JP2005330229A - 4-trifluoromethoxyphenyl(oxy)ethylamine derivative and antimicrobial agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new 4-trifluoromethoxyphenyl(oxy)ethylamine derivative of formula(1), and to provide an antimicrobial agent with the derivative as active ingredient. <P>SOLUTION: The new 4-trifluoromethoxyphenyl(oxy)ethylamine derivative of formula(1) is useful as an antimicrobial agent. In formula(1), A is a heterocyclic ring containing 1-2 nitrogen atom(s) in the respective rings represented by formulas(A-1 to A-5); Y is an oxygen atom or single bond; in the formulas(A-1 to A-5), R<SP>1</SP>is H, OH, mercapto, a lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, halogen atom, 2-pyridyloxy or 2-pyridylthio; n is an integer of 1-3; R<SP>2</SP>, R<SP>3</SP>, R<SP>5</SP>and R<SP>6</SP>are each H or a lower alkyl; and R<SP>4</SP>is H, OH or a lower alkyl. <P>COPYRIGHT: (C)2006,JPO&NCIPI

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-trifluoromethoxyphenyl (oxy) ethylamine derivative.

（式中、Ａは、下式（Ａ−１〜Ａ−５）で表される環中に１〜２個の窒素原子を含む複素環を表し、Ｙは、酸素原子又は単結合を表す。）

(In the formula, A represents a heterocyclic ring containing 1 to 2 nitrogen atoms in the ring represented by the following formulas (A-1 to A-5), and Y represents an oxygen atom or a single bond. )

(In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a mercapto group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, a 2-pyridyloxy group or 2-pyridylthio group. In the case of 2-pyridyloxy group and 2-pyridylthio group, the 3-position carbon atom and the nitrogen atom of the amide bond in the above formula (1) may be bonded to form a ring. R represents an integer of 1 to 3, R ² , R ³ , R ⁵ and R ⁶ represent a hydrogen atom or a lower alkyl group, and R ⁴ represents a hydrogen atom, a hydroxyl group or a lower alkyl group.

Since the 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the formula (1) of the present invention is a novel compound, it is not known to have antibacterial activity.
Synthesis, 1982, p. 922 Beilstein, 6,142 Japanese Patent Laid-Open No. 15-176247

  An object of the present invention is to provide a novel 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the above formula (1) and an antibacterial agent containing it as an active ingredient.

As a result of investigations to solve the above problems, the present inventors have found that the novel 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the formula (1) is useful as an antibacterial agent. The present invention has been completed.
That is, the present invention is as follows.
The first invention relates to a 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the following formula (1).

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

  The second invention relates to a 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the following formula (2).

(Wherein R ⁷ represents a hydrogen atom, a halogen atom or a lower alkyl group, R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower haloalkyl group, X represents an oxygen atom or a sulfur atom, Y represents Same as above.)

  The third invention relates to an antibacterial agent comprising 4-trifluoromethoxyphenyl (oxy) ethylamine represented by the above formula (1) as an active ingredient.

  The fourth invention relates to an antibacterial agent comprising 4-trifluoromethoxyphenyl (oxy) ethylamine represented by the above formula (2) as an active ingredient.

  The 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the formula (1) of the present invention has an excellent antibacterial effect.

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

[A in Compound (1)]
A represents a heterocyclic ring containing 1 to 2 nitrogen atoms in the ring represented by the following formulas (A-1 to A-5).

(1) In A-1, R ¹ is a hydrogen atom, a hydroxyl group, a mercapto group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, or a 2-pyridyloxy group. Alternatively, it is a pyridyl group substituted with a 2-pyridylthio group. N represents an integer of 1 to 3. In the case of a pyridyl group substituted with a 2-pyridyloxy group, the 3-position carbon atom and the nitrogen atom of the amide bond in the above formula (1) may be bonded to form a ring. The compound represented by 2) is also included.

(Wherein R ⁷ , R ⁸ , X and Y are as defined above.)

As the lower alkyl group for R ^{1, 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, an n-butyl group, and the like. Examples thereof include a methyl group and an ethyl group.

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. Preferably, it is a methoxy group or an ethoxy group.
Examples of the lower alkylthio group include a linear or branched alkylthio group having 1 to 4 carbon atoms, such as a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, and an n-butylthio group. A methylthio group and an ethylthio group are preferable.

Examples of the lower alkylsulfinyl group include linear or branched alkylsulfinyl groups having 1 to 4 carbon atoms, such as methylsulfinyl group, ethylsulfinyl group, n-propylsulfinyl group, i-propylsulfinyl group, n-butyl. A sulfinyl group can be exemplified, and a methylsulfinyl group is preferred.
As the lower alkylsulfonyl group, a linear or branched alkylsulfonyl group having 1 to 4 carbon atoms such as a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group, an i-propylsulfonyl group, and n-butyl. Although a sulfonyl group etc. can be mentioned, Preferably it is a methylsulfonyl group.

  Examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, and a chlorine atom is preferable.

Examples of the 2-pyridyloxy group and 2-pyridylthio group are unsubstituted or substituted with a lower haloalkoxy group, a lower alkyl group or a halogen atom as a substituent. The 3-position carbon atom of the 2-pyridyloxy group and 2-pyridylthio group may be bonded to the nitrogen atom of the amide bond in the above formula (1) to form a ring, and examples thereof include compound (2). .
Here, as the lower haloalkoxy group, a linear or branched haloalkyl group having 1 to 4 carbon atoms, such as a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a pentafluoroethyl group, a perfluoropropyl group. Group, perfluorobutyl group and the like, and a trifluoromethyl group is 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. it can.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Of these substituents of 2-pyridyloxy group and 2-pyridylthio group, substitution with a halogen atom and a lower haloalkyl group is preferred, and 3-halogen-5-lower haloalkyl substitution is more preferred. Of these, 3-chloro-5-trifluoromethyl substitution is particularly preferred.

  n is an integer of 1 to 3, but 1 or 2 is preferable.

(2) In A-2, R ² is a hydrogen atom or a lower alkyl group.
As the lower alkyl group for R ^{2, 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, an n-butyl group, and the like. An ethyl group is preferable.

(3) In A-3, R ³ is a hydrogen atom or a lower alkyl group.
As the lower alkyl group for R ^{3, 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, an n-butyl group, and the like. A methyl group is preferable.

(4) In A-4, R ⁴ is a hydrogen atom, a hydroxyl group or a lower alkyl group, and R ⁵ is a hydrogen atom or a lower alkyl group.
The lower alkyl group for R ⁴ and R ⁵ is 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, or an n-butyl group. A group and the like can be mentioned, and a methyl group is preferred.
(5) In A-5, R ⁶ is a lower alkyl group.
As the lower alkyl group for R ^{6, 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, an n-butyl group and the like. A methyl group is preferable.

[Y in Compound (1)]
Y represents an oxygen atom or a single bond.

[X in Compound (2)]
X represents an oxygen atom or a sulfur atom.
[Y in Compound (2)]
Y represents an oxygen atom or a single bond.

[R ⁷ in Compound (2)]
R ⁷ is a hydrogen atom, a halogen atom or a lower alkyl group.
Examples of the halogen atom for R ⁷ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
As the lower alkyl group for R ^{7, 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, an n-butyl group, etc. The methyl group is preferable.
Of the above substituents for R ⁷ , a hydrogen atom is preferable.
[R ⁸ in Compound (2)]
R ⁸ is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower haloalkyl group.
Examples of the halogen atom for R ⁸ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
As the lower alkyl group for R ^{8, a} linear or branched alkyl group having 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, etc. The methyl group is preferable.
The lower haloalkyl group for R ⁸ is a linear or branched haloalkyl group having 1 to 4 carbon atoms, such as a trifluoromethyl group, difluoromethyl group, monofluoromethyl group, pentafluoroethyl group, perfluoropropyl group. Group, perfluorobutyl group and the like can be mentioned, and preferred is a trifluoromethyl group, and the substitution position is particularly preferred at the 3-position.
Of the above substituents for R ^8, a linear or branched haloalkyl group having 1 to 4 carbon atoms is preferable, and a trifluoromethyl group is more preferable. The substitution position is preferably the 3-position.

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 or 2 shown below.

(Synthesis method 1)
As shown below, compound (1) can be synthesized by reacting compound (3) and compound (4) in a solvent in the presence of a condensing agent.

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

Examples of the condensing agent include dehydrating condensing agents such as N, N′-dicyclohexylcarbodiimide (abbreviation: DCC) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (abbreviation: WSC). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (abbreviation: WSC) is preferable.
Although the usage-amount of a condensing agent is 1-5 mol with respect to 1 mol of compound (3), Preferably it is 1.0-1.5 mol.

  Although the molar ratio of the raw materials can be arbitrarily set, the compound (4) is usually in a ratio of 0.5 to 2 mol with respect to 1 mol of the compound (3), preferably 1.0 to 1.2 mol. It is a ratio.

  The type of the solvent is not particularly limited as long as it does not directly participate in this reaction. List chlorinated or non-chlorinated aromatic, aliphatic, alicyclic hydrocarbons such as dichloroethane, trichloroethylene, ethers such as tetrahydrofuran, dioxane, diethyl ether, etc. Can do.

  The amount of the solvent used can be such that the concentration of the compound (3) is 5 to 80% by weight, preferably 10 to 70% by weight.

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 8 hours.

The raw material compound (3) can be obtained as a commercial product.
Compound (4-1) in which Y is an oxygen atom (Y = O) in compound (4) can be produced according to the Gabriel method described in Non-Patent Document 1. (See the following formula)
Compound (5) can be produced from commercially available 4-trifluoromethoxyphenol and ethylene dihalide, for example, according to the method described in Non-Patent Document 2.

(In the formula, Z represents a chlorine atom, a bromine atom or an iodine atom.)

Compound (4-2) wherein Y is a single bond in compound (4) can be produced from commercially available trifluoromethoxybenzene according to the method described in Patent Document 1. (See the following formula)

(Synthesis method 2)
Compound (1) can also be synthesized by reacting compound (4) and compound (9) in a solvent in the presence of a base, as shown below.

(In the formula, R represents a lower alkyl group, and A and Y are as defined above.)

In the ester compound represented by the above formula (9), R is a lower alkyl group.
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. Preferably, it is a methyl group or an ethyl group.
A commercial item can be used for raw material compound (9).

Examples of the base include triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, potassium carbonate and sodium carbonate, with sodium methoxide being preferred.
Although the usage-amount of a base is 0.1-1 mol with respect to 1 mol of compound (9), Preferably it is 0.2-0.5 mol.
Although the molar ratio of the raw materials can be arbitrarily set, the compound (4) is usually in a ratio of 0.8 to 1.1 mol per 1 mol of the compound (9).

  The type of the solvent is not particularly limited as long as it does not directly participate in this reaction. Chlorinated or non-chlorinated aromatic, aliphatic, alicyclic hydrocarbons such as dichloroethane, trichloroethylene, ethers such as tetrahydrofuran, dioxane, diethyl ether, methanol, ethanol, n-propanol, i- Examples thereof include alcohols such as propanol, n-butanol, i-butanol, and t-butanol, and a mixture of the above solvents.

  The amount of the solvent used can be such that the concentration of the compound (4) is 5 to 80% by weight, but preferably 10 to 70% by weight.

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-80 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 8 hours.

(Synthesis method 3)
The compound (1-2) in which A of the compound (1) is A-1 and R ¹ is a lower alkoxy group, a lower alkylthio group, a 2-pyridylthio group or a 2-pyridyloxy group is represented by the following formula: The compound (1-1) and the compound (10) can also be synthesized by reacting in a solvent in the presence of a base.

(In the formula, R ⁹ represents a lower alkyl group or a 2-pyridyl group, and X, Y, and Z are as defined above.)

In the compound represented by the above formula (10), R ⁹ is a lower alkyl group or a 2-pyridyl group.

  Examples of the lower alkyl group include linear or branched alkyl groups 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. However, it is preferably a methyl group or an ethyl group.

Examples of the 2-pyridyl group are unsubstituted or substituted with a lower haloalkoxy group, a lower alkyl group or a halogen atom as a substituent.
Here, as the lower haloalkoxy group, a linear or branched haloalkyl group having 1 to 4 carbon atoms, such as a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a pentafluoroethyl group, a perfluoropropyl group. Group, perfluorobutyl group and the like, and a trifluoromethyl group is 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. it can.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
In these 2-pyridyl group substituents, substitution with a halogen atom and a lower haloalkyl group is preferred, and 3-halogen-5-lower haloalkyl substitution is more preferred. Of these, 3-chloro-5-trifluoromethyl substitution is particularly preferred.

  A commercial item can be used for compound (10).

Examples of the base include triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, potassium carbonate, and sodium carbonate, with potassium carbonate being preferred.
Although the usage-amount of a base is 0.5-2 mol with respect to 1 mol of compounds (1-1), Preferably it is 0.8-1.2 mol.

Although the molar ratio of the raw material compound (10) can be arbitrarily set, it is usually in a ratio of 0.8 to 1.1 mol with respect to 1 mol of the compound (1-1).
The type of the solvent is not particularly limited as long as it does not directly participate in this reaction, and examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide, acetone and methyl ethyl ketone. And a mixture of ketones and a previous solvent.

  The amount of the solvent used can be such that the concentration of the compound (1-1) is 5 to 80% by weight, preferably 10 to 70% by weight.

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-80 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 8 hours.

(Synthesis Method 4)
The compound (1-4) in which A of the compound (1) is A-1 and R ¹ is a lower alkylsulfinyl group or a lower alkylsulfonyl group is represented by the following formula (1-3): It can also be synthesized by reacting with an oxidizing agent (11) in a solvent.

(Wherein R ¹⁰ represents a lower alkyl group, p represents 1 or 2, and Y is as defined above.)

In the compound represented by the above formula (1-3), R ¹⁰ is a lower alkyl group.
Examples of the lower alkyl group include linear or branched alkyl groups 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. Can

Examples of the oxidizing agent (11) include oxidizing agents such as hydrogen peroxide, potassium peroxymonosulfate (trade name: OXONE), metachloroperoxybenzoic acid, and peracetic acid, but preferably potassium peroxymonosulfate (OXONE). ). These oxidizing agents can be obtained as commercial products.
Although the usage-amount of an oxidizing agent is 0.5-3 mol with respect to 1 mol of compounds (1-3), Preferably it is 1.5-2.2 mol.

  The type of the solvent is not particularly limited as long as it does not directly participate in this reaction, and examples thereof include water, alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl ethyl ketone, and a mixture of the above solvents. be able to.

  The amount of the solvent used can be such that the concentration of the compound (1-3) is 5 to 80% by weight, preferably 10 to 70% by weight.

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-80 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 5 hours.

(Synthesis Method 5)
Of the compounds in which A in compound (1) is A-2, compound (1-6) in which R2 is a lower alkyl group is represented by compound (1-5), compound (12), and Can also be synthesized by reacting in the presence of a base in a solvent.

(Wherein R ¹¹ represents a lower alkyl group, and Y and Z are as defined above.)

In the compound represented by the above formula (12), R ¹¹ is a lower alkyl group.
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. An ethyl group is preferable.

Examples of the base include triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, potassium carbonate, and sodium carbonate, with potassium carbonate being preferred.
Although the usage-amount of a base is 0.1-1 mol with respect to 1 mol of compounds (1-5), Preferably it is 0.8-1.0 mol.

  Although the molar ratio of the raw materials can be arbitrarily set, the compound (12) is usually in a ratio of 0.8 to 1.1 mol with respect to 1 mol of the compound (1-5).

  The type of the solvent is not particularly limited as long as it does not directly participate in the reaction, and examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide, acetone and methyl ethyl ketone Mention may be made of ketones and mixtures of the aforementioned solvents.

  The amount of the solvent used can be such that the concentration of the compound (1-5) is 5 to 80% by weight, preferably 10 to 70% by weight.

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-80 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 8 hours.

  The starting compound (12) can be obtained as a commercial product.

  Specific examples of the compound (1) include compounds 1 to 40 shown in Table 1 described later.

(Synthesis Method 6)
The compound which is the compound (2) can be synthesized by reacting the compound (1-7) and the compound (13) in a solvent in the presence of a base, as shown in the following formula.

(Wherein R ⁷ , R ⁸ , X, Y and Z are as defined above.)

Examples of the base include triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium butoxide, sodium hydride, potassium carbonate, and sodium carbonate, with potassium carbonate being preferred.
Although the usage-amount of a base is 1-3 mol with respect to 1 mol of compound (1-7), Preferably it is 1.8-2.2 mol.

A commercial item can be used for a raw material compound (13).
Although the molar ratio of the raw material compound (13) can be arbitrarily set, it is usually in a ratio of 0.8 to 1.1 mol with respect to 1 mol of the compound (1-7).

The type of the solvent is not particularly limited as long as it does not directly participate in this reaction, and examples thereof include amides such as N, N-dimethylformamide and N, N-dimethylacetamide, acetone and methyl ethyl ketone. And ketones and mixtures of the above solvents.
The amount of the solvent used can be such that the concentration of the compound (1-7) is 5 to 80% by weight, but preferably 10 to 70% by weight.

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-80 degreeC.
The reaction time varies depending on the concentration and temperature, but is usually 0.5 to 8 hours.

  Specific examples of the compound (2) include compounds 41 to 47 shown in Table 5 described later.

[Antimicrobial effect]
Examples of the bacteria in which the antibacterial effect is recognized in the compounds (1) and (2) of the present invention include E. coli, yeast (Saccharomyces. Ceribiciae AKU4103), and black mold (Aspergillus niger).

The antibacterial agent of this invention contains at least 1 sort (s) or more as an active ingredient among the group which consists of a compound (1) and a compound (2).
The compound (1) and the compound (2) can be used alone, respectively, but usually, in accordance with a conventional method, a solid diluent, a liquid diluent, a surfactant, a dispersant, a fixing agent, and the like are blended. , Powders, emulsions, fine granules, granules, wettable powders, granular wettable powders, aqueous suspensions, oily suspensions, emulsions, solubilized preparations, oils, microcapsules, aerosols, etc. It is preferable to use it after adjusting.

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), 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 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, and polyoxyethylene alkylamine.

In the production of this agent, the solid and liquid diluents, surfactants, dispersants and fixing agents described above can be used alone or in appropriate combination depending on the purpose.
When the compound (1) or / and (2) of the present invention is formulated, the concentration of the compound (1) or / and (2) is usually 1 to 50% by weight in the emulsion and usually 0.3 to 25 in the powder. 1% to 90% by weight, usually 0.5 to 10% by weight for granules, 0.5 to 40% by weight for suspensions, and usually 1 for emulsions. -30% by weight, usually 0.5-20% by weight for solubilized preparations, 0.1-5% by weight for aerosols and 0.5-20% by weight for microcapsules.
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.

Example 1 [Synthesis of Compound]
(1) Synthesis of 2-mercapto-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinic acid amide (Compound (1) represented by Compound No. 1)
2-mercaptonicotinic acid (7.8 g) and 2- (4-trifluoromethoxyphenoxy) ethylamine (11.0 g) were dissolved in dichloromethane (300 ml), and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide was dissolved. Hydrochloric acid salt (8.6 g) was added and stirred at room temperature for 6 hours.
After completion of the reaction, water was added to the reaction mixture, and the organic layer was separated, washed successively with hydrochloric acid having a concentration of 0.2 mol / L (liter), a saturated aqueous sodium hydrogen carbonate solution and 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 silica gel column chromatography (Wakogel C-200, developing solvent: n-hexane: ethyl acetate = 2: 1). 9.0 g of the target product of pale yellow cotton-like crystals was obtained.

  m. p. 172 to 174 ° C

¹ H-NMR (CDCl ₃ ) δ: 3.88 to 3.94 (2H, q),
4.16 to 4.19 (2H, q), 6.90 to 7.22 (5H, m),
7.65 to 7.67 (1H, m), 8.80 to 8.81 (1H, d),
10.98 (1H, s), 11.82 (1H, s)

(2) Synthesis of N- (2- (4-trifluoromethoxyphenyl) ethyl) isonicotinamide (Compound (1) represented by Compound No. 33)
Isonicotinic acid ethyl ester (1.5 g) and 2- (4-trifluoromethoxyphenyl) ethylamine (2.1 g) were dissolved in toluene (50 ml), and a sodium methoxide methanol solution (0.8 g) having a concentration of 28% by weight. And heated to reflux for 6 hours.
After completion of the reaction, water was added to the reaction mixture, toluene was distilled off under reduced pressure, and neutralized with dilute hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized with ethanol-water to obtain 2.8 g of the desired product as colorless powder crystals.

  m. p. 120-121 ° C

¹ H-NMR (CDCl ₃ ) δ: 2.94 to 2.98 ((2H, q),
3.69-3.76 (2H, q), 6.30 (1H, s),
7.17-7.26 (4H, m), 7.51-7.53 (2H, q),
8.70-8.72 (2H, q)

(3) Synthesis of 2-methylthio-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide [Compound (1) represented by Compound No. 3]
2-Mercapto-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide (1.6 g) was dissolved in acetone (30 ml), potassium carbonate (1 g) was added, and methyl iodide was stirred with stirring. (0.8 g) was added and heated to reflux for 4 hours.
After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The resulting organic layer 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 residue was purified by silica gel column chromatography (Wakogel C-200, developing solvent: n-hexane: ethyl acetate = 2: 1) to give a colorless powder. 1.1 g of the target product in the form of a crystal was obtained.

  m. p. 91-93 ° C

¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s),
3.82 to 3.88 (2H, q), 4.13 to 4.16 (2H, q),
6.85 to 7.16 (5H, m), 7.78 to 7.81 (1H, q),
8.49-8.51 (1H, q)

(4) Synthesis of 2-methylsulfonyl-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinic acid amide (Compound (1) represented by Compound No. 4) and 2-methylsulfinyl-N- (2 Synthesis of-(4-trifluoromethoxyphenoxy) ethyl) nicotinamide (Compound (1) represented by Compound No. 5)
2-Methylthio-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide (1.6 g) was dissolved in acetone (30 ml) and potassium peroxymonosulfate (OXONE) (2.6 g) was dissolved in water. A solution dissolved in (20 ml) was added, and the mixture was stirred at room temperature for 3 hours.
After completion of the reaction, acetone was distilled off from the reaction mixture under reduced pressure, the residue was extracted with ethyl acetate, and the resulting organic layer 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 residue was subjected to silica gel column chromatography (Wakogel C-200, developing solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate: ethanol = 3: 2). ) To obtain 0.9 g of a compound (1) represented by Compound No. 4 which is a methylsulfonyl compound from the first fraction as colorless powdery crystals, and from Compound No. 5 which is a methylsulfinyl compound from the next fraction. 0.5 g of the compound (1) shown was obtained as a pale yellow rod.

Compound (1) represented by Compound No. 4:
m. p. 97-98 ° C
Mass spectrometry: CI-MS m / e = 405 (m + 1)

Compound (1) represented by Compound No. 5:
Mass spectrometry: CI-MS m / e = 389 (m + 1)

(5) Synthesis of N- (2- (4-trifluoromethoxyphenoxy) ethyl) -1N-ethyl-2-pyridone-3-carboxylic acid amide (Compound (1) represented by Compound No. 11) and 2-ethoxy Synthesis of —N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide (Compound (1) represented by Compound No. 12)
2-Hydroxy-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide (1.7 g) is dissolved in N, N-dimethylformamide (30 ml), potassium carbonate (1 g) is added, and the mixture is stirred. To the bottom was added ethyl iodide (1.2 g), and the mixture was heated to reflux for 6 hours.
After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The resulting organic layer 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 residue was purified by silica gel column chromatography (Wakogel C-200, developing solvent: n-hexane: ethyl acetate = 4: 1). From the fraction, 0.2 g of Compound (1) represented by Compound No. 11 was obtained as colorless powdery crystals, and 1.4 g of Compound (1) represented by Compound No. 12 was obtained from the next fraction as a pale yellow bowl.

Compound (1) represented by Compound No. 11:
m. p. 97-98 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.42-1.46 (3H, t),
3.88 to 3.93 (2H, q), 4.13 to 4.16 (2H, t),
4.50 to 4.57 (2H, q), 6.89 to 7.19 (5H, m),
8.24 (3H, m), 8.51 to 8.54 (2H, q)

Compound (1) represented by Compound No. 12:
m. p. 67-69 ° C
¹ H-NMR (CDCl ₃ ) δ: 1.38 to 1.42 (3H, t),
3.82 to 3.87 (2H, q), 4.05 to 4.16 (4H, m),
6.40-6.45 (1H, t), 6.90-7.28 (4H, m),
7.51 to 7.54 (1H, t), 8.50 to 8.53 (1H, q),
10.17 (1H, s)

(6) Synthesis of Other Compound (1) in Table 1 According to the methods of (4) and (5) above, the other compound (1) in Table 1 was synthesized.
The compounds (1) synthesized by the above method and their physical properties are shown in Tables 1-4.

(7) N- (2- (4-trifluoromethoxyphenoxy) ethyl) -9-trifluoromethyl-dipyrido [2,3-b: 3 ′, 2′-f] 1,4-thiazepine-6 (5H ) -One synthesis [compound (2) represented by compound number 41]
2-mercapto-N- (2- (4-trifluoromethoxyphenoxy) ethyl) nicotinamide (04 g) and 2,3-dichloro-5-trifluoromethylpyridine (0.3 g) dissolved in acetone (30 ml) Potassium carbonate (0.3 g) was added, and the mixture was heated to reflux with stirring for 6 hours.
After completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The resulting organic layer 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 residue was purified by silica gel column chromatography (Wakogel C-200, developing solvent: n-hexane: ethyl acetate = 1: 1) to give a colorless powder. 0.58 g of the target product in the form of crystals was obtained.

  m. p. 123-124 ° C

¹ H-NMR (CDCl ₃ ) δ: 4.35 to 4.42 (2H, q),
4.72 to 4.85 (2H, q), 6.45 to 7.16 (4H, m),
7.30-7.38 (1H, m), 8.00-8.05 (1H, q),
8.20 to 8.25 (1H, d), 8.51 to 8.53 (1H, q),
8.65 to 8.70 (1H, d)

  Mass spectrometry: CI-MS m / e = 502 (m + 1)

(8) Synthesis of other compound (2) in Table 5 Other compounds (2) in Table 5 were synthesized according to the method of (7) above.
Table 5 shows the compound (2) synthesized by the above method (particularly, the compound (2) in which R ⁸ is a trifluoromethyl group (described as a compound (2-1) in the table)) and physical properties thereof.

Example 2 [Efficacy test]
[Materials and methods]
1) Sample 47 compounds shown in Tables 1 to 5 were used.
Each compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 100,000 mg / L (liter) solution.

2) Preparation of medium-E. coli and yeast (Saccharomyces. Ceribiciae)
Escherichia coli uses LB liquid medium and yeast uses MY medium.
(Final drug concentration 500 mg / L) was added to prepare a drug-added medium.
・ Black mold (Aspergillus niger)
After melting 10 mL of PDA medium, 50 μL of drug solution (final drug concentration (concentration of compound (1) or (2)) 500 mg / L) was added and stirred before agar solidified, and a test plate was prepared.

3) Antibacterial test-Escherichia coli and yeast After growth in liquid culture overnight, add 20 μL of the medium containing the cells to the drug-added medium,
Swivel culture was performed overnight at 100 rpm. 50 μL of medium is collected and fresh medium without drug 1
After transferring to 0 μL and culturing for 1 day, 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 The PDA medium (thickness: about 1 mm) containing about 1 × 10 ⁵ black mold spores / mL was cut into about 1.5 mm squares with a scalpel and used as an inoculum. Place 2 pieces of inoculum on the test plate, 2
Cultured at 5 ° C. for 4 days. The diameter of the bacterial flora formed by extending mycelia from the culture and inoculum 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%

As a result, Compound Nos. 9, 34 and 37 showed the effect of A against E. coli.
For yeast, compound numbers 18, 23, 34 and 37 showed the effect of A.
For black mold, compound number 23 shows the effect of A, compound numbers 4, 12, 13, 14, 33 and 39 show the effect of B, and compound numbers 5, 6, 9 and 41 show the effect of C Indicated.

Claims (4)

A 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the following formula (1):

(In the formula, A represents a heterocyclic ring containing 1 to 2 nitrogen atoms in the ring represented by the following formulas (A-1 to A-5), and Y represents an oxygen atom or a single bond. )

(In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a mercapto group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, a 2-pyridyloxy group, or a 2-pyridylthio group. In the case of a 2-pyridyloxy group and a 2-pyridylthio group, the 3-position carbon atom and the nitrogen atom of the amide bond in the above formula (1) may combine to form a ring. R represents an integer of 1 to 3, R ² , R ³ , R ⁵ and R ⁶ represent a hydrogen atom or a lower alkyl group, and R ⁴ represents a hydrogen atom, a hydroxyl group or a lower alkyl group. 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the following formula (2).

(Wherein R ⁷ represents a hydrogen atom, a halogen atom or a lower alkyl group, R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower haloalkyl group, X represents an oxygen atom or a sulfur atom, Y represents Same as above.)   An antibacterial agent comprising a 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the formula (1) according to claim 1 as an active ingredient. An antibacterial agent comprising a 4-trifluoromethoxyphenyl (oxy) ethylamine derivative represented by the formula (2) according to claim 2 as an active ingredient.