JP2000034287A - Antimycotic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel antimycotic agent that consists of a specific sulfur- containing heterocyclic compound, is useful as an antimycotic agent and is used in a medicinal composition for treatment, prevention of aggravation and prevention of recurrence of epidermomycosis and profound a mycosis. SOLUTION: This is a compound represented by formula I (R1 is thienyl; R2-R5 are each a 1-4C alkyl), typically N-(4-tert.-butylbenzyl)-N-methyl-2-(2- thienyl)-2-propenylamine. The compound of formula I is prepared by dissolving a compound of formula II in a solvent as benzene or the like, and allowing the compound to react with trimethylphosphonium bromide and n-butyl lithium. The compound of formula II is of a Lewis acid, substituting the hydrogen atom in this acetyl group with a halogen atom and condensing the product with a corresponding amine in the presence of an alkali. The daily dose of the compound of formula I is 1-10,000 mg/adult for oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antifungal agent,
It relates to a novel sulfur-containing heterocyclic compound.

[0002]

2. Description of the Related Art Superficial mycosis typified by athlete's foot has become more westernized and the wearing time of shoes has increased, and as a result, reliable treatments and remedies may not yet be found. It is counted as one of the diseases that have not been overcome in modern times. Therefore, many compounds were screened for antifungal activity. However, i
Few substances that have been found to be active at n vitro or animal levels have dropped out in the actual clinical stage, and few satisfactory results have been obtained so far. That is, discovery of a new mother nucleus having an antifungal effect has been awaited. In such a situation,
Not only superficial fungi, but also deeply fungal diseases such as Candida albicans and Aspergillus niger are extremely toxic, have only a small effect, and have to use amphotericin B in a very serious situation. is there. That is,
Development of an antifungal agent having a new mother nucleus has been desired.

On the other hand, the compounds represented by the following general formula (I) are all compounds which have not been described in the literature. Therefore, it has never been known that such compounds have an excellent antifungal activity. .

[0004]

SUMMARY OF THE INVENTION The present invention has been made under such circumstances, and an object of the present invention is to find a novel mother nucleus compound having an antifungal action.

[0005]

In view of such circumstances, the present inventors have made intensive research efforts in search of a novel mother nucleus compound having an antifungal action, and as a result, the compound represented by the general formula (I) ,
Among them, the compound having R2, R3, R4, and R5 in the formula as a methyl group and / or a physiologically acceptable salt thereof was found to have such an effect, thereby completing the invention. Hereinafter, the present invention will be described in detail focusing on embodiments.

[0006]

Embedded image Formula (I) (wherein, R1 represents a thienyl group which may have a halogen atom, and R2, R3, R4, and R5 each independently represent an alkyl group having 1 to 4 carbon atoms)

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION (1) The compound represented by the general formula (II) of the present invention The compound represented by the general formula (II) of the present invention is an important compound of the compound represented by the general formula (I). It is an intermediate. This is subjected to a Wittig reaction, and the oxygen atom of the carbonyl group is converted to a methylene group, whereby it can be converted to the compound represented by the general formula (I). R2, R in the formula
3, R4 and R5 each independently represent an alkyl having 1 to 4 carbons. Of these, particularly preferred are those in which all four are methyl groups. This is because the steric distortion is small and the antifungal action is strong. This compound is acetylated from thiophene or a halide thereof in the presence of a Lewis acid as shown in Reaction Scheme 1, and then the hydrogen atom of the methyl of the acetyl group is replaced with a halogen atom. In the presence of alkali,
It can be produced by condensation. All of these compounds are novel compounds not described in the literature. In addition, these general formulas (I
Preferable specific examples of the compound represented by I) include, for example, 2- [2- {N- (4-tert-butylbenzyl) -N-methylamino} acetyl] thiophene (compound 3) or 2- [ 2- {N- (4-tert-butylbenzyl) -N-methylamino} acetyl] -5-chlorothiophene (compound 4).

[0008]

Embedded image Reaction formula 1 (wherein, R1 represents a thienyl group which may have a halogen atom, and R2, R3, R4, and R5 each independently represent an alkyl group having 1 to 4 carbon atoms)

[0009]

Embedded image General formula (II) (wherein, R1 represents a thienyl group which may have a halogen atom, and R2, R3, R4 and R5 each independently represent an alkyl group having 1 to 4 carbon atoms)

[0010]

Embedded image (Compound 3)

[0011]

Embedded image (Compound 4)

(2) The compound represented by the general formula (I) of the present invention The compound represented by the general formula (I) of the present invention is obtained by subjecting the compound represented by the general formula (II) to a Wittig reaction. Is obtained by That is, it can be obtained by dissolving the compound of the general formula (II) in a solvent such as benzene and reacting trimethylphosphonium bromide with n-butyllithium. The compound of the general formula (I) thus obtained can be converted into a salt according to a conventional method. The salt of the compound of the present invention is not particularly limited as long as it is physiologically acceptable.For example, hydrochloride, sulfate, nitrate, mineral salts such as phosphate, citrate, oxalate, Organic acid salts such as tartrate can be preferably exemplified. Of these, the hydrochloride salt is particularly preferred. This is because of its excellent stability and efficacy. The compound of the general formula (I) of the present invention includes R2,
It is particularly preferred that R3, R4 and R5 are methyl groups, and as such a compound, N- (4-tert-butylbenzyl) -N-methyl-2- (2-thienyl)-
Preferred examples include 2-propenylamine (compound 1) and N- (4-tert-butylbenzyl) -N-methyl-2- (5-chloro-2-thienyl) -2-propenylamine (compound 2). This is because such compounds have excellent drug efficacy. This is because stability and economy are excellent. The thus-obtained compound represented by the general formula (I) and / or a salt thereof has excellent antifungal activity, and thus can be used as the antifungal agent of the present invention. Further, the antifungal agent of the present invention is also excellent in safety, and therefore, its administration route is not limited. The dose of the compound of the present invention as an antifungal agent varies depending on the condition and symptoms of the patient.
It is preferable to administer 1 to 10,000 mg in one or several divided doses. In the case of an external preparation for skin, it is preferable to apply an appropriate amount of 0.1 to 10% by weight. It is preferred that the suppository containing 1 to 10% by weight be replaced once or several times before administration.

[0013]

Embedded image (Compound 1)

[0014]

Embedded image (Compound 2)

(3) Pharmaceutical composition of the present invention The pharmaceutical composition of the present invention is characterized by containing the above-mentioned antifungal agent of the present invention. As shown in Examples below, since the antifungal agent of the present invention has an excellent antifungal activity, the pharmaceutical composition of the present invention is useful for treating superficial mycosis and preventing or relapsing deep mycosis, Very useful for prevention. Preferred examples of the pharmaceutical composition of the present invention include external preparations such as solutions, creams and ointments, oral preparations such as tablets, capsules and powders, dosage forms such as injections and vaginal suppositories. The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned antifungal agent, optional components usually used in pharmaceutical compositions. Such optional components include, for example, in the case of oral preparations and injections, excipients, binders, coating agents, lubricants, sugar coatings, disintegrants, bulking agents, flavoring agents, emulsification and solubilization. Dispersants, stabilizers, pH adjusters, isotonic agents, etc. can be exemplified, and in the case of skin external preparations and vaginal suppositories, hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gay wax. , Beef tallow, triglycerides such as olive oil, cetanol, higher alcohols such as oleyl alcohol,
Fatty acids such as stearic acid and oleic acid, polyhydric alcohols such as glycerin and 1,3-butanediol, nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, ethanol, carbopol, etc. Thickeners, preservatives, ultraviolet absorbers, antioxidants, pigments, powders and the like. The pharmaceutical composition of the present invention can be produced by treating these antifungal agents and optional components according to a conventional method.

[0016]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the compounds of the present invention are not limited only to these examples.

<Example 1> 30m of dimethylformamide
3 g of N- (4-tert-butylbenzyl) -N-methylamine and 1.63 g of sodium carbonate were mixed with 1 l, and 3.16 g of 2- (2-bromoacetyl) thiophene was added to 20 ml of the mixture while stirring under ice-cooling. A solution dissolved in dimethylformamide was added dropwise. After the dropwise addition, the ice was removed, the temperature was returned to room temperature, and the mixture was stirred for 45 minutes. After the reaction, the reaction solution was poured onto ice water, extracted with 150 ml of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and then concentrated on silica gel column chromatography (eluent: n-solvent). Hexane: ethyl acetate = 10:
Purification was performed in 1) to obtain Compound 3 in a yield of 62.9%. ¹ H
-NMR is shown below. (Solvent; CDCl ₃ , δ ppm,
Hereinafter, the NMR values represent the same. ) 1.31 (s, 9H), 2.37 (s, 3H), 3.6
5 (s, 2H), 3.66 (s, 2H), 7.10 (d
d, 1H, J = 4.86 Hz, 5.13 Hz), 7.2
9 (d, 2H, J = 8.37 Hz), 7.34 (d, 2
H, J = 8.37 Hz), 7.62 (d, 1H, J =
4.86 Hz), 7.87 (d, 1H, J = 5.13H)
z)

6.92 g of methyltriphenylphosphonium bromide was suspended in 23 ml of benzene, and 6.4 ml of a 3.04 M n-butyllithium / hexane solution was added dropwise with stirring at room temperature under a nitrogen atmosphere. After 10 minutes, 2.92 g of compound 3 was dissolved in 20 ml of benzene and added dropwise. Further, stirring was continued for 1 hour, and the mixture was poured into ice water to stop the reaction. The mixture was extracted with 100 ml of benzene, washed with saturated saline, dried over sodium sulfate, evaporated under reduced pressure, and purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 20: 1) to obtain Compound 1. Rate 6
Obtained at 7.9%. ¹ H-NMR is as follows. 1.
31 (s, 9H), 2.20 (s, 3H), 3.33
(S, 2H), 3.53 (s, 2H), 5.18 (s, 2H)
1H), 5.53 (s, 1H), 6.97 (m, 1
H), 7.17 to 7.35 (m, 6H)

1.97 g of the compound 1 thus obtained was dissolved in 5 ml of ethyl acetate, and 4N was stirred at room temperature.
3.3 ml of a hydrogen chloride-ethyl acetate solution was added dropwise. Ethyl acetate was distilled off under reduced pressure, and diisopropyl ether 1 was added to the residue.
After adding 00 ml, the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration and dried in a desiccator. (Yield 75.5
%) The melting point was 163.5-164 ° C. ¹ H-NM
R is as shown below. 1.32 (s, 9H), 2.63
(S, 3H), 3.90-4.28 (m, 4H), 5.
86 (s, 1H), 5.96 (s, 1H), 7.03
(M, 1H), 7.08 (m, 1H), 7.28 (m, 1H)
1H), 7.45 (d, 2H, J = 8.37 Hz),
7.52 (d, 2H, J = 8.37 Hz), 12.8
(Bs, 1H)

The infrared absorption spectrum was 3420, 296
2,2905,2869,2703,2631,146
4 (cm ^-1 ).

<Embodiment 2> As in Embodiment 1, 2- (2
-Bromoacetyl) -5-chlorothiophene,
Compound 2 was obtained via compound 4 to prepare a hydrochloride thereof. ^{The 1} H-NMR spectrum was as shown below. The melting point of the hydrochloride was 183 to 184 ° C. (Compound 4) 1.31 (s, 9H), 2.33 (s, 3
H), 3.50 (s, 2H), 3.63 (s, 2H),
6.94 (d, 1H, J = 4.32 Hz), 7.28
(D, 2H, J = 8.37 Hz), 7.36 (d, 2
H, J = 8.37 Hz), 7.70 (d, 1H, J =
(Compound 2) 1.32 (s, 9H), 2.18 (s, 3)
H), 3.26 (s, 2H), 3.52 (s, 2H),
5.13 (s, 1H), 5.43 (s, 1H), 6.7
7 (d, 1H, J = 3.51 Hz), 6.96 (d, 1
H, J = 3.51 Hz), 7.25 (d, 2H, J =
7.83 Hz), 7.34 (d, 2H, J = 7.83H)
z) (Hydrochloride of compound 2) 1.32 (s, 9H), 2.65
(D, 3H, J = 4.86 Hz), 3.80-4.28
(M, 4H), 5.85 (s, 2H), 6.83-6.
89 (m, 2H), 7.46 (d, 2H, J = 8.37)
Hz), 7.52 (d, 2H, J = 8.37 Hz), 1
2.9 (bs, 1H)

The infrared absorption spectrum of the hydrochloride of Compound 2 is 3423, 2964, 2905, 2692, 26
31, 1463 and 1451 (cm ^-1 ).

Example 3 Antibacterial Test (Measurement of Growth Inhibitory Concentration) The antifungal effect of the compound of the present invention on trichophyton was determined. That is, Trichophyton mentagrophytes TIMM1189 is preliminarily cultured on a slope of Sabouraud agar medium at 27 ° C. for 2 weeks to form sufficient conidia. This is washed with a platinum loop using a sterile physiological saline solution containing Tween 80 at 0.05% by weight / volume to float the conidia. This was filtered through two layers of gauze, and only the conidia were taken out in a form suspended in physiological saline. The concentration of conidia was adjusted test organism bacterial liquid to be 10 ⁵ cells / ml. On the other hand, 4 mg of the compound was taken and 1 ml of dimethyl sulfoxide was added to prepare a stock solution, which was successively diluted 2-fold with dimethyl sulfoxide to prepare a diluted drug solution. To each well of a 96-well microplate for tissue culture, add 175 μl of Sabouraud dextrose medium, 5 μl of a drug solution, and 20 μl of a test bacterial solution, mix well, culture at 27 ° C. for 1 week, and visually inhibit growth completely. The minimum concentration was sought and defined as the minimum inhibitory concentration. The results show that the hydrochloride of compound 1 is 0.4 μg / ml and the hydrochloride of compound 2 is 0.4 μg / ml.
g / ml. This indicates that the antifungal activity of the antifungal agent of the present invention is excellent.

Example 4 An ointment for treating athlete's foot, which is a pharmaceutical composition of the present invention, was prepared according to the following formulation.
That is, the ingredients were weighed and kneaded in a kneader to obtain an ointment. Vaseline 99 parts by weight Compound 1 hydrochloride 1 part by weight

Example 5 An ointment for treating athlete's foot, which is a pharmaceutical composition of the present invention, was prepared according to the following formulation.
That is, the ingredients were weighed and kneaded in a kneader to obtain an ointment. Vaseline 99 parts by weight Compound 2 hydrochloride 1 part by weight

[0026]

According to the present invention, a novel mother nucleus compound having an antifungal action can be provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takuto Nakajima 560 Pola, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Inside the Totsuka Laboratory, Inc. F-term in Totsuka Laboratory Co., Ltd. (reference) 4C023 CA04 DA02 4C086 AA01 AA02 AA03 AA04 BB02 MA01 MA04 NA14 ZA81 ZA82 ZA90 ZB35

Claims (8)

[Claims] 1. A compound represented by the general formula (I) and / or a physiologically acceptable salt thereof. Embedded image Formula (I) (wherein, R1 represents a thienyl group which may have a halogen atom, and R2, R3, R4, and R5 each independently represent an alkyl group having 1 to 4 carbon atoms) 2. In the above general formula (I), R2, R
3, wherein R4 and R5 are methyl groups,
A compound according to claim 1 and / or a physiologically acceptable salt thereof. 3. A compound represented by the general formula (I):
(4-tert-butylbenzyl) -N-methyl-2
-(2-thienyl) -2-propenylamine (compound 1) or N- (4-tert-butylbenzyl) -N
The compound according to claim 1 or 2, which is -methyl-2- (5-chloro-2-thienyl) -2-propenylamine (compound 2), and / or a salt thereof. Embedded image (Compound 1) (Compound 2) 4. An antifungal agent comprising the compound according to any one of claims 1 to 3 and / or a physiologically acceptable salt thereof. 5. A pharmaceutical composition comprising the antifungal agent according to claim 4. 6. A compound represented by the general formula (II). Embedded image Formula (II) (wherein, R1 represents a thienyl group which may have a halogen atom, and R2, R3, R4, and R5 each independently represent an alkyl group having 1 to 4 carbon atoms) 7. A compound represented by the general formula (II):
-[2- {N- (4-tert-butylbenzyl)-
N-methylamino diacetyl] thiophene (compound 3)
Or the compound according to claim 6, which is 2- [2- {N- (4-tert-butylbenzyl) -N-methylamino} acetyl] -5-chlorothiophene (compound 4). Embedded image (Compound 3) (Compound 4) 8. The method for producing a compound according to any one of claims 1 to 3, wherein the compound according to claim 6 or 7 is subjected to a Wittig reaction.