JPH09110692A - Bis quaternary ammonium salt compound having antimicrobial activity and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound represented by a specific formula, expressing an extremely excellent antimicrobial effect and an extremely wide antimicrobial spectrum, high in safety, and useful as an antimicrobial agent. SOLUTION: This compound is expressed by formula I (Z is a pyridine ring; R1 , R2 are each H, a 1-6C alkyl; R3 is a 3-18C alkylene, a 3-18C alkenylene; R4 is a 6-18C alkyl bound to the ring nitrogen atom of Z; X is an anion), e.g. N,N'-hexamethylene bis(4-carbamoyl-1-dodecylpyridinium bromide). The compound is preferably obtained by reacting an alkylene biscarbamoylpyridine compound of formula II with a compound of the formula: R4 X in an organic solvent such as N,N-dimethylformamide in approximately 10-100MPa at approximately 50-100 deg.C for 10-12hr, etc.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Bis-quaternary ammonium salt compounds exhibiting antibacterial activity against bacteria, fungi and the like have been known for a long time and are still widely used. However, since such compounds usually have excellent antibacterial activity and high residual toxicity of biodegradation products, their application range is limited in consideration of safety in actual use.

[0003] Therefore, there has been a strong demand for the development of bis-quaternary ammonium salt compounds which are extremely excellent in antibacterial activity, have low residual toxicity after biodegradation, and are environmentally friendly.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel bisquaternary ammonium compound which exhibits a very excellent bactericidal effect and a broad antibacterial spectrum as compared with known quaternary ammonium salt compounds, and is highly safe. An object of the present invention is to provide a salt compound and a method for producing the same.

[0005]

According to the present invention, there is provided a compound represented by the general formula (1):

[0006]

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[In the formula, Z represents a pyridine ring, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or a carbon number of 1 to 1;
6 represents an alkyl group, R ₃ represents a C 3-18 alkylene group or an alkenylene group, R ₄ represents a C 6-18 alkyl group bonded to a ring nitrogen atom of Z, and X represents an anion. The present invention provides a bis-quaternary ammonium salt compound having an antibacterial activity represented by [1].

In the above general formula (1), as the alkylene group and alkenylene group of R ₃ , those having 3 to 18 carbon atoms are used. From the viewpoint of bactericidal activity, 4 to 12 carbon atoms are used.
Are preferred. As the alkyl group for R ₄ , those having 6 to 18 carbon atoms are used, and those having 8 to 14 carbon atoms are preferable from the viewpoint of bactericidal activity. Further, the anion represented by X is not particularly limited,
Examples thereof include inorganic anions such as I ⁻ , Br ⁻ , Cl ⁻ , and NO ₃ ⁻ ; organic acid anions such as CH ₃ COO ⁻ .

The compound of the present invention has the general formula (2):

[0010]

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An alkylenebiscarbamoylpyridine compound represented by the formula: wherein Z, R ₁ , R ₂ and R ₃ have the above-mentioned meanings is represented by the general formula (3) R ₄ X (3) ₄ and X have the above meanings] and can be produced.

The above reaction is usually carried out in an organic solvent, for example,
It can be carried out in N, N-dimethylformamide, N-methylformamide, nitromethane, nitroethane or the like at a temperature of about 50 to about 100 ° C. Reaction time is 18
It can be about 48 hours.

Alternatively, the above reaction is carried out under pressure in an autoclave in the presence of a solvent, preferably about 10 to about 100M.
It can also be performed at a temperature of about 50 to 100 ° C. in Pa. The reaction time at this time can be about 10 to 120 hours.

The reaction ratio between the compound of the formula (2) and the compound of the formula (3) is not strictly limited, but is usually 1 mole of the compound of the formula (2) and the compound of the formula (3). To 2
It is preferably used in a proportion of 6 mol, especially 2.1 to 3 mol.

The compound of formula (1) produced by the above reaction can be purified by a purification method known per se, for example, recrystallization and the like.

The compound of the formula (2) used as a starting material in the above reaction includes some known compounds (JP-A-55-81861 and JP-A-3-81).
222), for example, a compound represented by the following formula (4) Z-COCl.HCl (4) [wherein Z has the above meaning] is represented by the following formula (5).

[0017]

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It can be synthesized by reacting with an α, ω-diaminoalkane represented by the formula [wherein R ₁ , R ₂ and R ₃ have the above-mentioned meanings].

The reaction of the compound of formula (4) with the compound of formula (5) is usually from room temperature to about 100 in a suitable organic solvent.
It can be carried out at a temperature of ° C. The ratio of the compound of the formula (5) to the compound of the formula (4) is not particularly limited, but usually 2 to 4 mol of the compound of the formula (4), particularly 2. It is preferably used in a ratio of 1 to 2.5 mol.

The resulting compound of formula (2) can be purified by means such as recrystallization, if necessary.

Examples of the compound of the formula (4) used in the above reaction include isonicotinic acid chloride, nicotinic acid chloride, picolinic acid chloride, and the like.
Further, as the α, ω-diaminoalkanes of the formula (5), for example, trimethylenediamine, tetramethylenediamine, pentamethylenediamine, hexamethylenediamine, octamethylenediamine, decamethylenediamine, dodecamethylenediamine, etc. are used. can do.

On the other hand, examples of the compound of formula (3) used in the reaction with the compound of formula (2) include hexane iodide, octane iodide, decane iodide, dodecane iodide, tetradecane iodide, and iodide. Hexadecane, 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, chloride Examples include hexadecane and octadecane chloride.

The anion (X) in the compound of the formula (1) produced as described above is, for example, if necessary, after dissolving the compound of the formula (1) in a soluble solvent, the desired anion is added. A desired anion can be exchanged by adding a salt contained therein, concentrating, drying and purifying after the reaction.

The compound of the formula (1) of the present invention has a broad bactericidal spectrum against various bacteria and fungi as shown in Test Examples 1 and 2 to be described later, and the conventional commercially available fourth compound is used. 1/10 to 1/100 compared to ammonium salts
It shows an excellent bactericidal activity of the minimum bactericidal concentration of.

Therefore, the compound of the formula (1) of the present invention can be expected to have the same bactericidal effect as that of the conventional bactericide at a use concentration much lower than that of the conventional commercially available bactericide of the same kind. It is economical and the safety to the human body is improved accordingly. Furthermore, since the biodegradation product of the compound of formula (1) of the present invention has a bactericidal activity reduced to 1/1000, it can be said that the compound of the present invention is an environmentally friendly drug.

[0026]

The present invention will be described more specifically with reference to the following examples and test examples.

Example 1 Synthesis of Intermediate 4BP-6 To 123 g (1.0 mol) of isonicotinic acid, excess thionyl chloride was added dropwise, and the mixture was stirred at room temperature until completely dissolved. After being left overnight, excess thionyl chloride is recovered, dry toluene is further added, and unrecovered thionyl chloride is distilled off from the reaction system together with toluene under reduced pressure as much as possible. The crystalline residue obtained was suspended in pyridine and further triethylamine was added to make it a free base.
5 mol) of pyridine solution is added dropwise. Furthermore, it stirred at room temperature for 24 hours. A 20% K ₂ CO ₃ aqueous solution is added to the reaction mixture, the mixture is neutralized and concentrated, and the precipitated crude crystals are collected by filtration. The crude crystals are
By recrystallization from isopropyl alcohol / water and drying under reduced pressure, a slightly yellowish brown N, N′-hexamethylenebis (isonicotinamide) (hereinafter abbreviated as 4BP-6) was obtained.

Example 2 Synthesis of final compound 4BP-6,12 2.00 g (6.13 mmol) of 4BP-6 was dissolved in 40 ml of N, N-dimethylformamide and dodecane bromide 3.07.
g (12.32 mmol) was added, and the mixture was refluxed for 2 days. After cooling,
The solvent was distilled off under reduced pressure, and the obtained crystals were repeatedly recrystallized from ethyl alcohol and dried under reduced pressure to obtain N, N′-hexamethylenebis (4-carbamoyl-1-dodecylpyridinium) as a slightly yellow powder having a melting point of 84 to 85 ° C. Bromide) (4 below)
(Abbreviated as BP-6,12) 2.2 g was obtained.

¹ H-NMR (CDCl ₃ ): 4BP-6,1
2 (δppm) 0.85 (6H, t, J = 6.5Hz), 1.29 (36H,
s), 1.37 (4H, br s), 1.58 (4H,
m), 1.92 (4H, m), 3.33 (4H, m), 4.
65 (4H, t, J = 7.3Hz), 8.45 (4H, d, J
= 6.8 Hz), 9.27 (6H, d, J = 6.8Hz) Elemental analysis: molecular formula C ₄₂ H ₇₂ Br ₂ N ₄ O ₂ CHN theoretical value (%) 61.16 8.80 6 .79 measured value (%) 61.10 8.93 6.68 halogen analysis (oxygen flask combustion method) Br theoretical value (%) 19.38 measured value (%) 19.56 Example 3 final compound 4BP-6, Synthesis of 14 In the same manner as in Example 2, 4BP-6 was subjected to bis-quaternary chlorination with tetradecane bromide, and then purified in the same manner to give a melting point of 11
A slightly yellow powder of N, N′-hexamethylenebis (4-carbamoyl-1-tetradecylpyridinium bromide) at 3 to 115 ° C. (hereinafter, abbreviated as 4BP-6,14) was obtained. Yield 78.2%.

¹ H-NMR (CDCl ₃ ): 4BP-6,1
4 (δppm) 0.85 (6H, t, J = 6.5Hz), 1.23 (44H,
s), 1.37 (4H, br s), 1.58 (4H,
m), 1.92 (4H, m), 3.34 (4H, m), 4.
65 (4H, t, J = 7.3Hz), 8.45 (4H, d, J
= 6.7 Hz), 9.27 (6H, d, J = 6.7 Hz) Elemental analysis: molecular formula C ₄₆ H ₈₀ Br ₂ N ₄ O ₂ CHN theoretical value (%) 62.72 9.15 6 .36 measured value (%) 62.61 8.93 6.47 halogen analysis (oxygen flask combustion method) Br theoretical value (%) 18.14 measured value (%) 17.98 Example 4 final compound 4BP-6, Synthesis of 16 In the same manner as in Example 2, 4BP-6 was subjected to bis-quaternary chlorination with hexadecane bromide and then purified in the same manner to give a melting point of 11
A slightly yellow powder of N, N′-hexamethylenebis (4-carbamoyl-1-hexadecylpyridinium bromide) at 2 to 113 ° C. (hereinafter abbreviated as 4BP-6,16) was obtained. Yield 86.5%.

¹ H-NMR (CDCl ₃ ): 4BP-6,1
6 (δppm) 0.85 (6H, t, J = 6.4Hz), 1.23 (52H,
s), 1.37 (4H, br s), 1.55 (4H,
m), 1.92 (4H, m), 3.28 (4H, m), 4.
65 (4H, t, J = 7.2Hz), 8.45 (4H, d, J
= 6.7 Hz), 9.27 (6H, d, J = 6.7 Hz) Elemental analysis: molecular formula C ₅₀ H ₈₈ Br ₂ N ₄ O ₂ CHN theoretical value (%) 64.09 9.47 5 .98 measured value (%) 63.91 9.38 6.07 halogen analysis (oxygen flask combustion method) Br theoretical value (%) 17.05 measured value (%) 16.96 Example 5 final compound 4BP-6, Synthesis of 10 In the same manner as in Example 2, 4BP-6 was subjected to bis-quaternary chlorination with decane bromide, and then purified in the same manner to give a melting point of 128-1.
N, N'-hexamethylenebis (4-
Carbamoyl-1-decylpyridinium bromide)
(Hereinafter, abbreviated as 4BP-6,10) was obtained. Yield 8
5.7%.

¹ H-NMR (CDCl ₃ ): 4BP-6,1
0 (δppm) 0.85 (6H, t, J = 6.5Hz), 1.28 (28H,
s), 1.37 (4H, br s), 1.58 (4H,
m), 1.92 (4H, m), 3.31 (4H, m), 4.
65 (4H, t, J = 7.3Hz), 8.45 (4H, d, J
= 6.8 Hz), 9.27 (6H, d, J = 6.8 Hz) Elemental analysis: molecular formula C ₃₈ H ₆₄ Br ₂ N ₄ O ₂ CHN theoretical value (%) 59.37 8.39 7 .29 measured value (%) 59.21 8.23 6.37 halogen analysis (oxygen flask combustion method) Br theoretical value (%) 20.79 measured value (%) 20.82 Example 6 final compound 4BP-6, Synthesis of 8 In the same manner as in Example 4, 4BP-6 was subjected to bis-quaternary chlorination with octane bromide, and then purified in the same manner to give a melting point of 90 to 9
N, N'-hexamethylenebis (4
-Carbamoyl-1-octylpyridinium bromide)
(Hereinafter, abbreviated as 4BP-6,8) was obtained. Yield 81.
7%.

¹ H-NMR (CDCl ₃ ): 4BP-6,8
(Δppm) 0.85 (6H, t, J = 6.5Hz), 1.27 (20H,
s), 1.37 (4H, br s), 1.58 (4H,
m), 1.92 (4H, m), 3.34 (4H, m), 4.
65 (4H, t, J = 7.2Hz), 8.45 (4H, d, J
= 6.8 Hz), 9.27 (6H, d, J = 6.8 Hz) Elemental analysis: molecular formula C ₃₄ H ₅₆ Br ₂ N ₄ O ₂ CHN theoretical value (%) 57.30 7.927 7 .86 measured value (%) 57.16 8.02 8.04 halogen analysis (oxygen flask combustion method) Br theoretical value (%) 22.42 measured value (%) 22.28 In addition, it was obtained in the above-mentioned Example. The compounds of the present invention are summarized in Table 1 below.

[0034]

[Table 1]

Test Example 1 Minimum inhibitory concentration against fungi
(MIC) measurement 500 pp of each of the compounds listed in Table 1 was added to ethanol.
It melt | dissolved so that it might become m (microgram / ml). This drug solution was serially diluted twice with sterile distilled water ten times to prepare a dilution series.

On the other hand, a spore solution was prepared with sterilized water containing a wetting agent so that the test bacteria cultivated in a PDA medium for 10 to 14 days would have a concentration of 10 ⁶ cells / ml. 1 ml of the diluted drug solution and 1 ml of the spore solution were mixed, and after culturing in an incubator at 27 ° C. for 1 week, the presence or absence of proliferation was determined by turbidity, and the minimum drug concentration when no turbidity was generated was defined as MIC. The results are shown in Table 2 below.

[0037]

[Table 2]

Test Example 2 Minimum inhibitory concentration against bacteria
(MIC) Measurement Drug (4BP-) was added to nutrient broth (NB medium).
6, 12) was dissolved to 500 ppm (μg / ml). This drug solution was diluted with Fresh NB medium and serially diluted 2-fold 10 times to prepare a dilution series.

On the other hand, an inoculum solution was prepared in the NB medium so that the test strains cultured in the NB medium for 24 hours became 10 ⁶ cells / ml. 1 ml of the diluted drug solution and 1 ml of the inoculum were mixed and cultured for 48 hours in an incubator, and then the presence or absence of proliferation was judged by turbidity, and the minimum drug concentration without turbidity was defined as MIC. The results are shown in Table 3 below.

[0040]

[Table 3]

[0041]

INDUSTRIAL APPLICABILITY The bis-quaternary ammonium salt compound of the present invention exhibits an extremely excellent bactericidal effect and a broad antibacterial spectrum as compared with known quaternary ammonium salt compounds, and is highly safe and useful as a bactericide. Is.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tetsuto Namba 1 Kosaihonmachi, Takamatsu City, Kagawa Inui Corporation

Claims (2)

[Claims] 1. A compound of the general formula (1) [In the formula, Z represents a pyridine ring, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₃ is an alkylene group having ₃ to 18 carbon atoms or an alkenylene group. And R ₄ represents an alkyl group having 6 to 18 carbon atoms bonded to the ring nitrogen atom of Z, and X represents an anion]. 2. A compound of the general formula (2) [In the formula, Z represents a pyridine ring, R ₁ and R ₂ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₃ is an alkylene group having ₃ to 18 carbon atoms or an alkenylene group. Is represented by the general formula (3) R ₄ X (3) [In the formula, R ₄ represents an alkyl group having 6 to 18 carbon atoms, and X
Represents an anion]. The method for producing a bis-quaternary ammonium salt compound represented by the general formula (I) according to claim 1, wherein