JP2006001889A - Bactericidal pyridine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new bactericidal pyridine compound by a simple process at a low cost using an easily available pyridine compound as a starting raw material. <P>SOLUTION: The bactericidal pyridine compound is represented by formula (1) [wherein R is a -(CH<SB>2</SB>)<SB>9</SB>CH<SB>3</SB>group or a -(CH<SB>2</SB>)<SB>11</SB>CH<SB>3</SB>group; and Z is chlorine, bromine, iodine or an OSO<SB>2</SB>R<SB>1</SB>group (wherein R<SB>1</SB>is a lower alkyl group or a substituted or nonsubstituted phenyl group)]. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel pyridine compound having bactericidal properties.

  Bis quaternary ammonium salt compounds that exhibit antibacterial activity against bacteria and fungi have been known for a long time and are still widely used as antibacterial agents. However, currently used antibacterial bis-quaternary ammonium salt compounds are usually excellent in antibacterial activity, but at the same time, the residual toxicity of biodegradation products is also high. There was a problem in the solubility and solubility in water and stability, and the application range was limited. In addition, conventional bis quaternary ammonium salt compounds have antibacterial activity antagonized by carbohydrates, proteins, lipids, etc., and the antibacterial activity decreases in the low pH (acidic) region and has no effect on cell spores. There were drawbacks.

（上記式中、Ｙはピリジン環、キノリン環、イソキノリン環またはチアゾリン環を、Ｒ¹は炭素数２〜１０のアルキレン基あるいはアルケニレン基を、Ｒ²はＹの窒素原子に結合した炭素数６〜１８のアルキル基を示し、いずれも置換基を含んでもよい。Ｘはアニオンを示す。） Therefore, bis quaternary ammonium salt compounds represented by the following general formulas (A) and (B) (see Patent Document 1),

(Wherein Y represents a pyridine ring, quinoline ring, isoquinoline ring or thiazoline ring, R ¹ represents an alkylene group or alkenylene group having 2 to 10 carbon atoms, and R ² represents 6 to 6 carbon atoms bonded to the nitrogen atom of Y. 18 represents an alkyl group, any of which may contain a substituent, and X represents an anion.)

（上記式中、Ｚはピリジン環を示し、Ｒ₁およびＲ₂は同一または異なり、各々水素原子または炭素数１〜６のアルキル基を示し、Ｒ₃は炭素数３〜１８のアルケニレン基を示し、Ｒ₄はＺの環窒素原子に結合した炭素数６〜１８のアルキル基またはアルケニル基を示し、Ｘはアニオンを示す。） Bis quaternary ammonium salt compound represented by the following general formula (C) (see Patent Document 2),

(In the above formula, Z represents a pyridine ring, R ₁ and R ₂ are the same or different, each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ₃ represents an alkenylene group having ₃ to 18 carbon atoms. R ₄ represents an alkyl or alkenyl group having 6 to 18 carbon atoms bonded to the ring nitrogen atom of Z, and X represents an anion.)

（上記式中、Ｚはピリジン環またはキノリン環を、Ｒ₃は炭素数２〜１８のアルキレン基あるいはアルケニレン基を、Ｒ₄はＺの窒素原子に結合した炭素数６〜１８のアルキル基を示し、いずれも置換基を含んでもよい。Ｒ₁およびＲ₂は同一または異なって、Ｚの窒素原子以外の原子に結合した炭素数１〜３のアルキル基、水酸基、アミノ基、炭素数１〜３のアルコキシ基あるいは水素原子を、Ｘはアニオンをそれぞれ示す。） A bis quaternary ammonium salt compound represented by the following general formula (D) (see Patent Document 3) has been reported.

(In the above formula, Z represents a pyridine ring or a quinoline ring, R ₃ represents an alkylene group or alkenylene group having 2 to 18 carbon atoms, and R ₄ represents an alkyl group having 6 to 18 carbon atoms bonded to the nitrogen atom of Z. R ₁ and R ₂ may be the same or different and each has an alkyl group having 1 to 3 carbon atoms, a hydroxyl group, an amino group, or 1 to 3 carbon atoms bonded to an atom other than the nitrogen atom of Z. And X represents an anion.)

JP-A-8-301703 Japanese Patent Laid-Open No. 10-095773 JP-A-6-321902

Development of a bis-quaternary ammonium salt compound that is extremely superior in antibacterial activity than the above-mentioned conventionally known bis-quaternary ammonium salt compounds and has little residual toxicity and is friendly to the global environment is strongly desired. ing.
Accordingly, an object of the present invention is to provide a novel bactericidal pyridine compound conveniently and inexpensively using a readily available pyridine compound as a starting material.

（上記式中のＲは−（ＣＨ₂）₉ＣＨ₃基または−（ＣＨ₂）₁₁ＣＨ₃基であり、Ｚは、塩素原子、臭素原子、ヨウ素原子もしくはＯＳＯ₂Ｒ₁基（Ｒ₁は、低級アルキル基もしくは置換あるいは無置換のフェニル基である）である。） The present invention provides a bactericidal pyridine compound represented by the following general formula (1).

(In the above formula, R is — (CH ₂ ) ₉ CH ₃ group or — (CH ₂ ) ₁₁ CH ₃ group, Z is chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is A lower alkyl group or a substituted or unsubstituted phenyl group).

  According to the present invention, a novel bactericidal pyridine compound can be provided simply and inexpensively using a readily available pyridine compound as a starting material.

Next, the present invention will be described in more detail with reference to preferred embodiments.
The compound represented by the general formula (1) of the present invention can be synthesized by various methods, and one example is as follows. That is, 3-chloromethylpyridine, 3-bromomethylpyridine, 3-iodomethylpyridine, 3- (methanesulfonyloxy) methylpyridine, 3- (benzenesulfonyloxy) methylpyridine or a salt thereof (hereinafter referred to as “raw pyridine compound”) ) And 1,4-butanediol are reacted to synthesize a pyridine compound of the following general formula (2). In the reaction, the amount of the raw material pyridine compound used relative to 1,4-butanediol is preferably 1 equivalent mole to 1.5 equivalent mole, and more preferably 1 equivalent mole to 1.1 equivalent mole.

  When producing the pyridine compound represented by General formula (2) by reaction with a raw material pyridine compound and 1, 4- butanediol, various reaction conditions are possible. The presence of a strong base is essential for carrying out this reaction because it is important to produce the corresponding alkoxide from 1,4-butanediol. Strong bases that can be used in this reaction include metallic lithium, metallic potassium, metallic sodium and hydrides thereof, alkyllithiums such as methyllithium and butyllithium, phenyllithium, lithium tertiary riboxide, potassium tertiary riboxide, sodium Tertiary alkali metal alkoxides such as tartaribtoxide are mentioned, and sodium tartariboxide and potassium tartariboxide are preferred from the viewpoint of economy, safety and simplicity. These strong bases may be used alone or in combination of two or more.

  In this reaction, when the free base of the starting pyridine compound is used as the starting material, the strong base used is about 1 equivalent mole. Further, when the raw pyridine compound forms a salt, the strong base used is about 2 equivalents, which is about 1 equivalent moles sufficient to neutralize the salt and about 1 equivalent moles consumed for the desired reaction. Is a mole. However, if the conversion rate is low, a strong base may be added until the starting pyridine compound disappears. The strong base used for neutralizing the salt and the strong base used for the desired reaction may be the same or different. In carrying out this reaction, since the starting pyridine compound is likely to change due to contact with a strong base, an alkoxide is generated in advance by a reaction between 1,4-butanediol and a strong base, and the alkoxide and the starting pyridine compound are treated. Alternatively, it is preferable that the raw material pyridine compound and 1,4-butanediol are mixed in advance, and then a strong base is added to the mixture. When the raw material pyridine compound forms a salt, it is possible to add in advance an amount of a strong base capable of liberating the compound, and to perform the treatment in the above-described procedure.

  This reaction can usually be carried out in the presence of various solvents, but as a solvent that does not adversely affect the desired reaction and gives good conversion and selectivity in the desired reaction, an aprotic polar solvent Is preferred. As the aprotic polar solvent, cyclic ether solvents such as tetrahydrofuran and dioxane, amide solvents such as dimethylformamide, N-methylpyrrolidone, and dimethylimidazolidinone are preferably used. Considering simplicity, dimethylformamide is the most suitable solvent. These solvents may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected in consideration of the solubility of the starting pyridine compound, the solubility of 1,4-butanediol, and the dispersion state of the alkali metal salt produced during the reaction.

  The temperature of this reaction can be selected from −20 ° C. to the boiling point of the solvent used at normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material.

  The pyridine compound represented by the general formula (2) obtained by this reaction can be removed from the reaction mixture by a conventional method. For example, the alkali metal salt generated by solid-liquid separation of the mixture after completion of the reaction is removed, the mother liquor is concentrated under reduced pressure, the residual liquid is extracted after dispersion in water, and the extract is concentrated under reduced pressure. Higher-purity compounds are produced by forming a salt of an inorganic or organic acid such as hydrochloride, acetate or sulfate of the pyridine compound represented by the general formula (2), and if necessary after recrystallization thereof. It can be obtained by neutralizing the salt and treating it in a conventional manner.

Next, the pyridine compound represented by the following general formula (3) can be produced by reacting the pyridine compound represented by the general formula (2) with the same raw material pyridine compound as described above in the presence of a strong base. it can.

  The pyridine compound represented by the general formula (3) can also be produced without isolating the compound represented by the general formula (2). For example, the pyridine compound represented by the general formula (2) is generated in the reaction system by the above-described operation, and then the raw material pyridine compound is allowed to act in the presence of a strong base. The amount of the pyridine compound represented by the general formula (2) or a salt thereof is preferably 1 to 1.5 equivalents, more preferably 1 to 1.1 equivalents, relative to the raw material pyridine compound.

  As described above, in the reaction of the raw pyridine compound and the pyridine compound represented by the general formula (2) or a salt thereof, the raw pyridine compound is easily changed by contact with a strong base. After the alkoxide is generated by the reaction of the base, the pyridine compound represented by the general formula (2) is added, or the pyridine compound represented by the general formula (2) and the raw material pyridine compound are mixed in advance, It is preferable to add a strong base. When the starting pyridine compound forms a salt, an amount capable of liberating the compound, usually about 1 equivalent mole of a strong base, is added in advance and can be treated by the procedure described above.

  In this reaction, the strong base selected in the reaction of the raw material pyridine compound and 1,4-butanediol can be used, and these may be used alone or in combination of two or more. When the starting pyridine compound is a free base, the amount of strong base used is preferably about 1 equivalent mole. However, when the conversion rate is low, a strong base may be added until the pyridine compound represented by the general formula (2) and the starting pyridine compound disappear.

  In this reaction, it is possible to use the solvent selected in the reaction of the raw material pyridine compound and 1,4-butanediol, which may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected according to the solubility of the pyridine compound represented by the general formula (2) and the raw material pyridine compound and the dispersion state of the alkali metal salt generated during the reaction.

  This reaction can be selected from −20 ° C. to the boiling point of the solvent used under normal pressure. A preferable reaction temperature is −20 ° C. to room temperature, and a more preferable reaction temperature is −10 ° C. to 10 ° C. The progress of the reaction can be traced by thin layer chromatography or high performance liquid chromatography, and the completion of the reaction can be confirmed by disappearance of the raw material. The pyridine compound represented by the general formula (3) can be taken out from the reaction mixture by a conventional method. When the compound is crystalline, a higher purity compound can be obtained by recrystallization. When the compound is non-crystalline, after forming an inorganic or organic acid salt such as monohydrochloride, dihydrochloride, monoacetate, diacetate, etc. of the compound and recrystallizing them as necessary A high-purity compound can be obtained by neutralizing the salt and removing it by a conventional method.

（上記式中のＲは−（ＣＨ₂）₉ＣＨ₃基または−（ＣＨ₂）₁₁ＣＨ₃基であり、Ｚは、塩素原子、臭素原子、ヨウ素原子もしくはＯＳＯ₂Ｒ₁基（Ｒ₁は、低級アルキル基もしくは置換あるいは無置換のフェニル基である）である。） Next, the bactericidal pyridine compound of the present invention represented by the general formula (1) is reacted by reacting the pyridine compound represented by the general formula (3) with the compound represented by the following general formula (4). Obtainable.

(In the above formula, R is — (CH ₂ ) ₉ CH ₃ group or — (CH ₂ ) ₁₁ CH ₃ group, Z is chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is A lower alkyl group or a substituted or unsubstituted phenyl group).

  In this reaction, the amount of the compound represented by the general formula (4) to the pyridine compound represented by the general formula (3) is theoretically 2 equivalent moles. However, when the conversion rate is low, a large amount of the compound represented by the general formula (4) may be used. If it is used in a large excess, it can be recovered and reused.

  In the reaction of the pyridine compound represented by the general formula (3) and the compound represented by the general formula (4), a solvent can be used. Preferred solvents include lower aliphatic alcohols and aprotic polar solvents. Specifically, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, acetonitrile, propionitrile, acetone, methyl ethyl ketone. , Methyl isobutyl ketone, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethylimidazolidinone, dimethyl sulfoxide and the like can be used. Dimethylformamide is the most preferred solvent because of good conversion and selectivity of the reaction, simple post-treatment, and excellent economic efficiency.

  These solvents may be used alone or in combination of two or more. The amount of the solvent used can be appropriately selected in consideration of the solubility of the pyridine compound represented by the general formula (3) and the compound represented by the general formula (4) in the solvent.

  On the other hand, this reaction can also be carried out using an excess of the compound represented by the general formula (4) without using a solvent. In this case, after completion of the reaction, the unreacted compound represented by the general formula (4) can be separated from the reaction mixture, recovered, and reused, which is extremely efficient and economical.

  This reaction can be carried out from 0 ° C. at the boiling point at normal pressure of the solvent used or the compound represented by the general formula (4). A preferred temperature is from room temperature to 100 ° C, and a more preferred temperature is from 40 ° C to 80 ° C. The progress of the reaction can be traced by high performance liquid chromatography or the like, and the end of the reaction can be judged from the disappearance of the raw materials and the amount of the desired bactericidal pyridine compound of the general formula (1).

  Further, the reaction is represented by the general formula (4) in the reaction mixture containing the pyridine compound represented by the general formula (3) without isolating the pyridine compound represented by the general formula (3). It is also possible to carry out continuously by adding a compound. In this case, what is necessary is just to use the solvent used for manufacture of the compound of General formula (3) as it is.

  The bactericidal pyridine compound of the present invention represented by the general formula (1) can be taken out by a conventional method, and a compound that is solid at room temperature can be crystallized from an appropriate solvent system. In this case, by selecting an appropriate solvent system, purification by recrystallization is possible, and a high-purity target product can be obtained.

ＤＭＦ（ジメチルホルムアミド）７５ｍｌに１，４−ブタンジオール８．２４ｇ（９１．４３ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド１０．３ｇ（９１．７９ｍｍｏｌ）を添加し、室温で１．５時間撹拌した。 The following examples further illustrate the present invention.
<Example 1>
[Synthesis of Compound (A) Represented by Structural Formula below]

To 75 ml of DMF (dimethylformamide), 8.24 g (91.43 mmol) of 1,4-butanediol was added, and 10.3 g (91.79 mmol) of potassium tert-butoxide was added under ice cooling, followed by stirring at room temperature for 1.5 hours. did.

  To this slurry solution, 1.0 g (6.10 mmol) of 3-chloromethylpyridine hydrochloride and 0.68 g (6.06 mmol) of potassium tert-butoxide were alternately added at −8 to −3 ° C., and this was repeated 15 times. In total, 15.0 g (91.45 mmol) of 3-chloromethylpyridine hydrochloride and 10.2 g (90.9 mmol) of potassium tert-butoxide were added.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, a peak of 3-chloromethylpyridine was confirmed. Therefore, potassium tert-butoxide was kept at 5 ° C. or lower until the peak of 3-chloromethylpyridine disappeared. Added. The added potassium tert-butoxide was 1.13 g (10.07 mmol).

  The reaction mixture was subjected to solid-liquid separation, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure to obtain 17.1 g of an oily crude product (compound (A)). When the obtained oil was analyzed by HPLC (condition 1), the area% of the compound (A) was 76.0%.

The crude product of the compound (A) was dissolved in 30 ml of water and washed with toluene. Thereafter, 6 g of sodium chloride was added to the aqueous layer, followed by extraction with 20 ml of dichloromethane, dehydration with anhydrous magnesium sulfate, the solvent was distilled off, and 9.21 g of the oily compound (A) (yield (1,4-butane) From the diol): 57.2%). When the obtained oily substance was analyzed by HPLC (condition 1), the area% was 99.4%. _{^{(1 H-NMR (CDCl 3}} ): δ1.67-1.75 (4H, m, - (C H 2) 2 -), δ2.35 (1H, s, O H), δ3.52-3. 56 (2H, t, J = 6.0 Hz, C H ₂ ), δ 3.64-3.68 (2H, t, J = 6.0 Hz, C H ₂ ), δ 4.52 (2H, s, C H ₂ ), δ 7.27-7.31 (1H, m, arom H ), δ 7.66-7.70 (1 H, m, arom H ), δ 8.52-8.56 (2H, m, arom H × 2), MS (APCl): m / z = 182 [M + H] ⁺ )

HPLC (condition 1)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: B = 70: 30 (constant)
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL

ＤＭＦ２５ｍｌに前記化合物（Ａ）５．０ｇ（２７．５９ｍｍｏｌ）を加え、氷冷下カリウムtert−ブトキシド３．１ｇ（２７．６３ｍｍｏｌ）を添加した。このスラリーに５〜６℃で３−クロロメチルピリジン塩酸塩０．５ｇ（３．０５ｍｍｏｌ）およびカリウムtert−ブトキシド０．３４ｇ（３．０３ｍｍｏｌ）を交互に添加し、これを９回繰り返し、全量で３−クロロメチルピリジン塩酸塩４．５ｇ（２７．４３ｍｍｏｌ）およびカリウムtert−ブトキシド３．０６ｇ（２７．２７ｍｍｏｌ）を添加した。 [Synthesis of Compound (B) Represented by Structural Formula below]

The compound (A) (5.0 g, 27.59 mmol) was added to DMF (25 ml), and potassium tert-butoxide (3.1 g, 27.63 mmol) was added under ice cooling. To this slurry, 0.5 g (3.05 mmol) of 3-chloromethylpyridine hydrochloride and 0.34 g (3.03 mmol) of potassium tert-butoxide were alternately added at 5 to 6 ° C., and this was repeated 9 times. 4.5 g (27.43 mmol) of 3-chloromethylpyridine hydrochloride and 3.06 g (27.27 mmol) of potassium tert-butoxide were added.

  After completion of the addition, the reaction mixture was analyzed by HPLC (condition 1). As a result, peaks of 3-chloromethylpyridine and the compound (A) were confirmed. Therefore, the peak of 3-chloromethylpyridine and the peak of the compound (A) were confirmed. Potassium tert-butoxide was added at 5 ° C. or lower until disappeared. The added potassium tert-butoxide was 0.62 g (5.53 mmol).

The reaction mixture was separated into solid and liquid, the cake was washed with 30 ml of DMF, and DMF was distilled off from the filtrate under reduced pressure. To this concentrated residue, 20 ml of dichloromethane was added, and the solution was washed with saturated brine, and then the solvent was distilled off to obtain 5.8 g of an oily substance. About 0.5 g of this crude product was purified by silica gel column chromatography (developing solvent: chloroform-methanol) to obtain 0.3 g of oily compound (B). ( ¹ H-NMR: δ 1.70-1.74 (4H, m,-(C H ₂ ) _2- ), δ 3.50-3.54 (4H, m, C H ₂ × 2), δ 4.51 (4H, s, C H ₂ × 2), δ 7.25-7.29 (2H, dd, J = 4.9 Hz, 7.9 Hz, arom H × 2), δ 7.65-7.69 (2H, dt, J = 1.7 Hz, 7.9 Hz, arom H × 2), δ 8.52-8.57 (4H, dd, J = 1.7 Hz, 4.9 Hz, arom H × 4), MS (APCl) : M / z = 273 [M + H] ⁺ )

前記化合物（Ｂ）５．０ｇ（１８．３６ｍｍｏｌ）にデシルブロマイド４０．６ｇ（１８３．８ｍｍｏｌ）を加え、７０〜８０℃で２０時間反応を行った。 [Synthesis of Compound (1) of Structural Formula below]

40.6 g (183.8 mmol) of decyl bromide was added to 5.0 g (18.36 mmol) of the compound (B), and the reaction was performed at 70 to 80 ° C. for 20 hours.

When the reaction mixture was analyzed by HPLC (condition 2), the peak of the compound (B) disappeared. The upper decyl bromide layer was separated from the reaction mixture, and the lower oil was poured into a mixture of acetonitrile-ethyl acetate = 1: 3 (v / v). The mixture was cooled, and the precipitated crystals were filtered at 0 ° C. and dried under reduced pressure to obtain 11.6 g of grayish white crystals (crude yield (from the compound (B)): 88.5%). When the crystals of the compound were analyzed by HPLC (Condition 1), the area% of the compound (1) was 98.4%. Melting points, NMR analysis values and elemental analysis values were as follows.
(Melting point: 76.8 to 79.2 ° C., ¹ H-NMR (CD ₃ OD): δ 0.9 (6H, t, C H ₃ × 2), δ 1.29 to 1.40 (28H, m, ( C H ₂ ) ₇ × 2), δ 1.77 to 1.84 (4H, m, C H ₂ × 2), δ 2.00 to 2.05 (4H, t, C H ₂ × 2), δ 3.69 ˜3.70 (4H, t, C H ₂ × 2), δ 4.64 to 4.68 (4H, t, C H ₂ × 2), δ 4.77 (4H, s, C H ₂ × 2), δ 8.07 to 8.11 (2H, dd, J =, arom H × 2), δ 8.55 to 8.57 (2H, d, arom H × 2), δ 8.93 to 8.94 (2H, d , arom H × 2), δ9.02 (2H, s, arom H × 2)

HPLC (condition 2)
Column: Inertsil ODS-3 (GL Sciences) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.5% ammonium acetate aqueous solution, B-acetonitrile A: 60% (5 min hold) → (10 min) → A: 30% (30 min hold) → A : 60%
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 10 μL

<Example 2>
13.0 g of the compound (2) represented by the following structural formula in the same manner as in Example 1 except that an equimolar amount of dodecyl bromide was used instead of decyl bromide in Example 1 (crude yield: 91.5% ) When the obtained compound (2) was analyzed by HPLC (condition 3), the peak area% of the compound (2) was 97.5%. The melting point, NMR analysis value, and elemental analysis value were as follows.

(Melting point: 90.0 to 91.4 ° C., ¹ H-NMR (CD ₃ OD): δ 0.89 (6H, t, C H ₃ × 2), δ 1.26 to 1.39 (36H, m, ( C H ₂ ) ₉ × 2), δ 1.79 to 1.82 (4H, m, C H ₂ × 2), δ 1.84 to 2.05 (4H, m, C H ₂ × 2), δ 3.67 ˜3.70 (4H, t, C H ₂ × 2), δ 4.65 to 4.68 (4H, t, C H ₂ × 2), δ 4.77 (4H, s, C H ₂ × 2), δ 8.07 to 8.11 (2H, dd, arom H × 2), δ 8.55 to 8.57 (2H, d, arom H × 2), δ 8.93 to 8.94 (2H, d, arom H × 2), δ9.02 (2H, s, arom H × 2)

HPLC (condition 3)
Column: CAPCELL PAK C ₁₈ SG120 (Shiseido) 4.6 mmφ × 250 mm
Column temperature: constant temperature around 15 ° C. Mobile phase: A-0.1M potassium dihydrogen phosphate (0.05% phosphoric acid) aqueous solution, B-80% acetonitrile aqueous solution A: B = 30: 70
・ Flow rate: 1.0ml / min
・ Detector: UV254nm
・ Injection volume: 20μL

Test Example 1 <Bacteriostatic activity against various bacteria of the compounds (1) to (2) of the present invention>
The minimum inhibitory concentration (MIC) was measured using benzalkonium chloride as a control compound. The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method. Using a nutrient broth, a steady-state bacterial solution adjusted to a cell suspension concentration of 10 ⁶ cells / ml was serially diluted. The MIC value was determined based on the presence or absence of proliferation after mixing with the drug solution and standing culture at 37 ° C. for 24 hours. Ten gram-negative bacteria and six gram-positive bacteria were used as test bacteria. The results are shown in Table 1.

Test Example 2 <Bactericidal activity (MBC) against various bacteria of the compounds (1) to (2) of the present invention>
Benzalkonium iodide was used as a control compound. Five gram-negative bacteria and four gram-positive bacteria were used as test bacteria, and the minimum bactericidal concentration (MBC) was measured in the same manner as described above. The results are shown in Table 2.

Test Example 3 <Measurement of Minimum Growth Inhibitory Concentration (MIC) for Fungi of Compounds (1) to (2) of the Present Invention>
TBZ (2- (4′-thiazolyl) benzimidazole) was used as a reference compound. The minimum inhibitory concentration (MIC) was measured according to a general broth dilution method, using a Sabouraud medium, and preparing a spore solution of pre-cultured test bacteria with humectant-added sterilized water. Diluted drug solution (1 ml) and spore solution (1 ml) were mixed, cultured in an incubator at 30 ° C. for 1 week, the presence or absence of growth was determined by turbidity, and the place where no turbidity occurred was defined as MIC. The results are shown in Table 3.

According to the present invention, a novel bactericidal pyridine compound can be provided conveniently and inexpensively using a readily available pyridine compound as a starting material.

Claims (1)

A bactericidal pyridine compound represented by the following general formula (1):

(In the above formula, R is — (CH ₂ ) ₉ CH ₃ group or — (CH ₂ ) ₁₁ CH ₃ group, Z is chlorine atom, bromine atom, iodine atom or OSO ₂ R ₁ group (R ₁ is A lower alkyl group or a substituted or unsubstituted phenyl group).