JP2006151912A - 4-pyridylamino pyrimidine derivative and antimicrobial agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new antimicrobial agent excellent in antimicrobial activity. <P>SOLUTION: The novel 4-pyridylamino pyrimidine derivative of formula (1) (wherein R<SP>1</SP>is a hydrogen atom or a fluorine atom; R<SP>2</SP>is a halogen atom, a lower alkyl group, a lower haloalkyl group or a nitro group; X is a chlorine atom, a bromine atom or an iodine atom; and n is an integer of 0-4) is excellent in antimicrobial activity against E.-coli, Sacchalomyces. celibiciae, Aspergillus niger, Trametes vesicola and Fomitopsis palustris. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention is a novel product represented by the formula (1) that is useful as an antibacterial agent for industrial products and raw materials, household products, household materials, earthenware / paints, machinery / equipment, medical, livestock, and fishery. It relates to 4-pyridylaminopyrimidine derivatives.

(Wherein R ¹ represents a hydrogen atom or a fluorine atom, R ² represents a halogen atom, a lower alkyl group, a lower haloalkyl group or a nitro group, X represents a chlorine atom, a bromine atom or an iodine atom, and n represents Represents an integer of 0 to 4)

Since the 4-pyridylaminopyrimidine derivative of the present invention represented by the formula (1) is a novel compound, it is not known to have antibacterial activity.
Japanese Patent Laid-Open No. 2000-7762 JP 2002-275164 A JP 11-171834 A JP-A-11-255552 Journal of Chemical Society, 1955, p. 3478-3481

  The subject of this invention is providing the novel 4-pyridylamino pyrimidine derivative represented by Formula (1), and the antibacterial agent which uses it as an active ingredient.

As a result of studies to solve the above-mentioned problems, the present inventors have found that a novel 4-pyridylaminopyrimidine derivative represented by the formula (1) is useful as an antibacterial agent, and completed the present invention.
That is, the present invention is as follows.

  The first invention is the following formula (1):

(Wherein R ¹ , R ² , X and n are as defined above)

It is related with the 4-pyridylamino pyrimidine derivative shown by these.

  The second invention relates to an antibacterial agent comprising a 4-pyridylaminopyrimidine derivative represented by the formula (1) of the first invention as an active ingredient.

  The 4-pyridylaminopyrimidine derivative represented by the 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 “compound (number, symbol, etc.)” with a number in parentheses attached to a chemical formula, a symbol, etc. [For example, a compound represented by formula (1) is represented by Also called. ].

[R ¹ in Compound (1)]
R ¹ is a hydrogen atom or a fluorine atom.

[R ² in Compound (1)]

R ² is a halogen atom, a lower alkyl group, a lower haloalkyl group, or a nitro group.

Here, examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and a chlorine atom and a bromine atom are preferable.
Examples of the lower alkyl group include a linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, and an n-butyl group. A methyl group is preferred.
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.

[X in Compound (1)]

  X is a chlorine atom, a bromine atom or an iodine atom.

[N in Compound (1)]
n is an integer of 0 to 4, preferably 0, 1, or 2.

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.

Further, in the compound (1) of the present invention, when R ¹ is a fluorine atom, it contains an asymmetric carbon atom, and therefore any of the individual optical isomers, racemates, 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 Synthesis Method 1 shown below.

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

(Wherein R ¹ , R ² , X and n are as defined above)

  Although the molar ratio of the raw materials can be arbitrarily set, the ratio of compound (3) is usually 0.5 to 2 mol, preferably 1.0 to 1.2 mol, relative to 1 mol of compound (2). It is.

The reaction temperature in the absence of a solvent is not particularly limited, but is within a temperature range of 50 to 180 ° C, preferably 80 to 140 ° C.
Although reaction time changes with the said temperature, it is 0.1 to 2 hours normally.

  The type of the solvent used is not particularly limited as long as it does not directly participate in this reaction. For example, it is chlorinated such as benzene, toluene, xylene, methylnaphthalene, chlorobenzene, dichlorobenzene. Aromatic hydrocarbons that are not or not, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, alcohols such as ethanol, propanol, ethylene glycol, diethyl ether, dioxane , Ethers such as tetrahydrofuran, and mixtures 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, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, preferably , Sodium hydride.
Although the usage-amount of a base is 0.8-2 mol with respect to 1 mol of compound (3), Preferably it is 0.8-1.2 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 room temperature-50 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 6 hours.

  The raw material compound (3) can be obtained as a commercial product.

In the compound (2), when R ¹ is a fluorine atom (compound (2-1)), it can be produced according to the method described in Patent Document 1 or Patent Document 2 shown in the following formula.

(Wherein X is as defined above.)

  Here, the compound (4) can be produced according to the method described in Patent Document 3 or Patent Document 4, as shown in the following formula.

In the compound (2), when R ¹ is a hydrogen atom (compound (2-2)), it can be produced according to the method described in Non-Patent Document 1 shown by the following formula.

[Antimicrobial effect]
Examples of the bacteria in which the antibacterial effect is recognized in the compound (1) of the present invention include E. coli, yeast (Saccharomyces. Ceribiciae), black mold (Aspergillus niger), kawaratake (Trametes vesicola), and quail bamboo (Fomiprus). 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 diluent, a surfactant, a dispersant, a fixing agent, etc., by a conventional method, for example, powders, emulsions, fine granules, granules, It is preferable to prepare and use as a composition such as a wettable powder, a granular wettable powder, an aqueous suspension, an oily suspension, an emulsion, a solubilized preparation, an oil, a microcapsule or an aerosol.

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) ), Amide compounds (N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), sulfoxy compounds (dimethylsulfoxide, etc.), urea compounds (N, N-dimethylimidazolidinone, etc.) - dimethyl imidazolidinone), and 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 production of this agent, the above-mentioned 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 by way of examples. In addition, these Examples do not limit the scope of the present invention.

Example 1 [Synthesis of Compound (1)]
(1) Synthesis of 4- (5-chloropyridin-2-ylamino) -5-chloro-6- (1-fluoroethyl) pyrimidine [Compound (1) represented by Compound No. 1] 4,5-Dichloro-6 2-amino-5-chloropyridine (0.65 g) was added to-(1-fluoroethyl) pyrimidine (1.0 g), and the mixture was heated and stirred at 120 to 140 ° C. for 4 hours.
After completion of the reaction, ethanol (10 ml) was added to the reaction product to dissolve it, and a 10% strength by weight sodium hydroxide aqueous solution was added to make it weakly alkaline, followed by extraction with ethyl acetate. The obtained extract 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 = 1/2) to give a slightly yellow color. 0.7 g of the target product as powder crystals was obtained.
The physical properties are shown below.

  m. p. 75-77 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.67 to 1.77 (3H, m), 5.86 to 6.08 (1H, q-q)
7.70-7.74 (1H, q), 8.09 (1H, s),
8.27-8.29 (1H, d), 8.50-8.53 (1H, d),
8.74 (1H, s)

(2) Synthesis of 5-bromo-4- (5-chloropyridin-2-ylamino) -6- (1-fluoroethyl) pyrimidine [Compound (2) represented by Compound No. 1] 2-amino-5-chloro Pyridine (1.3 g) was dissolved in tetrahydrofuran (20 ml), 60% by weight oily sodium hydride (0.4 g) was added with stirring at room temperature, and the mixture was stirred for 30 minutes. Next, a solution of 5-bromo-4-chloro-6- (1-fluoroethyl) pyrimidine (2.4 g) dissolved in tetrahydrofuran (5 ml) was added dropwise, and the mixture was heated and stirred at room temperature for 2 hours.
After completion of the reaction, water was added to the reaction product and extracted with ethyl acetate. The obtained extract 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 a slightly orange color. 1.8 g of the target product which was a powdery crystal was obtained.
The physical properties are shown below.

  m. p. 108-110 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.66 to 1.77 (3H, m), 5.84 to 6.06 (1H, q-q)
7.69-7.73 (1H, q), 8.15 (1H, s),
8.27-8.28 (1H, d), 8.48-8.51 (1H, d),
8.74 (1H, s)

(3) Synthesis of 4- (5-chloropyridin-2-ylamino) -6- (1-fluoroethyl) -5-iodopyrimidine [Compound (3) represented by Compound No. 1] 2-amino-5-chloro Pyridine (1.3 g) was dissolved in tetrahydrofuran (20 ml), 60% by weight oily sodium hydride (0.4 g) was added with stirring at room temperature, and the mixture was stirred for 30 minutes. Next, a solution of 4-chloro-6- (1-fluoroethyl) -5-iodopyrimidine (2.9 g) dissolved in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred with heating at room temperature for 2 hours.
After completion of the reaction, water was added to the reaction product and extracted with ethyl acetate. The obtained extract 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 crystals were collected by filtration and purified by recrystallization from ethyl acetate / n-hexane to obtain 1.8 g of the desired product as colorless cotton crystals. Obtained.
The physical properties are shown below.

  m. p. 159-161 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.65 to 1.75 (3H, m), 5.78 to 6.00 (1H, q-q)
7.70-7.74 (1H, q), 8.17 (1H, s),
8.28-8.29 (1H, d), 8.46-8.49 (1H, d),
8.67 (1H, s)

(4) Synthesis of 5-chloro-4- (5-chloropyridin-2-ylamino) -6-ethylpyrimidine [Compound (4) represented by Compound No. 1] 2-amino-5-chloropyridine (1.3 g) ) Was dissolved in tetrahydrofuran (20 ml), 60% by weight oily sodium hydride (0.4 g) was added with stirring at room temperature, and the mixture was stirred for 30 minutes. Then, a solution of 4,5-dichloro-6-ethylpyrimidine (1.8 g) dissolved in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred with heating at room temperature for 2 hours.
After completion of the reaction, water was added to the reaction product and extracted with ethyl acetate. The obtained extract 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 a fine skin color. 1.1 g of the target product which was a powdery crystal was obtained.
The physical properties are shown below.

  m. p. 74-75 ° C

¹ H-NMR (CDCl ₃ , δ ppm)
1.28 to 1.36 (3H, m), 2.86 to 2.94 (2H, m),
7.67-7.71 (1H, q), 8.01 (1H, s),
8.25-8.26 (1H, d), 8.50-8.53 (1H, d),
8.69 (1H, s)

(5) Synthesis of Other Compound (1) in Table According to the methods of Examples 1 (1) to (4), other compounds (1) in Table 1 and Table 2 were synthesized.
The compounds (1) synthesized as described above and their physical properties are shown in Tables 1 and 2.

Example 2 [Efficacy test]
[Materials and methods]
1) Sample The compounds shown in Table 1 and Table 2 were used.
Each compound was dissolved in DMSO (dimethyl sulfoxide) to prepare a 100,000 mg / L (liter) solution.

2) Preparation of medium 2-1) Preparation of medium of E. coli and yeast (Sacchalomyces. Celibiciae) Using LB liquid medium for Escherichia coli and MY medium for yeast, the compounds shown in Table 1 above were added to 10 mL of medium. A drug-added medium was prepared by adding 50 μL of a drug solution (hereinafter referred to as drug solution) (final drug concentration 500 mg / L).

2-2) Preparation of Aspergillus niger, Trametes versicola and Fomitopsis palustris medium After melting 10 mL of PDA medium, add 50 μL of drug solution (final drug concentration 500 mg / L) before agar solidifies Then, a test plate was prepared by stirring.

3) Antibacterial test 3-1) Antibacterial test against Escherichia coli and yeast After growing in liquid culture overnight, 10 μL of the medium containing the bacterial cells was added to the above drug-added medium and swirl culture overnight at 25 ° C. and 100 rpm. did. After the culture, 10 μL of this medium was collected, transferred to 10 mL of a fresh medium not containing the drug and cultured, 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: Less than 50% inhibition rate

3-2) Antibacterial test against black mold, kawaratake, and sphagnum mushroom PDA plate on which the fungus of kawaratake or sphagnum mushroom has grown, or a PDA medium (thickness of about 1 mm) containing about 1 × 10 ⁵ spore of black mold The inoculation pieces were cut into about 1.5 mm squares with a scalpel. 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: Less than 50% inhibition rate

  As a result of the antibacterial test, compound numbers 5, 6 and 7 show the effect of A, compound numbers 10, 21 and 25 show the effect of B, and compound numbers 13 and 29 show the effect of C against E. coli. showed that.

  For yeast, compound numbers 1, 5, 6, 8, 10, 20, 21, 24, 25, 27 and 33 show the effect of A, compound numbers 9 and 13 show the effect of B, compound number 11, 15 and 32 showed the effect of C.

  For black mold, compound numbers 5, 6, 10, 20, 21, 22, 25, 26, 27, 32 and 33 show the effect of A, and compound numbers 1, 9, 13 and 29 show the effect of B. Compound Nos. 11 and 15 showed the effect of C.

  For Kawatake, Compound Nos. 1, 4, 5, 6, 8, 10, 15, 20, 21, 22, 25, 26, 27, 29, 32 and 33 show the effect of A, Compound No. 7, 9 and 13 showed the effect of B, and compound numbers 11 and 19 showed the effect of C.

For Prunus japonica, compound numbers 1, 4, 5, 6, 8, 10, 20, 21, 22, 25, 26 and 27 show the effect of A, and compound numbers 9, 13 and 29 show the effect of B. Compound Nos. 7, 11, 15, 23, 32 and 33 showed the effect of C.

Claims (2)

A 4-pyridylaminopyrimidine derivative represented by the formula (1).

(Wherein R ¹ represents a hydrogen atom or a fluorine atom, R ² represents a halogen atom, a lower alkyl group, a lower haloalkyl group or a nitro group, X represents a chlorine atom, a bromine atom or an iodine atom, and n represents Represents an integer of 0 to 4) An antibacterial agent comprising a 4-pyridylaminopyrimidine derivative represented by the formula (1) of claim 1 as an active ingredient.