JPS58124765A - Pyrrole derivative, its preparation, and antifungal containing the same as active ingredient - Google Patents

Abstract

NEW MATERIAL:A pyrrole derivative of formulaI[R<1>, R<2> are H, halogen; one of R<3> and R<4> is H, halogen and the other is nitro, lower alkoxycarbonyl, phenyl or substituted phenyl of formula IV (R<5>-R<7> are H, halogen, nitro)]. EXAMPLE:1-(gamma-Iodopropin-3'-yl)-2,3-dichloro-4-nitropyrrole. USE:Antifungal. PREPARATION:The reaction between a pyrrole of formula II such as 2,3-dichloro-4-nitropyrrole (pyrrolomycin A) and an iodopropyne derivative of formula III (X is halogen, hydroxyl activated by being converted into sulfonate) is carried out in an inert solvent in the presence of a base to give the compound of formulaI.

Description

Detailed Description of the Invention The present invention is based on the general formula (I) where one of H3 and R4 is a hydrogen atom or a hydrogen atom and the other is a nitro group or a lower alkoxycarbohydrate.
These are phenyl groups and substituted phenyl groups represented by ] The present invention relates to the production of pyrrole derivatives shown in * and an antifungal agent containing them as active ingredients.

The present inventors first obtained the antibiotic pyrrolomycin y A (5F-208OA) from the fermentation liquid of microorganisms, and filed a patent application for the substance, its production method, and an antifungal agent containing it as an active ingredient. 54-166'126゜55-1
41123). 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 pyrrole ring ii! on the tree,
We have found that the antifungal activity is significantly enhanced when an iodoglopargyl group is introduced.

Furthermore, the present inventors have discovered that the antifungal activity is significantly enhanced in other pyrryl compounds other than pyrrolomycin/A by introducing an iodoglopargyl group, and have accomplished the present invention.

The pyrrole derivative represented by the formula (I) of the present invention is a novel compound that has not been described in any literature.

Examples of pyrrole n4 bodies provided by the present invention include the following.

+l1l-(4-iodopropyl/-3'-yl)-2゜3-dichloro-4-nitrovirol (2) 1-(1'-iodopropyn-3'-yl)-
2-chloro-4-nitropyrrole (311-(1'-iodopropyl/-3'-yl)-3
-Nitrovirol H41t-(t'-iodopropyn-3'-yl)-2
゜3.5-) dichloro-4-nitropyrrole +511-
(1'-iodoglobin-3'-yl)-2゜3-dibromo-4-nitrovirol +611-(1'-iodopropyn-3'-yl)-2
゜3-') l clo 4-ethoxycarbonylpyrrole + 711-(1'-iodoglobin-3'-yl)-3
-! )-IF dicarbonylvirol +8) l-(1'-iodopropyn-3'-yl)-3
-Chloro-4-(,?-Cucuro-7-nitrophenylin pyrrole 19)1-(1'-iodopropyn-3'-yl)-3
-Phenylpyrrole n1t-(1'-iodopropyn-3'-yl)-2゜3-dichloro-5-methoxycarbonylpyrrole (Iυ 1-(1'-iodopropyn-3'-yl)-
2-methoxycarbonylpyrrole H1-(1'--1-)'propyn-3'-yl)-2
- Nitrovirol As shown in the reaction formula below, the virol d conductor (I) is a pyrrole compound (II) and an iodoglobin enzyme conductor (III) (in the reaction formula, π, W is a hydrogen atom or a halogen atom, R3, R4 represents a phenyl group or a substituted phenyl group in which one of R4 is a hydrogen atom or a halogen atom and the other is a phenyl group or a substituted phenyl group, and 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. The iodopropylene conductor (ilI) used in the production of the compounds of the present invention is a known compound, such as iodoglopargyl alcohol K, thionyl chloride or Iodoglopargyl halide can be obtained by reacting a halogenating agent such as thionyl bromide, or toluenesulfonyl chloride or benzenesulfonyl chloride is reacted with a sulfone halide such as methanesulfonyl chloride to produce iodoglopargyl halide. It is obtained as gyl alcohol sulfonate.

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, for example, 2,3-dichloro-4-nitropyrrole (hyloromycin A) and 03-10c+- 4-(3'-/Roro 2
-Nitrophenyl)pyrrole (pyrrolnidoline) is a well-known fermentation product of microorganisms, 3-
Nitropyrrole is called tetrahedron (Tetrahedr).
2,3-dichloro-4-ethoxycarbonylpyrrole was prepared by the method described in Canadian J. of Chemlitry (1966), Vol.
) M 50 @ 3223 Negative (1972), and other raw materials can be synthesized by those skilled in the art by applying the methods for producing the substances described above.

According to the present invention, the virol derivative represented by formula (I) is
The starting material pyrrole compound represented by formula (II) obtained according to the above is dissolved in an inert solvent, and the pyrrole compound represented by formula (III) is dissolved in an inert solvent.
) and a base to form a pyrrole ring nitrogen of a pyrrole compound represented by formula (TI).
It is produced by an N-alkylation reaction that introduces an iodoglopargyl group on the 1g atom. Examples of the inert solvent used in this reaction include benzene, dioxane, dichloromethane, NN dimethylformamide, etc., preferably N,N dimethylformamide, and examples of the base used in the reaction include alkali hydroxide. In addition to unlabeled bases such as alkali carbonate and the like, triethylamine and the like are used as a single base. The reaction proceeds rapidly when using an alkali hydroxide, preferably at very low temperatures, but in order to prevent side reactions, it is carried out under cooling, preferably at 0 to 5°C, or by using a sensitive base at 40 to 60°C. It can also be done in addition to 1
The target substance in the reaction mixture, a single pyrrole derivative represented by formula CI), can be obtained by a crystallization method by adding an inert solvent such as water or by an extraction method using an organic solvent such as benzene, ethyl acetate, etc. Alternatively, if necessary, well-known purification methods, such as chromatography using silica gel or a host crystal method using a silica medium, may be used in combination.

Part 2 of the production of the novel pyrrole derivative (1) of the present invention! This will be explained in detail below with an example.

? 1jll-(1'-iodoglobin-3'-yl)-
2,3-dichloro-4-nitropyrrole 2,3-dichloro-4-nitropyrrole (hyroromycin A) 18
1 ~ (1 mmol) in 10 d of dry dimethylformamide
II.
Add 340q (1 mmol) of toluene sulfone ester and 50~ of powdered sodium hydroxide,
Stir at ℃ for 1 hour. 3 o of water and 5 o of benzene in the reaction solution! was added for extraction, and the benzene residue was washed twice with water in the dispersion zone. After drying in a benzene bath, a little violet of methanol was added to the residue obtained by vertical pressure coagulation to precipitate L7'cl-(1'-
:i-dov-pin-3'-yl)-2,3-dichloro-4-ditropyrrole crystals were filtered. Yield 198+η
(58chi), melting point 128-131'C, elemental analysis value C:
24.48%.

H: 0.83%, N: 7.95%, ct
Admission rate: 57.78%.

C7H3N20□C121t L Tenometer A 11t C
: 24.35%, H20, 88%, N: 8.1
2%, CL: 20.56%, I: 36.7
9%.

Example 21-(1'-iodopropyn-3'-yl)-3-
Nitropyrrole 3-Nitrovirol z24q (2 mmol) bath dissolved in completely dry dimethylformamide 5-, p-toluenesulfonic acid ester of iodoglopargyl alcohol 0.67f
(2 mmol) and sodium hydroxide powder were added and stirred at 10 to 5°C for 1 hour. Ethyl acetate and 50 volumes of water were added to the reaction solution for extraction, and the ethyl acetate/* was washed in a dispersion zone, washed with water, and dried.

Obtained by moving under ethyl acetate pressure. When 1.5-methanol was added to the product A, 1-(1'-iodopropyn-3'-yl)-3-nitrovirol precipitated and was collected by filtration. Yield 236~(43chi), FIS
1138-1413℃, elemental analysis +i C: ;n, 3
1%, )i: 1.89%, N: 10.0
6'A, I: 45.34%, C,)lsN
20. Total JL If C as I: 30.47%,
H: 1.83%, N: 10.14ch, I
: 45.97 chi.

Another 3l-(1"-iodoglobin/-3#-yl) = 3-
Chloro-4-(3'-chloro-2'-nitrophenyl)
iii,
Dissolved in dimethylformamide 5-, 0-5'CK&
Rejected. P-toluenesulfonic acid ester of iodoglopargyl alcohol 168~ and sodium chloride powder 24cm were added, stirred for 1 hour, and the anti-LC solution was poured into ice water 10~. The reaction solution was extracted with benzene-ethyl acetate mixture #I medium 20, and the solid medium layer was washed with water, dried, and concentrated under reduced pressure, leaving a dark brown solid. 1-(1#-iodopropyne-
I-yl)-3-chloro-4-(3'-chloro-2'-
(nitrophenyl)virol crystals were collected by filtration. Collection 9
7■ (46%), melting point 126-128C1 elemental analysis Hani C
: 38.34%.

11: 1.76chi, N: 6.83%, Ct
and I: 45.73%.

Total as C, H, N, 02CL, I: #111[C
: 37.09%, H: 1.08% + N: 6.6
5%, C1: 16.84%, I: 30.1
49&.

Example 4l-(1'-iodopropyn-3'-yl)-2-
Carbomethoxyvirol 2-carbomethoxyvirol 125■ (1 mmol) f
The mixture was dissolved in dry dimethylformamide (5-mL), and 340 μm (1 mmol) of p-toluenesulfone acid ester of iodoglopargyl alcohol was added thereto, and with thorough stirring, 46 cm of sodium hydroxide powder was obtained. After reacting at room temperature for 20 minutes, the reaction solution was separated into ethyl acetate and water. The ether acetate layer was fractionated, washed twice with saturated brine, and dried. Ethyl acetate solution #
Silica gel TL was applied to the dark colored Tsukuda Chi which was widened and then IA sardine.
Purification on C& afforded crystalline 1-(1'-iodopropyn-3'-yl)-2-carbomethoxyvirol.

Sound collection 149■ (51%) 0 Elemental analysis value C: 38.01
%, )i: 2.99%+N: 4.67%,
■=42.90%, C,) Calculated value C as 18NO2I: 37.39 excellent.

H: 2.79%, N: 4.85%, 1:
42.90%, IR spec book @ Ming's -j type CI)
The new virol cast conductor shown in is a compound of aqueous composition, and is useful as an anti-plane and anti-mold agent. The compound gI of the present invention has a growth inhibiting effect on mold #IVc, so it is used in medical, agricultural, and industrial applications due to the growth of mold and mildew. It is useful for numeric values of various conditions. That is, for medical purposes, ff! The active ingredient of the i-drug and ointment is 0.1 to 5, preferably 0.5 to 5.
It can be mixed in a range of 2% and applied to the affected area to achieve the therapeutic goal. In addition, it can be used as an active ingredient in RSM systems for machinery and equipment, for medical purposes, to prevent the growth of mold and mildew, and to preserve a free environment.

Furthermore, the pyrrole-bound conductor represented by formula (I) of the present invention exhibits Ishikawa properties when used in agricultural and industrial packaging. Particularly in these fields, examples include seeds, lumber, and woodwork, handicrafts, leather, leather, and l! The occurrence of spoilage bacteria and mold in the clothing, confectionary products, and their manufacturing environment, such as drinking water, causes a serious loss in the value of the product. Since the Hiroru absorbent material of the present invention exhibits a growth inhibiting effect on harmful molds in the agricultural and industrial fields, it can be used for the purpose of maintaining the quality of products in these fields and preserving the environment. be able to.

In the agricultural and industrial fields, the virol I conductor of the present invention can be used in preparations held on commonly used carriers, such as oil solvents, emulsions, pastes, powders, wettable powders, aerosols, and antifungal paints. It can be opened. Examples of carriers used include clay, talc, bentonite, kaolin, silicic anhydride, inorganic solid carriers such as rehydrated calcium, tyrosine, ligroin, xylene, DNLF', D
Gas carriers such as MSO-ji's bathing medium, dimethyl ether, and chlorofluorocarbon gas are used, and ionic and nonionic viscosity agents are used as additives to enhance the formulation effect. There are polymer compounds such as vinyl acetate and methylcellulose, and they can be used in combination with other antiseptics and fungicides such as thiapendazole, and insecticides such as chlordane.

The content of the virol derivative of the present invention in actual use may be determined depending on the formulation, but is generally 0.
Examples of formulations as industrial and industrial antibacterial and antifungal agents having a suitable range of 0.01 to 951 weight, preferably 0.2 to 10 weight are given below. Formulation Example 1 Wettable powder 1-( 1'-iodopropyn-3'-yl)-2,3-
Cycloro 4-nitropyrrole 40 K 1 tm and polyoxine ethylene alkylaryl ether 5 K mold part, lignin sulfone CI! 3m [k section and 52mkl of clay
By uniformly pulverizing and mixing 1.5 lbs., a water) Fl agent containing 40 g of the active ingredient is obtained.

formulation? 1"2 Edge agent 1-(1'-iodopropyn-3'-yl)-2,3-
12 parts by weight of dichloro-4-nitrovirol, 1 part by weight of IJ calcium geninsulfonate, 30 parts by weight of bentonite and 57 parts by weight of clay were uniformly ground and mixed, then an appropriate amount of water was added and kneaded. Formulation Example 3 Emulsion 1-(1'-iodopropyn-3'-yl)-3-nitrovirol 20 parts by weight, dimethylformamide 30 parts by weight. ili [parts, 3511 parts of xylene, 1st part of polyoxyethylene alkylaryl ether 151 parts] When uniformly mixed, an emulsion containing 20 parts of the active ingredient is obtained. Formulation Example 4
Powder 1-(1'-iodopropyn-32-yl)-2,3-
Dichloro-4-nitropyrrole 3m [fi part, anhydrous silica #
Value powder 0.5m Sumirebe, calcium stearate 0.5
By uniformly crushing and mixing the m-type part, clay 50 base part, and talc 46 JL part, a powder containing 3% of the active ingredient can be obtained.

Next, as an example specifically demonstrating the usefulness of the virol derivative of the present invention, 3-(1'-iodopropyn-3'-yl)
-2,3-dichloro 4-nitrovirol [addition product (1
)], 1-(1'-iodopropyn-31-yl)-3
- Acute toxicity of nitrovirol (compound '#12)) (Table 1
) The antibacterial, antifungal activity (clothes 2, 3, and 4) and the effects on athlete's foot infection in guinea pigs are described in detail.

An autopsy was performed on the 8th #M festival after administration, but no toxic effects were found.

Table 3 Antifungal activity (industrial use) Table 4 Antifungal activity (agricultural use) Treatment experiment example White Hartly guinea pig (
- side 3 animals) dorsal skin 4 pieces/9r (left stone each 2, 4 x 6 m
) after removing the sutures, Trichophyton mentagrophytenu suspension (liquid Sabouraud medium, raw I11! number 2 x 10'/
, / ) on each area by applying 0.5 d of it with a brush.

Regarding the left and right valleys of the diseased fruit skin from the 28th bacterium phase,
0.25 ml of test compound vehicle (Table 5) once a day;
It was applied continuously for 8 days.

Table 5 &! Formulation example (medical use) The same procedure was carried out for viroltodrine [3-chloro-4-(2
'-nito o-3'-10a7z nil) hia -r) 1
% fissure 4. , and clotrimazole (1-(0-chloro-
A 1% preparation of α,α-diphenylbenzyl)imidazoyl) was also tested and used as a comparison control along with a non-treatment group. Effect evaluation based on macroscopic findings included thickening of the affected skin, 1@red, m
The compounds of the present invention achieved good therapeutic results in all cases of IgI debris (Table 6).

1 Table 6 Written amendment to the procedure for therapeutic effect June 3, 1980 Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office 1 Indication of the case 1982 Patent Application No. 6609 2 Name of the invention Virol derivative and its production method and its active ingredient Relationship with the case of anti-mold law 3, person making the amendment Patent applicant address name (609) Meiji Seika Co., Ltd. 4, agent name (82) 6 > Patent attorney Masu Kobori (1) Specification page 14 page 13 Insert Example 5 below after row Example 4.

"Example 5 l-(1'-iodo10pin-3'-yl)-2-nitropyrrole

Claims (1)

[Claims] [In the formula, R1 and R2 are hydrogen atoms or halogen atoms, R
3. Either one of R4 is a hydrogen atom or halo and R
7 represents a hydrogen atom, a halogen atom, or a nitro group) and a phenyl group and a II-7enyl group. ] Pyrrole a fathom represented by. [In the formula, Rt and R2 are hydrogen atoms or] rogene atom,
Either one of BB and R4 represents a hydrogen atom or an I.rotro group. ) and substituted phenyl groups. ] The virol derivative represented by formula (III) IC! IC
-C)12X (1■) (wherein X represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester) is reacted with an iodopropylene derivative represented by formula (I) (wherein R' + R2+ R" and W have the same meanings as above). 3. Moxibustion method of virol derivative of the formula [wherein, R1, fU hydrogen atom or/・rogen atom,
An anti-fungal agent containing a pyrrole derivative represented by the following as an active ingredient.