JPS59196303A - Biguanide polymer - Google Patents

Abstract

PURPOSE:A biguanide polymer having a biguanide residue in a side chain and a high antimicrobial activity and useful as an external bactericide or a bactericide for industrial water, etc., prepared by polymerizing a specified vinyl compound having a biguanide residue. CONSTITUTION:The present invention biguanide polymer of an excellent antibacterial activity is represented by formula I or II (wherein R1 and R2 are each H or a halogen, A is a group -CHR3-CHR4-, n>=2, p and q each >=1, R3 is carboxy, alkoxy-carbonyl, phenyl, 2-pyridyl, carbamoyl or the like and R4 is H or methyl). The biguanide polymer of formula I can be prepared by polymerizing a biguanide residue-containing vinyl compound of formula III. The biguanide polymer of formula II can be obtained by polymerizing a vinyl compound of formula III with a compound of formula IV (e.g., acrylic acid).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antibacterial polymeric compound having a biguanide group.

Antimicrobial agents such as antibacterial agents, antibacterial agents, bactericidal agents, and antifungal agents are being used more and more every year, and are used not only as pharmaceuticals but also in the food industry,
Various performances are required in various fields such as the mechanical industry, paper industry, textile industry, and environmental hygiene management. Generally required performance is high antimicrobial activity and a wide spectrum of action. Although a wide variety of drugs have been developed to date, the performance of which determines their practical value, it is extremely difficult to satisfy all of these requirements at the same time. (See "Chemistry of sterilization and anti-mold"). As a result of intensive research in search of a compound with excellent properties both industrially and in terms of environmental hygiene, the present inventors synthesized a new vinyl compound having a biguanide residue, and then polymerized this vinyl compound. , a polymer compound having biguanide residues in the side chain was obtained.

We have discovered that this polymer compound is not only an excellent antibacterial agent that satisfies the above conditions, but also has superior antibacterial activity than the monomer.

The present invention is based on the general formula (wherein R1 and R2 are hydrogen atoms or halogen atoms, A is a group -CHR3-CHR4-1n is an integer of 2 or more, p and q are integers of 1 or more, and the group R3 is a carbamoyl group. , carboxy group, alkoxycarbonyl group, phenyl group, 2
-pyridyl group or 2-oxopyrrodinyl group, R4 means a hydrogen atom or a methyl group).

As the halogen atom for the substituents R2 and R3 in the compounds of formulas (1) and (H), a chlorine atom is particularly preferred. n is usually 10-500, p+q is 10-500, q:p
The ratio is 1:0.5-100.

The polymer compound of the present invention is water-soluble in the case of an acid salt having a low degree of polymerization, and is also soluble in organic solvents such as alcohol. Solubility decreases as the degree of polymerization increases. Further, a crosslinked polymer having a six-dimensional network structure is insoluble but has antibacterial properties.

Although it is already known that compounds containing biguanide groups have antibacterial properties, the idea of utilizing them by bonding them to polymer side chains and the technical advantages derived therefrom are as follows. ■) Since biguanide residues are cationic, they interact with the negatively charged cell membrane surface. The effect of polymerization is that many cations synergistically participate in the interaction. As a result, it becomes possible to significantly increase the concentration of biguanide residues near the cell membrane. n) Pharmacological studies have shown that biguanide residues are antibacterial agents that attack cell membranes, so there is no need for them to be incorporated into bacterial cells. Therefore, the decrease in cell membrane permeability due to polymerization does not become a disadvantageous factor, and a positive polymer effect is exerted due to the effect (2) above.

I) Being a polymer is advantageous in terms of all secondary performances such as reduced toxicity to humans and animals, odorlessness, storage stability, and ease of handling. IV) As is clear from the mechanism of action described in n), this compound is not a metabolism-inhibiting antibacterial agent, so it is unlikely to produce antibacterial degrading enzymes that cause the development of resistant bacteria within bacterial cells.

The compound of formula (2) can be obtained by polymerizing a compound represented by general formula (2) (in which R8 and R2 have the above-mentioned meanings).

The compound of formula 1 is a new substance and can be produced, for example, by the following synthetic route (see patent application specification dated the same date).

(2) The compound (2) is preferably used as an acid addition salt, such as a hydrochloride or a nitrate. These acid addition salts can be produced by conventional methods.

The compound of formula ■ is a compound of formula ■ and the general formula CHR3=CH
It can be obtained by polymerizing a compound represented by R4 (in the formula, R5 and R4 have the above-mentioned meanings).

As the compound (2), for example, acrylic acid, methacrylic acid or other esters thereof, acrylamide, vinylpyrrolidone, vinylpyridine, styrene, hydroxyethyl methacrylate, methylenebisacrylamide, etc. are used.

The compound of formula C1 is 0.5% per mole of the compound of formula II.
It is preferable to use it in a proportion of 100 moles.

When carrying out a polymerization reaction, the above compound is dissolved in a solvent, and then a polymerization initiator is added thereto.

Examples of solvents used include water, methanol, ethanol, dimethylformamide, and mixtures thereof. As a polymerization initiator, for example, 2,2'-azobis=(
2-amidinopropane), 2,2'-azobisisobutyronitrile, benzoyl peroxide, t-butyl hydroperoxide, and the like.

The reaction temperature is preferably 60 to 80°C. The reaction usually completes in 60 minutes. Although the reaction time can be shortened by increasing the reaction temperature, the degree of polymerization tends to decrease.

After the reaction is complete, the reaction mixture is poured into a large amount of acetone,
The desired polymer compound can be obtained by collecting the precipitate.

The compounds of formulas ■ and ■ have high antimicrobial activity (and are useful as antibacterial agents. These compounds can be used, for example, as external disinfectants,
Used as a disinfectant for textiles, cloth, etc., sanitary processing, swimming pools, industrial water, etc.

Synthesis example of compound 2■ p-aminophenethyl alcohol 51 jj (0゜3
7 mol) in 550 ml of dioxane.

After passing hydrogen chloride gas through this solution at room temperature for 60 minutes, the precipitate was separated to obtain 50.9 g of p-aminophenethyl alcohol hydrochloride (yield: 77 yu, melting point: 17
0-172°C). This p-aminophenethyl alcohol hydrochloride 17.4.9 (o, 1 mol) and sodium dicyanimide 9.0.9 (0.1 mol) were added to 20 d of water.
When heated to 90'C and reacted for 2 hours in p-
Hydroxyethyl phenyl disia, diamide 16. a
g (yield 68%, melting point 172-175°C)
.

p-Hydroxyethylphenyldicyandiamide 15.
Oi (0,074 mol) in tetrahydrofuran 82
uj! - Dissolve in a mixed solvent of 9 ml of water, and add acrylic acid chloride 48me dropwise in a water bath.

After completion of the dropwise addition, the mixture was allowed to stand overnight at room temperature, and the precipitate was collected to give p-acryloylethylphenyldicyandiamide 1''7.8 F (yield 94%, melting point 157-159°C).

p-acryloylethylphenyldicyandiamide s,
7. y (o, o64 mol) and p-chloroaniline hydrochloride 5.59 (0,034 mol) are heated under reflux for 10 minutes in 60 ml of Inglovir alcohol. After cooling,
When the precipitate was collected, 9.7I of loylethylphenyl-5-p-1'lolylethylphenyl biguanide hydrochloride was obtained (yield 69%, melting point: 204-20
6°C, decomposition).

Similarly, the following compounds are obtained.

1-Acryloylethylphenyl-5-phenylbiguanide hydrochloride, melting point: 182-185.C1 (decomposed).

1-Acryloylethylphenyl-5-(3,4-dichlorophenyl)biguanide hydrochloride, melting point: 186-18
9°C, (decomposition).

Example 1 1-4'Cryloylethylphenyl-5-p-chlorophenyl biguanide hydrochloride 2.08. ! Dissolve the solution in 10 ml of methylformamide, add 12.4 R9 of 2,2'-azobis-2-amidinopronone hydrochloride, and degas and seal the tube. Leave this at 60°C for 6.5 hours. After polymerization, it was poured into a large excess of acetone, and the precipitate that precipitated was counted.
69g is obtained.

Example 2 1.2 g (6.1 mmol) of 1-acryloylethylphenyl-5-phenylbiguanide hydrochloride and 14 m57 of 2,2'-azobis(2-amidinopropane) dihydrochloride as a polymerization initiator were dissolved in dimethyl 12ml formamide
dissolve in Thereafter, the same treatment as in Example 1 is performed to obtain 0.84 g of poly(1-acryloylethylphenyl-5-phenylbiguanide hydrochloride) (yield 70%).

4,8 (s, proton of biguanide group) Example 6 1-acryloylethylphenyl-5- (3.4-
dichlorophenyl) biguanide hydrochloride 1.2 g (2.6
mmol) was polymerized in the same manner as in Example 2, poly[
0.6'6 g of 1-acryloylphenyl-5-(6.4-dichlorophenyl)biguanide hydrochloride is obtained (yield 57%).

wR (aD, oD) 4, 8 (s, proton of biguanide group) Example 4 1-acryloylethylphenyl-5-I-p-chlorophenyl biguanide hydrochloride 4.5 g, acrylamide 0
．． 51 g and 60 m9 of 2,2'-azobis-2-amidinopropane hydrochloride were dissolved in dimethylformamide-water (1:1
) in 50 ml of a mixed solvent, and after degassing and sealing the tube in the same manner as in Example 2, polymerization was carried out at 60°C. After 20 minutes, the reaction mixture was poured into a large amount of acetone and the precipitate was collected, resulting in the desired copolymer 3. 8 6 g is obtained. The composition of this copolymer was determined by absorption spectroscopy, and the content of biguanide-containing units was 42.6Δ mol%, and the content of acrylamide' units was 57.7%.

Example 5 1-Acryloylethylphenyl-5-p-chlorophenyl biguanide hydrochloride 2.15 g (5.

1 mmol) and N-vinylpyrrolidone 0.85j; l
(7.7 mmol) in dimethylformamide 25
ml under degassing. Using 25 m9 of 2,2'-azobis-(2-amidinopropane) dihydrochloride as a polymerization initiator, it was left at 60°C for 20 minutes, and after cooling, the reaction mixture was poured into a large amount of acetone to remove the precipitate. When mixed, 1.6 g of the desired copolymer was obtained.

NMR (CD30D, s) 1,0-2J (br, vinylpyrrolidone polymer) 2,6
~4.0(br, vinylpyrrolidone polymer) 4,67(
s, proton of biguanide group) 7, 30 (s, proton of aromatic nucleus) Test Example 1 Micrococcus pyogenes of compounds of formulas ■ and ■
Antibacterial activity against Burl aureus was measured by solution dilution method.

Solution dilution method 2 A predetermined amount of bacteria was inoculated into a drug dilution solution with a predetermined concentration, and a portion of the solution was taken out at regular contact times to measure the number of bacteria. The more remarkable the decrease in the number of bacteria with respect to the contact time, the stronger the antibacterial activity. The numbers in the table are the number of bacteria (numbers/
rue).

The results for the compound of formula (2) are shown in Table 1, and the results for the compound of formula (2) are shown in Table 2. As the compound of formula (2), a copolymer obtained by reacting the same monomers as in Example 4 with different mixing ratios was used.

Also, as a comparative example, the formula ■ where R and R2 are chlorine atoms
The compound was used.

Note: The q:p ratio is shown in parentheses.

Another test example. Micrococcus pyocenes var aureus (M, P) and Bacillus subtilis (B, S)
0.5 ml of the bacterial solution (approximately 106 cells/ml) was sprinkled on the test piece and the surrounding medium. This was cultured at 67°C for 72 hours, and the degree of bacterial growth was observed.

The results are shown in Table 6. The compound of Example 2 was used as the compound (2), the same compound as in Test Example 1 was used as the compound of formula H, and a film-like test piece of an acrylamide polymer was used as a comparative example.

Claims (1)

[Claims] General formula (wherein R8 and -1 (2 is a hydrogen atom or a halogen atom,
A is a group -CHR3CHR4-1n is an integer of 2 or more, p and q are integers of 1 or more, and the group R3 is a carboxy group, an alkoxycarbonyl group, a phenyl group, a 2-pyridyl group,
A biguanide polymer represented by a carbamoyl group or a 2-oxopyrrodinyl group (R4 means a hydrogen atom or a methyl group).