JPH08151363A - New salicylic acid derivative and salicylic acid-based compound and antifungal agent - Google Patents

Abstract

PURPOSE: To obtain a new compound exhibiting selectively excellent antifungal activity against fungi, hardly exhibiting toxicity to human and animals, scarcely having adverse effect, safe and useful as an antifungal agent applicable to a wide range of mycotic infections. CONSTITUTION: This compound is expressed by formula I (R<1> is H or an alkoxyalkyl; R<2> is a lower alkoxy, an amino, etc.; X is a halogen or a halogen- substituted phenyl; Y is a halogen or H), e.g. 3,3-dichloro-4-ethyl-1-(3- methoxymethoxy-4-methoxycarbonylphenyl)-2-pyrrolidinone. The compound is preferably obtained by reductively subjecting a salicylic acid-based compound of formula II (Z is Cl or Br) to cyclization reaction with a cyclization agent such as tributyltinhydride, Furthermore, the compound of formula II is preferably obtained by reacting, e.g. an alkyl 4-amino-2-alkoxyalkoxybenzoate with an alkyl 1-halogenated-2-butene to afford a new compound of formula III and reacting the compound with trichloroacetyl chloride, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel salicylic acid derivative, a salicylic acid compound which is an intermediate for producing the salicylic acid derivative, and an antifungal agent containing the salicylic acid derivative as an active ingredient. More specifically, the present invention relates to a novel salicylic acid derivative which can be suitably used as a highly useful antifungal agent with few side effects and can be applied to a wide range of fungal diseases, an intermediate thereof, and an antifungal agent containing the derivative as an active ingredient. .

[0002]

BACKGROUND OF THE INVENTION In recent years, fungal diseases are increasing worldwide due to widespread use of broad-spectrum antibiotics, steroid hormones, anticancer agents, immunosuppressants, etc. It has been desired to develop an antifungal agent which has less side effects than the polyene macrolide compounds and imidazole compounds used as fungal agents, can be applied to a wide range of mycoses, and is highly useful.

Therefore, the present inventors have few side effects,
As a result of intensive research to develop a more useful antifungal agent that can be applied to a wide range of fungal diseases, a novel salicylic acid derivative, which is completely different from previously known antifungal agents, has been investigated. The inventors have found that they have high activity against fungi and have completed the present invention.

The following compounds (1) to (4) have been heretofore known, and it has been taught that these compounds are useful as herbicides. Compounds represented by the following general formula described in JP-A-4-154760:

[0005]

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(In the formula, A represents a fluorine atom or a chlorine atom, X represents the same or different and is a fluorine atom, a chlorine atom or a hydrogen atom substituted at the 3rd, 4th or 5th position, and n represents 1 or 2) A compound represented by the following general formula described in JP-A-4-282360:

[0007]

[Chemical 6]

(In the formula, X represents a bromine atom, a chlorine atom or a cyano group substituted in the 3-position, and a fluorine atom substituted in the 3-position, the 4-position, or the 3-position and the 5-position. A compound represented by the following general formula described in JP-A-5-170607:

[0009]

[Chemical 7]

(In the formula, X represents a fluorine atom substituted in the 3-position, a chlorine atom, a bromine atom, or a fluorine atom substituted in the 3-position and 4-position or the 3-position and 5-position.) Compounds represented by the following general formula described in JP-A-5-125042:

[0011]

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(Wherein R represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkoxy group having 1 to 4 carbon atoms, a cyano group, and an alkylthio group having 1 to 4 carbon atoms, and n
Represents an integer of 1 to 5. When n is 2 or more, R may be the same or different. X represents a hydrogen atom or a halogen atom, and Y represents a halogen atom. ) A compound represented by the following general formula described in U.S. Pat. No. 4,956,006:

[0013]

[Chemical 9]

(R ₁ represents a methoxyiminomethyl group, methoxyimino-1-ethyl, etc., R ₂ represents a phenyl group substituted with a halogen atom or a trifluoromethyl group, and R ₃ represents an alkyl group or an alkenyl group. , X and Y represent a hydrogen atom or a halogen atom, Z represents an oxygen or sulfur atom, and m and n represent 0 or 1.)

[0015]

SUMMARY OF THE INVENTION The present invention is intended to solve the problems associated with the prior art as described above, and has a low toxicity and side effects on humans and livestock, and is applicable to a wide range of fungal diseases. It is an object of the present invention to provide a fungal agent and a novel compound that can be suitably used for such applications.

Another object of the present invention is to provide a salicylic acid compound which is a novel intermediate for the production of such a novel compound.

[0017]

SUMMARY OF THE INVENTION The novel salicylic acid derivative according to the present invention is represented by the following general formula (1).

[0018]

[Chemical 10]

[In the formula (1), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y represents Represents a halogen atom or a hydrogen atom. ] The novel salicylic acid compound (intermediate) according to the present invention is
It is represented by the following general formula (2) and is suitably used for producing the novel salicylic acid derivative represented by the above formula (1).

[0020]

[Chemical 11]

In the formula (2), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y Represents a halogen atom or a hydrogen atom, and Z represents a chlorine atom or a bromine atom. The novel salicylic acid compound (intermediate) represented by the above formula (2) according to the present invention is produced by using the novel salicylic acid compound (intermediate) represented by the following general formula (3),
It is preferably used for producing a novel salicylic acid derivative represented by the above formula (1).

[0022]

[Chemical 12]

[In the formula (3), R ¹ represents a hydrogen atom or an alkoxyalkyl group, and R ² represents a lower alkoxy group, an amino group or a hydroxyl group. The antifungal agent according to the present invention contains the salicylic acid derivative represented by the general formula (1) as an active ingredient.

According to the present invention, there is provided a novel compound which has less toxicity and side effects on humans and domestic animals, and can be suitably used as an antifungal agent against a wide range of fungi. Moreover, according to this invention, the novel intermediate body which can be used for manufacture of such a novel compound is provided.

[0025]

DETAILED DESCRIPTION OF THE INVENTION The salicylic acid derivative according to the present invention, a salicylic acid compound which is an intermediate for producing the salicylic acid derivative, and an antifungal agent containing the salicylic acid derivative as an active ingredient are specifically described below. explain.

[Salicylic Acid Derivative and Its Use] The novel salicylic acid derivative according to the present invention has the following general formula (1):
It is represented by.

[0027]

[Chemical 13]

[In the formula (1), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y represents Represents a halogen atom or a hydrogen atom. In the general formula (1), when R ¹ is an alkoxyalkyl group, the number of carbon atoms is usually 2 to 4, and examples of such an alkoxyalkyl group include an ethoxymethyl group, a methoxyethyl group, Examples thereof include ethoxyethyl group.

When R ² is a lower alkoxy group, it usually has 1 to 6 carbon atoms, and examples of such a lower alkoxy group include a methoxy group,
Examples thereof include ethoxy group, n-propoxy group, isopropoxy group, butoxy group, pentyloxy group and phenoxy group. Examples of the halogen atoms X and Y include chlorine atom and fluorine atom.

Specific examples of the novel salicylic acid derivative represented by the general formula (1) include those shown in Table 1. Of these, the salicylic acid derivative represented by the number (1) -1 is shown. : [3,3-dichloro-4-ethyl-1- (3-
Methoxymethoxy-4-methoxycarbonylphenyl) -2-
Pyrrolidinone] is particularly preferably used as the antifungal agent. The compound numbers are also referred to in the following examples and test examples. The salicylic acid-based compound (intermediate) as a starting compound corresponding to the compound number “(1) -A _{(A: 1-11)} ” which is a salicylic acid derivative is “(2) -A
_{(A: 1-11)} ", etc., for example," (1) "
The salicylic acid compound corresponding to "-1" is "(2) -1"
And the like (however, except for the compounds described in Table 3). In addition, compound (1) shown in each of the following tables,
The structures of the compound (2), the compound (3) and the like are determined from the measurement results of NMR and mass spectrum (MS), and are identified by measuring the refractive index (n _D ²³ ) and the melting point.

The novel compound represented by the general formula (1) has a strong antibacterial effect, especially against fungi,
It is preferably used as an antifungal agent. Among such compounds represented by the general formula (1), in particular, "3,3-dichloro-4-ethyl-1- (3-methoxymethoxy) represented by compound number (1) -1 in the table is shown. A composition containing "-4-methoxycarbonylphenyl) -2-pyrrolidinone" as an active ingredient is suitably used in the pharmaceutical field as an antifungal agent.
This antifungal agent can take various dosage forms such as a liquid agent, an ointment, and a cream, and various components such as those contained in ordinary antifungal agents may be blended. Such various components include, for example, petrolatum, liquid paraffin, stearyl alcohol, glyceryl monostearate, benzalkonium chloride, sodium benzoate, cetanol, propylene glycol, paraoxybenzoyl methyl, propyl paraoxybenzoate, sorbitan sesquioleate. , Polyoxy stearate, purified water and the like. Such antifungal agents are suitable for topical administration to the affected area.

The novel compound represented by the above-mentioned general formula (1) according to the present invention is not only used as such an antifungal agent, but may be optionally blended with other components to be used for veterinary medicine, seafood medicine. As a drug such as a food preservative, an agricultural fungicide, etc., it can be used in various dosage forms according to a conventional method.

Among various drugs containing such a novel salicylic acid derivative, the novel salicylic acid derivative according to the present invention is usually 0.05 to 10 though it varies depending on the kind of salicylic acid derivative, administration method and dosage form. It is desirable that the content is such that the content is wt%, preferably 0.1 to 5 wt%.

[0034]

[Table 1]

[ Synthesis of Novel Salicylic Acid Derivative (1)] Next, the following reaction formula [I] will be used to synthesize the novel compound (salicylic acid derivative (1)) represented by the general formula (1).
It will be described based on. Reaction formula [I]:

[0036]

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(In the formula, R ¹ , R ² , X, Y and Z are the same as above.) That is, the novel salicylic acid derivative represented by the above general formula (1) (hereinafter referred to as “salicylic acid derivative (1)”). Can also be produced by subjecting the acetamide derivative represented by the general formula (2) (salicylic acid compound (2)) to a reductive cyclization reaction. Examples of the cyclizing agent used in this reaction include trialkyltin hydrides, and tributyltin hydride, which is a compound of trialkyltin hydrides, is preferably used. In the present invention, such a cyclizing agent is used in an amount of 1 time mol (equal mol) or 2 times mol of the salicylic acid compound (2) as a raw material compound represented by the general formula (2). The above reaction [I] can be carried out in a one-step reaction. The above reaction [I] is
Generally, it is carried out in an aromatic solvent such as benzene, toluene or xylene. In such a reaction, α,
A radical generator such as α-azobisisobutyronitrile or benzoyl peroxide is added to the reaction raw material in a catalytic amount, and the reaction is preferably carried out at a temperature of 50 to 140 ° C., more preferably 80 to 110 ° C. Moreover, when performing such a reaction, light irradiation may be performed.

Further, for example, 3,3-dichloro-4-ethyl-1-
The novel salicylic acid derivative (1) according to the present invention such as (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -1) may be optionally mixed with a solvent such as methanol. Then, by adding hydrogen halide such as hydrochloric acid and reacting at a reflux temperature of 60 to 80 ° C. for about 5 to 30 minutes, the alkoxyalkoxy group bonded to the carbon atom at the third position of the phenyl group becomes an OH group. Substituted [3,3-dichloro-4-ethyl-1- (3-hydroxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No.
(1) -8)] and other salicylic acid derivatives (1) can also be produced.

Further, 3,3-dichloro-4-ethyl-1- (3-hydroxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -8) and other novel compounds according to the present invention can be used. If necessary, an alkali such as sodium hydroxide is added to the salicylic acid derivative (1) in the presence of a solvent such as methanol, and a hydrolysis reaction is carried out at a reflux temperature of 60 to 80 ° C. for about 30 to 60 minutes, The alkoxy group in the alkoxycarbonyl group bonded to the 4th carbon atom of the phenyl group was replaced with an OH group (that is,
Book of 3,3-dichloro-4-ethyl-1- (3-hydroxy-4-carboxyphenyl) -2-pyrrolidinone (compound No. (1) -9) etc. The novel salicylic acid derivative (1) according to the invention can also be produced.

[ Salicylic acid system for producing salicylic acid derivative
Synthesis of Compound (2)] The novel salicylic acid compound (2) [intermediate (2)] used in the above reaction formula [I] is obtained by the reaction formula [II] shown below. Reaction formula [II]:

[0041]

[Chemical 15]

(In the formula, R ¹ , R ² , X, Y and Z have the same meanings as described above.) In the above reaction formula [II], the acetamide derivative represented by the general formula (2) [compound (2 )] Is, for example, N- (2-butenyl
3-Methoxymethoxy-4-methoxycarbonylaniline (Compound No. (3) -1) and other N- (2- represented by the general formula (3)
It can be produced by reacting a butenyl) aniline derivative with a halogenated acetyl derivative represented by the general formula (4). Such a reaction [II] can be carried out in the presence or absence of a solvent,
When carrying out in the presence of a solvent, an inert solvent, an aprotic solvent or the like is used. Examples of the inert solvent include aromatics such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran and diethyl ether; esters such as ethyl acetate and butyl acetate; dichloromethane, chloroform and tetrachloride. Examples thereof include halogenated hydrocarbons such as carbon, and aromatic hydrocarbons such as dichlorobenzene are preferably used. Further, examples of the aprotic solvent include dimethylformamide and dimethylsulfoxide. You may use such a solvent 1 type or in combination of 2 or more types. The above reaction [II] can be carried out at any temperature, for example, 10 to 50 ° C.
It can proceed at a moderate temperature. Such reaction [II] may be carried out in the presence of a base such as triethylamine, pyridine, N, N-dimethylaniline, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate.

As the compound represented by the above formula (4),
Examples thereof include dichloroacetic acid chloride, trichloroacetic acid chloride, tribromoacetic acid bromide, chlorophenylchloroacetic acid chloride, and trichloroacetic acid chloride and dichloroacetic acid chloride are preferably used. N- (2-butenyl) aniline derivative represented by the above formula (3) [also referred to as salicylic acid compound (3) and compound (3)]. ] And its manufacturing method are mentioned later.

Specific examples of the salicylic acid compound (2) obtained by the above reaction formula [II] include those shown in Table 2 below. In addition, R ¹ in the table,
R ² , X, Y and Z have the same meanings as described above.

[0045]

[Table 2]

[ Salicylic acid system for producing salicylic acid derivative ]
Synthesis of Compound (3)] N- (2-butenyl) which is a novel salicylic acid compound (3) used in the above reaction formula [II]
Examples of the aniline derivative [intermediate (3)] include those shown in Table 3 below.

[0047]

[Table 3]

The novel salicylic acid compound (3) shown in Table 3 can be produced by using a commercially available raw material or by appropriately utilizing a known method (reference: JP-A-5-125042).

For example, N- (2-butenyl) -3-methoxymethoxy-4-methoxycarbonylaniline [Compound No. (3) -1], which is a novel intermediate, N- (2-butenyl) -3-methoxy Methoxy-4-ethoxycarbonylaniline [Compound No.
(3) -5] etc. N- (2-butenyl) -3-alkoxyalkoxy
-4-Alkoxycarbonylaniline is an alkyl 4-amino-2-alkoxyalkoxybenzoate such as methyl 4-amino-2-methoxymethoxybenzoate or ethyl 4-amino-2-methoxymethoxybenzoate, and 1-chloro- 2- 1 such as butene
Halogenated-2-butene is mixed with, for example, an aprotic solvent such as dimethylformamide described above in the presence of a base such as anhydrous potassium carbonate described above at a temperature of about 50 to 100 ° C, if necessary. It is obtained by reacting for about 4 to 24 hours.

Further, in Table 3, the novel salicylic acid compounds (3) -2, (3) -3, (3) -4 and the like are 4-amino-
It can be obtained by reacting 2-methoxymethoxybenzamide, methyl 4-amino-2-hydroxybenzoate and 4-amino-2-hydroxybenzoic acid as starting materials in the same manner as above.

In Table 3, salicylic acid compounds (3) -1 are salicylic acid derivatives (1) -1, (1)-
2, (1) -5, (1) -6, and salicylic acid derivative (1) -10 are used for the production, and salicylic acid compound (3) -2 is salicylic acid derivative (1) -3, (1)-
4, used in the production of (1) -7, the salicylic acid compound (3) -3 is used in the production of salicylic acid derivative (1) -8, and the salicylic acid compound (3) -4 is used in the salicylic acid derivative (1) -8. ) -9, and the salicylic acid compound (3) -5 is used for producing the salicylic acid derivative (1) -11.

[0052]

INDUSTRIAL APPLICABILITY According to the present invention, a novel salicylic acid derivative and a salicylic acid compound which is an intermediate for producing the salicylic acid derivative are provided. This novel salicylic acid derivative shows excellent antifungal activity selectively against fungi, shows almost no toxicity to humans and animals, and is used as a highly safe antifungal agent.

[0053]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by these examples.

[0054]

EXAMPLE 1 3,3-Dichloro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonyl-phenylene) -2- pyrrolidinone (Compound N
Preparation of o. (1) -1) [Preparation of compound of formula (1)] N- (2-butenyl) -N- in a 200 ml four-necked flask.
A mixture of 1.0 g of (3-methoxymethoxy-4-methoxycarbonylphenyl) -2,2,2-trichloroacetamide and 40 ml of toluene was added, and while stirring at reflux temperature, 1.45 g of tributyltin hydride (2 times Mol) and a catalytic amount of α, α-azobisisobutyronitrile (AIBN). After continuing stirring for 4 hours, the reaction mixture was concentrated by an evaporator, and the residue was purified by silica gel column chromatography using a hexane-ethyl acetate mixed solvent to give the title compound [3,3-dichloro-4- Ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -1)] 0.7
g (yield 74%, n _D ²³ = 1.5403) was obtained.
The NMR spectrum and mass spectrum measurement results are shown below.

NMR spectrum (CDCl ₃ , TMS standard, δ value): 1.24 (t, 3H), 3.52 (s, m, 5H), 3.88 (s, 3H),
5.28 (s, 2H), 7.14-7.40 (m.1H), 7.64-7.96 (m, 2H) Mass spectrum (MS): m / Z 340 (M ⁺ -C)
l), 264

[0056]

Example 2 Preparation of 3-chloro-3-fluoro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -10) [formula ( manufacturing of the compound of 1)
Build]
To 40 ml of benzene, 2.0 g of N- (2-butenyl) -N- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2,2-dichloro-2-fluorofucetamide was added and stirred at reflux temperature. However, 1.5 g of tributyltin hydride (1 mol) and α, α-azobisisobutyronitrile (AIB
N) A catalytic amount was added. After stirring for 1 hour, the reaction mixture solvent was concentrated with an evaporator, and the residue was mixed with hexane for 1 hour.
Purification by silica gel column chromatography using -ethyl acetate mixed solvent gave the title compound [3-chloro-3-fluoro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2 as a colorless oil. -Pyrrolidinone (Compound No. (1) -10)] 1.4 g (yield 72%, n _D
²³ = 1.5395) was obtained.

[0057]

Example 3 3,3-Dichloro-4-ethyl-1- (3-hydroxy-4-methoxycarbonylphenyl) -2 -pyrrolidinone (Compound No. (1)-
8) Preparation of 3,3-dichloro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -1) 2 in a 200 ml eggplant-shaped flask. .2g,
40 ml of methanol and 10 ml of 1N hydrochloric acid were added. 1
After stirring for 0 minutes at the reflux temperature, the precipitated crystals were recrystallized from methanol to give colorless crystals of the title compound [3,3-dichloro-4-ethyl-1- (3-hydroxy-4-methoxycarbonylphenyl). ) -2-Pyrrolidinone (Compound No.
(1) -8)] 1.6 g (81% yield, m, p. 108-110 ° C) were obtained.

[0058]

Example 4 3,3-Dichloro-4-ethyl-1- (3-hydroxy-4-carboxyphenyl) -2-pyrrolidone Zinon Ltd. (Compound No. (1) -9)
Preparation [Preparation of compound of formula (1)] 3,3-dichloro-4-ethyl-1- (3-hydroxy-4-methoxycarbonylphenyl) in a 200 ml eggplant-shaped flask.
-2-Pyrrolidinone (Compound No. (1) -8) (0.9 g), methanol (40 ml) and 1N sodium hydroxide (15 ml) were added, and the mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated with an evaporator, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the precipitated crystals were recrystallized from methanol to give the title compound as a colorless crystal [3,3-dichloromethane].
-4-ethyl-1- (3-hydroxy-4-carboxyphenyl)-
2-pyrrolidinone (Compound No. (1) -9)] 0.7 g (yield 8
5%, m, p. 210-212 ° C) was obtained.

Next, the synthesis examples of the novel intermediates for synthesizing the salicylic acid derivative according to the present invention will be specifically described.

[0060]

Example 5 Production of N- (2-butenyl) -N- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2,2,2-trichloroacetamide (Compound No. (2) -1) four-necked flask of 100ml capacity N-(2-butenyl-3-methoxymethoxy-4-methoxycarbonyl aniline (compound [synthesis of compound of formula (2)] No. (3) -1) 1.0g and Add 30 ml of dichloromethane,
With stirring at room temperature, 0.7 g of pyridine and 0.75 g of trichloroacetic acid chloride were added. After stirring at room temperature for 2 hours, 60 ml of saturated aqueous sodium hydrogen carbonate was poured, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate and evaporating the solvent with an evaporator, the residue was purified by silica gel column chromatography using a hexane-acetone mixed solvent to give the title compound as a colorless oil [N- (2-butenyl)].
-N- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2,2,2-trichloroacetamide (Compound No. (2)-
1)] 1.0 g (n _D ²³ = 1.5708, MS spectrum; m / Z 410 (M ⁺ ), yield 66%) were obtained.

[0061]

Example 6 Production of N- (2-butenyl) -3-methoxymethoxy-4-methoxycarbonylaniline (Compound No. (3) -1) [Formula (3)
Synthesis of Compound] In 20 ml of dimethylformamide, 1.0 g of methyl 4-amino-2-methoxymethoxybenzoate, 0.7 g of anhydrous potassium carbonate and 0.5 g of 1-chloro-2-butene were added, and 8
The mixture was stirred at 0 ° C to 90 ° C for 12 hours. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. Then, the obtained extract was dried over anhydrous sodium sulfate, concentrated using an evaporator, and purified by silica gel column chromatography using a hexane-ethyl acetate mixed solvent to give the colorless wavy title compound [N- (2 0.6 g (yield 50%) of -butenyl) -3-methoxymethoxy-4-methoxycarbonylaniline (Compound No. (3) -1)] was obtained.

The NMR spectrum and mass spectrum (MS) measurement results are shown below. Mass spectrum (MS): m / Z 265 (M ⁺ ) NMR spectrum (CDCl ₃ , TMS standard, δ value):
1.72 (d, 3H), 3.54 (s, 3H), 3.6
4 to 3.80 (m, 2H), 3.84 (s, 3H),
4.10 to 4.40 (m, 1H), 5.24 (s, 2
H), 5.50-5.80 (m, 2H), 6.20-
6.44 (m, 2H), 7.96 (d, 1H). (Method for Formulating Antifungal Agent) Next, the antifungal agent containing the novel salicylic acid derivative according to the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these Examples. Absent.

[0063]

[Example 7] (Liquid formulation) 200 ml of "Macrogol 400" (manufactured by Sanyo Kasei Co., Ltd.) as a filler was dissolved in 750 ml of ethanol, and 3,3-dichloro-4-ethyl-produced in Example 1 was dissolved therein. 5 g of 1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone (Compound No. (1) -1) was added and dissolved.
Ethanol was further added to the obtained solution to make the total amount 1000 ml, to prepare a liquid preparation.

In place of the above compound No. (1) -1, a compound
Compound No. (1) -2 to compound (1) -10 in the same manner as above except that salicylic acid derivatives of compound (1) -2 to compound (1) -10 are used.
The liquid preparation according to the present invention containing the salicylic acid derivative can be obtained.

[0065]

Example 8 (Ointment) 400 g of white petrolatum, 180 g of cetanol, 1 g of propyl paraoxybenzoate and 50 g of sorbitan sesquioleate were dissolved in a water bath while maintaining the temperature at 80 ° C., and then compound No. (1) -1 [ 3,3-dichloro-4-ethyl-1- (3-
Methoxymethoxy-4-methoxycarbonylphenyl) -2-
Pyrrolidinone] 5 g was added and dissolved (liquid (a)).

On the other hand, 1 g of paraoxybenzoic acid was added with water, heated to 80 ° C., and dissolved to obtain the above-mentioned liquid (liquid).
(a)) was gradually added and mixed. Then, it cooled and prepared the ointment.

It should be noted that the ointment according to the present invention can be obtained in the same manner as described above by using compounds No. (1) -2 to (1) -10 instead of the above compound No. (1) -1. it can.

[0068]

Example 9 (Cream) White petrolatum 15 g, liquid paraffin 200 g, stearyl alcohol 50 g, glyceryl monostearate 4
0 g, 145 g of propylene glycol and 1 g of propyl paraoxybenzoate were added to a mixture of 80 g on a water bath.
Dissolves while maintaining at ℃, and further [3,3-
10 g of dichloro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone] was added and dissolved (liquid (b)).

On the other hand, 40 g of polyoxy 4 stearate
0 and 1 g of methyl paraoxybenzoate in purified water 49
8 g was added and heated to 80 ° C. to prepare a solution, which was dissolved and added to the above solution (liquid (b)), and then sufficiently stirred.

After stirring, the mixture was further stirred with cooling water until it solidified to prepare a cream. In place of the compound No (1) -1, the compound No (1) -2 to (1) -11 was used, except that the compound No (1) -2 to (1) -11 was used. It is possible to obtain a cream containing

(Usefulness Test of Salicylic Acid Derivatives) Next,
Test examples for the usefulness of the salicylic acid derivative of the present invention are shown in 1-3.

[0072]

[Test Example 1] In vitro antifungal activity test After completely dissolving a test compound (test compound) as shown in Tables 4 to 6 below in a minimum volume of dimethyl sulfoxide, acetone was added to a concentration of 1 mg / ml. A test compound solution was prepared.

On the other hand, the test bacterial solution was prepared as follows. That is, yeast-like fungi were pre-cultured on a potato sucrose agar slope at 27 ° C. for 24 hours and then collected.
The suspension was suspended in a physiological saline solution containing 0.1% "Tween 80", and the bacterial concentration was adjusted to about 10 ⁶ CFU / ml before use.
For filamentous fungi, 2 on the potato sucrose agar slope
Pre-incubate at 7 ° C for 8 days, scrape hyphae or conidia on the slope surface with ase, suspend in physiological saline containing 0.1% "Tween 80", then filter with sterile triple gauze,
The filtrate was used as a test bacterial solution (about 10 ⁷ CFU / ml).

The antifungal activity was measured according to the agar plate dilution method. That is, the test compound solution prepared above was added to 1
To the volume, 9 volumes of Sensitive Disc Medium-N (Nissui) were added to prepare 2-fold dilution series agar plates containing the test compound at a final concentration of 0.78-100 μg / ml. Then, about 5 μl of the test bacterial solution for inoculation prepared by the above method was spotted on an agar plate.

The determination of the antifungal activity was carried out at 27 ° C. for 2 days in the case of yeast fungi, and in the case of filamentous fungi at 27 ° C.
After culturing at ℃ for 1 week, the minimum inhibitory concentration (MI
C, μg / ml).

The test results are shown in Tables 4 and 5.

[0077]

[Table 4]

[0078]

[Table 5]

[0079]

[Test Example 2] (Treatment test for ringworm) Four back parts of male Hartley guinea pigs (body weight 600 to 700 g) were hair-extracted using gum tape and the like, and lightly rubbed with sandpaper to exfoliate the stratum corneum.
Then Trichophyton mentagrophytes conidia suspension of (T. mentagrophytes) (2 × 10 ⁷ conidia / ml) were coated infected by 50 [mu] l. Treatment was started 72 hours after infection, and the test compound No. (1) -1 [3,3-dichloro-4-ethyl-1- (3-methoxymethoxy-4-methoxycarbonylphenyl) -2-pyrrolidinone] 0.2 ml of the above solution was applied once a day for a total of 10 times. Two days after the final treatment day, guinea pigs were dissected, and 10 pieces of skin tissue at the infection / treatment site were directly placed on Sabouraud agar plates and cultured at 27 ° C. for 7 days to determine the presence or absence of growth of Trichophyton.

The indications in the table are shown by the inhibition rate obtained by the following formula. Suppression rate = [1-Number of Tinea ring positive tissue pieces / Total number of tissue pieces] x 1
The test results are shown in Table 6.

"Tolnaftate" is a compound name:
2 Naphthyl-N-methyl-N- (3-tolyl) thionocarbamate, which is a therapeutic agent for tinea cinerea manufactured by Yamanouchi Pharmaceutical Co., Ltd.

[0082]

[Table 6]

[0083]

[Test Example 3] (Acute toxicity test) An acute toxicity test was carried out on an ICR mouse (20.0 ± 0.5 g) by an oral administration method. That is, the test compounds shown in the following table were suspended and administered in an aqueous carboxymethylcellulose solution containing 0.05% dimethyl sulfoxide. The 50% lethal concentration (LD50 value) was determined from the mouse survival rate two weeks after the administration.

The test results are shown in Table 7.

[0085]

[Table 7]

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Claims (4)

[Claims] 1. General formula (1): [In the formula (1), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y represents a halogen atom. Or represents a hydrogen atom. ] The salicylic acid derivative represented by these. 2. General formula (2): [In the formula (2), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y represents a halogen atom. Alternatively, a hydrogen atom is shown, and Z is a chlorine atom or a bromine atom. ] The salicylic acid type compound represented by these. 3. General formula (3): [In the formula (3), R ¹ represents a hydrogen atom or an alkoxyalkyl group, and R ² represents a lower alkoxy group, an amino group or a hydroxyl group. ] The salicylic acid type compound represented by these. 4. General formula (1): [In the formula (1), R ¹ represents a hydrogen atom or an alkoxyalkyl group, R ² represents a lower alkoxy group, an amino group or a hydroxyl group, X represents a halogen atom-substituted phenyl group or a halogen atom, and Y represents a halogen atom. Or represents a hydrogen atom. ] The antifungal agent characterized by containing the salicylic acid derivative represented by these as an active ingredient.