JPH107619A - Iodoacetates and antibacterial and antifungal agent containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antibacterial and antifungal agent containing a specific iodoacetate as an active ingredient, capable of simply and inexpensively producing, having excellent antibacterial and antifungal activities and useful as a fungicide used after applying a coating material for outside wall, etc., a fungicide for fungicidal paper, a textile processing agent, etc. SOLUTION: This antibacterial and antifungal agent contains a compound of the formula ICH2 COOR R is a (substituted)cinnamyl, a (substituted)phenyl, a (substituted)benzyl, or a 2-[ (substituted)phenyl]ethyl}, preferably, cinnamyl iodoacetate, p-bromobenzyl iodoacetate or p methoxybenzyl iodoacetate as an active ingredient. In addition, the compound of the formula is obtained by reacting, e.g. a chloroacetyl chloride with the corresponding alcohol in an inert solvent in the presence of a base to afford a chloroacetyl ester and sub jecting the resultant compound to substitution reaction with a metal iodide in an inert solvent.

Description

[Detailed description of the invention]

[0001]

TECHNICAL FIELD The present invention relates to a novel iodoacetate, and further to an antibacterial and antifungal agent containing as an active ingredient the iodoacetate which is a novel or documented compound.

[0002]

2. Description of the Related Art As for iodoacetic esters, a large number of compounds have been synthesized for various purposes. Among these, as a prior document describing a compound having antibacterial and antifungal activity, JP-A-48-4442
0, JP-B-52-21577, JP-B-63-6164
5, JP-A-56-22702, JP-A-57-75902
It has been known. In the specification of JP-A-48-44420, although the claim describes the general formula _XCH2COOR (where X is a halogen atom), as examples, X is chloro,
It is limited to bromine and there are no examples of X being iodine. Moreover, R has a completely different chemical structure from the compounds related to the present invention. JP-B-63-61645 and JP-A-5
The iodoacetic esters described in the examples of the specification of No. 6-22702 also have a chemical structure at the ester group portion that is clearly different from that of the compounds related to the present invention, and they are compatible with other agents. The composition has served its primary purpose. Further, although ethyl iodoacetate described in the specification of JP-A-57-75902 has a certain degree of antibacterial activity, it is described as being volatile and lachrymatory. These drawbacks are not observed in the compounds according to the invention.

[0003]

As described above, the iodoacetic esters having antibacterial and antifungal activity described in prior art documents are of a very limited variety, and the activity can be further enhanced by converting the ester moiety. There was plenty of room for improvement. In addition, antibacterial agents other than iodoacetic esters,
It cannot be said that the large number of existing compounds with antifungal activity qualitatively satisfies the recent demand for antibacterial and antifungal agents. At present, there is a strong demand for the development of antifungal agents.

[0004] Therefore, in the present invention, by synthesizing iodoacetic esters which are completely different in chemical structure from the above iodoacetic esters, they can be obtained easily and inexpensively,
The objective was to discover compounds with excellent antibacterial and antifungal activity and to develop new antibacterial and antifungal agents.

[0005]

Means for Solving the Problems As a result of repeated investigations aimed at developing novel antibacterial and antifungal agents, the present inventors have found iodoacetic esters that are completely different in chemical structure from the above iodoacetic esters. In addition, focusing on the high antibacterial activity and high antifungal activity of the iodoacetic esters, which are novel compounds of the present application or known compounds in literature, iodoacetic esters are used for industrial and agricultural and livestock industries found to be useful as an antibacterial and antifungal agent for
The present invention was completed to solve the problem.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to the general formula (I) ICH ₂ COOR (I) [wherein R is an optionally substituted cinnamyl group, an optionally substituted phenyl group, a benzyl group optionally having a substituent, or a phenyl group optionally having a substituent 2-
phenylethyl group].

Specific examples include cinnamyl iodoacetate,
phenyl iodoacetate, p-nitrophenyl iodoacetate,
p-chlorophenyl iodoacetate, p-bromophenyl iodoacetate, p-methoxyphenyl iodoacetate, p-tolyl iodoacetate, benzyl iodoacetate, p-nitrobenzyl iodoacetate, p-chlorobenzyl iodoacetate, p-bromobenzyl iodoacetate , p-methoxybenzyl iodoacetate, p-methylbenzyl iodoacetate, 2- iodoacetate
Phenylethyl can be mentioned. However, the invention is not limited to this.

[0008] The compound represented by the general formula (I) of the present invention is produced in the following two steps. [Step 1] Chloroacetyl chloride and alcohol are reacted in an inert solvent in the presence of a base to give a chloroacetate. [Second step] A chloroacetate and a metal iodide are subjected to a substitution reaction in an inert solvent to obtain an iodoacetate.

[0009] Iodoacetic acid and iodoacetic anhydride have serious problems in terms of stability and cost. with considerable difficulty. From this point of view, the present inventors conducted various studies on the synthesis of iodoacetic esters, and found that the synthesis method consisting of the above two steps combining the chemical reactions described in the literature is simple, practical, and inexpensive. I found something.

The iodoacetic esters of the compounds of the present invention have excellent antibacterial and antifungal activities and can be used in a wide variety of applications. Specific uses of value include: Antibacterial, antifungal, deodorant, antibacterial, antifungal, antifungal agent for antifungal agent in paper manufacturing, antiseptic antifungal agent for coating slurry, antifungal agent for antifungal paper. As processing agents, antiseptic and antifungal agents for various building materials such as wood, fiber walls, wallpaper, tatami mats, carpets, caulking agents, paste agents,
For example, starch, printing paste,
Addition to laundry paste and coating adhesive for the purpose of anti-mildew effect after cloth adhesion, addition of sterilization, antiseptic, and sterilization effects to various wet wipes such as paper towels and toilet seat cleaners, liquid detergent , inks, paints, paper clay, Buddhist altar incense sticks, leather, blankets, etc.

[0011]

EXAMPLES Representative production examples and test examples of the compounds of the present invention are described below, but the present invention is not limited to these.

Example 1 Iodoacetic acid cinnamyl ester Cinnamyl alcohol (13.5 g) and triethylamine (11.1 g) were dissolved in anhydrous methylene chloride (90 ml), and chloroacetyl chloride (11.4 g) was added to 10 ml under ice-cooling.
°C or less, and reacted at the same temperature for 1 hour. The reaction mixture was washed with water (100 ml twice), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue (chloroacetic acid cinnamyl ester) was treated with acetone (210 m
l) and add sodium iodide (30 g)
The reaction was allowed to proceed at room temperature for 3 hours. After acetone was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (300 ml) and diluted with water (3
00 ml), then aqueous sodium thiosulfate (200
ml) and then water (200 ml), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent.
The title compound (25.9 g, yield 85.8) as a pale yellow oil
%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 3.71
(2H, s, _ICH2COOCH2CH = _CHC6H5 ), 4.77 _{( 2
H} , d, J= ₆ Hz, ICH2COOCH2CH _{= CHC6H5} ), 6.2
_1-6.31 ( 1H , m, _{ICH2COOCH2CH = CHC6H5} ),
6.67 ( 1H , d, J= _16Hz , _ICH2COOCH2CH =CHC
_6H5 ), _7.23-7.40 (5H, m, _{ICH2COOCH2CH =
CHC6H5 )}

Example 2 Iodoacetic acid benzyl ester benzyl alcohol (10 g) and triethylamine (1
8 ml) was dissolved in anhydrous methylene chloride (200 ml),
Chloroacetyl chloride (12.6 g) was added dropwise at 10°C or lower under ice-cooling, and the mixture was further reacted at the same temperature for 1 hour. The reaction solution was washed with water (200 ml twice), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue (chloroacetic acid benzyl ester) was dissolved in acetone (170 ml), sodium iodide (27.8 g) was added and reacted at room temperature for 3 hours. After acetone was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (260 ml) and water (300 ml) was added.
l), then aqueous sodium thiosulfate solution (200 m
l) and then water (200 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a pale yellow oil (23.8 g, yield 93.0).
%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 3.71
(2H, _s , _{ICH2COOCH2C6H5} ), _{5.16 (} 2H, s,
_{ICH2COOCH2C6H5} ), _{7.36 ( 5H} , _{s , ICH2COOCH2C6
H5} )

Example 3 Iodoacetic acid p-nitrobenzyl ester p-Nitrobenzyl alcohol (10 g) and triethylamine (12.7 ml) were mixed with anhydrous methylene chloride (100 ml).
l) and added to chloroacetyl chloride (6.2 m) under ice-cooling.
l) was added dropwise at 10° C. or lower, and the mixture was further reacted at the same temperature for 1 hour. The reaction mixture was washed with water (100 ml twice), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue (chloroacetic acid p-nitrobenzyl ester) was dissolved in acetone (150 ml), sodium iodide (19.5 g) was added, and the mixture was reacted at room temperature for 3 hours.
After acetone was distilled off under reduced pressure, the residue was treated with ethyl acetate (20
0 ml), water (300 ml), then aqueous sodium thiosulfate solution (200 ml), and further water (200 ml).
l) and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give the title compound (1
8.9 g, yield 90.6%).

¹ H-NMR (CDCl ₃ ) δ: 3.80
₍ 2H, _s , _{ICH2COOCH2C6H4NO2 -} p), 5.29 ( _2
H , _s , _{ICH2COOC H2C6H4NO2 -} p), 7.57, 8.24
(each 2 H, each d, each J = 9 Hz, ICH ₂ COOCH _{2
C6H4NO2 - p} )

Example 4 Iodoacetic acid p-bromobenzyl ester Synthesized in the same manner as in Example 3 using p-bromobenzyl alcohol. ¹ H-NMR (CDCl ₃ ) δ: 3.72 (2H, s,
_{ICH2COOCH2C6H4Br -} p), 5.10 ₍ 2H, _s , _{ICH2COO
CH2C6H4Br -} p), 7.24, 7.49 ( _each 2H, each
_d , each J= _8Hz , _{ICH2COOCH2C6H4Br -} p)

Example 5 Iodoacetic acid p-methoxybenzyl ester Synthesized in the same manner as in Example 3 using p-methoxybenzyl alcohol. ¹ H-NMR (CDCl ₃ ) δ: 3.69 (2H, s,
_{ICH2COOCH2C6H4OCH3 -} p), _{3.81 ( 3H} , s, OC
H3) _{, 5.11 ( 2H} , s _{, ICH2COOCH2C6H4OCH3-}
p), 6.90, 7.32 (each 2H, each d, ea
chJ _{= 8Hz , ICH2COOCH2C6H4OCH3 -} p)

Test Example 1 Antifungal Activity Test The compound of the present invention was dissolved in 100-fold dimethyl sulfoxide, and this solution was further diluted with 500-fold water to give a concentration of 20.
ppm, and a medium consisting of potato, glucose, and agar (P
DA medium) to prepare a plate medium (sample concentration: 10 ppm).

On the other hand, five kinds of fungi, Aspergillus niger, Penicillium funiculosum, Aureobasidium
Aureobasidium pullulans, Cladosporium cladospori
oides), Gliocladium virens
ens), respectively, spores were collected from a slant culture medium and suspended in an aqueous solution of dioctyl sodium sulfosuccinate to obtain a spore suspension. Five kinds of spore suspensions thus obtained were combined to form a mixed spore suspension, which was cultured by spraying a fixed amount on the plate medium. The results are shown in Table 1.

[0022] Cultivation conditions: temperature 28±2° C., relative humidity 95% or more, period 7 days −: Absolutely no fungal growth was observed on the surface of the plate medium. ±: Almost no fungal growth is observed on the surface of the plate medium. +: Fungi growing on the surface of the plate medium was less than 10% of the surface area. +++: Fungi developed on the surface of the plate medium accounted for 10 to 70% of the surface area. ++++: Fungi developed on the surface of the plate medium accounted for 70 to 100% of the surface area.

Since thiabendazole used as a comparative example is a substance well known as an excellent antifungal agent,
This result fully satisfies the antifungal activity currently required.

Test Example 2 Antibacterial/Antifungal Activity Test The minimum inhibitory concentrations (MIC μg/mg) of the compounds of the present invention against various bacteria and fungi are shown in Table 2 below.

Test Example 3 Weather Resistance Test of Mixed Painted Surface In order to evaluate applicability as an antibacterial/antifungal agent for paint mixture, a weather resistance test of mixed painted surface was carried out. A predetermined amount of the compound of the present invention is mixed in a urethane paint for wood, applied to a piece of wood to make a test piece, and subjected to an accelerated weather resistance test by the 9.8.1 sunshine carbon arc lamp method in JISK5400 (1990) general test methods for paints. rice field. test time is 30
0 hours (observations were made at 100 hours and 200 hours as intermediate progress), and evaluation was made by visual inspection.

[0026] The evaluation criteria were the following five grades. Evaluation criteria A: Almost no change B: Change observed (no abnormality in the coating film) C: Some coating film defects (cracks, peeling, etc.) D: About half of the coating film defects E: Defects in the coating film were observed throughout. The test results are shown in Table 3. TPN: Tetrachloroisophthalonitrile

From the above results, it was found that the addition of the compound of the present invention to the urethane paint for wood did not impair the weatherability of the painted surface compared to the non-additive control paint. Also, 1.0
% addition group showed improvement in weather resistance equivalent to that of the control compound in both test compounds, and in addition, in the 0.5% addition group, both test compounds exhibited weather resistance improvement superior to that of the control compound. From these facts, the compound of the present invention is a control compound TPN
It was also suggested that it could be used as an antibacterial and antifungal agent for paints.

[0028]

INDUSTRIAL APPLICABILITY The iodoacetic esters of the compounds of the present invention exhibit excellent antibacterial and antifungal activities. INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide novel or literature-known compounds that can be widely used in various applications as antibacterial agents and antifungal agents.

──────────────────────────────────────────────────── ──── continuation of the front page (72) Inventor Yasushi Murai Meiji Seika, 788 Kayayama, Odawara City, Kanagawa Prefecture Pharmaceutical Technology Laboratory Co., Ltd. (72) Inventor Katsuharu Iinuma Meiji Seika, 788 Kayayama, Odawara City, Kanagawa Prefecture Pharmaceutical Technology Laboratory Co., Ltd.

Claims (11)

[Claims] 1. The following general formula (I): ICH ₂ COOR (I) [wherein R is an optionally substituted cinnamyl group, an optionally substituted phenyl group, an optionally substituted a benzyl group, or a phenyl group which may have a substituent 2
-Phenylethyl group], an antibacterial and antifungal agent containing an iodoacetic acid ester as an active ingredient 2. The antibacterial and antifungal agent according to claim 1, wherein in the general formula (I), R is a cinnamyl group. 3. The antibacterial and antifungal agent according to claim 1, wherein in formula (I), R is a substituted cinnamyl group. 4. The antibacterial and antifungal agent according to claim 1, wherein R in general formula (I) is a benzyl group. 5. The antibacterial and antifungal agent according to claim 1, wherein in general formula (I), R is a benzyl group having a substituent. 6. The antibacterial and antifungal agent according to claim 1 or 5, wherein in general formula (I), R is a p-nitrobenzyl group. 7. The antibacterial and antifungal agent according to claim 1 or 5, wherein in general formula (I), R is a p-bromobenzyl group. 8. The antibacterial and antifungal agent according to claim 1 or 5, wherein in general formula (I), R is a p-methoxybenzyl group. 9. Of the compounds represented by formula (I), R
is a cinnamyl group iodoacetic acid cinnamyl ester 10. Among the compounds represented by formula (I),
iodoacetic acid p-bromobenzyl ester wherein R is p-bromobenzyl group 11. Among the compounds represented by formula (I),
iodoacetic acid p-methoxybenzyl ester wherein R is p-methoxybenzyl group