JPH0144182B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ¹ and R ² represent a hydrogen atom, a chlorine atom, a nitro group, or a methoxycarbonyl group, except when both represent a hydrogen atom, and R ³ represents a hydrogen atom, a nitro group, or a 3-chloro-2- The present invention relates to a novel pyrrole derivative represented by the following formula (indicating a nitrophenyl group) and an antifungal agent containing the same as an active ingredient. The present inventors previously obtained a new antibiotic, pyrrolomycin A (SF-2080A), from a fermentation solution of microorganisms, and filed a patent application for the substance, its production method, and an antifungal agent containing it as an active ingredient (Japanese Patent Application Laid-Open No. Publication No. 56-90099,
(Japanese Patent Application Laid-open No. 57-67557). Next, the present inventors modified the structure of pyrrolomycin A through a chemical reaction for the purpose of enhancing its antifungal activity, and found that the antifungal activity was significantly enhanced when an iodopropargyl group was introduced onto the nitrogen of the pyrrole ring of the substance. I found out that it can be done. Furthermore, the present inventors have found that the antifungal activity is significantly enhanced in pyrrole compounds other than pyrrolomycin A by introducing an iodopropargyl group, and have completed the present invention. The pyrrole derivative represented by the above formula () of the present invention is a novel compound that has not been described in any literature. Examples of the pyrrole derivatives provided by the present invention include the following. (1) 1-(1'-iodopropyn-3'-yl)2-,
3-dichloro-4-nitropyrrole (2) 1-(1'-iodopropyn-3'-yl)-2-
Chloro-4-nitropyrrole (3) 1-(1'-iodopropyn-3'-yl)-3-
Nitropyrrole (4) 1-(1'-iodopropyn-3'-yl)-3-
Chloro-4-(3″-chloro-2″-nitrophenyl)pyrrole (5) 1-(1′-iodopropyn-3′-yl)-2-
Methoxycarbonylpyrrole (6) 1-(1'-iodopropyn-3'-yl)-2-
Nitropyrrole The pyrrole derivative () according to the present invention is a pyrrole compound () and an iodopropylene derivative () [in the reaction formula, R ¹ , R ² ,
R ³ has the same meaning as above, X represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester] in an inert solvent in the presence of a base. Among the raw materials used in the production of the compounds of the present invention, iodopropyne derivatives () are known compounds.For example, iodopropargyl halide can be obtained by reacting iodopropargyl alcohol with a halogenating agent such as thionyl chloride or thionyl bromide. Alternatively, it can be obtained as iodopropargyl alcohol sulfonate by reacting a sulfonic acid halide such as toluenesulfonyl chloride, benzenesulfonyl chloride or methanesulfonyl chloride. Among the pyrrole compounds represented by the above formula (), which are the other raw materials used in the production of the compound of the present invention, examples include 2,3-dichloro-4-nitropyrrole (pyrrolomycin A) and 3-chloro-
4-(3'-Chloro-2'-nitrophenyl)pyrrole (pyrrolnitrine) is a well-known microbial fermentation product, and 3-nitropyrrole is reported in Tetrahedron, Vol. 22, p. 57 ( (1966), and other raw materials can be synthesized by those skilled in the art by applying the above-mentioned methods for producing the substances. According to the present invention, the pyrrole derivative represented by the formula () can be obtained by dissolving the pyrrole compound represented by the formula (), which is the starting material obtained according to the above method, in an inert solvent. It is produced by an N-alkylation reaction in which an iodopropyl derivative and a base are added to introduce an iodopropargyl group onto the nitrogen atom of the pyrrole ring of a pyrrole compound represented by formula (). Examples of inert solvents used in this reaction include benzene, dioxane, dichloromethane, N,
Examples of bases used in the reaction include inorganic bases such as alkali hydroxide and alkali carbonate, as well as organic bases such as triethylamine. When using alkali hydroxide, the reaction proceeds rapidly at room temperature, but in order to prevent side reactions, the reaction is preferably carried out under cooling, preferably at zero temperature.
Perform at ~5°C or use an organic base.
It can also be carried out by heating to 40 to 60°C. The target pyrrole derivative represented by formula () can be isolated from the reaction mixture by a crystallization method by adding an insoluble solvent such as water or an organic solvent such as benzene,
Extraction using ethyl acetate or the like or, if necessary, a well-known purification method such as chromatography using silica gel or recrystallization using an organic solvent may be used in combination. A production example of the novel pyrrole derivative () according to the present invention is shown below. Example 1 1-(1'-iodopropyn-3'-yl)-2,3
-Dichloro-4-nitropyrrole 181 mg (1 mmol) of 2,3-dichloro-4-nitropyrrole (pyrrolomycin A) was dissolved in 10 ml of dry dimethylformamide, and 340 mg (1 mmol) of p-toluenesulfonic acid ester of iodopropargyl alcohol was dissolved. ) and 50 mg of powdered sodium hydroxide were added and stirred at 0 to 5°C for 1 hour. 30 ml of water and 50 ml of benzene were added to the reaction solution for extraction, and the benzene layer was separated and washed twice with water. After drying the benzene solution, a small amount of methanol was added to the residue obtained by concentrating the benzene solution under reduced pressure, and the precipitated 1-(1'-iodopropyn-3'-yl)-2,3-dichloro-4-
Nitropyrrole crystals were collected by filtration. Yield 198 mg (58
%), melting point 128-131℃, elemental analysis value C: 24.48%
H: 0.83%, N: 7.95%, Cl and I: 57.78%,
Calculated value as C ₇ H ₃ N ₂ O ₂ Cl ₂ I C: 24.35%, H:
0.88%, N: 8.12%, Cl: 20.56%: I: 36.79%. Example 2 1-(1'-iodopropyn-3'-yl)-3-nitropyrrole 224 mg (2 mmol) of 3-nitropyrrole was dissolved in 5 ml of dry dimethylformamide and 0.67 g of p-toluenesulfonic acid ester of iodopropargyl alcohol was prepared. (2 mmol) and 100 mg of sodium hydroxide powder were added and stirred at 10-5°C for 1 hour. Add 50ml each of ethyl acetate and water to the reaction solution,
After extraction, the ethyl acetate layer was separated, washed with water, and dried. When 1.5 ml of methanol was added to the residue obtained by concentrating the ethyl acetate solution under reduced pressure, 1-(1'-iodopropyn-3'-yl)-3-nitropyrrole crystals precipitated and were collected by filtration. Yield 236mg (43%),
Melting point 138-140℃, elemental analysis value C: 31.31%, H:
1.89%, N: 10.06%, I: 45.34%, Calculated value as C ₃ H ₅ N ₂ O ₂ I C: 30.47%, H:
1.83%, N: 10.14%, I: 45.97% Example 3 1-(1'-iodopropyn-3'-yl)-3-chloro-4-(3'-chloro-2'nitrophenyl)
Pyrrole Dissolve 130 mg of 3-chloro-4-(3'-chloro-2'-nitrophenyl)pyrrole (pyrrolnitrine) in 5 ml of dry dimethylformamide,
Cooled to ℃. 168 mg of p-toluenesulfonic acid ester of iodopropargyl alcohol and 24 mg of sodium hydroxide powder were added, and after stirring for 1 hour, the reaction solution was poured into 10 ml of ice water. The reaction solution was extracted with a benzene-ethyl acetate mixture (20 ml cm ^{2 )} , and the organic solvent layer was washed with water, dried, and concentrated under reduced pressure to leave a dark brown solid. Add 1 ml of methanol to precipitate 1-(1″-iodopropyn-3″-yl)-3-
Chloro-4-(3'-chloro-2-nitrophenyl)
Pyrrole crystals were collected by filtration. Yield 97 mg (46%), melting point 126-128°C, elemental analysis C: 38.34%, H:
1.76%, N: 6.83%, Cl and I: 45.73%,
Calculated value C as C ₁₃ H ₇ N ₂ O ₂ Cl ₂ I ₂ : 37.09%,
H: 1.08%, N: 6.65%, Cl: 16.84%, I:
30.14%. Example 4 1-(1'-iodopropyn-3'-yl)-2-methoxycarbonylpyrrole 125 mg (1 mmol) of 2-carbomethoxypyrrole was dissolved in 5 ml of dry dimethylformamide to prepare p-toluenesulfonic acid ester of iodopropargyl alcohol. 340 mg (1 mmol) was added and 46 mg of sodium hydroxide powder was added with vigorous stirring.
After reacting at room temperature for 20 minutes, the reaction solution was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed twice with saturated brine, and dried. After concentrating the ethyl acetate solution, the dark oil that remained was purified on a silica gel TLC plate to obtain crystalline 1-
(1'-iodopropyn-3'-yl)-2-methoxycarbonylpyrrole was obtained. Yield 149 mg (51
%). Elemental analysis value C: 38.01%, H: 2.99%,
N: 4.67%, I: 42.90%, Calculated value as C ₉ H ₈ NO ₂ I C: 37.39%, H: 2.79%, N: 4.85%,
I: 42.90%, IR spectrum 2180 ^Cm-1 (-C≡C
−), 1685 ^Cm-1 (−COO−). Example 5 1-(1'-iodopropyn-3'-yl)-2-nitropyrrole 1.12 g (10 mmol) of 2-nitropyrrole was dissolved in 20 ml of dimethylformamide, and 0.45 g (11 mmol) of sodium hydroxide powder was added. , stir well to dissolve. Cool this solution on ice, add 3.36 g (10 mmol) of iodopropargyl alcohol/p-toluenesulfonic acid ester, and cool on ice for 1 hour.
The reaction was further continued for 15 hours at room temperature. 30 ml of ice water was added to the reaction solution, and the precipitated 1-(1'-iodopropyn-3'-yl)-2-nitropyrrole crystals were filtered, washed with water, and dried. Yield: 2.28g (82%) Crude crystals were recrystallized from methanol, melting point: 102~
Purified crystals at 104°C were obtained. Elemental analysis value C: 30.40
%, H: 1.81%, N: 9.99%, I: 44.52% Calculated value as C ₇ H ₅ N ₂ O ₂ I C: 30.46%, H:
1.83%, N: 10.14%, I: 45.97% The novel pyrrole derivative of the present invention represented by the above formula () is a low toxicity compound and is useful as an antibacterial and antifungal agent. In particular, the compound of the present invention exhibits a growth inhibiting effect on a wide range of fungi, and is therefore useful in improving unfavorable conditions caused by the growth of bacteria and fungi in various fields of medicine, agriculture, and industry. It is something. That is, for medical use, for example, as a therapeutic agent for external diseases caused by fungi such as Candida, Aspergillus, Trichophyton, and Cryptococcus, the active ingredient in liquid preparations and ointments ranges from 0.1 to
It can be blended in an amount of 5%, preferably in the range of 0.5 to 2%, and applied to the affected area to achieve the therapeutic purpose.
Furthermore, for medical purposes, it can be included as a disinfectant for machinery and equipment and other active ingredients for the purpose of preventing the growth of pathogenic bacteria and molds and maintaining a sterile environment. Furthermore, the pyrrole derivative represented by formula () of the present invention also shows usefulness in the agricultural and industrial fields. In particular, in these fields, for example, agricultural and industrial products such as seeds, seedlings, wood and woodwork, paper crafts, leather, adhesives, paints, and synthetic resins, and their manufacturing environments, such as the occurrence of spoilage bacteria and mold in drinking water. causes a significant loss in the value of the product. Since the pyrrole derivative of the present invention exhibits a growth inhibiting effect on harmful bacteria and fungi in the agricultural and industrial fields, it can be used for the purpose of maintaining the quality of products in the field and preserving the environment. In the agricultural and industrial fields, the pyrrole derivative of the present invention can be used in formulations supported on commonly used carriers, such as oil solvents, emulsions, pastes, powders, wettable powders, aerosols, and antifungal coatings. It will be done. Examples of carriers used include inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic anhydride, and calcium carbonate, organic solvent carriers such as tyrosine, ligroin, xylene, DMF, and DMSO, and gases such as dimethyl ether and chlorofluorocarbon gas. Examples include carriers, and adjuvants to further enhance formulation effects include ionic and nonionic surfactants, as well as polymeric compounds such as vinyl acetate and methylcellulose. It is also possible to use it in combination with preservatives, fungicides, and insecticides such as chlordane. The content of the pyrrole derivative of the present invention in actual use may vary depending on the formulation, but it is generally 0.01 to 95% by weight, preferably 0.2 to 95% by weight.
A range of 10% by weight is suitable. Examples of formulations as agricultural and industrial antibacterial and antifungal agents are listed below. Formulation example 1 Wettable powder 1-(1'-iodopropyn-3'-yl)-2,3
- If 40 parts by weight of dichloro-4-nitropyrrole, 5 parts by weight of polyoxyethylene alkyl aryl ether, 3 parts by weight of lignin sulfonic acid, and ±52 parts by weight of diatom are uniformly ground and mixed, 40% of the active ingredient will be contained. Obtain a hydrating powder. Formulation example 2 Granules 1-(1'-iodopropyn-3'-yl)-2,3
- 12 parts by weight of dichloro-4-nitropyrrole, 1 part by weight of calcium lignosulfonate, 30 parts by weight of bentonite and 57 parts by weight of clay are uniformly ground and mixed, then an appropriate amount of water is added and kneaded, followed by granulation. When dried, granules containing 12% of the active ingredient are obtained. Formulation Example 3 Emulsion 20 parts by weight of 1-(1'-iodopropyn-3'-yl)-3-nitropyrrole, 30 parts by weight of dimethylformamide
By uniformly mixing 35 parts by weight of xylene and 15 parts by weight of polyoxyethylene alkylaryl ether, an emulsion containing 20% of the active ingredient is obtained. Formulation example 4 Powder 1-(1'-iodopropyn-3'-yl)-2,3
-3 parts by weight of dichloro-4-nitropyrrole, 0.5 parts by weight of silicic anhydride fine powder, calcium stearate
By uniformly pulverizing and mixing 0.5 parts by weight, 50 parts by weight of clay, and 46 parts by weight of talc, a powder containing 3% of the active ingredient is obtained. Next, as a concrete example showing the usefulness of the pyrrole derivative of the present invention, 1-(1'-iodopropyne-
3'-yl)-2,3-dichloro-4-nitropyrrole [Compound ()], 1-(1'-iodopropyn-3'-yl)-3-nitropyrrole [Compound (2)]
acute toxicity (Table 1), the above compounds (1) and (2) and 1-
(1′-iodopropyn-3″-yl)-3-chloro-
4-(3'-chloro-2'-nitrophenyl)pyrrole [compound (3)], 1-(1'-iodopropyne-3'-
The antibacterial and antifungal activities (Tables 2.3 and 4) of 2-methoxycarbonylpyrrole (compound (4)) and the experimental treatment of athlete's foot infection in guinea pigs are described in detail.

[Table] No toxic effects observed.

【table】

【table】

【table】

[Table] Treatment experiment example: 4 dorsal skin areas (2, 4 x 6 on each left and right) of white Hartly guinea pigs (3 animals per group)
After removing the sutures (cm), remove the Trichophyton mentagrophytes suspension (liquid Sabouraud medium, 2x viable bacteria).
Apply 0.5 ml of 10 ⁷ /ml to each area with a brush. Two days after inoculation, 0.25 ml of the test compound formulation (Table 5) was applied once a day for 8 consecutive days to one site on each side of the skin of the lesion.

[Table] Similar operations were performed on pyrrolenitrine [3-chloro-
4-(2'-nitro-3'-chlorophenyl)pyrrole] 1% preparation and clotrimazole [1-(0-
A 1% formulation of chloro-α,αdiphenylbenzyl)imidazole was also tested and used as a control, along with a non-treated group. When efficacy was evaluated based on macroscopic findings, the compound of the present invention achieved good therapeutic results in all cases of thickening, flushing, and scaling of the affected skin (Table 6).

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ¹ and R ² represent a hydrogen atom, a chlorine atom, a nitro group, or a methoxycarbonyl group, except when both represent a hydrogen atom, and R ³ represents a hydrogen atom, a nitro group, or a 3-chloro-2- A pyrrole derivative represented by [representing a nitrophenyl group]. 2 formulas [In the formula, R ¹ and R ² represent a hydrogen atom, a chlorine atom, a nitro group, or a methoxycarbonyl group, except when both represent a hydrogen atom, and R ³ represents a hydrogen atom, a nitro group, or a 3-chloro-2- An antifungal agent whose active ingredient is a pyrrole derivative represented by the following formula, which represents a nitrophenyl group.