JPH04264003A - Poly-p-hydroxystyrene derivative-based antimicrobial and mildewproofing agent containing nitrogen-containing substituent group - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

[Industrial Field of Application] The present invention relates to cationic poly-p-
This invention relates to an antibacterial/antifungal agent containing a hydroxystyrene derivative as an active ingredient. More specifically, the present invention provides poly-p-
A poly-p-hydroxystyrene derivative in which hydroxystyrene is used as a basic polymer and a pyrrolidinomethyl group or piperidinomethyl group is introduced therein, or the pyrrolidinomethyl group or piperidinomethyl group is made into a quaternary ammonium salt using a certain alkyl halide. poly-p
-An antibacterial/antifungal agent containing as an active ingredient a hydroxystyrene derivative or a poly-p-hydroxystyrene derivative into which a nitrogen-containing substituent and a halogen as described above are introduced.

[0002] As damage caused by bacteria and fungi, humans,
Diseases of animals, plants, etc. and spoilage of food have been well known for a long time, but with the advancement of industry, the damage caused by these diseases has now increased to include metals, plastics, paints, fibers, adhesives, electrical and electronic materials, packaging materials, etc. Damage countermeasures are becoming increasingly important in a wide range of fields, including water-based lubricants, wood products, and cosmetics. The present invention provides a polymeric antibacterial/antifungal agent that can be widely applied to the various fields mentioned above.

0003

BACKGROUND OF THE INVENTION Antibacterial and antifungal agents that prevent or suppress the growth of bacteria and mold are a category of disinfectants in a broad sense. In the past, organic mercury compounds such as phenymercuric acetate, organic tin compounds such as tributyltin acetate, and organic chlorine compounds such as pentachlorophenol were frequently used as disinfectants, but they became a major social problem due to their toxicity, and are currently being used as disinfectants. Its use is prohibited. As an alternative, many types of disinfectants containing sulfur and nitrogen have been developed, but most of these are low-molecular compounds and pose a risk of dissipating and causing secondary pollution, and lack toxicity and antibacterial performance. There are still problems in that the results are not completely satisfactory. In order to improve these problems, attempts have recently been made to polymerize drugs. For example, cationic polymers such as vinylbenzylammonium salts, vinylpyridinium salts, and biguanidines have been used as polymeric disinfectants. Well known. Among these, biguanidine-based polyhexamethylene biguanide hydrochloride (trade name: Proxel 1B
) is one of the few commercialized examples. Literature (
For example, Kawabata, "Polymer Processing" 37, 574 (1988
)), quaternary ammonium salts and biguanidine derivatives have stronger bactericidal power when made into polymers as described above, and although they exhibit excellent bactericidal effects against Gram-positive bacteria, they are effective against Gram-negative bacteria and fungi. It has been reported that the bactericidal effect is extremely low regardless of its molecular weight.

[0004] Also, as a polymeric bactericidal agent, JP-A-56
Publication No. 120601 describes poly-p-hydroxystyrene, those in which a halogen or sulfonic acid group is introduced into the core, those in which the phenolic hydroxyl group is made into a salt, and those in which the phenolic hydroxyl group is made into an ether bond or an ester bond. In addition to the proposed anti-bacterial and anti-mildew products, 8
, (9), 1 (1990) describes antibacterial and antibacterial properties of poly-p-hydroxystyrene in which a dimethylaminomethyl group has been introduced into the nucleus and the dimethylaminomethyl group has been made into a quaternary ammonium salt with methyl bromide. Mold properties have been reported. Poly-p-hydroxystyrene and its derivatives disclosed in the above-mentioned JP-A-56-120601 exhibit appropriate antibacterial and antifungal properties against Gram-negative bacteria and molds, but against Gram-positive bacteria. shows no antibacterial activity. In addition, poly-p-hydroxystyrene having a dimethylaminomethyl group and its quaternary ammonium salt shown in the above-mentioned document "Bacteria and Mildew" exhibit some degree of antifungal activity, but their antibacterial activity is extremely low. low.

[0005]

[Problems to be Solved by the Invention] The purpose of the present invention is to solve the problems of conventional antibacterial and antifungal agents, and to provide a polymer-based antibacterial and antifungal agent that has a wide antibacterial spectrum and is nonvolatile and long-lasting. Our goal is to provide fungicides. Another object of the present invention is to provide an antibacterial/antifungal agent that is harmless to the human body without causing environmental pollution or abnormalities in the ecological distribution system. Still other objects of the present invention are that the present invention is stable against heat, light, etc., does not deteriorate over a long period of time, and has good compatibility and dispersibility with various applicable materials such as plastics, paints, and adhesives. The object of the present invention is to provide a so-called multifunctional antibacterial/antifungal agent that exhibits functions such as reactivity (crosslinking) and catalytic action with respect to the matrix polymer depending on the type of material to which it is applied.

[0006]

[Means for Solving the Problems] As a result of intensive research to achieve the above object, the present inventors have developed a poly-p-hydroxystyrene-based polymer having a pyrrolidinomethyl group or a piperidinomethyl group introduced therein. -p-
Introducing a hydroxystyrene derivative, a poly-p-hydroxystyrene derivative in which the pyrrolidinomethyl group or piperidinomethyl group is made into a quaternary ammonium salt using a certain alkyl halide, or a nitrogen-containing substituent and a halogen as described above. The present invention was made based on the discovery that the poly-p-hydroxystyrene derivatives obtained above exhibit a wide antibacterial spectrum and are harmless to the human body, and that the above objects can be achieved by using the poly-p-hydroxystyrene derivatives as an active ingredient. completed.

Therefore, the gist of the present invention is that the general formula (I
)

embedded image In the formula, X1 is a halogen atom selected from bromine, chlorine, and iodine. Y is

[Chemical formula 8]

[Chemical formula 9]

[Chemical formula 10]

[Chemical formula 11] (However, R is an alkyl group having 6 to 14 carbon atoms, and
2 is a halogen atom selected from bromine, chlorine, and iodine. ) is a nitrogen-containing substituent selected from p is 0 or 2; when q is 1, p is 0 or 1; when q is 2, p is 0; ] is an essential constituent unit, and if a constituent unit other than the essential constituent unit is included, the remaining constituent units are represented by general formula (II).

[
embedded image where X1 is the same as above, and p' is 0, 1 or 2. ], and when it contains a structural unit represented by the above general formula (II), each of the structural units represented by the above general formula (I) and general formula (II) are randomly combined, Degree of polymerization is 5-100
0, and the number of halogens (X1) introduced per hydroxystyrene unit is in the range of 0 to 1.9 on average with respect to all hydroxystyrene units, and the nitrogen-containing substituent (Y) is hydroxystyrene. The number of units introduced per unit is 0 on average for all hydroxystyrene units.
．． 1 to 2, and the sum of the average number of halogens and the average number of nitrogen-containing substituents is 2 or less;
The present invention relates to an antibacterial/antifungal agent containing as an active ingredient a poly-p-hydroxystyrene derivative having a nitrogen-containing substituent and with or without halogen.

In the poly-p-hydroxystyrene derivative used as an active ingredient in the antibacterial/antifungal agent of the present invention, the degree of polymerization is suitably 5 to 1000, preferably 1.
It is 0-500. It is optional whether or not a halogen (X1) selected from bromine, chlorine, and iodine is introduced, and the number of halogens (X1) introduced per hydroxystyrene unit is the average number relative to all hydroxystyrene units. The value ranges from 0 to 1.9, preferably 0 to 1.9.
The range is 5.

The number of nitrogen-containing substituents (Y) selected from pyrrolidinomethyl groups, piperidinomethyl groups, and certain quaternary ammonium salts thereof introduced per hydroxystyrene unit is the average value for all hydroxystyrene units. It is in the range of 0.1 to 2, preferably in the range of 0.5 to 2. If the average number of nitrogen-containing substituents introduced per hydroxystyrene unit is 0.1 or less, initial antibacterial/antifungal activity cannot be expected. The maximum number of halogens (X1) and/or nitrogen-containing substituents (Y) that can be introduced per one hydroxystyrene unit is usually up to two. Needless to say, for example, poly-
In the p-hydroxystyrene derivative, since the constitutional unit represented by the general formula (I) is used as an essential constitutional unit as described above, the average number of nitrogen-containing substituents introduced per one hydroxystyrene unit is at least 0. .2 pieces. The quaternizing agent for converting the pyrrolidinomethyl group or piperidinomethyl group into a quaternary ammonium salt is selected from chlorides, bromides, and iodides of alkyl having 6 to 14 carbon atoms, preferably 8 to 12 carbon atoms. The alkyl group of this alkyl halide may be linear or branched, but is preferably linear. These alkyl halides can be used alone or in combination. As a quaternizing agent, the above-mentioned carbon number 6-14
If a quaternary ammonium salt is prepared using a quaternizing agent other than the alkyl halide, initial antibacterial and antifungal activity cannot be expected. The degree to which the pyrrolidinomethyl group or piperidinomethyl group is used as a quaternary ammonium salt is arbitrary, and there is no problem even if the pyrrolidinomethyl group or piperidinomethyl group and its quaternary ammonium salt are mixed, and the proportion of their mixture can also be determined. Optional.

When the poly-p-hydroxystyrene derivative according to the present invention is a derivative in which only nitrogen-containing substituents (Y) are introduced, for example, the average number of nitrogen-containing substituents introduced per one hydroxystyrene unit is In the case of a derivative having about 1 or more of Mainly composed of 0 to 10 mol% of the structural unit represented by (c) (
In the formula, Y is the same as above).

[0011]

[Chemical formula 13]

[Chemical formula 14]

[Chemical formula 15]

[0012] Furthermore, a nitrogen-containing substituent (Y) and a halogen (X
1) is introduced, for example, in the case of a derivative in which the average number of nitrogen-containing substituents introduced per one hydroxystyrene unit is 0.5 to 1.5, the following general formula ( 10 to 50 mol% of the structural unit represented by a)
, 10 to 30 mol% of the structural unit represented by general formula (b), 0 to 10 mol% of the structural unit represented by general formula (c), and 0 to 50 mol% of the structural unit represented by general formula (d) %, the structural unit represented by general formula (e) is 0 to 20 mol%, and the structural unit represented by general formula (f) is 10 to 8 mol%.
It mainly consists of 0 mol% (wherein, X1 and Y are the same as above).

[0013]

[Chemical formula 16]

[Chemical formula 17]

[Chemical formula 18]

[Chemical formula 19]

[C20]

[C21]

The poly-p-hydroxystyrene derivative according to the present invention is usually produced as follows.

First, poly-p used as a basic polymer
-Hydroxystyrene is, for example, JP-A-48-2218
No. 7, No. 51-109097, No. 52-23193, No. 52-31235, No. 53-13694, No. 5
It can be prepared by the method shown in each publication of No. 3-52594. That is, it is prepared by cationically, radically or thermally polymerizing p-hydroxystyrene, and a polymer having a desired degree of polymerization can be obtained by appropriately selecting polymerization conditions. It can also be prepared by radical polymerizing p-methoxystyrene or p-acyloxystyrene, such as p-acetoxystyrene, and then hydrolyzing it with acid or alkali. The degree of polymerization of the poly-p-hydroxystyrene used as base polymer should be between 5 and 1000, preferably between 10 and 500.

Furthermore, in producing a derivative into which a nitrogen-containing substituent and a halogen are introduced, the basic polymer, poly-p-hydroxystyrene, is generally halogenated in advance. This halogenation is carried out, for example, in Japanese Patent Publication No. 52-3368
A method such as that shown in Publication No. 0, that is, poly-p
-Hydroxystyrene is treated with bromine, a common halogenating agent, in a solvent such as methanol or a halogenated hydrocarbon.
This can be carried out by a method of reacting with chlorine, iodine, etc., or N-bromosuccinimide, chloramine T, etc. A nuclear halide having a desired degree of halogenation can be obtained by appropriately selecting reaction conditions for this halogenation, but in order to produce the derivatives related to the present invention, it is necessary to The average number of halogens introduced per hydroxystyrene unit is 1.
．． The number should be 9 or less. Further, the poly-p-hydroxystyrene according to the present invention has a nitrogen-containing substituent, that is, a pyrrolidinomethyl group, a piperidinomethyl group, or a quaternary ammonium salt thereof, introduced into the basic polymer poly-p-hydroxystyrene or its nuclear halide. Hydroxystyrene derivatives are disclosed in, for example, JP-A-49-10992.
It can be manufactured by the method shown in the above publication. That is, a predetermined amount of poly-p-hydroxystyrene or its nuclear halide, an amine compound selected from pyrrolidine or piperidine, and formaldehyde is dissolved in a solvent such as ethanol or dioxane, and the mixture is heated at a predetermined temperature of 70 to 120°C. A poly-p-hydroxystyrene derivative into which a pyrrolidinomethyl group or a piperidinomethyl group has been introduced is obtained by the so-called Mannich reaction, which is carried out over a period of time. In producing this derivative, formalin, paraformaldehyde, etc. can also be used as the formaldehyde. Further, the ratio of the amine compound and formaldehyde to be used in the reaction system is generally 0.5 to 1.5 mol, preferably 0.8 to 1.2 mol, of formaldehyde per 1 mol of the amine compound. . Further, the amount of the amine compound to be supplied to the reaction system is appropriately selected depending on the desired introduction rate of the nitrogen-containing substituent into the desired derivative. The reaction for introducing this nitrogen-containing substituent generally proceeds approximately stoichiometrically.

In addition, when it is desired to introduce a quaternary ammonium salt of a pyrrolidinomethyl group or a piperidinomethyl group into the desired derivative, generally the pyrrolidinomethyl group or piperidinomethyl group obtained as described above is introduced. The obtained poly-p-hydroxystyrene derivative was dissolved in hexyl, hexyl, etc. in a solvent such as alcohol or chloroform.
By reacting each alkyl such as heptyl, octyl, nonyl, decyl or dodecyl with an alkyl halide such as chloride, bromide or iodide at 40 to 60°C for a predetermined period of time, the pyrrolidinomethyl group or piperidinomethyl group is converted into a quaternary ammonium salt. By doing so, a poly-p-hydroxystyrene derivative into which the quaternary ammonium salt is introduced can be obtained. In quaternizing this pyrrolidinomethyl group or piperidinomethyl group, the degree of quaternization can be arbitrarily selected as necessary, and the amount of the alkyl halide used is determined as appropriate depending on the desired degree of quaternization. All you have to do is choose.

[0018] Further, the derivative according to the present invention into which a nitrogen-containing substituent and a halogen are introduced can also be obtained as follows, if necessary. That is, such derivatives are generally produced by halogenating poly-p-hydroxystyrene as described above and then introducing a pyrrolidinomethyl group or piperidinomethyl group by Mannich reaction. It can also be produced by reversing the order of the Mannich reaction and performing halogenation after introducing a pyrrolidinomethyl group or piperidinomethyl group by the Mannich reaction.

Furthermore, in the production of the poly-p-hydroxystyrene derivative according to the present invention, the poly-p-hydroxystyrene used as the basic polymer can be subjected to the above-mentioned halogenation reaction, Mannich reaction, or introduced pyrolidine reaction. During the quaternization reaction of the dinomethyl group or piperidinomethyl group, the basic structure such as the degree of polymerization does not substantially change.

Various poly-p-hydroxystyrene derivatives were produced as described above, and their structures were analyzed by 13C-NMR.
It was determined by measuring spectra and IR spectra, and their solubility in solvents was also tested. Table 1 shows the structures and solubility in solvents determined for representative examples of the above various poly-p-hydroxystyrene derivatives.
, shown in Tables 2, 3 and 4. Among the representative examples shown in Tables 1 to 4, compound No. The derivatives 1 to 7, 9 and 10 have a weight average molecular weight of 1900 and a number average molecular weight of 1300.
of poly-p-hydroxystyrene (average degree of polymerization 10.8
) was derived using as the basic polymer,
Compound no. The derivative of No. 8 has a weight average molecular weight of 6200.
, which was derived using brominated poly-p-hydroxystyrene having a number average molecular weight of 3200 (average degree of polymerization 17.4) as a basic polymer.

In the table, the average number of introduced units is the average number of introduced units per hydroxystyrene unit, Ya means a non-quaternized nitrogen-containing substituent Y, and Yb
means a quaternized nitrogen-containing substituent Y.

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

The poly-p-hydroxystyrene derivative used as the active ingredient of the antibacterial/antifungal agent in the present invention as described above is
It is usually obtained in powder form, is stable against heat and light, and does not deteriorate even when stored for a long period of time. In addition, when using this poly-p-hydroxystyrene derivative as an active ingredient of an antibacterial/antifungal agent, it can be used in various forms, such as using this poly-p-hydroxystyrene derivative as it is or dispersing it in a material. It can be added to the material to which it is applied, or dissolved in a solvent. The method of addition is also
Various methods may be employed as needed, such as simple mixing, coating, spraying, kneading, dipping (impregnation), and the like.

[0027] In addition, various materials can be applied, such as wood, pulp, bamboo, polymeric substances such as plastics, lubricating oils such as water-soluble metal processing oil and hydraulic oil, and paints. , adhesives, glue, starch, pasting agents, leather, foods, pharmaceuticals, cosmetics, etc.

Since this poly-p-hydroxystyrene derivative is a polymeric substance, it not only has no sublimation or volatilization properties, but also no blooming or bleeding phenomena that seep onto the surface of the applied material, and therefore has antibacterial and antifungal properties. It has a long-lasting effect and does not adversely affect the physical properties or appearance of the applied material. In addition, when the present poly-p-hydroxystyrene derivative is blended with, for example, polyolefin, polyvinyl chloride, polyurethane, polyester, epoxy resin, etc., the present poly-p-hydroxystyrene derivative is compatible or not compatible with these polymers. Since it has good dispersibility, a homogeneous blend without phase separation can be obtained by casting or kneading. In addition to its antibacterial and antifungal properties, this poly-p-hydroxystyrene derivative also functions as a curing catalyst or curing agent for polyurethane and epoxy resins. This function is due to the joint action of the phenolic hydroxyl group and the nitrogen-containing substituent of this poly-p-hydroxystyrene derivative, and is due to the large size of this poly-p-hydroxystyrene derivative that is not found in conventional antibacterial polymers. This can be said to be one of its characteristics. In addition, when the present poly-p-hydroxystyrene derivative is blended into a coating agent such as a paint, a phenomenon in which the adhesion to the substrate is improved due to the phenolic hydroxyl group contained therein is also observed.

Further, the present poly-p-hydroxystyrene derivative is harmless or has very low toxicity. That is, poly-p-hydroxystyrene, which is the basic polymer of the present poly-p-hydroxystyrene derivative, has been orally administered alone (1000 mg/kg), orally continuously (500 mg/kg x 7 times), and subcutaneously administered (100 mg/kg) to mice.
(g/kg), there were no significant changes in symptoms, and no abnormalities were observed in internal organs. Furthermore, among the nuclear halides of poly-p-hydroxystyrene, which is a basic polymer, for example, nuclear brominated compounds did not significantly change the symptoms after continuous oral administration (500 mg/kg x 15 times), but abnormalities were observed in various internal organs. I can't do it. The present poly-p-hydroxystyrene derivatives derived from such harmless to very low toxicity polymers through the Mannich reaction and optionally the subsequent quaternization reaction are also harmless to very low toxicity. Yes, LD50>5000 (
mg/kg).

[0030] Considering the above-mentioned properties, the present poly-p
-Hydroxystyrene derivatives are particularly suitable as active ingredients in antibacterial and antifungal agents used in articles that require long-term storage, food packaging materials, wallpaper, paints, synthetic leather, textile products such as clothing and filter cloth, etc. .

[0031]

[Example] As an example of the antibacterial/antifungal agent according to the present invention, the results of an antibacterial/antifungal property test of the poly-p-hydroxystyrene derivative according to the present invention are shown below. In this antibacterial/antifungal test, Staphylococcus aureus was used as a Gram-positive bacterium.
cus aureus), Bacillus subtilis (Ba
cillus subbutilis), Micrococcus luteu
Gram-negative bacteria include Escherichia coli and Salmonella typhi.
), Pseudomonas aeruginosa
onus aeruginiosa), yeast,
Candida albicans (C.
andida albicans), Saccharomyces ce
revisiae), Trichophyton interd.
igital), Microsporum gypseum (M
icrosporium gypseum), Penicillium chrysogenum
chrysogenum) and Aspergillus niger, a total of 12 types of bacteria were used. Furthermore, poly-p according to the present invention
- Ten types of poly-p-hydroxystyrene derivatives shown in Tables 1 to 4 above were used as the hydroxystyrene derivatives. For comparison, brominated poly-p-hydroxystyrene and dimethylaminomethylated poly-p-hydroxystyrene were also subjected to antibacterial and antifungal tests. This brominated poly-p-hydroxystyrene has a weight average molecular weight of 6200, a number average molecular weight of 3200, and an average number of bromine introduced per one hydroxystyrene unit of 1.8. -p-hydroxystyrene has a weight average molecular weight of 7,200, a number average molecular weight of 3,600, and an average number of dimethylaminomethyl groups introduced per one hydroxystyrene unit of 1.5.

Examples 1 to 10 and Comparative Examples 1 to 2 Above 1
Among the two types of test bacteria, for bacteria, ordinary agar medium (
Manufactured by Eikensha, meat extract 0.05g, peptone 0.1g, sodium chloride 0.05g, agar 0.15g, water 10ml
, pH 7.0), and Sabouraud for fungi.
Medium (glucose 0.3g, peptone 0.1g, agar 0.
15 g, water 10 ml, pH 6.8) was used as a test medium, and the test medium contained 10 types of poly-p-hydroxystyrene derivatives (examples) shown in Tables 1 to 4 above and brominated poly-p - injecting ethanol solutions of hydroxystyrene (Comparative Example 1) and dimethylaminomethylated poly-p-hydroxystyrene (Comparative Example 2), respectively;
A test medium containing a predetermined concentration of these poly-p-hydroxystyrene derivatives, brominated poly-p-hydroxystyrene, or dimethylaminomethylated poly-p-hydroxystyrene was prepared.

[0033] Each test bacteria was inoculated into the prepared test medium, and bacteria were incubated at 37°C for 48 hours, and fungi at 25°C.
The cells were cultured for 5 days, and the presence or absence of growth was observed to determine the minimum inhibitory concentration (MIC). The results are shown in Table 5.

[0034]

[Table 5]

[0035]

Effects of the Invention According to the present invention, a polymer-based antibacterial and antifungal compound that has a wide antibacterial spectrum, has excellent antibacterial and antifungal activity, and is harmless or extremely low toxicity to the human body, animals, etc. A fungicide is provided. Furthermore, the antibacterial/antifungal agent according to the present invention is stable against heat, light, etc., and has a long-lasting antibacterial/antifungal effect.
It has good compatibility or dispersibility with various applicable materials such as paints and adhesives, forms a homogeneous compound with these various applicable materials, and has antibacterial and antibacterial properties depending on the type of applicable materials. In addition to its mold effect, it is multifunctional, showing catalytic activity and reactivity (crosslinking properties).

Claims (1)

[Claims] Claims: 1. General formula (I) [In the formula, X1 is a halogen atom selected from bromine, chlorine, and iodine. Y is [Formula 2] [Formula 3] [Formula 4] [Formula 5] (However, R is an alkyl group having 6 to 14 carbon atoms, and
2 is a halogen atom selected from bromine, chlorine, and iodine. ) is a nitrogen-containing substituent selected from p is 0 or 2; when q is 1, p is 0 or 1; when q is 2, p is 0; ] The structural unit represented by [
[In the formula, X1 is the same as above, and p' is 0, 1 or 2. ], and when it contains a structural unit represented by the above general formula (II), each of the structural units represented by the above general formula (I) and general formula (II) are randomly combined, Degree of polymerization is 5-100
0, and the number of halogens (X1) introduced per hydroxystyrene unit is in the range of 0 to 1.9 on average with respect to all hydroxystyrene units, and the nitrogen-containing substituent (Y) is hydroxystyrene. The number of units introduced per unit is 0 on average for all hydroxystyrene units.
．． 1 to 2, and the sum of the average number of halogens and the average number of nitrogen-containing substituents is 2 or less;
An antibacterial/antifungal agent containing as an active ingredient a poly-p-hydroxystyrene derivative having a nitrogen-containing substituent and with or without halogen.