JP2662343B2 - Monobiguanide derivative and disinfectant containing this derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel monobiguanide derivative used for disinfecting humans, animals and medical instruments, and a disinfectant containing this derivative.

[0002]

2. Description of the Prior Art It is known that various guanidine derivatives have bactericidal properties, and British Patent No. 1,095,902 discloses 1,4-dimethylenecyclohexane type biguanide derivatives.

[0003]

The main object of the present invention is to provide a novel monobiguanide derivative or a salt thereof having a higher activity than conventional biguanide derivatives, and a disinfectant containing the derivative or a salt thereof. Is.

[0004]

Means and Actions for Solving the Problems The monobiguanide derivative of the present invention for achieving the above object has the general formula:

[0005]

[Chemical 1]

(Where R is¹Is 3,4-dichlorobenzyl
Group, 4-chlorophenyl group, 3,4-dichlorophenyl
Group, a benzyl group or a 4-chlorobenzyl group, R
^TwoIs an octyl group, 3,4-dichlorobenzyl group, dodecyl group
Group, decyl group, 3-trifluoromethylphenyl group,
4-bromophenyl group, 4-iodophenyl group, 2,4
-Dichlorophenyl group, 3,4-dichlorophenyl group,
2,3,4-trichlorophenyl group, 3,4-dimethyl
Phenyl group, 3,4-methylenedioxyphenyl group, 4
-T-butylphenyl group, 4-ethylthiophenyl group,
1,1,3,3-tetramethylbutyl group, hexyl group,
Three-Diethylaminopropyl group, (2-diethylami
No)-ethyl group, 3-(Di-n-butylamino)propyi
Group, cyclohexylmethyl groupFour-Chlorbenzyl
Group, 2,4-dichlorobenzyl group, 4-acetylamino
Phenyl groupThree, 4-methylenedioxybenzyl group,I
SobutylBaseShow. ), N¹-(3,4-dichlorobenzyl)-N
⁵-Octyl-Biguanide, N¹-(4-chlorophenyl)-N⁵-(3,4-Ziku
Lorbenzyl)-biguanide, N¹-(3,4-dichlorophenyl)-N⁵-Octyl
-Biguanide, N¹-Benzyl-N⁵-Dodecyl-Biguanide, N¹-Benzyl-N⁵-Decyl-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(3-T
Lifluoromethylphenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵−⁽4-bu
Romphenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(4-Yo
Dephenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(2,4
-Dichlorophenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Dichlorophenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(2
3,4-trichlorophenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Dimethylphenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Methylenedioxyphenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(4-t
-Butylphenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(4-E
Cylthiophenyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(N-de
Sill)-Biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-(1,
1,3,3-tetramethylbutyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-Hexyl
-Biguanide, _N¹-(3,4-dichlorobenzyl)-N⁵-(3-di
Ethylaminopropyl)-biguanide, N¹-(3,4-dichlorobenzyl)-N⁵-[(2-
Diethylamino)-ethyl]-biguanide, _N¹-(3,4-dichlorobenzyl)-N⁵-[3−
(Di-n-butylamino)propyl-biguanide, N¹-(4-Chlorophenyl)-N⁵-Cyclohexyl
Methyl-biguanide, N¹-(4-Chlorophenyl)-N⁵-(3-Trifle
Oromethylphenyl)-biguanide, N¹-(4-Chlorophenyl)-N⁵-(4-ethylchi
Offyl)-biguanide, N¹-(4-Chlorophenyl)-N⁵-(4- chlorbe
)-Biguanide, N¹-(4-Chlorophenyl)-N⁵-(2,4-Ziku
Lorbenzyl)-biguanide, N¹-(4-Chlorophenyl)-N⁵-(4-acetyl
Aminophenyl)-biguanide, N¹-(4-Chlorophenyl)-N⁵-(3,4-Meth
Dioxyphenyl)-biguanide, N¹-(4-Chlorophenyl)-N⁵-(3,4-Meth
(Dioxybenzyl)-biguanide, N¹-(4-chlorobenzyl)-N⁵-Octyl-big
Anide, _N¹-(4-chlorobenzyl)-N⁵-Decyl-bigua
Nido, N¹-(4-chlorobenzyl)-N⁵-Dodecyl-Bigg
Anide, N¹-(4-chlorobenzyl)-N⁵-Isobutyl-bi
Guanaid, N¹-(4-chlorobenzyl)-N⁵-(3,4-Ziku
Lorphenyl)-biguanide, N¹-(3,4-dichlorophenyl)-N⁵-(3,4
-Methylenedioxybenzyl)-biguanide, N¹-(3,4-dichlorophenyl)-N⁵-Hexyl
-Biguanide, or N¹-(3,4-dichlorophenyl)-N⁵-Decyl-
With biguanide derivative which is biguanide or its salt
is there.

The monobiguanide derivative (1) or a salt thereof of the present invention has a higher bactericidal action or antibacterial action as compared with conventionally known monobiguanide. Therefore, the disinfectant of the present invention contains the monobiguanide derivative represented by the general formula (1) or a salt thereof as an active ingredient. Since the monobiguanide derivative (1) of the present invention is a basic compound, it can react with an organic acid or an inorganic acid to form a corresponding acid addition salt.
Examples of the acid that forms such a salt include formic acid, acetic acid, lactic acid, butyric acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, and oxalic acid. ,
Citric acid, glycolic acid, gluconic acid, sugar acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid,
Sulfuric acid, phosphoric acid, nitric acid, carbonic acid and the like can be used and are not particularly limited. Further, the ratio of the monobiguanide derivative forming the acid addition salt to the acid is not particularly limited, and salts having various ratios such as 1:2 can be used in addition to 1:1.

The acid addition salt may be prepared by directly mixing an acid and a base, dissolving one or both of them in a solvent such as water in advance and mixing them, or adding an acid and a base into the solvent to dissolve and mix them. It is manufactured by adopting an ordinary salt forming method such as. After the reaction, the obtained acid addition salt is filtered if insoluble or hardly soluble in the reaction medium, and if soluble in the reaction medium,
It is recovered by evaporating the reaction medium.

Such an acid addition salt exerts a high bactericidal effect or antibacterial effect by itself, and is also useful for purification and isolation of the free base. Also, the acid addition salt is preferably pharmaceutically acceptable. The monobiguanide derivative (1) of the present invention may form a stable coordination compound with a metal salt. Such a coordination compound also exhibits a bactericidal effect. The coordination compound is a derivative or its acid addition salt of a predetermined amount of metal salt, preferably V, Cr, Mn, Co, N.
It can be obtained by reacting with a heavy metal salt such as i, Cu, Zn, Pd, Re and Os.

Next, a method for producing the monobiguanide derivative of the present invention will be described.

[0011]

[Chemical 2]

(In the formula, R ¹ and R ² are the same as above.) As shown in the above reaction formula, the monobiguanide derivative (1) of the present invention comprises an amine represented by the general formula (a): It is obtained by reacting with the N ¹ -cyanoguanidine compound represented by the general formula (b). At this time, the amine (a) is used in an approximately equimolar amount with respect to the compound (b).
The amine (a) may also be in the form of a suitable acid addition salt such as hydrochloride.

The above components (a) and (b) are reacted by heating in the presence or absence of an inert solvent such as 2-ethoxyethanol, 2-methoxyethanol or o-dichlorobenzene. When the product is an acid addition salt,
It can be converted into a free base form by reacting it with an alkali such as sodium hydroxide, or can be converted into another acid addition salt by ion exchange or the like.

The starting material represented by the above general formula (b) is
For example, it can be produced by the following reaction formula.

[0015]

[Chemical 3]

(In the formula, M represents an alkali metal and R ² is the same as above.) That is, an amine represented by the general formula (c) or an acid addition salt thereof (hydrochloride, etc.) is added with an alkali of dicyanamide. It is obtained by reacting a metal salt (d) (for example, sodium dicyanamide, potassium dicyanamide, etc.) in an inert solvent. Further, the monobiguanide derivative (1) of the present invention can also be produced by the following reaction formula.

[0017]

[Chemical 4]

(In the formula, R ¹ and R ² are the same as described above.) This reaction can be carried out under substantially the same conditions as the above-mentioned reaction. The monobiguanide derivative (1) of the present invention or a salt thereof has higher antibacterial activity (bactericidal or antibacterial action) than conventionally known monobiguanide derivatives, and may also have antiviral activity. Furthermore, the monobiguanide derivative (1) of the present invention or a salt thereof has a broad antibacterial spectrum, is excellent in fast-acting, stability, safety and the like, and has an effect that its activity lasts for a long time. In addition, it is non-irritating, odorless and soluble in water. In particular, the compounds of Examples 1 to 4 and salts thereof described below are excellent in these various characteristics, and in particular, the compound of Example 1 and salts thereof have a wide antibacterial spectrum and high short-term bactericidal activity including the above-mentioned characteristic points. , Long-lasting medicinal effect, no problem in color, smell and taste,
It is excellent in that it has low toxicity. Further, the salt of the compound of the present invention is excellent in terms of high solubility, low irritation and toxicity, high stability, and the like, including the above-mentioned characteristic points.

Therefore, the biguanide derivative (1) of the present invention or a salt thereof is useful as an active ingredient of a disinfectant for humans, animals and medical instruments. The disinfectant of the present invention is used in the form of a solution, dispersion or suspension in which a predetermined amount of the biguanide derivative (1) or a salt thereof is dissolved, dispersed or suspended in water or an organic solvent. Representative examples thereof include external liquid preparations such as eye drops, nasal drops, gargles, detergents and cleaning agents. In this case, the addition amount of the biguanide derivative (1) or its salt is usually appropriate to be about 0.01 to 20% by weight based on the total amount.

The biguanide derivative (1) of the present invention
Alternatively, the salt is used in various cosmetics such as various creams,
Lotions, powdered whites, beniches, makeups, brushes, shampoos, soaps, depilatories, bleaches, hair coloring agents, hair styling agents, bath agents, nail polish, antiperspirants, deodorants, aerosol cosmetics, infants It can also be contained in cosmetics for cosmetics.

In the case of producing a cosmetic, a predetermined amount of the biguanide derivative (1) or a salt thereof is dissolved, dispersed or suspended in water or other solvent or various cosmetic base materials together with other components. To be done. The amount of the biguanide derivative (1) or its salt to be added to the cosmetics is usually about 0.001 to 1% by weight based on the total amount.

[0022]

[Production of N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide hydrochloride]

200 ml of mesitylene was added to 20 g of N ¹ -cyano-N ³ -octyl-guanidine and 20.2 g of 3,4-dichlorobenzylamine hydrochloride, and the mixture was heated under reflux for 1.5 hours. After the reaction, the temperature was returned to room temperature to remove mesitylene. To the residue was added 10% aqueous ethanol solution (200 ml), and the mixture was heated and then stirred at room temperature for 3 hours to solidify. This is collected by filtration, 1
It was washed with 0% ethanol solution, water and then isopropyl ether to obtain 28.1 g of a crude product. This was recrystallized from ethyl acetate to obtain 22.1 g of the title compound.

White ridge crystals mp. 177-179°C Elemental analysis value C₁₇H₂₈Cl_ThreeN₅ CHN calculated value 49.95 6.90 17.13 measured value 49.67 7.18 17.01 Example 2 [N¹-(4-Chlorophenyl)-N⁵-(3,4-di
Chlorobenzyl)-Production of biguanide hydrochloride] N¹-Cyano-N⁵-(3,4-dichlorobenzyl)-
20 g of guanidine and 4-chloroaniline hydrochloride 13.5
200 ml of water was added to g and the mixture was heated under reflux for 2 hours. After reaction
Crystals were precipitated when allowed to cool. The crystals are collected by filtration and ethyl acetate
For drying the crystals obtained after heat treatment with 300 ml.
From this, 21.8 g of the title compound was obtained.

White ridge mp. 238-240°C Elemental analysis value C₁₅H₁₅Cl_FourN₅ CHN calculated value 44.25 3.71 17.20 measured value 44.19 3.66 17.17 Example 3 [N¹-(3,4-dichlorophenyl)-N⁵-Oct
Production of ru-biguanide hydrochloride] 3,4 in place of 3,4-dichlorobenzylamine hydrochloride
− Dichloroaniline hydrochloride was used in the same amount except that the same molar amount was used.
28.2 g of the title compound was obtained in the same manner as in Example 1.

White ridge mp. One hundred seventy-six to one hundred and seventy-seven ° C. Elemental analysis _{C 16 H 26 Cl 3 N 5} C H N Calculated 48.68 6.64 17.74 Found 48.52 6.50 17.77 Example 4 ^{N 1} - benzyl -N ⁵ -Production of Dodecyl-Biguanide Hydrochloride] 20 g of N ¹ -cyano-N ³ -benzyl-guanidine, 25.4 g of dodecylamine hydrochloride and 200 ml of mesitylene.
Was added and the mixture was heated under reflux for 2 hours. After the reaction, the same procedure as in Example 1 was carried out to obtain 23.7 g of the title compound.

White ridge mp. 135-137°C Elemental analysis value C₂₁H₃₈ClN₅ C H N calculated value 63.69 9.67 17.68 measured value 63.47 9.41 17.73 Example 5 [N¹-Benzyl-N⁵-Decyl-biguanide hydrochloride
Production of decylamine hydrochloride was used instead of dodecylamine hydrochloride.
The title compound was prepared in the same manner as in Example 4 except that it was used in a molar amount.
20.3 g was obtained.

White ridge crystals mp. 133-135°C Elemental analysis value C¹⁹H³⁴ClN₅ C H N Calculated value 62.02 9.31 19.03 Measured value 62.29 9.57 18.91 Example 6 [N¹-(3,4-dichlorobenzyl)-N⁵-(3-
Of trifluoromethylphenyl)-biguanide hydrochloride
Production] 3-trifluoromethine instead of 4-chloroaniline hydrochloride
Example 2 except that tilaniline hydrochloride was used in the same molar amount.
In the same manner as above, 23.2 g of the title compound was obtained.

White ridge crystals mp. 185-188°C Elemental analysis value C₁₆H₁₅Cl_ThreeF_ThreeN₅ C H N calculated value 43.61 3.43 15.89 measured value 43.57 3.24 16.10 Example 7 [N¹-(3,4-dichlorobenzyl)-N⁵-(4-
Production of bromophenyl)-biguanide hydrochloride] 4-bromoaniline instead of 4-chloroaniline hydrochloride
In the same manner as in Example 2 except that the hydrochloride was used in the same molar amount.
21.6 g of the title compound was obtained.

White ridge crystals mp. 223-225°C Elemental analysis value C₁₅H₁₅BrCl_ThreeN₅ C H N calculated value 39.90 3.35 15.51 measured value 40.34 3.16 15.82 Example 8 [N¹-(3,4-dichlorobenzyl)-N⁵-(4-
Production of iodophenyl)-biguanide hydrochloride] 4-iodoaniline instead of 4-chloroaniline hydrochloride
In the same manner as in Example 2 except that the hydrochloride was used in the same molar amount.
22.6 g of the title compound was obtained.

White ridges mp. 215 to 217°C Elemental analysis value C₁₅H₁₅Cl_ThreeIN₅ C H N calculated value 36.14 3.03 14.05 measured value 36.25 2.80 14.21 Example 9 [N¹-(3,4-dichlorobenzyl)-N⁵-(2
Production of 4-dichlorophenyl)-biguanide hydrochloride] 2,4-dichloroa instead of 4-chloroaniline hydrochloride
Same as Example 2 except that niline hydrochloride was used in the same molar amount.
This gave 20.4 g of the title compound.

White ridge mp. 217 to 220°C Elemental analysis value CHN calculated value 40.80 3.20 15.86 Measured value 41.25 2.93 15.79 Example 10 [N ¹ -(3,4-dichlorobenzyl)-N ^5- (3,
Production of 4-dichlorophenyl)-biguanide hydrochloride] The title compound 21 was prepared in the same manner as in Example 2 except that 3,4-dichloroaniline hydrochloride was used in the same molar amount instead of 4-chloroaniline hydrochloride. 0.7 g was obtained.

White ridges mp. 205-208°C Elemental analysis value C₁₅H₁₄Cl₅N₅ C H N calculated value 40.80 3.20 15.86 measured value 41.03 2.94 15.94 Example 11 [N¹-(3,4-dichlorobenzyl)-N⁵-(2
Of 3,4-trichlorophenyl)-biguanide hydrochloride
Production] 2,3,4-tric acid instead of 4-chloroaniline hydrochloride
Example 2 except that loraniline hydrochloride was used in the same molar amount
In the same manner as above, 23.2 g of the title compound was obtained.

White ridge mp. Two hundred twenty-seven to two hundred twenty-eight ° C. Elemental analysis _{C 15 H 13 Cl 6 N 5} C H N Calculated 37.85 2.75 14.71 Found 38.09 2.55 14.81 Example 12 ^[N 1 - (3, 4-di-chlorobenzyl) ^-N 5 - (3,
Production of 4-Dimethylphenyl)-Biguanide Hydrochloride] 20.3 g of the title compound in the same manner as in Example 2 except that 3,4-dimethylaniline hydrochloride was used in the same molar amount in place of 4-chloroaniline hydrochloride. Got

White ridge crystals mp. 190-191°C Elemental analysis value C₁₇H₂₀Cl_ThreeN₅ CHN Calculated value 50.95 5.03 17.48 Measured value 50.66 4.78 17.56 Example 13 [N¹-(3,4-dichlorobenzyl)-N⁵-(3
4-Methylenedioxyphenyl)-biguanide hydrochloride
Production of] 4-chloroaniline hydrochloride instead of 3,4-methylenedi
Example except that oxyaniline hydrochloride was used in the same molar amount
25.7 g of the title compound was obtained in the same manner as in 2.

White ridges mp. 204-206°C Elemental analysis value C₁₆H₁₆Cl_ThreeN₅O_Two C H N calculated value 46.12 3.87 16.81 measured value 45.83 3.69 16.97 Example 14 [N¹-(3,4-dichlorobenzyl)-N⁵-(4-
Production of t-butylphenyl)-biguanide hydrochloride] 4-t-butylaniline instead of 4-chloroaniline hydrochloride
Same as Example 2 except that phosphorus hydrochloride was used in the same molar amount.
This gave 22.5 g of the title compound.

White ridge crystals mp. 228-230°C Elemental analysis value C₁₉H₂₄Cl_ThreeN₅ C H N calculated value 53.22 5.64 16.33 measured value 52.93 5.38 16.16 Example 15 [N¹-(3,4-dichlorobenzyl)-N⁵-(4-
Production of ethylthiophenyl)-biguanide hydrochloride] 4-ethylthioaniline instead of 4-chloroaniline hydrochloride
Same as Example 2 except that phosphorus hydrochloride was used in the same molar amount.
This gave 20.7 g of the title compound.

White ridge mp. One hundred ninety-nine to two hundred ° C. Elemental analysis _{C 17 H 20 Cl 3 N 5} S C H N Calculated 47.18 4.66 16.18 Found 47.12 4.46 16.04 Example 16 ^[N 1 - (3 , 4-di ^{chlorobenzyl)} -N 5 - (n-
Production of Decyl)-Biguanide Hydrochloride] N ¹ -cyano-N ³ -octyl-guanidine instead of N ¹ -cyano-N ³ -octyl-guanidine
^The title compound 2 was prepared in the same manner as in Example 1 except that ¹ -cyano-N ³ -(n-decyl)-guanidine was used in the same molar amount.
4.5 g was obtained.

White ridge crystals mp. 135-137°C Elemental analysis value C₁₉H₃₂Cl_ThreeN₅ CHN calculated value 52.24 7.38 16.03 measured value 52.08 7.12 16.31 Example 17 [N¹-(3,4-dichlorobenzyl)-N⁵-(1,
1,3,3-Tetramethylbutyl)-biguanide hydrochloric acid
Production of salt] N¹-Cyano-N^Three-Octyl-N instead of guanidine
¹-Cyano-N^Three-(1,1,3,3-tetrabutyl)
-As in Example 1 but using guanidine in the same molar amount
This gave 23.1 g of the title compound.

White ridge crystals mp. 196-198°C Elemental analysis value C₁₇H₂₈Cl_ThreeN₅ C H N calculated value 49.95 6.90 17.13 actual value 49.78 6.81 17.01 Example 18 [N¹-(3,4-dichlorobenzyl)-N⁵-Hexi
Production of rubiguanide hydrochloride] N¹-Cyano-N^Three-Octyl-N instead of guanidine
¹-Cyano-N^Three-Hexyl-guanidine in the same molar amount
The title compound 19.7 was prepared in the same manner as in Example 1 except that it was used.
g was obtained.

White ridge mp. 155-157°C Elemental analysis value C₁₅H₂₄Cl_ThreeN₅ CHN calculated value 47.32 6.35 18.39 measured value 47.21 6.17 18.50_ Example19 [N¹-(3,4-dichlorobenzyl)-N⁵-(3-
Production of Diethylaminopropyl)-Biguanide] N¹-Cyano-N^Three-Octyl-N instead of guanidine
¹-Cyano-N^Three-(3-Diethylaminopropyl)-
Same as Example 1 except that guanidine was used in the same molar amount.
To obtain a crude product. Dissolve this in 100 ml of methanol
Then, equimolar 1N sodium hydroxide was added and concentrated under reduced pressure.
And recrystallizing the residue with isopropanol 1
6.7 g of the title compound was obtained.

White ridge mp. 156-158°C Elemental analysis value C₁₆H₂₆Cl_TwoN₆ C H N Calculated value 51.48 7.02 22.51 Measured value 51.21 6.83 22.76 Examples below20 and 21Is a suitable starting material
Each compound was prepared in the same manner as in Example 1.
Of. _

Example20 [N¹-(3,4-dichlorobenzyl)-N⁵-[(2
-Diethylamino)-ethyl]-biguanide] White ridges mp. 137-140°C Elemental analysis value C₁₅H₂₄Cl_TwoN₆ C H N Calculated value 50.14 6.73 23.39 Measured value 50.01 6.48 23.15_ Example21 [N¹-(3,4-dichlorobenzyl)-N⁵-[3−
(Di-n-butylamino)propyl-biguanide
2 Hydrochloride White Rhombus mp. 122-124°C Elemental analysis value C₂₀H₃₆Cl_FourN₆ CHN calculated value 47.82 7.22 16.73 measured value 47.72 7.01 16.65 Example22 [N¹-(4-Chlorophenyl)-N⁵-Cyclohex
Production of Rumethyl-Biguanide Hydrochloride] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-Cyclohex
Example except using the same molar amount of lumethyl-guanidine
20.4 g of the title compound was obtained in the same manner as in 2.

White ridges mp. 240-241°C Elemental analysis value C₁₅H₂₃Cl_TwoN₅ C H N calculated value 52.33 6.73 20.34 measured value 52.24 6.61 20.48 Example23 [N¹-(4-Chlorophenyl)-N⁵-(3-Triff
Production of Luoromethylphenyl)-Biguanide Hydrochloride] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-(3-Triff
Luoromethylphenyl)-guanidine in the same molar amount
22.7 g of the title compound was prepared in the same manner as in Example 2 except for the above.
Obtained.

White ridges mp. 213-215°C Elemental analysis value C₁₅H₁₄Cl_TwoF_ThreeN₅ C H N calculated value 45.93 3.60 17.86 measured value 46.03 3.55 18.04 Example24 [N¹-(4-Chlorophenyl)-N⁵-(4-ethyl
Production of thiophenyl)-biguanide hydrochloride] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-(4-ethyl
Except that thiophenyl)-guanidine was used in the same molar amount.
In the same manner as in Example 2, 20.76 g of the title compound was obtained.

White ridge mp. 243-245 ° C. Elemental analysis _{C 16 H 19 Cl 2 N 5} S C H N Calculated 50.00 4.98 18.22 Found 50.04 4.82 18.10 Example 25 ^[N 1 - (4 - chlorophenyl) ^-N 5 - (4-chlorobenzyl) - preparation of biguanide hydrochloride] N ¹ - cyano ^-N 3 - (3,4-di-chlorobenzyl) -
21.6 g of the title compound was obtained in the same manner as in Example 2 except that N ¹ -cyano-N ³ -(4-chlorobenzyl)-guanidine was used in the same molar amount instead of guanidine.

White ridge crystals mp. 225 to 227°C Elemental analysis value C₁₅H₁₆Cl_ThreeN₅ C H N calculated value 48.34 4.33 18.79 measured value 48.32 4.19 18.86 Example26 [N¹-(4-Chlorophenyl)-N⁵-(2,4-di
Chlorobenzyl)-Production of biguanide hydrochloride] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-(2,4-di
Chlorbenzyl)-guanidine was used in the same molar amount
In the same manner as in Example 2, 20.1 g of the title compound was obtained.

White ridges mp. 234-236°C Elemental analysis value C₁₅H₁₅Cl_FourN₅ CHN calculated value 44.25 3.71 17.20 measured value 44.42 3.50 16.95 Example27 [N¹-(4-Chlorophenyl)-N⁵-(4-acetyl
Production of Luminophenyl)-Biguanide Hydrochloride] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-(4-acetyl
Luaminophenyl)-guanidine was used in the same molar amount.
In the same manner as in Example 2, 18.6 g of the title compound was obtained.
It was

White ridge mp. Two hundred and fifty-three to two hundred fifty-five ° C. Elemental analysis _{C 16 H 18 Cl 2 N 6} O C H N Calculated 50.40 4.76 22.04 Found 50.63 4.51 21.92 Example 28 ^[N 1 - (4 - ^{chlorophenyl)} -N 5 - (3,4-methylenedioxyphenyl) - preparation of biguanide hydrochloride] N ¹ - cyano ^-N 3 - (3,4-di-chlorobenzyl) -
19.7 g of the title compound in the same manner as in Example 2 except that N ¹ -cyano-N ³ -(3,4-methylenedioxyphenyl)-guanidine was used in the same molar amount instead of guanidine.
Got

White ridges mp. 237-239°C Elemental analysis value C₁₅H₁₅Cl_TwoN₅O_Two C H N Calculated value 48.93 4.11 8.69 Measured value 48.76 3.95 8.47 Example29 [N¹-(4-Chlorophenyl)-N⁵-(3,4-me
Tolylenedioxybenzyl)-made of biguanide hydrochloride
Structure] N¹-Cyano-N^Three-(3,4-dichlorobenzyl)-
N instead of guanidine¹-Cyano-N^Three-(3,4-me
Tolylenedioxybenzyl)-guanidine in the same molar amount
22.4 g of the title compound in the same manner as in Example 2 except that
Got

White ridge crystals mp. 231-233°C Elemental analysis value C₁₆H₁₇Cl_TwoN₅O_Two CHN calculated value 50.27 4.48 18.32 measured value 50.44 4.29 18.31 ExampleThirty [N¹-(4-chlorobenzyl)-N⁵-Octyl-bi
Production of Guanide Hydrochloride] In place of 3,4-dichlorobenzylamine hydrochloride, 2.4
-Chlorbenzylamine hydrochloride was used in the same molar amount
In the same manner as in Example 1, 21.3 g of the title compound was obtained.

White ridges mp. 156-158°C Elemental analysis value C₁₇H₂₉Cl_TwoN₅ C H N calculated value 54.54 7.81 18.71 actual value 54.76 7.68 18.69 Reference example 1 [N¹-(4-chlorobenzyl)-N⁵-(4-chloro
Production of benzyl)-biguanide hydrochloride] N¹-Cyano-N^Three-(4-Chlorobenzyl)-guani
20.85 g of gin and 4-chlorobenzylamine hydrochloride 1
Using 7.8 g, the title compound was prepared in the same manner as in Example 1.
21.4 g of the product was obtained.

White ridge mp. 200-202°C Elemental analysis value C₁₆H₁₈Cl_ThreeN₅ C H N Calculated value 49.69 4.69 18.11 Measured value 49.62 4.61 18.37 Example31 [N¹-(4-chlorobenzyl)-N⁵-Decyl-big
Production of Anide Hydrochloride] In place of 4-chlorobenzylamine hydrochloride, dodecyl chloride
Other than using the same molar amount of min hydrochlorideReference example 1alike
This gave 24.3 g of the title compound.

White ridges mp. 161 to 163°C Elemental analysis value C₁₉H₃₃Cl_TwoN₅ C H N Calculated value 56.71 8.27 17.40 Measured value 56.60 8.12 17.63 Example32 [N¹-(4-chlorobenzyl)-N⁵-Dodecyl-bi
Production of Guanide Hydrochloride] In place of 4-chlorobenzylamine hydrochloride, dodecyl chloride
Other than using the same molar amount of min hydrochlorideReference example 1alike
This gave 22.3 g of the title compound.

White ridges mp. 158-160°C Elemental analysis value C₂₁H₃₇Cl_TwoN₅ C H N Calculated value 58.59 8.66 16.27 Measured value 58.41 8.53 16.55 Example33 [N¹-(4-chlorobenzyl)-N⁵-Isobutyl-
Production of biguanide hydrochloride] In place of 4-chlorobenzylamine hydrochloride, isobutyl
Other than using the same molar amount of amine hydrochlorideReference example 1same as
This gave 18.7 g of the title compound.

White ridges mp. 219-221°C Elemental analysis value C_ThirteenH₂₁Cl_TwoN₅ CHN Calculated value 49.06 6.65 22.01 Measured value 48.87 6.52 22.23 Example34 [N¹-(4-chlorobenzyl)-N⁵-(3,4-di
Production of Chlorophenyl)-Biguanide Hydrochloride] Instead of 4-chlorobenzylamine hydrochloride, 3,4-diphenyl chloride
Except that chloraniline hydrochloric acid was used in the same molar amountReference example 1
In the same manner as above, 21.7 g of the title compound was obtained.

White ridge mp. 183 to 185°C Elemental analysis value C₁₅H₁₅Cl_FourN₅ C H N calculated value 44.25 3.71 17.20 actual value 44.37 3.66 17.42 Example35 [N¹-(3,4-dichlorophenyl)-N⁵-(3
4-Methylenedioxybenzyl)-biguanide hydrochloride
Manufacturing] N¹-Cyano-N^Three-(3,4-dichlorophenyl)-
21.5 g of guanidine and 3,4-methylenedioxyben
The same procedure as in Example 1 was carried out using 18.8 g of dilamine hydrochloride.
By operation, 27.3 g of the title compound was obtained.

White ridges mp. 175-177°C Elemental analysis value C₁₆H₁₆Cl_ThreeN₅O_Two C H N calculated value 46.12 3.87 16.81 measured value 46.01 3.76 16.97 Example36 [N¹-(3,4-dichlorophenyl)-N⁵-Hexi
Production of ru-biguanide hydrochloride] In place of 3,4-methylenedioxybenzylamine hydrochloride
Except that the same molar amount of hexylamine hydrochloride was used.
Example35In the same manner as above, 22.3 g of the title compound was obtained.

White ridge mp. 154-156°C Elemental analysis value C₁₄H₂₂Cl_ThreeN₅ C H N Calculated value 45.85 6.05 19.10 Measured value 45.66 6.17 19.03 Example37 [N¹-(3,4-dichlorophenyl)-N⁵-Decyl
-Production of biguanide hydrochloride] Instead of 3,4-methylenedioxybenzylamine hydrochloride
Other than using the same molar amount of decylamine hydrochloride
An example3524.2 g of the title compound was obtained in the same manner as.

White ridges mp. 131-133°C Elemental analysis value C₁₈H_ThirtyCl_ThreeN₅ CHN Calculated value 51.13 7.15 6.56 Measured value 51.02 7.32 16.37 Example38 [N¹-(3,4-dichlorobenzyl)-N⁵-Oct
Production of rubiguanide lactate] N¹-(3,4-dichlorobenzyl)-N⁵-Octyl
20 g of biguanide hydrochloride in 200 ml of methanol
Dissolve and add 24.5 ml of 5N NaOH and evaporate the solvent.
Left. After washing the remaining white solid with water, 200 ml of water
Then, 13 g of lactic acid was added and dissolved by heating. Ice cold
The precipitated crystals were collected by filtration to give 12.14 g of the title compound.
Obtained.

White ridge mp. 45-46 ° C. EXAMPLE 39 ^[N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide preparation of glycolate] except for using glycolic acid in place of lactic acid as in Example 38 To give the title compound.

White ridge mp. 109 to 110° C. Example 40 [Production of N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide monomethanesulfonate] Example except that methanesulfonic acid was used instead of lactic acid. Three
The title compound was obtained in the same manner as in 8 .

White ridge mp. 174 to 176° C. Example 41 [Production of N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide hydrobromide] In addition to using 47% hydrobromic acid in place of lactic acid Is Example 3
The title compound was obtained in the same manner as in 8 .

White ridges mp. 120-121 ° C. EXAMPLE 42 ^[N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide preparation of phosphate] but using phosphoric acid in place of lactic acid as in Example 38 To give the title compound.

White ridge mp. 96 to 98 ° C. EXAMPLE 43 ^[N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - preparation of biguanide di methanesulfonate] N ¹ - (3,4-di-chlorobenzyl) -N 25 g of ⁵ -octyl-biguanide hydrochloride was dissolved in 250 ml of methanol, 30.6 ml of 5N NaOH was added, and the solvent was distilled off. After washing the remaining white solid with water, acetone 50
It was dissolved in 0 ml and 14.7 g of methanesulfonic acid was added. The precipitated crystals were collected by filtration and recrystallized from ethanol-ether to give the title compound (25.8 g).

White ridge mp. One hundred seventy-one to one hundred seventy-two ° C. Elemental analysis _{C 17 H 27 N 5 Cl 2} · 2CH 3 SO 3 H C H N Calculated 40.42 6.25 12.41 Found 40.40 6.55 12.31 Reference Example 2 [ Production of N ¹ -(3,4-dichlorobenzyl)-N ³ -cyanoguanidine] 3,4-dichlorobenzylamine hydrochloride 63.7 g (3
00 mM) and sodium dicyanamide 30.9 g
(1.1 eq) with 950 ml acetonitrile (15 V)
The mixture was heated under reflux for 3 and a half hours. The solvent was distilled off, and 600 ml of water was added to the residue (white solid) for dispersion washing. The obtained crystals were collected by filtration and dispersed and washed with 600 ml of dichloromethane. Remaining amine was found, 600m water again
l, dichloromethane (500 ml), the crystals were collected by filtration and dried overnight at 60° C. to give the title compound 57.
7 g (78.9%) were obtained.

White crystals mp. 173℃ Elemental analysis value C₉H₈Cl_TwoN_Four CHN Calculated value 44.47 3.32 23.05 Measured value 44.32 3.08 23.30 Example44 [N¹-(3,4-dichlorobenzyl)-N⁵-Oct
Production of rubiguanide dihydrochloride] N¹-(3,4-dichlorobenzyl)-N^Three-Cyanog
Anidine 10.0 g (41.1 mM) and n-octy
5.31 g (1.0 equivalent) of ruamine was added to 100 m of xylene.
l, and add 3.5 ml of concentrated hydrochloric acid (1.1 eq).
And stirred for a few minutes. This is the Dean-Stark
The mixture was reacted for 8 hours under reflux using a wrap. Evaporate the solvent
Then, xylene was removed by azeotropic distillation with ethanol. The rest
Dissolve the residue with 40 ml of 70% acetonitrile and add concentrated hydrochloric acid.
6.8 ml (2.0 eq) was added. 70% acetonite
Recrystallization was carried out by adding 90 ml of ril. The obtained crystals
Was collected by filtration and dried overnight at 60° C. to give a white crystalline product 1
Obtained 4.3 g (78.2%). The crude crystals obtained are 70
Recrystallize twice with% acetonitrile (6-7V) to give the title
7.16 g (50.1%) of the compound was obtained.

Mp. 176-178°C Elemental analysis value C₁₇H₂₉Cl_FourN₅ CHN Calculated value 45.86 6.56 15.73 Measured value 45.54 6.66 15.79 In addition, the produced compound (dihydrochloride) is used as a solvent having a high water content.
(CH_ThreeWhen recrystallized in CN, ethanol, etc.)
Converted to the same monohydrochloride salt obtained in Example 1. Prescription Example 1 of Disinfectant 5 g of monobiguanide derivative of Example 1 3.75 g of nonionic surfactant (polyoxyethylene phenyl ether)Distilled water for injection Total amount 100 ml Disinfectant formulation example 2 Monobiguanide derivative of Example 1 0.5 g Nonionic surfactant 0.375 g (polyoxyethylene phenyl ether) ethanol 83 mlDistilled water for injection Total amount 100 ml <Antibacterial activity test> The compound obtained in each Example was tested against various bacteria.
The most standard method of the Japanese Society of Chemotherapy to investigate antibacterial activity
The small growth inhibitory concentration (MIC) was determined. However, in the medium
Using a medium for sensitive discs [CHEMOTHERA
PY, vol. 29, No. 1,76-79,198
1. Also, chlorhexidine gluconate as a control drug
(Sumitomo Pharmaceutical Co., Ltd. product name “Hibiten”)
Tested. The results are shown in Tables 1 to 7.

Various bacteria are 1×10 ⁶ bacteria/ml
(0.07 to 0.16 at OD 600 nm).

[0069]

[Table 1]

[0070]

[Table 2]

[0071]

[Table 3]

[0072]

[Table 4]

[0073]

[Table 5]

[0074]

[Table 6]

[0075]

[Table 7]

<Bactericidal activity test> For each of the compounds obtained in Examples 1 and 2, the bactericidal activity at room temperature (25°C) was measured for a short time with reference to the phenol coefficient measurement method. (1) Medium used Mueller Hinton B for pre-culture of test bacteria
roth (DIFCD) was used. In addition, for the enrichment medium for surviving bacteria in the test solution after the sterilization treatment, S of the disinfectant inactivating medium is used.
A CDLP medium (“Daigo” manufactured by Nippon Pharmaceutical Co., Ltd.) was used. (2) Test method The compound obtained in each Example was dissolved in distilled water to adjust the concentration to twice the test concentration, and after aseptic filtration, serially diluted 1/2 in the required test concentration range. 50 μl was dispensed into a 96-well microplate. On the other hand, a test bacterium obtained by repeating preculture for 16 hours twice was adjusted to 10 ⁸ cell/ml with sterile distilled water in order to remove the influence of the medium (O.
D. 0.3 at 660 nm, 5 ml or 10 m
Dilute 1/100 with 1 liter of sterile distilled water to obtain 10 ⁶ cells
/Ml, and 50 μl of the test solution in the microplate was injected and mixed with 50 μl of an equal amount. After 1 minute and 3 minutes, remove 5 μl of the test solution from the microplate,
Suspend in 150 μl inactivation medium, 16-18 at 37° C.
Incubated for hours. Determine the life and death of the bacteria in the test solution by turbidity, 1
The minimum bactericidal concentration was determined after 3 minutes and after 3 minutes. The results are shown in Table 8.

[0077]

[Table 8]

[0078]

INDUSTRIAL APPLICABILITY As described above, the monobiguanide derivative of the present invention or a salt thereof has a high bactericidal action and antibacterial action, so that it can be suitably used as a disinfectant for human skin.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Hisashi Tamaoka 5-32, Ekogawa, Shinkirai, Kitajima-cho, Itano-gun, Tokushima Prefecture (56) Reference JP-A-46-2068 (JP, A) JP-A-59-206347 (JP, A) JP-B 44-25342 (JP, B1) JP-B 43-29741 (JP, B1) JP-B 38-14914 (JP, B1) JP-B 38-14913 (JP, B1)

Claims (10)

(57) [Claims] 1. N¹-(3,4-dichlorobenzyl)-N
⁵-Octyl-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(3,4-Ziku
Lorbenzyl)-biguanide or a salt thereof, N¹-(3,4-dichlorophenyl)-N⁵-Octyl
-Biguanide or its salt, N¹-Benzyl-N⁵-Dodecyl-biguanide or
The salt, N¹-Benzyl-N⁵-Decyl-biguanide or
Salt of N¹-(3,4-dichlorobenzyl)-N⁵-(3-T
Lifluoromethylphenyl)-biguanide or its
Salt, N¹-(3,4-dichlorobenzyl)-N⁵-(4-bu
Romphenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(4-Yo
Dephenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(2,4
-Dichlorophenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Dichlorophenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(2
3,4-trichlorophenyl)-biguanide or its
Salt of N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Dimethylphenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(3,4
-Methylenedioxyphenyl)-biguanide or
Salt of N¹-(3,4-dichlorobenzyl)-N⁵-(4-t
-Butylphenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(4-E
Tilthiophenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(N-de
Sil)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-(1,
1,3,3-tetramethylbutyl)-biguanide
Is its salt, N¹-(3,4-dichlorobenzyl)-N⁵-Hexyl
-Biguanide or its salt, N¹-(3,4-dichlorobenzyl)-N⁵-(3-di
Ethylaminopropyl)-biguanide or a salt thereof, N¹-(3,4-dichlorobenzyl)-N⁵-[(2-
Diethylamino)-ethyl]-biguanide or its
Salt, _N¹-(3,4-dichlorobenzyl)-N⁵-[3−
(Di-n-butylamino)propyl-biguanide
Is its salt, N¹-(4-Chlorophenyl)-N⁵-Cyclohexyl
Methyl-biguanide or its salt, N¹-(4-Chlorophenyl)-N⁵-(3-Trifle
Oromethylphenyl)-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(4-ethylchi
Ophenyl)-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(4- chlorbe
)-Biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(2,4-Ziku
Lorbenzyl)-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(4-acetyl
Aminophenyl)-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(3,4-Meth
Dioxyphenyl)-biguanide or a salt thereof, N¹-(4-Chlorophenyl)-N⁵-(3,4-Meth
Dioxybenzyl)-biguanide or a salt thereof, N¹-(4-chlorobenzyl)-N⁵-Octyl-big
Anide or salt thereof, N¹-(4-chlorobenzyl)-N⁵-Decyl-bigua
Nido or salt thereof, N¹-(4-chlorobenzyl)-N⁵-Dodecyl-Bigg
Anide or salt thereof, N¹-(4-chlorobenzyl)-N⁵-Isobutyl-bi
Guanide or its salt, N¹-(4-chlorobenzyl)-N⁵-(3,4-Ziku
Lorphenyl)-biguanide or a salt thereof, N¹-(3,4-dichlorophenyl)-N⁵-(3,4
-Methylenedioxybenzyl)-biguanide or its
Salt of N¹-(3,4-dichlorophenyl)-N⁵-Hexyl
-Biguanides or salts thereof,and N¹-(3,4-dichlorophenyl)-N⁵-Decyl-
Biguanide or itsSalt?Biguanide invitation selected from
Conductor or its salt. 2. N ¹ -(3,4-dichlorobenzyl)-N
⁵ -octyl-biguanide or a salt thereof, N ¹ -(4-chlorophenyl)-N ⁵ -(3,4-dichlorobenzyl)-biguanide or a salt thereof, N ¹ -(3,4-dichlorophenyl)- A biguanide derivative or a salt thereof selected from N ⁵ -octyl-biguanide or a salt thereof and N ¹ -benzyl-N ⁵ -dodecyl-biguanide or a salt thereof. 3. N ^1- (3,4-dichlorobenzyl)-N
⁵ -octyl-biguanide or a salt thereof. 4. N ¹ -(3,4-dichlorobenzyl)-N
⁵ - octyl - biguanide hydrochloride, ^N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide lactate, ^N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide Glycolate, N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide monomethanesulfonate, N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide odor hydroiodide, ^N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide phosphate, ^N 1 - (3,4-di-chlorobenzyl) -N ⁵ - octyl - biguanide di The salt of the biguanide derivative according to claim 3, which is selected from methanesulfonate and N ¹ -(3,4-dichlorobenzyl)-N ⁵ -octyl-biguanide dihydrochloride. 5. N ¹ -(4-chlorophenyl)-N
^5- (3,4-dichlorobenzyl)-biguanide or a salt thereof. 6. A disinfectant containing the monobiguanide derivative according to claim 1 or a salt thereof as an active ingredient. 7. A disinfectant containing the monobiguanide derivative according to claim 2 or a salt thereof as an active ingredient. 8. A disinfectant containing the monobiguanide derivative according to claim 3 or a salt thereof as an active ingredient. 9. A disinfectant containing the monobiguanide derivative according to claim 5 or a salt thereof as an active ingredient. 10. N ¹ -(3,4-dichlorobenzyl)-
N ⁵ - octyl - biguanide monomethanesulfonate salt.