkyl groups represented by R₁ in formula (I) are linear, branched, or cyclic alkyl groups of a C₁₋₁₀ carbon atom content. Specific examples of especially preferable alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, octyl and cyclopropyl groups. Alkyl groups for R₂ of formula (I) include, for example, linear, branched, or cyclic alkyl groups of a C₁₋₁₆ carbon atom content. Given as examples of aralkyl groups for R₂ of formula (I) are phenylalkyl groups and naphthylalkyl groups. The substituted groups for the alkyl group are selected from a halogen atom, a lower alkoxy group, a lower alkanoyl group, a cyano group. When R₂ is an aralkyl group, the substituted groups for the aryl group of the aralkyl portion may be a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a cyano group. Among the compounds of formula (I) those having a hydrogen atom for R₂, i.e., Compound (Ia), can be prepared according to the following reaction formula, i.e., by reacting 1-(2-hydroxyphenacyl)imidazole (II) and a Grignard reagent (III). Compounds of formula (I) in which the R₂ is an alkyl or aralkyl group which may have a substituent, i.e., Compound (Ib), can be prepared by reacting Compound (Ia) with an alkylation or aralkylation reagent (IV) according to the following reaction formula: wherein R₁ has the meaning defined previously, X₁ and X₂ represent halogen atoms, and R₂, represents an alkyl or aralkyl group which may have a substituent. The reaction for preparing Compound (Ia) is performed by using 1 to 5 moles of compound (III) for 1 mole of compound (II) in a solvent such as ether, tetrahydrofuran, or the like. The reaction is carried out at a temperature between 0°C and the boiling point of the reaction mixture for 1 to several hours. After completion of the reaction, the surplus amount of compound (III) and addition salt produced in the reaction are decomposed using an aqueous solution of ammonium chloride, or the like. The mixture is extracted with a solvent such as chloroform or the like and, after evaporation of the solvent, pure Compound (Ia) can be obtained by silica gel chromatography or the like. The reaction for the preparation of Compound (Ib) may be carried out using 1 to 2 moles of compound (IV) per one mole of Compound (Ia) in the presence of an alkali from room temperature to the boiling point of the solvent used, for 1 hour to 50 hours. Solvents which can be used include dimethylformamide, dimethylsulfoxide, acetone, ethanol, methanol, chloroform, methylene chloride, and the like. Given as examples of alkali which can be used in the reaction are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like. After completion of the reaction, the reaction mixture is charged into water, and this mixture is extracted with a solvent such as ether or the like. After evaporation of the solvent, pure Compound (Ib) can be obtained by silica gel chromatography or the like. The compound of formula (I) of this invention can be converted into an acid adduct through any conventional method. Given as examples of such acid adducts are those of pharmaceutically or medicinally permissible acids, including inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and the like; and organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid, citric acid, malic acid, succinic acid, and the like. Hereinafter are presented experimental examples to further illustrate the effectiveness of the invention. These examples are given for illustration of the invention and are not intended to be limiting thereof. EXPERIMENTAL EXAMPLES Antimicrobial activities of certain representative compounds of this invention, which had been obtained in the above-described manner, were investigated. Results are summarized in Table 1, in which the compound numbers correspond to those to be given in Examples which will be described herein. Compound (I) prepared as fully described above has strong antimicrobial activity, especially against those fungi belonging to the genera Candida, Trichophyton, Microsporum, Epidermorphyton, and the like, as well as Gram-positive bacteria, and thus is useful as a antimicrobial agent. Other features of the invention will become apparent in the course of the following description of the exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof. EXAMPLES Example 1 Preparation of 1-[2-hydroxy-2-(2-hydroxyphenyl)pentyl] imidazole (Compound 18) To a tetrahydrofuran solution of Grignard reagent prepared from 73 mg of magnesium and 369 mg of n-propyl bromide, 202 mg of 1-(2-hydroxyphenacyl) imidazole (II) was added dropwise under ice-cooled conditions while stirring, and the mixture was refluxed for 2 hours. After ice-cooling, an aqueous solution of ammonium chloride was added to the mixture to decompose the surplus amount of the Grignard reagent and addition salts produced in the reaction. Extraction with chloroform was performed on this mixture and the chloroform layer was washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: chloroform) to produce 70 mg of the title compound at a yield of 29%. Example 2 Preparation of 1-[2-hydroxy-2-(2-ethoxyphenyl)pentyl] imidazole (Compound 20) 34 mg of 1-[2-hydroxy-2-(2-hydroxyphenyl)pentyl] imidazole (Compound 18) was dissolved into 10 ml of dimethylformamide, and 33 mg of ethyl iodide and 10 mg of sodium hydroxide was added to this solution. The mixture was stirred at room temperature for 20 hours. The reaction mixture, after being charged into ice water, was subjected to extraction with ether. The ether layer was then washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: methylene chloride) to produce 22 mg of the title compound at a yield of 58%. Example 3 Reactions were carried out in the same manner as in Examples 1 and 2 to synthesize the compounds listed in Table 2. The compounds produced in Examples 1 and 2 are also listed in the table.

Claims: Claims for the following Contracting States : CH, DE, FR, GB, IT, LI An imidazole derivative represented by the following formula (I): wherein R₁ represents an alkyl group, R₂ represents a hydrogen atom, an alkyl group which may have a substituent, selected from a halogen atom, a lower alkoxy group, a lower alkanoyl group, and a cyano group, or an aralkyl group, in which the aryl moiety may be substituted by a member selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group and a cyano group, provided that R₁ and R₂ are not both methyl groups at the same time; or an acid adduct thereof. A process for preparing an imidazole derivative of claim 1 or an acid adduct thereof, characterized in that for preparing a compound (Ia) a 1-(2-hydroxyphenacyl)imidazole (II) and a Grignard reagent (III) are reacted in a solvent at a temperature between 0°C and the boiling point of the reaction mixture for one to several hours according to the following reaction formula: and for preparing a compound (Ib) the compound (Ia) is reacted with an alkylation or aralkylation reagent (IV) according to the following reaction formula: wherein R₁ has the meaning defined previously, X₁ and X₂ represent halogen atoms and R 2' represents an alkyl or aralkyl group which may have a substituent as defined in claim 1, in the presence of an alkali from room temperature to the boiling point of the solvent used, for one hour to fifty hours. Claim for the following Contracting State : ES A process for preparing an imidazole derivative represented by the following formula (I) : wherein R₁ represents an alkyl group, R₂ represents a hydrogen atom, an alkyl group which may have a substituent, selected from a halogen atom, a lower alkoxy group, a lower alkanoyl group, and a cyano group, or an aralkyl group, in which the aryl moiety may be substituted by a member selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group and a cyano group, provided that R₁ and R₂ are not both methyl groups at the same time; or an acid adduct thereof, characterized in that for preparing a compound (Ia) a 1-(2-hydroxyphenacyl)imidazole (II) and a Grignard reagent (III) are reacted in a solvent at a temperature between 0°C and the boiling point of the reaction mixture for one to several hours according to the following reaction formula: and for preparing a compound (Ib) the compound (Ia) is reacted with an alkylation or aralkylation reagent (IV) according to the following reaction formula: wherein R₁ has the meaning defined previously, X₁ and X₂ represent halogen atoms and R 2' represents an alkyl or aralkyl group which may have a substituent as defined in claim 1, in the presence of an alkali from room temperature to the boiling point of the solvent used, for one hour to fifty hours.

Inventors: HIDEAKI MATSUDA, MINORU TOKIZAWA, TAKEMITSU ASAOKA, TATSUHIKO KATORI, HIDEAKI, MATSUDA, MINORU, TOKIZAWA, TAKEMITSU, ASAOKA, TATSUHIKO, KATORI
Applicants: SS PHARMACEUTICAL CO, SS PHARMACEUTICAL CO., LTD.
Application year: 1988
Main classification: C07D233
IPC codes: C07D521, C07D233