JP3482473B2 - Bis-type quaternary ammonium salt compound and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bis-type quaternary ammonium salt compound and a method for producing the same.

[0002]

2. Description of the Related Art No. 4 which exhibits antibacterial activity against bacteria and fungi
Ammonium salt compounds, such as benzalkonium chloride and N-alkylpyridinium iodide, have been known for a long time and are still widely used as antibacterial agents.

[0003]

The conventional bis-type quaternary ammonium salt compound is usually excellent in antibacterial activity, but in a combination system with other drugs, the antibacterial activity is lowered due to the hydrophobicity of the drug. There is a drawback that. Furthermore, since the conventional bis-type quaternary ammounium salt compound has a high residual toxicity of biodegradation products, its application range is limited in terms of environmental safety in actual use.

An object of the present invention is to provide a bis-type quaternary ammonium salt compound having excellent antibacterial activity, low residual toxicity after biodegradation, and high safety to the environment and animals.

[0005]

The present invention relates to a bis-type quaternary ammonium salt compound represented by the formula (1) and a method for producing the same.

[0006]

[Chemical 3]

[In the formula, R is the same or different and has 5 to 5 carbon atoms.
18 alkyl groups are shown. R ¹ represents a lower alkyl group. X represents an anion. l shows the integer of 0-2. m
And n show the integer of 1-4. ]

The bis-type quaternary ammonium salt compound of the present invention represented by the above formula (1) (hereinafter referred to as "the compound (1) of the present invention") has an excellent antibacterial activity, more specifically against various bacteria. It exhibits high bacteriostatic and bactericidal activity and has a broad antibacterial spectrum. Moreover, it also has desirable characteristics that its bacteriostatic activity and bactericidal activity are hardly affected by temperature and pH.

Further, the compound (1) of the present invention exhibits the above-mentioned excellent antibacterial activity even at a concentration of about 1/10 to 1/100 of the conventional quaternary ammonium salt, and, in addition, after biodegradation. Since it has low residual toxicity, it has favorable characteristics that it is very safe for the environment, humans and animals.

Furthermore, the compound (1) of the present invention has the property that the antibacterial activity is not reduced by other hydrophobic drugs. Further, the compound (1) of the present invention has an advantage that it can be immobilized on the surface of various base materials such as glass, synthetic resin, ceramics, metal, etc., since a hydroxyl group is introduced into the molecule.

In the above formula (1), R has 5 to 1 carbon atoms.
8 and preferably 6 to 18 alkyl groups are shown. R ¹ represents a lower alkyl group having 1 to 4 carbon atoms. The anion represented by X is not particularly limited, and examples thereof include those derived from various inorganic acids and organic acids described below. Among them, for example, anions derived from inorganic acids such as I ⁻ , Br ⁻ , Cl ⁻ , and NO ₃ ⁻ , CH ₃ SO ₃ ⁻ , C.
Sulfonate anion such as ₂ H ₅ SO ₃ ⁻ , CH ₃ COO
Anions and the like introduced from organic acids such as ⁻ and C ₂ H ₅ COO ⁻ .

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The bis-type quaternary ammonium compound (1) of the present invention is a novel compound and is produced, for example, by reacting a compound represented by the formula (2) with a compound represented by the formula (3). it can.

[0013]

[Chemical 4]

[Wherein R ¹ , l, m, n and X are the same as defined above. ] R-X (3) [In formula, R and X are the same as the above. ]

The compound (2) is, for example, a pyridine compound represented by the formula (4) and α, ω-represented by the formula (5).
It can be produced by reacting a dihalogenoalcohol to obtain a hydrogen halide salt of compound (2) and treating it with a base.

[0016]

[Chemical 5] [Wherein R ¹ and l are the same as defined above. ]

[0017]

[Chemical 6] [In formula, Y shows a halogen atom. m and n show the integer of 1-4. ]

In formula (5), examples of the halogen atom represented by Y include chlorine, bromine and iodine. Specific examples of the pyridine compound (4) include, for example,
4-mercaptopyridine, 2-amino-4-mercaptopyridine, 3-amino-4-mercaptopyridine, 4-
Examples thereof include mercapto-5-methylpyridine, 2-methyl-4-mercaptopyridine and 3-methyl-4-mercaptopyridine. Specific examples of the α, ω-dihalogeno alcohol (5) include 1,3-dibromo-2-propanol, 1,3-dichloro-2-propanol, and 1,3-diiodo-2-propanol. be able to.

The reaction of the pyridine compound (4) with the α, ω-dihalogeno alcohol (5) is preferably carried out in an organic solvent at a temperature of about 50 to 120 ° C., usually 3 to
It will be finished in about 24 hours. Pyridine compound (4) and α,
The ratio of the ω-dihalogenoalcohol (5) to be used is not particularly limited, but usually about 2.0 to 4.0 mol, preferably 2.1 of the compound (4) per 1 mol of the compound (5). ~ 2.
About 5 mol may be used. The organic solvent is not particularly limited as long as it is inert to the reaction, but lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene and xylene, acetone and the like. Examples thereof include ketones. If necessary, two or more kinds of organic solvents may be used in combination. The amount of the organic solvent used is not particularly limited, but is usually about 1 to 10 times mol, preferably about 1 to 5 times mol of the compound (4). In treating the hydrogen halide salt of compound (2) obtained by this reaction with a base, any ordinary method can be adopted. The base is not particularly limited, and examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.

The compound (2) thus obtained can be easily purified from the reaction mixture by a usual separation and purification means such as recrystallization, but can be directly used in the next reaction without purification.

The reaction between the compound (2) and the compound (3) is preferably carried out in an organic solvent under pressure or without pressure. When it is carried out under pressure, it is carried out at a temperature of about 50 to 100 ° C. and a pressure of about 15 to 120 MPa, for 1 to 24
It will finish in about time. 8 when performing the reaction under no pressure
The reaction may be performed at a temperature of about 0 to 120 ° C. for about 48 to 96 hours.

The compound (3) is not particularly limited as long as the alkyl portion has 5 to 18 carbon atoms, and for example, hexane iodide, octane iodide, decane iodide, dodecane iodide, tetradecane iodide, Hexadecane iodide, octadecane iodide, hexane bromide, octane bromide, decane bromide, dodecane bromide, tetradecane bromide, hexadecane bromide, octadecane bromide, hexane chloride, octane chloride, decane chloride, dodecane chloride, tetradecane chloride , Hexadecane chloride, octadecane chloride and the like, in which the alkyl portion is a linear or branched alkyl group having 6 to 18 carbon atoms. Also, a mixture of alkyl compounds having different carbon numbers derived from natural fats and oils can be used. The amount of the compound (3) used is not particularly limited, but it is usually about 2.0 to 4.0 mol, preferably about 2.1 to 2.5 mol per 1 mol of the compound (2).

The organic solvent is not particularly limited as long as it does not affect the reaction, but lower alcohols such as methanol and ethanol, N, N-dimethylformamide, N-methylformamide, nitromethane, nitroethane, acetonitrile. , Methyl cellosolve, ethyl cellosolve and the like. If necessary, two or more kinds of organic solvents may be used in combination. The amount of the organic solvent used is not particularly limited, but it is usually 1 to 10 times mol, preferably 1 to 5 times mol, of the compound (2).

The compound (1) of the present invention obtained by this reaction can be easily isolated and purified from the reaction mixture by a usual separation and purification means such as recrystallization.

In the compound (1) of the present invention, the anion represented by X in the molecule can be exchanged with another anion, if necessary, by a general treatment method. Examples of the anion include iodine, bromine, chlorine,
Anions derived from inorganic acids such as fluorine, iodic acid, bromic acid, chloric acid, periodic acid, perchloric acid, sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, Isovaleric acid, pivalic acid, octanoic acid, octylic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, suberic acid, azelaic acid, sebacic acid Fatty acids such as acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, sorbic acid, oleic acid, elaidic acid, maleic acid, citraconic acid, mesaconic acid, lactic acid,
Hydroxy acids such as malic acid, citric acid, and gluconic acid,
Oxo acids such as pyruvic acid, aromatic carboxylic acids such as benzoic acid, phthalic acid and naphthalene carboxylic acid, heterocyclic carboxylic acids such as furan carboxylic acid and pyridine carboxylic acid, amino acids, methane (alkyl) sulfonic acid, alkylbenzene sulfone Examples include organic sulfonic acids such as acids, anions derived from various organic acids such as erythorbic acid, ascorbic acid and dehydroacetic acid. Further, alcoholates, phenolates, and other hydroxyl group-containing organic compounds can also serve as anion sources.

The compound (1) of the present invention may be used as it is in a powder state. The compound (1) powder may be dissolved or dispersed in an appropriate solvent such as water or alcohol to be used in a liquid state. This liquid material is used for paper, ceramics, glass, metal, wood, synthetic resin (polypropylene,
Polyethylene, polystyrene, polyester, polyamide, polyacrylate, polyurethane, polyvinyl chloride, etc.), fibers (cotton, hemp, silk, wool, feathers, etc.)
It can be used by being applied or sprayed on the surface of various articles composed of one or more base materials such as. It can also be used as it is as a sterilizing liquid for disinfection. Furthermore,
Kneading the compound (1) into various synthetic resins, threads, fibers,
It can also be used by forming it into a film, a sheet, particles or any other shape.

The compound (1) of the present invention can be used in the same manner as conventional quaternary ammonium salts in various applications where antibacterial performance is required. Specific applications include, for example, tap water, cooling water, slime control, pools, fishing nets, ship bottoms, underwater structures, food packaging materials, building materials, agricultural materials, medical products, quasi drugs, disinfectants, oral cavity. Materials (toothbrush, toothpaste, etc.), eyeglass frames, clothing, household items, etc. can be mentioned.

[0028]

[Examples] The present invention will be specifically described below with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 1,3-Dibromo-2-propanol and 4-mercaptopyridine were refluxed in ethanol for 6 hours, the resulting pyridinium salt was desalted with 0.1N sodium hydroxide, and then iodine was added. With dodecyl chloride at 80 ℃ and 80MPa 2
The reaction was carried out for 4 hours. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were washed with diethyl ether and recrystallized with a mixed solution of water and ethyl alcohol to give 4,4 ′-(2-hydroxy-1,3-propylenedithio) bis ( 1-dodecylpyridinium iodide) (abbreviated as HTBP-3,12) was produced. The ¹ H-NMR spectrum of this product is as follows. Table 1 shows elemental analysis values, melting points, and yields. ¹ H-NMR (CD ₃ OD; δppm): 0.89 (6
H, t), 1.23 (24H, m), 1.38 (4H,
m), 1.97 (4H, m), 4.47 (4H, t), 8.
64 (4H, d), 8.00 (4H, d), 4.27 (4
H, m), 3.61 (1H, m)

Examples 2 to 6 4,4 '-(2-hydroxy-1) represented by the following formula (1A) was prepared in the same manner as in Example 1 except that other alkyl iodide was used instead of dodecyl iodide. , 3-Propylenedithio) bis (1-alkylpyridinium iodide) was prepared. The carbon number of the alkyl group is an integer of 6 to 18. The elemental analysis values, melting points and yields are shown in Table 1.

[0031]

[Chemical 7]

Example 7 The procedure of Example 1 was repeated except that a mixture of hexyl iodide and octyl iodide (1: 1, molar ratio) was used in place of dodecyl iodide to carry out the reaction. The reaction mixture was subjected to high performance liquid chromatography [column: ODS, developing solvent: acetonitrile / ethanol / water (volume ratio) =
10: 9: 1] and purified to 4,4 '-(2-hydroxy-1,3-propylenedithio) bis (1-hexyl, 1-
Octylpyridinium iodide) was produced. The ¹ H-NMR spectrum of this product is as follows. Table 1 shows elemental analysis values, melting points, and yields. ¹ H-NMR (CD ₃ OD; δppm): 0.88 (6
H, t), 1.23 (16H, m), 1.40 (4H,
m), 1.95 (4H, m), 4.46 (4H, t), 8.
66 (4H, d), 8.02 (4H, d), 4.24 (4
H, m), 3.63 (1H, m)

Example 8 The same procedure as in Example 1 was repeated except that 3-methyl-4-mercaptopyridine was used in place of 4-mercaptopyridine.
4,4 '-(2-Hydroxy-1,3-propylenedithio) bis (3-methyl-1-dodecylpyridinium iodide) was prepared. The elemental analysis values, melting points and yields are shown in Table 1.

Example 9 The same procedure as in Example 1 was repeated except that 3-ethyl-4-mercaptopyridine was used instead of 4-mercaptopyridine.
4,4 '-(2-Hydroxy-1,3-propylenedithio) bis (3-ethyl-1-dodecylpyridinium iodide) was prepared. The elemental analysis values, melting points and yields are shown in Table 1.

[0035]

[Table 1]

In the following test examples, the bacteriostatic action and bactericidal action of the compounds of the present invention of Examples 1 to 7 were compared with the following compounds. Control compound: (1) 4,4 ′-(1.3-trimethylenedithio) bis (1-alkylpyridinium iodide) (alkyl side chain has an even number of 8 to 18 carbon atoms) (2) N-alkylpyridinium Iodide (the number of carbon atoms in the alkyl side chain is an even number from 8 to 18)

Test Example 1 (bacteriostatic activity) The influence of the alkyl side chain length of the compound of the present invention and the control compound on the bacteriostatic activity was examined. Es as the test bacteria
cherichia coli K12W3110 was used. The compounds of Examples 1 to 6 were used as the compounds of the present invention. As the control compound, the control compounds of (1) and (2) above were used. In each case, the alkyl side chain is an even number having 8 to 18. The minimum inhibitory concentration (MIC) was measured according to the broth dilution method, using a nutrient broth to prepare a bacterial suspension at a concentration of 10 ⁶ cells / ml. To 37 ° C for 2
After static culture for 4 hours, the MIC value was determined based on the presence or absence of proliferation. The bacteriostatic activity is the logarithm of the reciprocal of the MIC value,
It was used as an index of bacteriostatic force. The results are shown in Fig. 1. Note that FIG.
In the table,-●-is the compound of the present invention,-○-is the control compound (1)
And -⋄-indicate the control compound (2), respectively. Less than,
The same applies to FIGS. 2 to 4.

Test Example 2 (bactericidal activity) The effect of the length of the alkyl side chain in the compound of the present invention and the control compound on the bactericidal activity was examined. Esc as a test organism
Herichia coli K12W3110 was used as the test compound in Test Example 1. Minimum bactericidal concentration (MB
C) was measured according to a sterile water dilution method using a nutrient broth to prepare a bacterial suspension concentration of 10 ⁶ cells / ml. After contacting for 30 minutes, the cells were transplanted to nutrient broth, and after static culture at 37 ° C. for 24 hours, the MBC value was determined by the presence or absence of proliferation. In addition, bactericidal activity is MBC
The logarithm of the reciprocal of the value was used as an index of bactericidal activity. The result is shown in Figure 2.
Shown in.

Test Example 3 (antibacterial spectrum) The antibacterial spectrum against various bacteria was examined. As the compound of the present invention, the compound of Example 1 having 12 carbon atoms in the alkyl side chain and the compound of Example 7 having 6 and 8 carbon atoms in the alkyl side chain were used. Further, also for the control compounds (1) and (2), those having 12 carbon atoms in the alkyl side chain were used. As the test bacteria, 6 types of Gram-negative bacteria and 5 types of Gram-positive bacteria in the stationary phase were used, and the bacteriostatic spectrum was shown by the minimum inhibitory concentration (MIC). The results are shown in Table 2 below. In addition, 5 types of gram-negative bacteria and 3 types of gram-positive bacteria in the stationary phase were used, and the bactericidal spectrum was shown by the minimum bactericidal concentration (MBC). The results are shown in Table 3.

[0040]

[Table 2]

[0041]

[Table 3]

Test Example 4 (Effect of pH on bactericidal activity) The effect of pH on bactericidal activity was examined. As the test bacteria
Escherichia coli K12W3110 was used as a compound of the present invention having an alkyl side chain of 12 carbon atoms in Example 1, and as a control compound, a control compound (1) having an alkyl side chain of 12 carbon atoms and a control compound (2 ) Each having 12 carbon atoms in the alkyl side chain, and the MBC was measured with 0.1 mol of phosphate buffer at pH 5.0 and pH 6.
Performed at 0, 7.0, 8.0 and 8.5. The results are shown in Fig. 3.

Test Example 5 (Effect of temperature on bactericidal activity) The effect of temperature on bactericidal activity was investigated. As the test bacteria
Escherichia coli K12W3110 was used as the test compound in the same manner as in Test Example 4, and MBC was measured at 10 ° C, 20 ° C, 30 ° C and 40 ° C. The results are shown in Fig. 4. In FIG. 4, the temperature on the horizontal axis is shown by the reciprocal of the absolute temperature.

Test Example 6 (Effect of hydrophobicity of drug molecule on bactericidal activity) The effect of hydrophobicity of drug molecule on bactericidal activity was examined. As test bacteria, Escherichia coli K12W3110,
As test compounds, the same compounds as in Test Example 1 were used. Hydrophobic parameter of the drug was used R _M value calculated from Rf value obtained from the movement distance of the reverse phase type thin layer chromatography. Results are shown in FIG.

[0045]

According to the present invention, it is possible to obtain a bis-type quaternary ammonium salt compound having excellent antibacterial activity, low residual toxicity after biodegradation, and high safety to the environment and animals.

[Brief description of drawings]

FIG. 1 is a graph showing the influence of the alkyl side chain lengths of the compound of the present invention and a control compound on bacteriostatic activity.

FIG. 2 is a graph showing the influence of the alkyl side chain lengths of the compound of the present invention and the control compound on bactericidal activity.

FIG. 3 is a graph showing the effect of pH on bactericidal activity.

FIG. 4 is a graph showing the effect of temperature on bactericidal activity.

FIG. 5 is a graph showing the effect of drug molecule hydrophobicity on bactericidal activity.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yuriko Nakanishi 179 Mitsushima Nitta, Kawashima-cho, Asabe-gun, Tokushima Prefecture Nihon Funen Co., Ltd. (72) Emiko Daimon 463 Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima Otsuka Chemical Co., Ltd. Tokushima In-lab (72) Inventor Yoshihisa Tomaki 2-9 Kandaji-cho, Chiyoda-ku, Tokyo Otsuka Chemical Co., Ltd. (56) Reference JP-A-6-321902 (JP, A) JP-A-2000-159608 (JP, A) JP 2001-107082 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 213/70 A01N 43/40 A61K 31/44 A61P 31/00 CA (STN) CAOLD ( STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A bis-type quaternary ammonium salt compound represented by the formula (1). [Chemical 1] [In formula, R is the same or different and shows a C5-C18 alkyl group. R ¹ represents a lower alkyl group. X represents an anion. l shows the integer of 0-2. m and n are 1 to 4
Indicates an integer. ] 2. A compound represented by formula (2) and formula (3)
Characterized by reacting with a compound represented by
A method for producing the bis-type quaternary ammonium salt compound according to claim 1. [Chemical 2] [In the formula, R ¹ , l, m, n and X are the same as defined above. ] R-X (3) [In formula, R and X are the same as the above. ]