JP2000229949A - Nitrogen-containing heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an antimycotic agent or agricultural/horticultural germicide. SOLUTION: This new compound is a compound of formula I [A is N or CH; R1 and R2 are each a halogen; R3 is a (substituted) phenyl, (substituted) pyridyl or (substituted) 3-8C cycloalkyl; and R4 is H, cyano, a halogen, 1-6C alkyl or the like], e.g. 4-(2,6-dichlorophenyl)-2-(4-chlorophenylamino)-6- methylthiopyrimidine. The compound of formula I is obtained by reaction between a compound of formula II (R4' is a halogen, 1-6C alkoxycarbonyl or the like; and Y is an eliminable group such as an alkylthio) and a compound of the formula: H2N(NH=)C-NHR3.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a nitrogen-containing heterocyclic derivative.

[0002]

BACKGROUND OF THE INVENTION Compounds similar to the compounds of the present invention include:
VT Klimko et.al., Zhurnal Obshckei Khimii, 3
0 1258-64 (1960) describes a method for synthesizing 2,4-substituted pyrimidines and physical properties of 2-phenylamino-4-phenylpyrimidine, but does not describe any physiological activity. Also, A. Kreutzberger & J. Gillessen, Arch. Pharm.,
318 (4), 370-4 (1985), A. Kreutzberger & J. Gilless
en, J. Heterocycl. Chem., 22 (1), 101-3 (1985)
Synthesis of the following compounds and grape downy mildew ( Plasmopara Vi
ticola ) is described as Antimycotic agents.

[0003]

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[0004]

The present invention relates to an antifungal agent,
An object of the present invention is to provide a nitrogen-containing heterocyclic derivative useful as an agricultural and horticultural fungicide.

[0005]

According to the present invention, there is provided a compound represented by the general formula (1):

[0006]

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[In the formula, A represents N or CH. R ¹
And R ² each independently represent a halogen atom. R ³ represents (nitro group, halogen atom, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _1-6
Phenyl group which may be substituted with ( _1-6 haloalkoxy group), (nitro group, halogen atom, C _1-6 alkyl group, C
Pyridyl group which may be substituted with _1-6 haloalkyl group, C _1-6 alkoxy group, C _1-6 haloalkoxy group) or C _3- which may be substituted with (halogen atom or C _1-6 alkyl group). Represents an ₈ cycloalkyl group. R ⁴ represents a hydrogen atom, a cyano group, a halogen atom, a C _1-6 alkyl group,
_1-6 alkoxy group, C _1-6 alkoxycarbonyl group, C
_1-6 alkylthio group, C _1-6 alkylsulfinyl group,
Represents a C _1-6 alkylsulfonyl group or a C _1-6 alkyl mono- or di-substituted an amino group which may be a group. ] It is a nitrogen-containing heterocyclic derivative represented by these.

In the present invention, R ¹ and R ² each independently represent a halogen atom such as chlorine, bromine, fluorine and iodine.

R ³ represents a halogen atom such as chlorine, fluorine, bromine or iodine, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl; , Dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,
C such as 1-difluoroethyl and pentafluoroethyl
_1-6 haloalkyl group, methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy group such as butoxy, trifluoromethoxy, difluoromethoxy, trifluoromethoxy, substituted by C _1-6 haloalkoxy groups) such as chloromethoxy Phenyl group or pyridyl group (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), halogen atom such as chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- Represents a C _3-8 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl which may be substituted by a C _1-6 alkyl group such as butyl and t-butyl;

R ⁴ is a hydrogen atom, a cyano group, a halogen atom such as chlorine, fluorine, bromine or iodine, methyl,
A C _1-6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
Methoxy, ethoxy, propoxy, isopropoxy, C _1-6 alkoxy group such as butoxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, C _1-6 alkoxycarbonyl group such as t- butoxycarbonyl,
A C _1-6 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, methylsulfinyl, ethylsulfinyl,
C such as propylsulfinyl, isopropylsulfinyl, butylsulfinyl, t-butylsulfinyl, etc.
_1-6 alkylsulfinyl group, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, C _1-6 alkylsulfonyl groups such as t- Buchirusuruhoni, methyl, C, such as ethyl
Represents an amino group that may be mono- or di-substituted by a _1-6 alkyl group.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The main method for producing the compound of the present invention will be described below.

Production method 1 When A = CH

[0013]

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(Wherein R ¹ , R ² and R ³ have the same meanings as described above, and R ⁴ ′ is a halogen atom, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a C _{1- 6}
Y represents an amino group which may be mono- or di-substituted by an alkyl group, and Y represents a leaving group such as an alkylthio group. )

This method comprises the steps of reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) or a salt thereof.
The compound of the present invention represented by the general formula (1-1) is obtained by reacting in a conventional manner.

The solvent is not particularly limited as long as it is a solvent inert to the reaction. Examples of the solvent include ethers such as tetrahydrofuran (THF) and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene and xylene. Hydrogens,
Halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, esters such as ethyl acetate and butyl acetate, alcohols such as ethanol, t-butanol and isopentyl alcohol, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide ( DMS
O), sulfolane, pyridine and the like can be used. As the base, for example, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undece-
Examples thereof include amines such as 7-ene (DBU) and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and sodium hydroxide. The reaction temperature is from 0 ° C. to about the boiling point of the solvent, preferably from 0 to 1
00 ° C.

[0017] R ⁴ is, R ⁴ 'compounds other than the by conventional synthetic chemistry methods, R ^4' substituent, an object - a hydrogen atom, a cyano group, C _1-6 alkyl groups, C _1- It can be obtained by converting into a ₆ alkoxy group, a C _1-6 alkylsulfinyl group, a C _1-6 alkylsulfonyl group and the like.

Manufacturing method 2 When A = N

[0019]

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Wherein R ¹ , R ² , R ³ and R ⁴ are
Represents the same meaning as above. )

In this method, the compound represented by the general formula (6) and the compound represented by the general formula (5) are reacted in the absence of a solvent or in a solvent, if necessary, in the presence of a base. The compound of the present invention represented by the general formula (1-3) is obtained.

In the present invention, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment. The structure of the compound of the present invention was determined from the results of analysis such as MASS, NMR and IR.

(Antifungal agent) The compound of the present invention exhibits excellent antibacterial activity. Further, some of the compounds of the present invention exhibit an antihyperlipidemic effect. The antifungal agent containing the compound of the present invention is useful as a therapeutic agent for mycosis involving fungi such as mold and yeast included in humans, and for treating mammals. Ointments, emulsions,
Suspension, powder, liquid, tincture, aerosol, tablet,
Capsules and elixirs can be used in various dosage forms similar to known antifungal agents. The dose is
It may vary depending on the severity of the disease, the weight of the patient and other factors recognized by those skilled in the art. The compounds of the present invention are mixed with physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavoring agents and the like in the usual unit dosage form. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

(Agricultural and Horticultural Fungicide) The compound of the present invention is also useful as an agricultural and horticultural fungicide. When the compound of the present invention is applied as a pesticide, it can be used in a pure form without adding other components, and can be in the form of a general pesticide for use as a pesticide, that is, wettable powders, granules, Powder, emulsion,
It can also be used in the form of a water solvent, a suspending agent and the like. As an additive and a carrier, when a solid agent is intended,
Vegetable powders such as soy flour and flour, diatomaceous earth, apatite, gypsum, talc, pyrophyllite, clay, mineral oil, and vegetable oils are used. When a liquid dosage form is intended, kerosene, mineral oil, petroleum, solvent naphtha, xylene, cyclohexane, cyclohexanone, D
MF, DMSO, alcohol, acetone, mineral oil, vegetable oil, water, etc. are used as solvents. In these preparations, a surfactant can be added, if necessary, to obtain a uniform and stable form. The wettable powders and emulsions thus obtained are used as a suspension or emulsion by diluting to a predetermined concentration with water, and the powders and granules are used by spraying them on plants as they are.

[0025]

Next, the present invention will be described more specifically with reference to examples. However, this does not limit the present invention in any way.

Example 1 Preparation of 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-methylthiopyrimidine

[0027]

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1,1-bismethylthio-3- (2,6-dichlorophenyl) propene-3 in 50 ml of DMF
Dissolve 2.8 g of potassium carbonate, 1.8 g of potassium carbonate,
Subsequently, 2.1 g of 4-chlorophenylguanidine nitrate was added and reacted at 70 to 80 ° C. for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the obtained residue was separated and purified on a silica gel column to give the desired product, 4- (2,6-dichlorophenyl) -2-.
1.8 g of (4-chlorophenylamino) -6-methylthiopyrimidine were obtained. m. p. 120-122 ° C

Example 2 Preparation of 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) pyrimidine

[0030]

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4- (2,6-dichlorophenyl) -2-
1.8 g of (4-chlorophenylamino) -6-methylthiopyrimidine was dissolved in 50 ml of ethyl alcohol.
To this, 3.2 g of nickel chloride hexahydrate was added, and 1.5 g of sodium borohydride dissolved in 10 ml of a 40% aqueous NaOH solution was added dropwise over 10 to 20 minutes with stirring at room temperature. After the completion of the dropwise addition, the mixture was refluxed for 5 minutes. After the reaction mixture was filtered while hot, ethyl alcohol was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then ethyl acetate was distilled off under reduced pressure. The obtained residue was separated and purified on a silica gel column,
4- (2,6-dichlorophenyl) -2- (4
0.32 g of -chlorophenylamino) pyrimidine were obtained.
m. p. 183-184 ° C

Example 3 Preparation of 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-methylsulfonylpyrimidine

[0033]

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4- (2,6-dichlorophenyl) -2-
1.6 g of (4-methylphenylamino) -6-methylthiopyrimidine was dissolved in 30 ml of chloroform, and 2 g of m-chloroperbenzoic acid was added thereto. 30
After stirring at room temperature for one minute, the precipitated m-chlorobenzoic acid was filtered off, and the chloroform layer was washed with an aqueous solution of sodium thiosulfate. Then, after washing with water, drying over anhydrous magnesium sulfate and filtration, the chloroform solution was distilled off under reduced pressure to give 4-
1.3 g of (2,6-dichlorophenyl) -2- (4-methylphenylamino) -6-methylsulfonylpyrimidine
I got m. p. 65-70 ° C

Example 4 Preparation of 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-methoxypyrimidine

[0036]

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4- (2,6-dichlorophenyl) -2-
0.5 g of (4-chlorophenylamino) -6-methylsulfonylpyrimidine was dissolved in 20 ml of methanol.
1.3 g of sodium methoxide was added thereto, followed by stirring at room temperature. After 2 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then ethyl acetate was distilled off under reduced pressure. The resulting residue was separated and purified on a silica gel column to give the desired product 4-
0.1 g of (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-methoxypyrimidine was obtained.
m. p. 102-103 ° C

Example 5 Preparation of 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-cyanopyrimidine

[0039]

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4- (2,6-dichlorophenyl) -2-
0.6 g of (4-chlorophenylamino) -6-methylsulfonylpyrimidine was dissolved in 30 ml of DMSO, 0.26 g of sodium cyanide was added, and the mixture was reacted at 70 to 80 ° C. for 1 hour. The reaction solution cooled to room temperature was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then ethyl acetate was distilled off under reduced pressure. The obtained residue was separated and purified by a silica gel column to obtain 0.1 g of the desired product, 4- (2,6-dichlorophenyl) -2- (4-chlorophenylamino) -6-cyanopyrimidine. m. p. 185-190 ° C

Example 6 Preparation of 2- (4-chlorophenylamino) -4- (2,6-dichlorophenyl) -6-methyl-1,3,5-triazine

[0042]

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0.5 g of 2-chloro-4- (2,6-dichlorophenyl) -6-methyl-1,3,5-triazine
To the mixture was added 4-chloroaniline (1.2 g), and the mixture was heated at 180 ° C. without a solvent. One hour later, the reaction solution which had been returned to room temperature was poured into ice water, and extracted with ethyl acetate. The reaction mixture was washed with 2N HCl.
After washing, it was washed with water, dried over anhydrous magnesium sulfate, and filtered, and then ethyl acetate was distilled off under reduced pressure. The obtained residue is separated and purified by a silica gel column, and the target substance, 2- (4-chlorophenylamino) -4- (2,6-dichlorophenyl) is obtained.
0.4 g of -6-methyl-1,3,5-triazine was obtained.
m. p. 134-136 ° C

Table 1 shows typical examples of the compounds of the present invention including the above Examples.

[0045]

[Table 101]

[0046]

[Table 102]

[0047]

[Table 103]

[0048]

Next, the biological activity of the compound of the present invention will be described.

Test Example 1 Antibacterial Activity The antibacterial activity was examined by a liquid culture method using a 96-well microplate. Compounds dissolved in DMSO were diluted so that the final concentration of DMSO did not exceed 1%. For Trichophyton [ T. mentagrophytes (sometimes abbreviated as Tm)], use a Sabouraud glucose (SG) medium, inoculate a spore suspension (200,000-500,000 spores / ml), and culture for 7 days did. Kidney gray mold [ Botr
ytis cinerea (sometimes abbreviated as Bc)], a spore suspension (200,000-500,000 spores / ml) was inoculated in a potato dextrose (PD) medium and cultured for 3 days. The absorbance at 450 nm was measured with a microplate photometer, and the concentration when the absorbance was less than 0.02 was determined by MIC.
(μg / ml). EC ₅₀ is the control 50
The value showing% absorbance was determined from the graph. Table 2 shows the results.

[0050]

[Table 2]

Test Example 2 Squalene Epoxidase Inhibitor Botrytis cinerea 2.7
× 10 ⁵ spores / ml in 50 ml PD medium at 25 ° C, 1
The cells were cultured with shaking at 100 rpm for 8 hours. The mycelial pellet collected by centrifugation was suspended in 50 ml of a PD medium, and 1.9 ml was dispensed into a test tube. 10 μl of a DMSO solution was added, and the cells were cultured with shaking at 28 ° C. for 30 minutes. Thereafter, 100 μl of 1 μCi sodium ^14C- acetate solution was added, and the cells were cultured with shaking at 30 ° C. for 2 hours. After completion of the reaction, the cells were collected by centrifugation, and 60% ethanol / 15%
5 ml of an aqueous solution of KOH was added, and the mixture was saponified at 80 ° C. for 2 hours, and the unsaponifiable lipid was extracted twice with 4 ml of hexane.
After concentrating hexane, it was developed by TLC (heptane-isopropyl ether-acetic acid) to prepare a radioautogram. The darkened part of TLC was cut out, extracted with 5 ml of methanol, and measured with a liquid scintillation counter.
Each fraction was quantified. Squalene accumulation rate (%)
Was calculated from squalene ÷ total unsaponifiable lipid × 100. The results are shown in Table 2.

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Claims (1)

[Claims] 1. A compound of the general formula (1) [Wherein, A represents N or CH. R ¹ and R
² represents a halogen atom each independently. R
³ represents (nitro group, halogen atom, C _1-6 alkyl group,
A phenyl group which may be substituted with a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, (nitro group, halogen atom, C _1-6 alkyl group, C _1-6 haloalkyl Group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group) or a pyridyl group optionally substituted with a (halogen atom or C _1-6 alkyl group)
Represents a _3-8 cycloalkyl group. R ⁴ is a hydrogen atom, a cyano group, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxycarbonyl group, a C _1-6 alkylthio group, a C _1-6 alkylsulfinyl group, represents a C _1-6 alkylsulfonyl group or a C _1-6 alkyl mono- or di-substituted an amino group which may be a group. ] The nitrogen-containing heterocyclic derivative represented by these.