JPH0368031B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has the structural formula [] (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group, and Ar ₂ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkokene group. (1-imidazoyl)methyl-2-(substituted phenyl)-1,3
-dioxolan-4-yl]methyl-(substituted benzate) derivatives, a method for producing the same, and an antibacterial agent. The substance represented by the structural formula [] exhibits a broad antibacterial spectrum, unlike conventional antifungal agents on the market, and is characterized by exhibiting antifungal and even antibacterial effects. The compound of the present invention [] can be produced by the method shown in the following reaction. (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group, and Ar ₂ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkokene group). That is, 2-[(1-imidazoyl)methyl]-2- represented by the structural formula []
The target compound represented by the structural formula [] can be produced by reacting (substituted phenyl)-1,3-dioxolane-4-methanol with substituted benzoyl chloride in the presence of a base. This reaction requires the presence of a base, and generally triethylamine, etc. is added to pyridine or an organic solvent (benzene, toluene, etc. and an aprotic solvent such as THF), and the reaction proceeds at room temperature, but with mild heating or Heating can shorten the reaction time. Further, the addition of a phase transfer catalyst such as a tetramethylammonium salt tends to improve the yield of the condensation reaction. The compounds of the present invention can be administered both externally and internally as antifungal and antibacterial agents,
I think this is a promising compound for the future. Until now, there were not many commercially available antifungal agents that were effective against Candida, Trichophyton, and bacteria, and most of them were drugs of one type or another, but this compound is effective against fungi and Pseudomonas aeruginosa. This is where the compound differs from conventional antifungal agents. As will be described later, I believe that the present invention is effective because it has low toxicity and exhibits an unprecedented broad antibacterial spectrum. Examples of the present invention will be described below using reference examples. Example 1 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-chlorobenzatocis-2[(1-imidazoyl)methyl]-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 5 ml of dry pyridine, and then dissolved at 5°C for 4 min.
-Chlorobenzoyl chloride 0.53g (3m mol)
was added, stirred for 22 hours, added to ice, extracted with methylene chloride, further washed with 5 ml of 5% NaOH to remove the methylene chloride, dried over magnesium sulfate, filtered,
Methylene chloride was distilled off, and the residue was recrystallized from ethyl acetate to form colorless needle crystals, the properties of which are shown in Table 1.

[Table] Example 2 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-bromobenzato cis-2[(1-imidazoyl)methyl]-2-
Dissolve 0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol in 5 ml of dry pyridine, then add 4-bromobenzoyl chloride in the same manner as above, and proceed in the same manner. do. Recrystallized with ethyl acetate, colorless needle crystals,
The properties are shown in Table 2.

[Table] Example 3 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-fluorobenzato cis-2[(1-imidazoyl)methyl]-2-
Dissolve 0.66 g (2 mm mml) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol in 5 ml of dry pyridine, then add 4-fluorobenzoyl chloride in the same manner as above, and proceed in the same manner. Process. Recrystallized from ethyl acetate, white powder, properties are shown in Table 3.

[Table] Example 4 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-methylbenzato cis-2[(1-imidazoyl)methyl-2-
Dissolve 0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol in 5 ml of dry pyridine, then add 4-methylbenzoyl chloride in the same manner as above, and proceed in the same manner. Process. Recrystallized from ethyl acetate, colorless needle crystals, properties are shown in Table 4.

[Table] Example 5 Cis-2[(1-imidazoyl)methyl-2-
(4-methoxyphenyl)-1,3-dioxolan-4-yl]methyl-4-chlorobenzato cis-2[(1-imidazoyl)methyl]-2-
Dissolve 0.58 g (2 mmol) of (4-methoxyphenyl)-1,3-dioxolane-4-methanol in 5 ml of dry pyridine, then add 4-chlorobenzoyl chloride in the same manner as above, and proceed in the same manner. . Recrystallized from ethyl acetate, colorless needle crystals, properties are shown in Table 5.

[Table] The minimum inhibitory concentration (MIC) of various fungi and bacteria was determined using the compounds obtained in the above examples and comparative compounds. The results are shown in Table 6. Note (1) Bacterial species 1 Candida albicans IFO No 1061 2 Trichophyton mentagrophytes 5812 3 Trichophyton rubrum 9185 4 Microsporum canis 7864 5 Aspergillus fumigatus 8867 6 Aspergillus niger 8541 7 Staphylococcus aureus FDA 209 p 8 Escherichia coli NIHJ JC −2 9 Pseudomonas aeruginosa NC− 5

【table】

[Table] Note (2) Comparative compound 1' is undecylenic acid, which is currently commercially available as an antifungal agent. Comparative compound 2' is griseofulvin, which is currently commercially available as an antifungal agent. Comparative compound 3' is miconazole, which has been most commonly used commercially in recent years. The compound of Example 1 was orally administered at 300 mg/Kg to 7 mice, but no harmful side effects were observed.

Claims (1)

[Claims] 1. Structural formula [] (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group, and Ar ₂ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkokene group. (1-imidazoyl)methyl-2-(substituted phenyl)-1,3
-dioxolan-4-yl]methyl-(substituted benzate) derivative. 2 Structural formula [] (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoke group) 2-[(1-imidazoyl)methyl]-2-(substituted phenyl)-1,3-dioxolane-4-methanol is reacted with substituted benzoyl chloride in the presence of a base [] (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group, and Ar ₂ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkokene group. (1-imidazoyl)methyl-2-(substituted phenyl)-1,3
-dioxolan-4-yl]methyl-(substituted benzate) derivative. 3 Structural formula [] (In the formula, Ar ₁ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group, and Ar ₂ represents a phenyl group in which positions 2 to 4 of the benzene nucleus are substituted with one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkokene group. (1-imidazoyl)methyl-2-(substituted phenyl)-1,3
-Dioxalan-4-yl]methyl-(substituted benzate) derivative as an active ingredient.