JPH0441147B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has the structural formula [I] [In the formula, When X is carbon, R is an aliphatic hydrocarbon represented by the general formula CnH _2o+1 (however, n
is an integer from 1 to 15), when X is nitrogen, the general formula
Aliphatic hydrocarbon represented by CnH _o+1 (where n is an integer from 1 to 15) or 2 to 4 benzene nuclei
represents a phenyl group and a naphthyl group substituted with one, two, or three substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group. ] Cis and trans 2-[(1-imidazoyl or triazoyl)methyl-2-(substituted phenyl)-
The present invention relates to a 1,3-dioxolan-4-yl]methyl-acylate derivative, a method for producing the same, and an antibacterial agent. The substance represented by structural formula [I] exhibits a broad antibacterial spectrum, unlike conventional antifungal agents on the market, and is characterized by exhibiting antifungal and even antibacterial effects. The compound [I] of the present invention can be produced by the method shown in the following reaction. [In the formula, When X is carbon, R is an aliphatic hydrocarbon represented by the general formula CnH _2o+1 (however, n
is an integer from 1 to 15), when X is nitrogen, the general formula
An aliphatic hydrocarbon represented by CnH _2o+1 (where n is an integer from 1 to 15), or one selected from the group consisting of halogen atoms, lower alkyl groups, and lower alkoxy groups in positions 2 to 4 of the benzene nucleus Or it represents a phenyl group and a naphthyl group substituted with two or three substituents. ] That is, cis and trans 2- expressed by the structural formula []
By reacting [(1-imidazoyl or triazoyl)methyl]-2-(substituted phenyl)-1,3-dioxolane-4-methanol with an aliphatic acyl chloride or a substituted benzoyl chloride in the presence of a base, the structural formula The target compound represented by [I] can be produced. 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 compound of the present invention can be administered both externally and internally as a medicine, especially as an antifungal agent, and is also a promising compound that can be widely used as a bactericidal agent. Furthermore, 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-triazoyl)methyl-2-2
-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-chlorobenzato cis-2[(1-triazoyl)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 4-
Add 0.53 g (3 mmol) of chlorobenzoyl chloride, stir for 22 hours, add to ice, extract with methylene chloride, wash the methylene chloride with 5 ml of 5% NaOH, dry over magnesium sulfate, filter, and distill off the methylene chloride. , the residue was recrystallized from ethyl acetate, colorless needle crystals, melting point 97-98℃, yield 60%, mass spectrum m/e: 467 (M ⁺ ), elemental analysis value (%): C,
51.04; H, 3.42; N, 8.85. Example 2 Cis-2[(1-triazoyl)methyl-2-2
-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-methylbenzato cis-2[(1-triazoyl)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 0.46 g (3 mmol) of 4-methylbenzoyl chloride was dissolved in the same manner as above. In addition, the following processes are performed in the same manner. Recrystallized from ethyl acetate, colorless needle crystals, melting point 103-104°C, yield 55%, mass spectrum m/e: 446 (M ⁺ ), elemental analysis (%): C, 56.25; H, 4.26; N , 9.36. Example 3 cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-acetylate cis-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 in acetyl chloride.
Add 0.24g (3m mol) dropwise at 5℃, stir at room temperature for 30 minutes, add to ice, make weakly alkaline with sodium carbonate, extract with methylene chloride, wash with water, dry over magnesium sulfate, filter, and distill off methylene chloride. and the residue is purified by chromatography on silica gel in chloroform solvent. Pale yellow oil, yield
80.6%, mass spectrum m/e: 370 (M ⁺ ), elemental analysis value (%): C, 49.91; H, 4.46; N, 7.21. Example 4 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-propionylate cis-2[(1-inidazoyl)methyl]-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 9 ml of dry pyridine, and then 0.28 g (3 mmol) of propionic acid chloride was added in the same manner as above. The same process is performed below. Pale yellow oil, yield 60.6%, mass spectrum m/e: 384 (M ⁺ ), elemental analysis (%): C, 52.97; H, 4.65; N, 6.84. Example 5 Cis-2 [(1 -imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-butylate cis-2[(1-imidazoyl)methyl]-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 9 ml of dry pyridine, followed by 0.32 g of butyric acid chloride.
(3m mol) was added in the same manner as above, and the following treatment was carried out in the same manner. Pale yellow oil, yield 25.1%, mass spectrum m/e: 398 (M ⁺ ), elemental analysis value (%): C,
54.06; H, 5.20; N, 7.17. Example 6 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-valerylato cis-2[(1-imidazoyl)methyl-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 9 ml of dry pyridine, and then 0.36 g (3 mmol) of n-valeryl acid chloride was added in the same manner as above. In addition, the following processing is performed in the same manner. Pale yellow oil, yield 24.1%, mass spectrum m/e: 412 (M ⁺ ), elemental analysis (%): C, 55.20; H, 5.08; N, 6.77. Example 7 Cis-2 [(1 -imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-caprolate cis-2[(1-imidazoyl)methyl]-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 9 ml of dry pyridine, and then 0.4 g (3 mmol) of n-caproic acid chloride was added in the same manner as above. In addition, the following processes are performed in the same manner. Pale yellow oil, yield 39%, mass spectrum m/e: 426 (M ⁺ ), elemental analysis (%):
C, 56.19; H, 5.57; N, 6.81. Example 8 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-caprylylate cis-2[(1-imidazoyl)methyl]-2-
Dissolve 0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol in 9 ml of dry pyridine, add 0.5 g (3 mmol) of n-caprylic acid chloride under cooling, The mixture was stirred at room temperature for 1 hour, and then treated in the same manner as described above. pale yellow oil,
Yield 29.2, % mass spectrum m/e: 454 (M ⁺ ),
Elemental analysis value (%): C, 58.06; H, 5.93; N,
6.14. Example 9 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-palmitoylate cis-2[(1-imidazoyl)methyl]-2-
0.66 g (2 mmol) of (2,4-dichlorophenyl)-1,3-dioxolane-4-methanol was dissolved in 9 ml of dry pyridine, and then 0.82 g (3 mmol) of palmitic acid chloride was added in the same manner as above. Process as above. Recrystallized with ethanol, white powder, melting point 55-58℃, yield 41.2%, mass spectrum m/e: 566 (M ⁺ ), elemental analysis value (%): C,
63.88; H, 8.31; N.4.58. Example 10 Cis-2[(1-imidazoyl)methyl-2-
(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl-4-chlorobenzato cis-2[(1-imidazoyl)methyl]-2-
(2,4-dichlorophenyl)-1,3-dioxolane 0.99 g (3 mmol) of 4-methanol was dissolved in 10 ml of dry pyridine, and 0.88 g (5 mmol) of the corresponding 4-chlorobenzoyl chloride was added dropwise under ice cooling. do.
After stirring for 30 minutes at 10°C, water was added, extracted with methylene chloride, shaken with 5% sodium hydrogen carbonate solution, dried the methylene chloride layer over anhydrous magnesium sulfate, filtered, and evaporated the solvent. The residue was chromatographed on silica gel using chloroform as a solvent. Purify by applying graphite. Colorless needle crystals, melting point 75-76℃, yield 60%, mass spectrum m/e: 466 (M ⁺ ), elemental analysis value (%): C,
53.60; H, 3.70; N, 5.73. Example 11 Cis-2[(1-imidazoyl)methyl-2-
(4-fluorophenyl)-1,3-dioxolane-
4-yl]methyl-4-(2,4-dichlorobenzate) cis-2[(1-imidazoyl)methyl]-2-
(4-fluorophenyl)-1,3-dioxolane-
4-Methanol 0.83g (3m mol) in dry pyridine
Dissolve in 10 ml, then add 1.1 g (5 mmol) of 2,4-dichlorobenzoyl chloride in the same manner as above,
The same process is performed below. Pale yellow resin, yield 78
%, mass spectrum m/e: 450 (M ⁺ ), elemental analysis value (%): C, 55.62; H, 4.03: N, 6.44. Example 12 Cis-2[(1-imidazoyl)methyl-2-
(4-chlorophenyl)-1,3-dioxolane-
4-yl]methyl-4-(4-chlorobenzate) cis-2[(1-imidazoyl)methyl]-2-
(4-chlorophenyl)-1,3-dioxolane-
4-Methanol 0.88g (3m mol) in dry pyridine
Then, 0.88 g (5 mmol) of 4-chlorobenzoyl chloride was added in the same manner as above, and the following procedure was repeated. Pale yellow resinous material, yield 59%, mass spectrum m/e: 432 (M ⁺ ), elemental analysis (%): C, 58.42; H, 3.82; H, 6.25 Example 13 Cis-2 [(1 -imidazoyl)methyl-2-
(4-chlorophenyl)-1,3-dioxolane-
4-yl]methyl-4-(2,4-dichlorobenzate) cis-2[(1-imidazoyl)methyl]-2-
(4-chlorophenyl)-1,3-dioxolane-
4-Methanol 0.88g (3m mol) in dry pyridine
Dissolve in 10 ml, then add 1.1 g (5 mmol) of 2,4-dichlorobenzoyl chloride in the same manner as above,
The same process is performed below. Pale yellow resin, yield 52
%, mass spectrum m/e: 466 (M ⁺ ), elemental analysis value (%): C, 55.42; H, 3.72; N, 6.24 Example 14 Cis-2[(1-imidazoyl)methyl-2-
(4-bromophenyl)-1,3-dioxolane-
4-yl]methyl-4-(4-chlorobenzate) cis-2[(1-imidazoyl)methyl]-2-
(4-bromophenyl)-1,3-dioxolane-
4-Methanol 1.02g (3m mol) in dry pyridine
Then, 0.88 g (5 mmol) of 4-chlorobenzoyl chloride was added in the same manner as above, and the following procedure was repeated. Pale yellow resinous material, yield 42%, mass spectrum m/e: 476 (M ⁺ ), elemental analysis (%): C, 51.60; H, 3.72; N, 5.51. Example 15 Cis-2 [( 1-imidazoyl)methyl-2-
(4-bromophenyl)-1,3-dioxolane-
4-yl]methyl-4-(2,4-dichlorobenzate) cis-2[(1-imidazoyl)methyl]-2-
(4-bromophenyl)-1,3-dioxolane-
4-Methanol 1.02g (3m mol) in dry pyridine
Dissolve in 10 ml, then add 1.1 g (5 mmol) of 2,4-dichlorobenzoyl chloride in the same manner as above,
The following processing is performed in the same manner as above. Pale yellow resinous substance, yield 65%, mass spectrum m/e: 510 (M ⁺ ), elemental analysis value (%): C, 49.02; H, 3.46; N, 5.21 Compound obtained in the above example and Minimum inhibitory concentrations (MICs) of various fungi and bacteria were determined by comparison compounds. The results are shown in Table 1. Note (1) Bacterial species 1 Candida albicans IFO 1061 2 Trichophyton mentagrophytes IFO 5812 3 Trichophyton rubrum IFO 9185 4 Sabouraundites canis IFO 7864 5 Aspergillus fumigatus IFO 8867 6 Aspergillus niger IFO 8541 7 Staphylococcus aureus FDA 209-P 8 Es cherichia coli NIHJ JC-2 9 Pseudomonas aeruginosa KM 274 10 Pseudomonas aeruginosa NC-5 Note (2) Comparative compound 1' is ketoconazole, a drug that will soon be marketed as an oral antifungal agent, and there are many compounds that show higher MICs.
In addition, the compound of Example (3) was orally administered at 300 mg/Kg to 5 mice, but no harmful side effects were observed.

【table】

【table】 It was not recognized.

Claims (1)

[Claims] 1 Structural formula [I] [In the formula, When X is carbon, R is an aliphatic hydrocarbon represented by the general formula C _o H _2o+1 (where n is an integer from 1 to 15); when X is nitrogen, R is an aliphatic hydrocarbon represented by the general formula
an aliphatic hydrocarbon represented by C _o H _2o+1 (where n is an integer from 1 to 15), or positions 2 to 4 of the benzene nucleus are selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group It represents a phenyl group and a naphthyl group substituted with 1, 2 or 3 substituents. ] Cis and trans 2-[(1-imidazoyl or triazoyl)methyl-2-(substituted phenyl)-
1,3-Dioxolan-4-yl]methyl-acylate derivative. 2 Structural formula [] (wherein, 2-[(1-imidazoyl or triazoyl)methyl]-2-(substituted phenyl)-1,
Structural formula [I] characterized in that 3-dioxolane-4-methanol is reacted with an aliphatic acyl chloride or a substituted benzoyl chloride in the presence of a base. [In the formula, X is carbon or nitrogen, and Ar is substituted at positions 2 to 4 of the benzene nucleus with one, two, or three substituents selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group. When X is carbon, R is an aliphatic hydrocarbon represented by the general formula C _o H _2o+1 (where n is an integer from 1 to 15); when X is nitrogen, R is an aliphatic hydrocarbon represented by the general formula
an aliphatic hydrocarbon represented by C _o H _2o+1 (where n is an integer from 1 to 15), or positions 2 to 4 of the benzene nucleus are selected from the group consisting of a halogen atom, a lower alkyl group, and a lower alkoxy group It represents a phenyl group and a naphthyl group substituted with 1, 2 or 3 substituents. ] Cis and trans 2-[(1-imidazoyl or triazoyl)methyl-2-(substituted phenyl)
A method for producing a -1,3-dioxolan-4-yl]methyl-acylate derivative.