JPS6150950B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel salts of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine, a method for producing the same, and a method containing the same which exhibits particularly bacteriostatic (bacteriostatic and bactericidal) activity. include)
A composition having the following. 1,3-bis-(β-ethylhexyl)-5-, known by the generic name hexetidine (formula)
Amino-5-methyl-hexahydropyrimidine is used as a bactericidal agent for the oral mucosa, especially due to its bactericidal action. Usually used M. Senkus (M. Senkus, J.
Am.Chem.SOc., 68 (1946) 1611-1613), when hexetidine was synthesized by the method of
By-products accounting for ~30% are generated. Separation of this by-product by fractional distillation is substantially difficult as the boiling ranges of hexetidine and the main by-product are very similar. These by-products are mainly N(1) and N(3)
-bis-(β-ethylhexyl)-2-methyl-propane-triamine-(1,2,3), i.e. triamine and 2,6-bis-(β-ethylhexyl)-
It consists of hexahydro-7-α-methyl-1H-imidazo[1.5-C]imidazole, ie hexedine. The presence of by-products in hexetidine causes undesirable side effects. For example, when hexetidine or its salts are used as an oral or pharyngeal cavity disinfectant, their taste is adversely affected. Attempts to obtain high-purity hexetidine by separate synthesis have not been practically successful, and various attempts have been made to purify the above-mentioned crude hexetidine by converting it into an insoluble salt instead. . For example, the following example claims an acid that forms an insoluble salt with crude hexetidine. Namely, naphthalene-1,5-disulfonic acid (German patent
2011078) nicotinic acid (German Patent Publication 2310337 and German Patent Publication 2310338) and oxalic acid (German Patent Publication 2323150). According to these prior art, the reactions are mostly carried out under heat and some with a large excess of acid. The salt formed must be recovered from solution by precipitation with water or concentrated under reduced pressure, and must be further crystallized for further purification. The object of the present invention is to convert crude hexetidine, especially at the industrial production level mentioned above, in a simple manner into a completely pure compound which can be used as active ingredient in fungicidal compositions. For this purpose, a novel salt of hexetidine is used in the present invention, which is obtained by reacting crude hexetidine with a special aromatic carboxylic acid. This salt is hardly soluble in common organic solvents at room temperature, and is obtained as a highly pure precipitated product in the solvent, and can be used in compositions with bactericidal action or to recover high-purity hexetidine. can do. The first object of the present invention is to provide 1,3-bis-
(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine (hexetidine) and general formula [Wherein, X is -COOH, -OH, _-NH2 and -
A group selected from the group consisting of SO ₂ NH ₂ ] An object of the present invention is to provide a novel salt with an aromatic carboxylic acid represented by: Surprisingly, it has been found that hexetidine forms insoluble salts in common organic solvents at room temperature with reactive carboxylic acid derivatives such as carboxylic acids of the general formula or salts thereof. On the other hand, the by-products contained in the industrial crude hexetidine form soluble salts with the same acids, and in this way it is possible to easily separate the starting base into hexetidine or hexetidine salts and undesired by-products. I can do it. Therefore, according to the present invention, high purity hexetidine compounds can be directly produced in high yield using less labor, solvents and acids. Moreover, this new salt has good stability on storage and is tasteless, making it extremely convenient for use in the production of compositions with antibacterial activity. Particularly important among the acids of the general formula are terephthalic acid (X is -COOH in the 4-position) and 4-sulfamoylbenzoic acid. Terephthalic acid has been found to be particularly good at effectively separating hexetidine from coexisting by-products, especially triamines and hexedine. Terephthalic acid reacts with crude hexetidine in a suitable solvent at room temperature to precipitate in high yield as a salt containing 2 moles of hexetidine per mole of terephthalic acid. This salt, obtained in pure form, can be mechanically separated from the soluble components of the reaction mixture with only a few final washings. It can be used as an active ingredient with bacteriostatic action, but also, in particular, as an intermediate for the preparation of pure hexetidine from its crude mixture. Pure hexetidine base can be obtained from this salt, or also from other salts according to the invention, in a manner known per se, for example by dissolving the salt in an alkaline aqueous solution and in a water-insoluble organic solvent such as petroleum ether, methyl chloride or benzene. can be separated by extraction). Pure hexetidine is obtained by carefully evaporating this solvent under reduced pressure. At room temperature (room temperature is often preferred), the other acid of the general formula is usually in a molar ratio of 1:1 with hexetidine.
Forms a salt of 1. These salts are also used to effectively separate industrially produced hexetidine from its by-products. Of particular interest in this regard are the salts of 4-sulfamoylbenzoic acid and hexetidine. This salt is characterized by being relatively easily soluble in aqueous alcoholic solutions and being very stable to light and heat. Hydroalcoholic solutions are stable up to temperatures of -15°C. Moreover, this pure salt is completely tasteless. Therefore, they are of particular interest when used as bacteriostatic active ingredients in compositions for the treatment of the oral cavity and pharyngeal cavity. The novel salts of hexetidine according to the present invention are as follows. 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-terephthalate (formula below) 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-4
-Sulfamoyl-benzoate 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-4
-Hydroxybenzoate 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-4
-Aminobenzoate 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-4
-Amino-salicylate 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine-5
-Sulfosalicylate Another object of the present invention is to combine a 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine base of the formula with an aromatic carboxylic acid of the general formula above. An object of the present invention is to provide a novel method for producing salt. This production method is characterized by reacting the base with the acid in a solvent and recovering the salt by precipitating it. The molar ratio of base to acid used is usually 1:1. However, in the case of terephthalic acid and sulfobenzoic acid, 2 moles of base are used per mole of acid.
When crude hexetidine is used as the starting base, by-products contained as impurities are also included in the stoichiometric calculation. The reaction is carried out simply by mixing a solution or suspension of crude hexetidine in an organic solvent with a solution or suspension of the acid or the corresponding acid derivative in the above molar ratio and leaving the mixture at room temperature until the hexetidine salt formed precipitates, or as needed. or stir as desired. The precipitate formed is separated, washed, optionally crystallized and dried. Suitable solvents for this reaction include alcohols that are liquid at room temperature, especially alcohols having 1 to 6 carbon atoms, aliphatic hydrocarbons, cyclic hydrocarbons or aromatic hydrocarbons that are liquid at room temperature, and carboxylic acids. Examples include esters, acid amides, ketones, aliphatic and cyclic ethers and/or nitriles. It may be either a straight chain alcohol or a branched alcohol. A particularly suitable solvent is isopropanol. Examples of further suitable solvents include methanol, ethanol, n-propanol or butanol, ketones such as acetone or methyl ethyl ketone, ethyl or butylacetic acid, low-boiling petroleum ether fractions, low-boiling hydrocarbons such as n-hexane, benzene, toluene. ethers such as dimethylformamide, diisopropyl ether or dioxane, or acetonitrile. Formation of the salts of the invention may be carried out by a salt exchange reaction. If no troublesome precipitation side reactions occur in the salt exchange reaction, soluble salts of one or both reactants can be used in a manner known per se. It is particularly advantageous to use alkali metal salts of carboxylic acids of the general formula. Yet another object of the present invention is the use of the new salts of hexetidine as active ingredients in antibacterial compositions, such as cosmetic and pharmaceutical compositions. In these compositions, the active ingredient of the invention is usually present in admixture with a diluent and/or carrier. Other bacteriostatic agents and compositions may be included in the composition as needed or desired. The present invention particularly aims at cleaning compositions and laxatives which inhibit the growth of bacteria in the oral cavity when administered in a suitable formulation. Examples include gargles, gargles, mouth rinses, gargle concentrates, mouth sprays, infant lozenges and tablets, regular or clear toothpaste, chewing gum, gum ointments, creams or gels, etc. . These compositions containing the salt of the present invention exhibit strong antibacterial activity against Gram-positive cocci, Gram-negative bacteria and certain fungi. The physiologically acceptable compositions are therefore effective in preventing bacterial infections, especially those caused by microorganisms normally found in the oral cavities, and they are administered orally or topically. The bactericidal active ingredient of the present invention comprises one or more of the above-mentioned salts and may also be used in a mixture with other conventional bactericidal agents. Usually, the amount of active ingredient or acidic active ingredient contained in the composition per dosage unit is 0.01 to 2%. Known pharmaceutically acceptable solvents and/or carrier materials and/or solvent mediators and/or emulsifiers can be used for the above-described dosage forms. Examples of this include ethanol, glycerin and other pharmaceutically acceptable alcohols and/or water soluble solvents for mouthwashes, gargles, mouthwashes and gargle concentrates; sweeteners such as sucrose or saccharin (with inert substances such as one or more binders, fillers or lubricants); insoluble phosphates as abrasives such as dicalcium phosphate for toothpaste; Examples of caries preventive agents include fluorine-containing compounds such as sodium monofluorophosphate. The salts of the invention can also be incorporated into commercially available chewing gum bases. Sucrose-free carrier mixtures are preferred. Antimicrobial activity test A serial dilution test was conducted in a liquid ordinary medium to determine the MIC of the hexidine salt of the present invention against the following five bacterial strains.
(minimum inhibitory concentration) was measured. Staphylococcus aureus SG 511, Streptococcus faecalis R1, Proteus SP.R3, Pseudomonas aeruginosa R2, and Candida albicans
A1626/76. Standard I broth (E-Merck, Darmstadt, West Germany) was used as a medium for bacteria, and Sabourauglucose (E-Merck) was used for yeast (Candida albicans). The material tested was not sufficiently soluble in this aqueous normal medium, so 2% methanol was added. In a preliminary test, it was confirmed that all fungi could grow sufficiently even when 2% methanol was added. The test substance was added to each culture medium at 0.5, 0.1,
Concentrations of 0.03, 0.01, 0.003 and 0.001 mg/ml were tested. Put each concentration into two test tubes,
Inoculate each fungus and incubate at 37°C for 24 hours (bacteria) and at 30°C for 48 hours (Candida albicans).
The cells were incubated and visually inspected for fungal growth. The criteria for evaluating and grading fungal growth was the presence or absence of significant turbidity and/or clearly visible sedimentation of the broth. Pre-incubate each fungus at 37
°C (fungi), at 30 °C (Candida albicans)
One drop of a 1:100 dilution of standard I broth (bacteria) or wort grown for 24 hours was used as inoculum. The measured MIC values (mg/ml) are shown in Table 1 below.

[Table] Acute toxicity test Male mice (10 mice) and female mice (10 mice) weighing 18-24 g were used for the test. The test compound was suspended in carboxymethyl cellulose and administered into the gastric cavity. The administered dose was 20 ml/Kg (body weight), and the observation period was 7 days. The obtained results were analyzed by GTLichfield and FGWilcoxon [Pharmacol.Exp.
The following _LD50 value (mg/Kg, oral administration) was obtained as a result of calculation according to the method of [Therap.) 96 99 , 1949]. Terephthalate: 4980-7470 (male, female) 4-Sulfamoylbenzoate: 2459-3816 (male, female) 4-Aminobenzoate: 5600 or more (male, female) 4-Hydroxybenzoate: 2359-3527 (male): 2731 -4175 (Female) Nicotinate: 1331-2516 (Female) (West German Patent Publication No. 2310338) As a result of the above tests, the compound according to the present invention is less toxic than hexetidine nicotinate and has a wide range of therapeutic activity. It was found that it has Furthermore, the compound of the present invention has 3 to 3 in the case of hexetidine nicotinate.
It can be seen that even a 10-fold dilution inhibits the growth of yeast (Candida albicans). Examples of the present invention are listed below. This does not limit the invention. Example 1 17.0 g of crude hexetidine (about 80% purity) is dissolved in 15 ml of isopropanol. A suspension of 4.2 g of terephthalic acid in 35 ml of isopropanol is added to this solution while stirring. After stirring for about 3 hours,
The reaction mixture is left at room temperature overnight. The mixture turns pink. Separate the precipitate, wash with a small amount of ether or acetone and dry. Melting point: 155-156℃, Yield:
15.1 g (89% of theoretical yield based on hexetidine contained in the starting material) Elemental analysis (C ₅₀ H ₉₆ N ₆ O ₄ ) Molecular weight (MW) 845.37 C H N Theoretical % 71.04 11.45 9.94 Actual % 70.64 11.50 9.95 Example 2 6.8 g of crude hexetidine (about 80%) and 4.0 g of 4-sulfamoyl-benzoic acid are dissolved in about 40 ml of isopropanol with stirring at room temperature. A white precipitate separates out in a short time. After standing for a while, the precipitate is filtered off with suction, washed with a small amount of isopropanol, and dried. Melting point: 134-135℃, Yield:
6.6 g (76% of theoretical yield based on hexetidine contained in the starting material) Elemental analysis (C ₂₈ H ₅₂ N ₄ O ₄ S) MW 540.82 C H N Theoretical % 62.18 9.69 10.36 Actual % 62.05 9.73 10.28 Performed Example 3 6.8 g of crude hexetidine (approximately 80%) and 2.7 g of 4-amino-benzoic acid were prepared in the same manner as in Example 2.
React in 30 ml of isopropanol. The product is washed with a small amount of ether and dried. Melting point: 118-120
°C Example 4 10.2 g of crude hexetidine (approximately 80%) is dissolved in 20 ml of isopropanol. A solution of 4.2 g of 4-hydroxybenzoic acid dissolved in 40 ml of isopropanol is added to this solution with stirring. A white precipitate separates out after a short time. The reaction mixture is worked up analogously to Example 2. Melting point: 155-156°C Reference Example 1 6.8 g of crude hexetidine (approximately 80%) and 3.0 g of 4-amino-2-hydroxy-benzoic acid are dissolved in 40 ml of isopropanol with stirring. A precipitate separates out after a short time. The reaction mixture is worked up analogously to Example 3. Melting point: 141-143° C. Reference Example 2 3.4 g of crude hexetidine (approximately 80%) and 1.4 g of 2-amino-benzoic acid are dissolved in 20 ml of isopropanol at room temperature with stirring. After stirring for 8 hours, the mixture is left in the refrigerator overnight. The product is filtered off with suction, washed with a little isopropanol and dried. Melting point: 98-100℃ Reference Example 3 6.8 g of crude hexetidine (approximately 80%) and 2.5 g of 2-hydroxybenzoic acid-5-sulfonic acid (containing 2 moles of water of crystallization) were prepared in the same manner as in Reference Example 2, and mixed with 40 ml of isopropanol. to produce acid salts. Melting point: 153-156℃ Example 5 17.0g of crude hexetidine (approximately 80%) was dissolved in methanol.
Add to 50ml and heat to 50℃. Add 4.2g of terephthalic acid little by little to this. After stirring the mixture for a further 30 minutes, half of the solvent is distilled off at about 40° C. under reduced pressure. The mixture is cooled, the precipitate is filtered off with suction, washed with a little ether and dried. Melting point: 154-155
°C, yield: 11.8 g (approx. 68% of theoretical yield based on hexetidine used) Example 6 17.0 g of crude hexetidine (approx. 80%) and 10.0 g of 4-sulfamoyl-benzoic acid are dissolved in 100 ml of ethanol with stirring at room temperature. do. After stirring for about 5 hours, the mixture is left in the refrigerator overnight. Concentrate to about half the volume under reduced pressure, and when cooled, a white precipitate separates out. The precipitate is filtered off with suction and washed with about 25 ml of a mixed solvent of ether/methanol (95:5). Melting point:
134-136°C Example 7 17.0 g of crude hexetidine (approximately 80%) and 10.0 g of 4-sulfamoyl-benzoic acid are dissolved in 100 ml of n-propanol at room temperature with stirring. After stirring for 6 hours, the solution is left in the refrigerator overnight.
If you rub it with a sharp glass rod, the precipitate will separate out all at once. The product is filtered off with suction and washed with approximately 30 ml of ether. Melting point: 133-136°C Example 8 The procedure is as in Example 7, except that 100 ml of acetone is used instead of n-propanol. Melting point:
134-135°C Example 9 6.8 g of crude hexetidine (approximately 80%) is dissolved in 40 ml of n-butanol. This solution is stirred at room temperature and 3.9 g of 4-sulfamoylbenzoic acid is added little by little. After stirring for 6 hours, the solution is left in the refrigerator overnight. The precipitate formed is filtered off with suction and washed with a small amount of ether. Melting point 134-135°C Example 10 6.8 g of crude hexetidine (approximately 80%) are dissolved in 40 ml of petroleum ether (40-60°C). Add 4.0 g of 4-sulfamoylbenzoic acid little by little while stirring. After stirring for about 2 hours, the mixture becomes a gray transparent gel. The product is filtered off with suction and recrystallized from approximately 25 ml of isopropanol. Melting point: 134-135°C Example 11 The same procedure as in Example 10 is repeated using 50 ml of n-hexane instead of 40 ml of petroleum ether. The residue is washed with approximately 20 ml of a mixture of ether/methanol (95:5). Melting point: 133-135°C Example 12 17.0 g of crude hexetidine (approximately 80%) is dissolved in 100 ml of benzene with stirring. Then, 10.0 g of 4-sulfamoylbenzoic acid is added little by little while stirring at room temperature. After stirring for 8 hours, the mixture is left in the refrigerator overnight. Aspirate the crystal slurry and add a mixture of ether/methanol (95:5) to approx.
Wash with 30ml. Melting point: 134-136°C Example 13 The procedure is the same as in Example 12, except that 100 ml of ethyl acetate is used instead of benzene. Melting point: 134~
135°C Example 14 17 g of crude hexetidine (approximately 80%) and 10.0 g of 4-sulfamoylbenzoic acid are dissolved in 75 ml of dimethylformamide. After stirring at room temperature for 5 hours, leave in the freezer overnight. The solution is concentrated to half its volume under reduced pressure. The salt precipitated by adding ether is recrystallized with about 40 ml of isopropanol and washed with about 20 ml of ether. Melting point: 133-135
°C Reference Example 4 6.8 g of crude hexetidine (approximately 80%) and 2.6 g of 4-sulfobenzoic acid monosodium salt (2H ₂ O)
Stir in 40 ml of ethanol at room temperature. After stirring for 8 hours, the mixture is left at room temperature overnight and the insoluble material separates from the solution. The precipitate obtained by concentration under reduced pressure is filtered off with suction and washed with 40 ml of acetone and then with a small amount of ether. Melting point: 152℃ Elemental analysis Di-hexetidine-4-sulfobenzoate (C ₄₉ H ₉₆ N ₆ O ₅ S) MW881.42 C H N Theoretical value % 66.77 10.98 9.53 Actual value % 66.37 11.02 9.50 Example 15 Crude hexetidine ( 80%) and 4.0 g of 4-sulfamoylbenzoic acid are stirred in 40 ml of isopropyl ether at room temperature for 4 hours. After standing overnight, the mixture is filtered with suction. The precipitate is washed three times with isopropyl ether and dried. Melting point: 128
~131°C Recrystallize from isopropanol. Melting point 134-136
°C Example 16 6.8 g of crude hexetidine (approximately 80%) are dissolved in 15 ml of cyclohexane with stirring at room temperature. A suspension of 4.0 g of 4-sulfamoylbenzoic acid in 25 ml of cyclohexane is added to this solution with stirring. After stirring for 6 hours at room temperature, the mixture is left in the refrigerator overnight. The precipitate is filtered off with suction and washed with a small amount of ether. Melting point: 126-129°C Recrystallized from isopropanol. Melting point: 134
~136°C Example 17 The same procedure as in Reference Example 4 is repeated except that 40 ml of tetralin is used instead of cyclohexane. Melting point:
133-135°C Example 18 17.0 g of crude hexetidine (approximately 80%) is dissolved in 100 ml of butyl acetate at room temperature. This solution is stirred at room temperature, and 10.0 g of 4-sulfamoylbenzoic acid is added little by little. After stirring for 8 hours at room temperature, the mixture is left in the refrigerator overnight. The crystal slurry is filtered by suction and washed with a small amount of ether. Melting point: 134
~135°C Example 19 6.8 g of crude hexetidine (approximately 80%) are dissolved in 40 ml of acetonitrile at room temperature with stirring. Add 4.0 g of 4-sulfamoylbenzoic acid to this solution in small portions with stirring. After further stirring for 5 hours at room temperature, the mixture is left in the refrigerator overnight.
The crystalline precipitate is filtered off with suction and washed with a little ether. Melting point 134-135°C Example 20 6.8 g of crude hexetidine (approximately 80%) and 4.0 g of 4-sulfamoylbenzoic acid are dissolved in 40 ml of dioxane with stirring at room temperature. After continuing stirring for an additional 5 hours, the solution is left in the refrigerator overnight.
The precipitate separated from the mixture is collected, washed with a small amount of ether and recrystallized from isopropanol. Melting point: 135-136°C Example 21 6.8 g of crude hexetidine (approximately 80%) and 4.0 g of 4-sulfamoylbenzoic acid are dissolved in 40 ml of methyl ethyl ketone with stirring at room temperature. 5 more
After continuing to stir for an hour, the solution is left in the refrigerator overnight. The precipitate separated from the mixture is collected, washed with a small amount of ether and dried. Melting point: 134-136°C Example 22 1,3-bis-(β-ethylhexyl)-5- obtained by the method described in Example 1 in order to purify and recover pure hexetidine from its crude crystals.
Amino-5-methyl-hexahydropyrimidine
Terephthalate 84.5g IN Sodium Hydroxide 3000g
Add to ml. Then petroleum ether (boiling point 60-80℃)
Add 500ml and stir the mixture until the salt is completely dissolved. Separate the organic layer, wash with water, and dry over sodium sulfate. The solvent is removed under reduced pressure. Yield of purified hexetidine: 61 g (approximately 90% of theory) Formulation examples of various compositions containing the novel salt of hexetidine according to the invention and having bacteriostatic activity are listed below. A particularly preferred formulation is one containing a salt consisting of 4-sulfamoylbenzoic acid and hexetidine. The amount of hexetidine salt according to the present invention to be used is preferably 2 to 10 mg per dose, and used once to several times a day, but depending on the purpose of use and the dosage form, the above Amounts outside the range can also be used as a single dose. Example 23 Solution Dilute solution for mouthwash or gargling (1 table spoon amount) Hexetidine salt 0.1-0.4g Ethanol (96%) 10.0-25.0g Non-ionic emulsifier 0.5-2.0g Aromatic oil 0.2-0.5g Water In addition, 100.0g Example 24 Oral Cleansing Concentrate (Oral Lotion) For oral cleaning, use one spoonful in half a cup of water; for oral lotion, add 20 to 40 drops in half a cup of water. Hexetidine salt 1.0-4.0g Ethanol (96%) 30.0-50.0g Non-ionic emulsifier 4.0-8.0g Satucalin sodium 0.1-0.4g Aromatic oil 6.0-8.0g Add water 100.0g Example 25 Chewing gum 1.0g Recipe required to produce 100 pieces of chewing gum: Chewing gum base 15.0-18.0g Glucose syrup (43゜Be´) 20.0-25.0g Powdered sucrose 55.0-65.0g Hexetidine salt 1.0-4.0g Glycerin 0.2-0.5g Aromatic Oil 0.2~0.5g Add water to 100.0g Example 26 Tablets for infants Prescription required to manufacture 200 tablets of 0.5g Hexetidine salt 2.0~8.0g Satucalin sodium 0.3~0.7g Menthol 0.4~0.8 g Mono- and diglyceride mixtures of higher fatty acids
10.0-40.0g Add granulated sorbitol 100.0g Example 27 Toothpaste Carboxymethyl cellulose 0.5-2.0g Amorphous silicic acid 2.0-4.0g Glycerin DAB7 15.0-30.0g Hexetidine salt 0.1-0.4g 4-hydroxybenzoic acid ester 0.05-0.2 g Satucalin sodium 0.1-0.3g Sodium monofluorophosphate
0.6~1.0g Dicalcium Phosphate Dihydrate
25.0-30.0g Dicalcium phosphate anhydride 0.8-2.0g Sodium lauryl sulfate 1.5-3.0g Aromatic oil 1.0-2.0g Add water 100.0g Example 28 Transparent toothpaste carboxyl cellulose 0.25-1.5g 4-hydroxy Benzoic acid ester 0.05-0.2g Polyethylene glycol 400 3.0-5.0g Glycerin 1.26g/ml 50.0-75.0g Hexetidine salt 0.1-0.4g Sodium monofluorophosphate
0.6-0.9g Satucharin sodium 0.1-0.3g High-purity precipitated silicic acid 17.0-22.0g Sodium lauryl sulfate 1.0-2.0g Aromatic oil 0.75-1.5g Add water 100.0g

Claims (1)

[Claims] 1 formula 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine (hexetidine) and the general formula [Wherein, X is -COOH, -OH, _-NH2 and -
is a group selected from the group consisting of SO ₂ NH ₂ ] A salt with an aromatic carboxylic acid represented by the following. 2 formulas 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine (hexetidine) or its salt and the general formula
[Wherein, X is -COOH, -OH, _-NH2 and -
is a group selected from the group consisting of SO ₂ NH ₂ ] 1,3-bis-( β-ethylhexyl)-
A method for producing a salt of 5-amino-5-methyl-hexahydropyrimidine (hexetidine) and an aromatic carboxylic acid represented by the general formula. 3 formulas 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine (hexetidine) and the general formula [Wherein, X is -COOH, -OH, _-NH2 and -
is a group selected from the group consisting of SO ₂ NH ₂ ] A bacteriostatic agent containing a salt with an aromatic carboxylic acid represented by the following as an essential component.