JPS5862159A - Pyrrole derivative, its preparation and anti-bacterial and antifungal agent containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The pyrrole derivative of formulaI[R<1> and R<2> are H or halogen; one of R<3> and R<4> is H or halogen and the other is nitro, lower alkoxycarbonyl or (substituted) phenyl of formula II (R<5>-R<7> are H, halogen or nitro)]. EXAMPLE:1-(2,3,3-Triiodoallyl)-2,3-dichloro-4-nitropyrrole. USE:Antibacterial agent and antifugal agent. It has high antifungal activity than pyrrolomycin and other pyrrole compounds. PROCESS:The compound of formulaIcan be prepared by reacting a reactive derivative of triiodopropene of formula II (X is halogen or OH esterified with sulfonic acid) with the pyrrole derivative of formula III in an inert solvent (e.g. N,N-dimethylformamide) in the presence of a base (e.g. triethylamine).

Description

[Detailed description of the invention] The present invention relates to general formula (I) Possible, CI=CI.

[In the formula, 'Et''m　R'' is a hydrogen atom or a halogen atom, and R'' and R' are either a hydrogen atom or a halogen atom, and the other is a nitro group, (in the formula, R'@R' w R' is a phenyl group or substituted phenyl group represented by a hydrogen atom, a halogen atom, or a nitro group]

The present invention relates to virol derivatives shown in the following, their production methods, and antibacterial and antifungal agents containing them as active ingredients.

The present inventors first detected a new antibiotic, 8F-208OA (pyrrolomycin A), in fermentation products of microorganisms at 4.1%.
A patent application was filed for the substance, its production method, and an antifungal agent containing it as an active ingredient (脣H@56-90099).

Patent, lid 55-141123). Next, the present inventors modified the structure of pyrolomycin A through a chemical reaction for the purpose of enhancing its antifungal activity, and found that when a triiodoallyl group was introduced onto the virole nitrogen of the pyrrolomycin substance, the antifungal activity was enhanced. They found that the antifungal activity was significantly enhanced not only in virolomycin but also in other virol compounds by introducing a triiodoallyl group. They discovered this and completed the present invention.

Examples of virol derivatives provided by the present invention include the following.

+111- (2,3,3-) lyodo allyl) -2,
3-dichloro-4-nitropyrrole+211- (2,3,3-triiodoallyl)-2-
Chloro-4-nitrovirol, +311- (2,3,3-)su■-dooryl)-3-
Nitrovirol + 411- (2,3,3-)su-doallyl)-2,
3-di10n-4-ethoxycarbonylvirol +51
1- (2,3,3-)lyodoallyl)-2,3-
dipaa-4-,+)oxycarbonylpyrol16)
1-(2,3,3-triladallyl)-2-chloro-4-ethoxycarbonylvirol+711-(2,3,3-triladallyl)-3-
Ethoxycarbonylvirol +811-(2,3,3-)lyodoallyl)-3-methoxycarbonylvirol+911-(2,3,3-triiodoallyl)-3-
Chloro0-4-(3'-chloro-2-21-day phenyl)virol Q ($1- (2,3,3-)rizono-doallyl)-3-
(3'-chlorophenyl)virol (1111-(2,3,1-)aryl)-3-
7-enylvirol function 1-(2,3,3-)sodium-doaryl)-2
,3,5-trichloro-4-nitrovirol (I-(2,3,3-)sulfur-doaryl)-2,3
-dichloro-5-methoxycarbonylvirollo 1-(
2,3,3-19iodoallyl)-4-chloro-2-methoxycarbonylvirol (1491-(2,3,3-)!1m-47shik)-2
-)) Medium dicarbonylvirol a.1-(2J,3-)su1-doaryl)-2-nitrovirol The novel compound (I) according to the present invention is produced by the following reaction formula: - Reactivity of conductor (II) (In the reaction formula, X represents a halogen atom or a hydroxyl group esterified with sulfonic acid, and R1, R1, R1 and R4 represent the above) and virol compound (III) as a base. It is produced by reacting in the presence of. Among the starting materials used in the production of the substances of the present invention, triiodopropene sieve conductors are produced by the method described in Jibun II 849-24445, and virol derivatives ([[I)051.2.
3-diIrolow 4-nitrovirol and 3-chloro-(
3′-chloro-21-nitrophenyl) virol is known as Arashi as a calling destination for microorganisms, and
-Nitrovirol Fif trahedron (T@trah@
dlon), page 2z@sr (1966);
ry), Vol. 50, p. 3223 (1972, 1), and the other starting materials are synthesized by applying the above-mentioned production method of Kuyume.

According to the present invention, the pyrrole derivative represented by the formula (I) is synthesized according to the above-mentioned method, and a pyrrole compound <m> which is a starting material is mixed with an inert solvent #l#L, and a base are added to form a triiodoallyl group on the pyrrole nitrogen of (III), which is the so-called N-alkylation reaction. Examples of inert solvents used in this reaction include Hiroshi, Pen, dioxane, and dichloromethane.

N,N dimethylformand is mentioned, preferably HN
, N dififylformamide, and t* base.

Examples include non-virtuous bases such as alkali hydroxides and alkali carbonates, as well as organic bases such as triethylamine. When using the reaction alkali hydroxide, it is carried out under cooling, preferably at 0 to 5°C, but at 40 to 50°C in the presence of an organic base.
Precipitation is carried out by adding a solvent such as water to 80° C., or an organic solvent such as ethyl acetate is used for extraction, or if necessary, a well-known sliding method is used, e.g. This is carried out in combination with silica gel chromatography or recrystallization.

An embodiment of the novel virole-conductor (I) manufacturing method according to the present invention will be described in detail below.

Example 1 1-(2,3,3-)lyodoallyl)-2,3-dichloro-4-nitrovirol 2,3-') lrolow-4-nitrovirol (hyloromycin A) 220 q (1,2 mmol) Dry N, N
- Dimetherforma 10dKII, 2,3.3
-triiodoaryl p-) luenesulfonate 606
q (1 mmol) and triethylamine 0.14 mg
(1 mmol) was added and heated to 60°C for 30 minutes. After cooling, add 20 - of cold water while stirring 11 tons.
After stirring for 11 hours, the precipitated 1-(2,C3-triiodoallyl)-C3-dichloro-4-nitrovirol crystals were filtered, washed with water, and dried.

Yield 5a7q (yield 95%), mp 126-1
27℃ single element analysis value C: 14.341 H: 0.5
3%, N: 4.611s, CL and Hi l-76
,15%, Calculated value C as CyHiNmO*CA*Im: 14.04 whisper, )l: 0.51-,
N: 4.68-, CL: 11.84*.

I: 6m, 59 arrogance, mass spectrum;? sssP1
i2 1-(2,3,3-)su-doaryl)-3-nitrovirol 3-nitrovirol 112q (1 mmol) was dissolved in 5.0 dK111 of dry dimethylformamide to give 2.3.3-
) Lyodoallyl p-toluenesulfonate 6061
9 and powdered sodium hydroxide 60111f (t,
S<limole) was added, stirred, and reacted for 15 minutes. Ethyl acetate) & 5o- and water 5o- were added to the reaction solution for extraction, and the ethyl acetate layer was separated. Wash the ethyl acetate layer with water,
After drying, it was evaporated under reduced pressure, and the residue was mixed with 2.
5- was added, and the precipitated 1-(2,3,3-triiodoallyl)-3-nitrovirol crystals were filtered. Yield 5 oeqc yield 56%), mp, 107-109
℃ 1 elemental analysis value C: 15.85%, H: 0.8
5-, N: 5.14% + I: 71.82-e
Calculated value C as c, a, N, o, r: 15.
86-, H: 0.95*, N: 5.29 Excellent, I: 71.85-〇Example 3 l-(2,3,3-)rimole-doaryl), -2,3-dichloro-4 -Ethoxycarbonylpyrrole 2,3-dichloro-4-ethoxycarbonylpyrrole 104 W (
0.5 mmol) was dissolved in dry N,N-dimethylformamide 5-, and 2,3.3-)
Toluene sulfonate aoa q (o, s mmol)
and 0.07 m (0.5 mmol) of triethylamine were added and heated to 60°C for 2 hours. Reaction Cool the S solution, add 10 sd of cold water while stirring, and precipitate 1.
-(2,3,3-trisulfate-doallyl)-2,3-cyclo-4-ethyl dicarbonylvirol crystals were filtered,
Washed with water and dried 90 Yield 281 wi (Yield sol)
lnp, 117-119℃ 1-element analysis value C: 1
9j! 3s.

S, H: 1.24-, N: 2.25$,
CL and I: 71.97%.

fart. ) Calculated value C as I, NO, OL, I: 19
191G, H: 1.2Q%, N: 224%
, CL: 1t, aa-, I: 60J4*.

Example 4 1-(2,3,3-)lyodoallyl)-3-chloro*
1s-4-(3'-chloro-2-nitrophenyl)
Virol 3-chloro-4-(3-chloro-2-nitrophenyl)
Virol t2g 1151 (0-5 mmol) was dissolved in dry N,N-dimethylformamide 5-4C, 2,3
．． 3-tvw-doaryl p-toluenesulfonate 3
03 q (0,5 mmol) and sodium hydroxide powder 24IIIP (o, 6 mmol) were added for 1 hour 25
The reaction was carried out at ℃. Add 30% of ethyl acetate and 30% of water to the reaction solution.
- was added for extraction, and the ethyl acetate layer was separated. The ethyl acetate solution was washed with water, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (solvent system: benzene) to give 1.1-(2,3,3-triiodoallyl)-3-chloro. -4-(3'-chloro-2'-nitrophenyl)virol 222q (yield 5olt-obtained).

Elemental analysis value C: 1% to 23, H: 1.08%
, N: 4.45%.

C11H7NI Ox Cts Is and teno analysis W
e: 23.15%, H: 1.05%, N
: 4.15%.

Example 5 125 K(1
ζlimol) was dissolved in dry dimethylformamide 5-,
Cool to 10°C 2, 3.3-)
-Add 590q (1 mol) of toluene sulfonate and 50q (1,2i!J mol) of powdered sodium hydroxide and stir for 1 hour.9.

Ethyl acetate and water were added to the reaction solution for extraction, and the 4-methyl acetate layer was separated, washed with water, and dried. Concentrate the ethyl acetate solution under reduced pressure, add 1.0-methanol to the remaining oil, and leave to stand to form crystals of 1-(2,3,3-tri-doaryl)-2-methoxycarbonylpyrrole. It precipitated, so filter it out. Yield 127 kg (Yield 2311)
, mp, 88-90℃ 0 element single analysis value C: 19.6
G-, H: 1.50-, N: 2.77%,
I: 69 ri, 6 rice cakes.

Calculated value C as C, H, No, I: 1G, 91%
, H: 1.411g, N: 258fk -
I: yo, ta*.

The novel virol derivative (I) of the present invention is a low toxicity compound and is useful as an antibacterial and antifungal agent. In particular, since the compound of the present invention has a growth inhibiting effect on a wide range of fungi, it is of little use in preventing or improving unfavorable conditions caused by the growth of fungi. That is, for medical purposes, it can be used as an active ingredient in products aimed at preventing and treating various infectious diseases caused by fungi, killing instruments and machines, and preserving a sterile environment. Furthermore, the compounds of the present invention can be used as agricultural and industrial fungicides and preservatives, for example, for the purpose of maintaining the quality of agricultural and industrial products such as seeds, wood and wood products, paper products, leather, and textile products. It can also be used as an active ingredient in cast mold paints.

The novel virol derivative (I) of the present invention is a low toxicity compound and is useful as an anti-9 antifungal agent. In particular, since the compound of the present invention exhibits anti-Wlili activity against a wide range of molds, it is used in various fields of medicine, agriculture, and industry to prevent unfavorable conditions caused by the growth of molds and molds. It is useful for improvement. That is,
For medical use, for example, as a therapeutic agent for external diseases caused by fungi such as Yandida, Aspergillus, Trichophyton, and Kligtococcus, the active ingredient of liquid preparations and ointments preferably ranges from 0.1 to 5-1. is 0.
Oj! can be mixed in the range of 5 to 2 and applied to the affected area to achieve the therapeutic goal! In addition, for medical purposes, it can be used as a disinfectant for machinery and tools, and as other active ingredients to prevent the growth of pathogens and fungi, and to maintain a sterile environment.

Next, the compound (I) of the present invention also shows usefulness in the agricultural and industrial O fields. 41. In these fields, for example, seeds, seedlings, wood, and wood products9 paper crafts and crafts,
The occurrence of mold and mildew in agricultural and industrial products such as leather, II adhesives, paints I, and synthetic resins, and their manufacturing environments, for example, in drinking water, causes a serious loss in the value of the products. Since the compound of the present invention exhibits a growth inhibiting effect on harmful S-1 molds in the agricultural and industrial fields, it can be used for the purpose of maintaining the quality of #1 products in these fields and preserving the environment. In the agricultural and industrial fields, the compound of the present invention is used in formulations supported on commonly used carriers, i.e., oil solvents,
Examples of carriers that can be used include emulsions, pastes, powders, wettable powders, aerosols, and antifungal paints. Examples of carriers that can be used include clay and Merck.

Inorganic solid carriers such as bentonite, kaolin, S-hydrosilicate, calcium vertical oxide, tyrosine, ligroin, xylene,
Examples include organic solvent carriers such as DMF and DMSO, dimethyl ether, and gas carriers such as chlorofluorocarbons.As adjuvants to further enhance the formulation effect, ionic and nonionic surfactants, vinyl acetate, methylcellulose, etc. It is a patented preservative characterized by a high molecular weight compound, thiabendazole, and can be used in combination with fungicides and insecticides such as chlordane.

The content of the compound of the present invention in actual use may vary depending on the formulation, but it is generally within the range of 0.01 to 95.
A suitable range is 0.2 to 10% by weight, preferably 0.2 to 10% by weight. Examples of formulations as agricultural and industrial antibacterial and antifungal agents are listed below.

Formulation Example 1 Wettable powder Compound-r (1140 parts by weight), 5 parts by weight of polyoxyethylene alkylaryl ether, 3 parts by weight of Ligni/Sulfone #3 and 52 parts by weight of diatomaceous earth are uniformly ground and mixed to form the active ingredient 40-. Formulation Example 2 A wheel compound (17112 parts by weight, 1 part by weight of calcicum lignosulfonate, 30 parts by weight of bentonite) was uniformly pulverized and mixed with 57 parts by weight of clay, and then an appropriate amount of After adding water and kneading, the mixture is granulated and dried to obtain granules containing 12 active ingredients.

Formulation Example 3 Emulsion compound f3+ 20 parts by weight, dimethylformamide 30
By uniformly mixing 1 part by weight, 35 parts by weight of xylene, and 151 parts by weight of polyoxyethylene alkylaryl ether, an emulsion containing 20 parts of 7 active ingredients is obtained.

Formulation Example 4 Powder Compound (1) 3 parts by weight, boric anhydride fine powder 0.5 parts by weight, stearin calcium 0.5 parts by weight, clay 50
By uniformly crushing and mixing 46 parts by weight of Merck and 46 parts by weight, a powder containing 3Ls of the active ingredient is obtained.

Next, as examples specifically showing the usefulness of the compounds of the present invention, acute toxicity (Table 1) and anti-1. Antifungal activity (Tables 2.3.4 and 5) and wood Table 2 in guinea pigs Antibacterial activity Table 3 Antifungal activity (medical use) Table 4 Antifungal activity (industrial use) 5I6 Antisodic, antifungal activity (agricultural use) Treatment experiment example: 4 dorsal skin areas (2.4 x 6 cl 11 each on the left and right) of a white Hartly strain (3 negative reviews)
After removing the sutures, Trichophyton mentagrophytes suspension (sabouraud culture medium, live number 2 x 1-0/wf)
Apply to each area (OA-1) with a brush. Two days after mw building, a preparation of the test compound (tI & 6) was applied at a dose of 0.25 l per day for 8 consecutive days to one site on each side of the skin of the lesion.

Table 6 Formulation example (medical use) Similar operations were performed to prepare virolnidoline [3-riha-ro'4-
(寥′-nitroj-chlorophenyl)virol]l-
formulation, and cusetripul (1-(0-ri p-low α,
The α-diphenylbenzyl)yl)xllll agent was also tested and combined with the untreated group to serve as a comparison control. When the effects were evaluated based on macroscopic findings, the compounds of the present invention showed good therapeutic results in terms of thickening, flushing, and flaking of the affected skin (Table 7).

After 8 days of application, the guinea pigs were sacrificed, three skin sections were taken from each lesion, and cultured on Sabouraud agar plates for 7 days.
The positive rate of reduced culture was measured and a clear decrease in the positive rate of reduced culture was observed when compared to the group administered with the compound of the present invention, the control drug administered group, and the Wuxi control group #PK (Table 8).

Table 8 Reduction culture positivity rate
given name)

Claims (1)

[Claims] [In the formula, &'*R'' is a hydrogen atom or a halogen atom, R''lB' is a hydrogen atom or a halogen atom, and the other is a nido group or a lower alkoxy A carbonyl group, or a phenyl group represented by the formula (wherein B', R@e R' is a hydrogen atom, p-gen atom or nitro group) and an Ili-substituted phenyl group] A pyrrole derivative represented by the following formula: 2. The reactive rust conductor CI, -eI-CH, -X (II) of triodogukpen represented by the formula (in the formula, X represents a halogen atom or a hydroxyl group esterified with sulfonic acid). in an inert solvent, in the presence of a base,
2■ [In the formula, Bl, R1 company hydrogen atom 4L<Hirohalogen atom
11. One of R4 is a hydrogen atom or a halogen atom, and the other is a nido group, (in the formula Ra, B@, R
1 is a phenyl group represented by a water bulk atom, a halogen atom (paternal nitro group), and a substituted phenyl group]. R'' and R4 represent the above-mentioned compounds.
``*R' is either a hydrogen atom or a halogen atom, and the other is a nitro group, (in the formula R'', a phenyl group represented by a hydrogen atom, a halogen atom, or a nido group) group and substituted phenyl group] An antibacterial and antifungal agent containing a pyrrole conductor represented by the following as an active ingredient.