JP4449580B2 - 4-Aralkylaminopyrimidine derivatives and antibacterial agents - Google Patents

Description

  The present invention is represented by the following formula (1) that is useful as an antibacterial agent for industrial products and raw material products, household products, living materials, construction / paints, machinery / equipment, medical, livestock, and fishery. The present invention relates to a novel 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative.

(In the formula, A represents a linear or branched alkylene group having 1 to 6 carbon atoms, and R represents a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, or an amino group. Represents a hydroxyl group or a phenoxy group, and n represents an integer of 0 to 5.)

Since the 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative of the present invention represented by the above formula (1) is a novel compound, it is not known to have antibacterial activity.
Japanese Patent Application No. 2004-140702 JP 11-171834 A JP-A-11-255552 Japanese Patent Laid-Open No. 15-176247 Synthesis, (1982), p. 92 Organic Reaction, 5,301 (1949) Organic Reaction, 3,268 (1946) Organic Synthesis Coll. Vol. , I, (1941) p. 107 Organic Synthesis Coll. Vol. , III, (1955) p. 720 Organic Synthesis Coll. Vol. , IV, (1963) p. 339

  An object of the present invention is to provide a novel 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the above formula (1) and an antibacterial agent containing the derivative as an active ingredient. is there.

As a result of investigations to solve the above problems, the present inventors have found that a novel 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the above formula (1) is antibacterial. It was found useful as an agent, and the present invention was completed.
That is, the present invention is as follows.

  The first invention is the following formula (1):

(In the formula, A, R and n are as defined above.)

The present invention relates to a 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the formula:

  The second invention relates to an antibacterial agent comprising a 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the above formula (1) as an active ingredient.

  The 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the above formula (1) of the present invention has an excellent antibacterial effect.

Various substituents represented by the above compound are as follows.
In the description of the present invention, a compound is also referred to as a “compound (number, symbol, etc.)” with numbers and symbols in parentheses attached to the chemical formula [for example, a compound represented by formula (1) is represented by compound (1) Also called. ].

[A in Compound (1)]
A is a linear or branched alkylene group having 1 to 6 carbon atoms, and includes a methylene group, a (methyl) methylene group, an (ethyl) methylene group, an (n-propyl) methylene group, (i- Propyl) methylene group, (n-butyl) methylene group, (i-butyl) methylene group, (n-pentyl) methylene group, ethylene group, 1-methylethylene group, 2-methylethylene group, propylene group, butylene group, Examples of the pentylene group include methylene group, (methyl) methylene group, (ethyl) methylene group, (i-butyl) methylene group, (n-butyl) methylene group, (dimethyl) methylene group, ethylene group, 2 -A methylethylene group, 2- (i-propyl) -2-methylethylene group and a propylene group are preferred.

[R in Compound (1)]
R is a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, an amino group, a hydroxyl group or a phenoxy group.

Examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and a chlorine atom, a bromine atom, and a fluorine atom are preferable.
The lower alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, or an i-butyl group. , T-butyl group, n-pentyl group, and the like, preferably methyl group, ethyl group, i-propyl group, and t-butyl group.
As the lower haloalkyl group, a linear or branched haloalkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, a difluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethyl group, 3 , 3,3-trifluoropropyl group and the like, and a trifluoromethyl group is preferable.

  Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, and an n-butoxy group. A methoxy group is preferable.

  As the lower haloalkoxy group, a linear or branched haloalkoxy group having 1 to 4 carbon atoms such as a difluoromethoxy group, a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, 3, 3, A 3-trifluoropropoxy group, a 4,4,4-trifluorobutoxy group and the like can be exemplified, and a difluoromethoxy group and a trifluoromethoxy group are preferred.

[N in Compound (1)]
n is an integer of 0 to 5, preferably 0 to 3.

Since the compound (1) of the present invention has an amino group, an acid addition salt derived therefrom is also included in the present invention.
Examples of acids that form acid addition salts include inorganic acids (hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.), carboxylic acids (formic acid, oxalic acid, fumaric acid, adipic acid, stearic acid, aconitic acid) Etc.), sulfonic acid (methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), saccharin and the like.

  In addition, since the compound (1) of the present invention contains 1 to 2 asymmetric carbon atoms, any of the individual optical isomers, racemates, diastereomers, or mixtures thereof derived therefrom are included in the present invention. included.

The method for synthesizing the compound (1) of the present invention will be described in more detail.
Compound (1) can be synthesized by the synthesis method shown below.

(Synthesis method)
Compound (1) can be synthesized by reacting compound (2) and compound (3) in a solvent in the presence of a base, as shown below.

(In the formula, A, R and n are as defined above.)

  Although the molar ratio of the raw materials can be arbitrarily set, the compound (3) is usually in a ratio of 0.5 to 2 mol per mol of the compound (2), preferably 1.0 to 1.2 times mol. Is the ratio.

  The type of solvent is not particularly limited as long as it does not directly participate in this reaction. For example, fragrances such as benzene, toluene, xylene, methylnaphthalene, chlorobenzene, and dichlorobenzene are not chlorinated. Group hydrocarbons, cyclic ethers such as dioxane and tetrahydrofuran, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, alcohols such as ethanol, propanol and ethylene glycol, And a mixture of these solvents.

  The amount of the solvent used can be such that the concentration of the compound (2) is 5 to 80% by weight, preferably 10 to 70% by weight.

Examples of the base include triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, potassium carbonate, and sodium carbonate, with triethylamine being preferred.
Although the usage-amount of a base is 0.8-2 mol with respect to 1 mol of compound (2), Preferably it is 1.0-1.5 mol.

Although reaction temperature is not specifically limited, It exists in the temperature range below -20 degreeC to the boiling point of a solvent, Preferably it is 80-140 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 3 to 12 hours.

  The raw material compound (2) can be produced by the method described in Patent Document 1 as shown in the following formula.

  Compound (4) can be produced according to the methods described in Patent Document 2 and Patent Document 3, as shown in the following formula.

  The compound in which A is a methylene group in the raw material compound (3) can be obtained as a commercial product, or can be produced by the method of the following formula described in Non-Patent Document 1 or the like.

(In the formula, R and n are as defined above.)

  In the raw material compound (3), a compound in which A is a monoalkyl-substituted methylene group can be obtained as a commercial product, or can be produced by the method of the following formula described in Non-Patent Document 2 or the like.

(Wherein R ¹ represents a lower alkyl group having 1 to 5 carbon atoms, and R and n are as defined above.)

  In the raw material compound (3), a compound in which A is a dialkyl-substituted methylene group can be obtained as a commercial product, or can be produced by the method of the following formula described in Non-Patent Document 3 or the like.

(In the formula, R ² and R ³ represent a lower alkyl group having 1 to 5 carbon atoms, and R and n are as defined above.)

  The compound in which A is an ethylene group in the raw material compound (3) can be obtained as a commercial product, or can be produced by the method of the following formula described in Non-Patent Document 4, Non-Patent Document 5, and Patent Document 4.

(In the formula, R and n are as defined above.)

  The target product (1) produced as described above can be subjected to usual post-treatments such as washing, extraction and concentration after the completion of the reaction, and can be purified by a known method such as distillation or chromatography as necessary. .

[Antimicrobial effect]
Examples of the bacterium in which the antibacterial effect is recognized by the compound (1) of the present invention include Escherichia coli (E.-coli), yeast (Sacchalomyces.celibiciae), black mold (Aspergillus niger), kawaratake (Trametes vesicola), and Oomizuratake (Fomitopsis palustris). Can be mentioned.

The antibacterial agent of the present invention contains at least one compound (1) as an active ingredient.
The compound (1) can be used alone, but usually contains a solid or liquid diluent, a surfactant, a dispersant, a fixing agent, etc., by a conventional method, for example, powders, emulsions, fine granules, It can be used as a composition such as granules, wettable powders, granular wettable powders, aqueous suspensions, oily suspensions, emulsions, solubilized preparations, oils, microcapsules and aerosols. preferable.

Examples of the solid diluent include talc, bentonite, montmorillonite, clay, kaolin, calcium carbonate, diatomaceous earth, white carbon, vermiculite, slaked lime, silica sand, ammonium sulfate, urea, and the like.
Examples of liquid diluents include hydrocarbons (such as kerosene and mineral oil), aromatic hydrocarbons (such as benzene, toluene, xylene, dimethylnaphthalene, and dimethylxylylethane), and chlorinated hydrocarbons (such as chloroform and carbon tetrachloride). Etc.), ethers (dioxane, tetrahydrofuran, etc.), ketones (acetone, cyclohexanone, isophorone, etc.), esters (ethyl acetate, ethylene glycol acetate, dibutyl maleate, etc.), alcohols (methanol, n-hexanol, ethylene glycol, etc.) ), Amide compounds (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like), sulfoxy compounds (dimethylsulfoxide and the like), urea compounds such as N, N-dimethylimidazolidinone ( N N- dimethyl imidazolidinone, etc.), etc. sulfolane and water.

Examples of the fixing agent and the dispersing agent include casein, polyvinyl alcohol, carboxymethyl cellulose, bentonite, xanthan gum, and gum arabic.
Examples of the aerosol propellant include air, nitrogen, carbon dioxide gas, propane, halogenated hydrocarbon (such as fluorocarbon) and the like.

  Examples of the surfactant include alcohol sulfates, alkyl sulfate salts, alkyl sulfonates, alkyl benzene sulfonates, lignin sulfonates, dialkyl sulfosuccinates, naphthalene sulfonate condensates, polyoxyethylene alkyl ethers, Examples thereof include polyoxyethylene allyl ether, polyoxyethylene alkyl ester, alkyl sorbitan ester, polyoxyethylene sorbitan ester, polyoxyethylene alkylamine and the like.

In the preparation of this agent, the solid or liquid diluent, surfactant, dispersant and fixing agent can be used alone or in appropriate combination depending on the purpose.
The active ingredient concentration when the compound (1) of the present invention is formulated is usually 1 to 50% by weight for emulsions, usually 0.3 to 25% by weight for powders, and usually 1 to 1 for wettable powders and granular wettable powders. 90% by weight, usually 0.5 to 10% by weight for granules, usually 0.5 to 40% by weight for aqueous and oily suspensions, usually 1 to 30% by weight for emulsions, and usually 0. 5 to 20% by weight, and usually 0.1 to 5% by weight for aerosols. In a microcapsule, it is usually 0.5 to 20% by weight.
These preparations can be used for various purposes by diluting them to appropriate concentrations and applying them according to their respective purposes.

  Hereinafter, the present invention will be specifically described with reference examples and examples. In addition, these Examples do not limit the scope of the present invention.

Reference Example 1 [Synthesis of Compound (5)]
(1) Synthesis of 5-bromo-6- (1-fluoroethyl) -4-hydroxypyrimidine 6- (1-fluoroethyl) -6-hydroxypyrimidine (71 g) was dissolved in acetic acid (300 ml) to obtain Bromine (84 g) was added dropwise to the solution with stirring at room temperature. After completion of dropping, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, acetic acid was distilled off under reduced pressure, water was added and stirred, and the precipitated crystals were collected by filtration. By recrystallizing and purifying the obtained crystals with acetone-water, 85.5 g of the desired product which was a slightly yellow platelet-like crystal was obtained.

  m. p. 187-188 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.51-1.62 (3H, m), 5.70-5.90 (1H, q-q),
8.62 (1H, s), 13.15 (1H, b)

Reference Example 2 [Synthesis of Compound (2)]
(2) Synthesis of 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine 5-bromo-6- (1-fluoroethyl) -6-hydroxypyrimidine (22.1 g) was dissolved in ethyl acetate (200 ml). N, N-dimethylformamide (0.7 g) was added to the resulting solution. While this solution was heated and stirred at about 70 ° C., thionyl chloride (14.3 g) was added dropwise. After completion of dropping, the mixture was stirred for 4 hours under reflux. After completion of the reaction, the reaction mixture was returned to room temperature, added to crushed ice water, neutralized with 30% aqueous sodium hydroxide solution, and extracted with toluene. The obtained extract was washed with water, dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off from the obtained filtrate under reduced pressure. The obtained residue was purified by distillation under reduced pressure to obtain 21.4 g of the desired product as a colorless liquid.

  b. p. 92-93 ° C / 7.8mmHg

¹ H-NMR (CDCl ₃ , δ ppm)
1.67 to 1.75 (3H, m), 5.90 to 6.12 (1H, q-q),
8.93 (1H, s)

Example 1 [Synthesis of Compound (1)]
(3) Synthesis of 5-bromo-4- (4-fluorobenzylamino) -6- (1-fluoroethyl) pyrimidine [Compound (1) represented by Compound No. 1] 4-fluorobenzylamine (0.7 g) And triethylamine (0.7 g) were dissolved in toluene (30 ml), 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine (1.2 g) was added, and the mixture was heated to reflux for 4 hours.
After completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (Wakogel C-200, developing solvent: ethyl acetate / n-hexane = 1/3) to give colorless. 1.4 g of the target product of powdery crystals was obtained.

  m. p. 97-98 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.61-1.72 (3H, m), 4.69-4.75 (2H, q)
5.47-5.99 (1H, qq), 5.88 (1H, s)
7.01 to 7.35 (4H, m), 8.56 (1H, s)

(4) Synthesis of 5-bromo-6- (1-fluoroethyl) -4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine [Compound (1) represented by Compound No. 11] 2- ( 4-Trifluoromethoxyphenyl) ethylamine (2.1 g) and triethylamine (1.2 g) were dissolved in toluene (50 ml), and 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine (2.4 g) was dissolved. ) Was added and heated to reflux for 4 hours.
After completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (Wakogel C-200, developing solvent: ethyl acetate / n-hexane = 1/3) to give colorless. 3.5 g of the target product of powdery crystals was obtained.

  m. p. 90-91 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.58 to 1.71 (3H, m), 2.93 to 2.98 (2H, t)
3.74 to 3.81 (2H, m), 5.63 (1H, s),
5.57 to 5.93 (1H, q-q), 7.16 to 7.27 (4H, m),
8.55 (1H, s)

(5) Synthesis of 5-bromo-4- (3-phenylpropylamino) -6- (1-fluoroethyl) pyrimidine [Compound (1) represented by Compound No. 20] With 3-phenylpropylamine (0.7 g) Triethylamine (0.7 g) was dissolved in toluene (30 ml), 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine (1.2 g) was added, and the mixture was heated to reflux for 4 hours.
After completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (Wakogel C-200, developing solvent: ethyl acetate / n-hexane = 1/3) to give colorless. 1.4 g of the target product of powdery crystals was obtained.

  m. p. 78-80 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.60 to 1.70 (3H, m), 1.95 to 2.02 (2H, q),
2.69-2.74 (2H, q), 3.52-3.58 (2H, m),
5.57 (1H, s), 5.74-5.96 (1H, q-q)
7.16 to 7.31 (5H, m), 8.52 (1H, s)

(6) Synthesis of 5-bromo-4- [1- (4-difluoromethoxyphenyl) ethylamino] -6- (1-fluoroethyl) pyrimidine [Compound (1) represented by Compound No. 22] 1- (4 -Difluoromethoxyphenyl) ethylamine (1.0 g) and triethylamine (0.7 g) were dissolved in toluene (30 ml), and 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine (1.2 g) was dissolved. In addition, the mixture was heated to reflux for 8 hours.
After completion of the reaction, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography (Wakogel C-200, developing solvent: ethyl acetate / n-hexane = 1/3). 1.3 g of the target product was obtained as a yellow liquid.

¹ H-NMR (CDCl ₃ , δ ppm)
1.59 to 1.63 (6H, m), 5.34 to 5.39 (1H, q),
5.75 (1H, s), 5.76-5.98 (1H, q-q),
6.48 to 6.74 (1H, t), 7.09 to 7.38 (4H, m),
8.50 (1H, s)

(5) Synthesis of Other Compound (1) in Table According to the methods of Examples 1 (3) to (6), other compounds (1) in Table 1 were synthesized.
Table 1 shows the compound (1) synthesized as described above and the physical properties thereof.

Example 4 [Efficacy test]
[Materials and methods]
1) Sample The compounds shown in Table 1 were used.
Each compound was dissolved in DMSO (dimethyl sulfoxide) to prepare a 100,000 mg / L (liter) solution.

2) Preparation of medium E. coli and yeast (Sacchalomyces. Celibiciae)
Escherichia coli uses LB liquid medium and yeast uses MY medium, and 10 μL of the drug solution of the compound shown in Table 1 above (hereinafter referred to as drug solution) 50 μL (final drug concentration 500 mg / L)
Was added to prepare a drug-added medium.
Aspergillus niger, Trametes versicola, and Fomitopsis palustris
After melting 10 mL of PDA medium, 50 μL of a drug solution (final drug concentration 500 mg / L) was added and stirred before the agar solidified to prepare a test plate.

3) Antibacterial test E. coli and yeast:
After growing in liquid culture overnight, 20 μL of the medium containing the bacterial cells was added to the above-mentioned drug-added medium, and the culture was swirled overnight at 25 ° C. and 100 rpm. After culturing, 50 μL of this medium was collected, transferred to 10 μL of fresh medium containing no drug and cultured for 1 day, and then the absorbance at 660 nm was measured, and the inhibition rate was calculated from the following formula.

A: Absorbance of untreated section
B: Absorbance of chemical treatment section

The effect was judged according to the following four criteria.
A: 90-100% inhibition B: 70-89% inhibition C: 50-69% inhibition D: Inhibition rate less than 50%

Black mold, Kawaratake and Ouzuratake:
A PDA medium (thickness: about 1 mm) containing about 1 × 10 ⁵ spore of black mold and a PDA plate on which the fungus of Kawaratake and Ozuuratake grew on the entire surface, each cut into about 1.5 mm squares with a scalpel Was used as an inoculum. These inoculums were placed on a test plate and cultured at 25 ° C. for 4 days. After culturing, the diameter of the flora formed by extending hyphae from the inoculated piece was measured, and the inhibition rate was calculated from the following formula.

A: Microflora diameter of untreated section (mm)
B: Microflora diameter (mm) of drug treatment area

The effect was judged according to the following four criteria.
A: 90-100% inhibition B: 70-89% inhibition C: 50-69% inhibition D: Inhibition rate less than 50%

As a result of the antibacterial test, Compound Nos. 26 and 27 showed the effect of C against E. coli.
For yeast, compound numbers 2, 3, 12, 19, 21, 25, 26, 27 and 30 show the effect of A, compound numbers 16, 17 and 18 show the effect of B, compound number 1, 22 and 23 showed the effect of C.

  For black mold, compound numbers 1, 2, 3, 10, 18, 20, 21, 25, 26 and 27 show the effect of A, compound numbers 14, 16, 19 and 22 show the effect of B, Compound numbers 5, 15, 23, 24, 28, 31, 32, and 33 showed the effect of C.

  For Kawaratake, compound numbers 1, 2, 3, 7, 8, 10, 12, 14, 15, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27, 30, 31 and 32 showed the effect of A, and compound numbers 5, 9, 19, 28 and 33 showed the effect of B.

  For Prunus cerevisiae, compound numbers 1, 2, 3, 10, 19, 21, 25, 26, 27 and 30 show the effect of A, compound numbers 5, 14, 15, 16, 18, 20, 22, 23, 24, 31, 32, and 33 showed the effect of B, and compound numbers 7, 9, 12, and 28 showed the effect of C.

Claims (2)

A 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the following formula (1):

(In the formula, A represents a linear or branched alkylene group having 1 to 6 carbon atoms, and R represents a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, or an amino group. Represents a hydroxyl group or a phenoxy group, and n represents an integer of 0 to 5.) An antibacterial agent comprising a 4-aralkylamino-5-bromo-6- (1-fluoroethyl) pyrimidine derivative represented by the formula (1) of claim 1 as an active ingredient.