JPH0558971A - Aminoester compound salt and disinfectant - Google Patents

Abstract

PURPOSE:To provide the subject low irritative novel compound high in biodegradability and bactericidal activity, thus useful as a disinfectant having a board antibacterial spectrum. CONSTITUTION:The objective compound for formula I (R<1> and R<2> are lower alkyl; R<3> is 1-19C alkyl; R<4> is phenyl lower alkyl; A is lower alkylene; X<-> is anion), for example, N-2-(4-chlorophenylacetoxy)ethyl-N,N-dimethyl-octylammonium bromide. This compound can be obtained by reacting a tertiary amine of formula II with a quaternarizing agent (e.g. alkyl halide) in the absence or presence of a solvent (e.g. ethyl acetate) at -20 to 60 deg.C. The compound has also antibacterial activity against resistant bacterial strains such as of MRSA, Pseudomonas aeruginosa or glucose nonfermentative bacteria and gives high bactericidal effects in a short time, is very effective for the sterilization and disinfection in human beings, livestock and medical utensils, etc.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel aminoester compound salt and a disinfectant containing the same as an active ingredient, and more particularly to a medical or household disinfectant used for disinfecting livestock, medical instruments and the like.

[0002]

2. Description of the Related Art Conventionally, various bactericidal disinfectants have been known, but they generally have strong skin irritation and low biodegradability, so that the waste liquid after use retains its activity for a long period of time. There is a drawback that even beneficial bacteria may be sterilized, and the emergence of resistant bacteria may be observed.
There is a current need for research and development of new disinfectants without defects.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is, of course, to solve all the drawbacks found in conventional disinfectants and to have a high bactericidal activity and a broad antibacterial spectrum.
It is another object of the present invention to provide a new disinfectant having less skin irritation, good biodegradability, and an effective bactericidal effect against known resistant bacteria.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors on the basis of the above objects, it was found that a salt of a new aminoester compound represented by the following general formula has excellent properties meeting the above objects. The present invention has been completed here.

That is, the present invention has the general formula

[0006]

[Chemical 2]

[Wherein R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is an alkyl group having 1 to 19 carbon atoms, and R ⁴ is a halogen atom or a lower alkoxy group as a substituent on the phenyl ring. 1 to 3 groups selected from the group consisting of groups
A represents a lower alkylene group, and X ⁻ represents an anionic group. ] It is related with the aminoester compound salt characterized by being represented by these, and the disinfectant characterized by containing this as an active ingredient.

In the above-mentioned general formula (1) showing the amino ester compound salt of the present invention, the halogen atom is a chlorine atom, a bromine atom, an iodine atom and a fluorine atom, and the lower alkoxy group is methoxy, ethoxy, propoxy and iso. Propoxy, butoxy, tert-butoxy groups, etc., lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl groups, etc., lower alkylene groups, ethylene, trimethylene, 1-methylethylene, 1 -Methyltrimethylene, a tetramethylene group, etc. can be illustrated respectively.

A group selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl ring as a substituent is 1 to
Examples of the phenyl lower alkyl group which may have 3 groups include unsubstituted phenyl lower alkyl groups such as benzyl, α-phenethyl, β-phenethyl, phenylpropyl and phenylbutyl groups, and 4-chlorobenzyl, 4-
Bromobenzyl, 4-fluorobenzyl, 4-iodobenzyl, 3,4-dichlorobenzyl, 3,4-dibromobenzyl, 3,4,5-trichlorobenzyl, 4-chloro-α-phenethyl, 4-bromo-β- Phenethyl, 4
-Chloro-phenylpropyl, 4-chloro-phenylbutyl, 3,4-dibromo-phenylbutyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5- Trimethoxybenzyl, 4-methoxy-α-phenethyl,
4-ethoxy-β-phenethyl, 4-methoxy-phenylpropyl, 4-ethoxy-phenylbutyl, 3,4-
As the substituents on the phenyl ring, such as dimethoxy-phenylbutyl, 3-chloro-4-methoxy-benzyl, 3-chloro-4-ethoxy-β-phenethyl, 3,4-dichloro-5-methoxy-benzyl group, etc. 1 of the groups selected from the group consisting of the exemplified halogen atom and lower alkoxy group
An example is a phenyl lower alkyl group having 3 to 3.

Examples of the anionic group include the above-exemplified halogen atom, sulfate ion, nitrate ion, alkylsulfonate ion, lower alkylcarboxylate ion, aromatic sulfonate ion and the like.

Further, as the alkyl group having 1 to 19 carbon atoms, in addition to the lower alkyl groups exemplified above, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl. , Octadecyl and nonadecyl groups can be exemplified, and among these, an alkyl group having 8 to 16 carbon atoms is preferable, and an alkyl group having 11 to 15 carbon atoms is particularly preferable.

The compound of the present invention can be easily obtained by reacting a suitable tertiary amine with a quaternizing agent such as an alkyl halide as shown in the following reaction scheme.

[0013]

[Chemical 3]

The reaction represented by the above formula can be carried out in a suitable solvent or without solvent. Examples of the solvent include alcohols such as methanol and ethanol, ethers such as methyl ethyl ether, dimethyl ether and diethyl ether, methyl acetate and acetic acid. Examples thereof include esters such as ethyl, aromatic hydrocarbons such as benzene, toluene, xylene, and methylbenzene. The reaction temperature is usually from room temperature to about 150 ° C,
Preferably, about 70 to 100 ° C. can be adopted, and the reaction is generally completed in about 3 to 7 days. The proportion of each raw material compound used is not particularly limited, but it is usually preferable to use the quaternizing agent in an equimolar amount or more, preferably in an amount of 1 to 2 times the molar amount of the tertiary amine.

The tertiary amine used as a starting material in the above reaction can be produced, for example, by the method shown in the following reaction process equation, taking the one represented by the above equation (4) as an example.

[0016]

[Chemical 4]

The above reaction is carried out, for example, by the alcohols, halogenated hydrocarbons, esters, ethers,
It can be carried out in a suitable solvent such as aromatic hydrocarbons or acetonitrile or in the absence of a solvent under a temperature condition of about -20 ° C to 60 ° C for 0.1 to 2 hours. The ratio of the acid chloride used as a raw material to the alcohol is preferably 1 mol of the former and 1 to 3 mol of the latter. Details of the production of this tertiary amine will be shown in the reference example below.

After completion of the above reaction, the desired compound of the present invention can be obtained by an isolation operation according to a conventional method. As the isolation operation, for example, a combination of filtration, recrystallization, solvent extraction, column chromatography and the like can be appropriately adopted.

The compound of the present invention thus obtained is hypoallergenic, has good biodegradability, has excellent bactericidal activity against various fungi, has a broad antibacterial spectrum, and has excellent antibacterial spectrum. It is also soluble and highly safe, and is therefore effective in various fields as medical and household sterilizers, disinfectants and the like.

Therefore, the present invention also provides a disinfectant containing the above-mentioned compound of the present invention as an active ingredient.

The disinfectant of the present invention is generally prepared by dissolving or dispersing a predetermined amount of the compound of the present invention in water or a suitable organic solvent.
Prepared in the form of a suspended solution, dispersion or suspension,
Although it is put into practical use, it may be put into practical use in any form such as a powder form, an ointment form, an aerosol form, and a spray form in addition to the above liquid form as required. The above-mentioned liquid drug forms include external liquid drug forms such as eye drops, nasal drops, gargles and detergents.

The compounding amount of the active ingredient compound in the disinfectant of the present invention is appropriately determined and is not particularly limited.
It is usually suitable to choose from the range of about 0.01 to 20% by weight of the total composition.

In addition to the above-mentioned active ingredients, the disinfectant of the present invention may contain other conventionally known sterilizing and disinfecting agent active ingredient compounds. Various additives known to be able to be added and compounded to this kind of sterilization and disinfectant can also be compounded.

Further, the disinfectant of the present invention, in addition to the above liquids, powders, ointments and the like, for example, various creams, lotions, white powders, reds, make-ups, toothpastes, shampoos, soaps, depilatories, bleaches. It can also be prepared in various cosmetic forms such as an agent, a hair coloring agent, a hair styling agent, a bath agent, a nail polish, an antiperspirant inhibitor, a deodorant, an aerosol cosmetic, and an infant cosmetic. The production of various cosmetics can basically follow the preparation technology of each cosmetic, except that a predetermined amount of the compound of the present invention is contained in the product cosmetics, and generally, The compound of the present invention may be dissolved, dispersed or suspended in water, an organic solvent, a cosmetic base material or the like together with the cosmetic ingredient to prepare a product cosmetic. The content of the compound of the present invention in such cosmetics is generally about 0.001 to 1% by weight.
It is suitable to be selected from the range.

[0025]

According to the present invention, skin irritation is low,
It has good biodegradability (it is easy to be decomposed by microorganisms and does not cause environmental damage), and has antibacterial activity against resistant bacteria such as MRSA, Pseudomonas aeruginosa and glucose non-fermenting bacteria. It has a high activity and a broader antibacterial spectrum, and can provide a sterilizing agent, an antiseptic agent and an active ingredient compound thereof that can exert a strong bactericidal effect in a short time, and the disinfecting agent of the present invention is very useful for sterilizing human animals and medical instruments, etc. Is effective for.

[0026]

EXAMPLES In order to explain the present invention in more detail, reference examples and examples will be given below.

[0027]

[Reference Example 1] 2- (N, N-dimethylamino) ethyl
Production of 4-chlorophenylacetate 17.06 g of 4-chlorophenylacetic acid and 50 m of toluene
Then, thionyl chloride 10.
94 g was added dropwise. After completion of the dropping, the mixture was stirred for 1.5 hours while heating at 60 ° C. After the solvent was distilled off under reduced pressure and concentrated,
100 ml of methylene chloride was added to dissolve the residue. While cooling with ice, 8.91 g of 2- (N, N-dimethylamino) ethanol was added dropwise thereto, and the mixture was stirred for 2 hours, then 5% N
The mixture was washed successively with 100 ml of an aHCO ₃ aqueous solution and 100 ml of water, added with Na ₂ SO ₄ and dried. Filter, concentrate the filtrate under reduced pressure and purify by distillation under reduced pressure to give the title compound 1
5.53 g was obtained. Boiling point = 130-150 ° C./1.8 m
mHg

[0028]

[Reference Example 2] 2- (N, N-dimethylamino) ethyl
Production of 3,4-dichlorophenylacetate 24.44 g of 3,4-chlorophenylacetic acid and 2- (N,
N-dimethylamino) ethanol 10.61 g was used and reacted in the same manner as in Reference Example 1 to give the title compound 18.3.
1 g was obtained. Boiling point = 146-148 ° C./0.5 mmHg

[0029]

[Reference Example 3] 2- (N, N-dimethylamino) ethyl
Production of 4-methoxyphenylacetate 24.93 g of 4-methoxyphenylacetic acid and 10 parts of toluene
After adding 0 ml, 18.21 g of triethylamine was added, and 21.41 g of thionyl chloride was further added dropwise. After the dropping was completed, the mixture was heated to 80 ° C. and stirred for 3.5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure and concentrated to obtain 100 m of methylene chloride.
1 was added to dissolve the residue, and then 26.74 g of 2- (N, N-dimethylamino) ethanol methylene chloride 1 was added.
The 00 ml solution was added dropwise at 0 ° C or lower while being cooled in an ice / methanol bath. After completion of dropping, the mixture was stirred for 15 minutes, washed successively with 200 ml of water, 200 ml of 5% NaHCO ₃ aqueous solution and 200 ml of water, and Na ₂ SO ₄ was added to dry the mixture. After filtration, the filtrate was concentrated under reduced pressure and purified by distillation under reduced pressure to obtain 24.61 g of the title compound. Boiling point = 132-1
36 ° C / 0.7mmHg

[0030]

[Reference Example 4] 2- (N, N-dimethylamino) ethyl
Preparation of 3-phenylpropionate 2- (N, N-dimethylamino) ethanol 21.25
100 ml of methylene chloride was added to g and cooled in an ice / methanol bath. To this, 20 g of 3-phenylpropionyl chloride was added dropwise at -10 to 0 ° C. 30 after dropping
Stir for 1 minute, then wash with 100 ml of water, 100 ml of 5% NaHCO ₃ aqueous solution and 100 ml of water successively, and wash with Na ₂
SO ₄ was added and dried. Filter, concentrate the filtrate under reduced pressure,
Purification by vacuum distillation gave 23.13 g of the title compound. Boiling point = 106-111 ° C./0.3 mmHg

[0031]

Example 1 Preparation of N-2- (4-chlorophenylacetoxy) ethyl-N, N-dimethyl-octylammonium bromide 4.93 g of 2- (N, N-dimethylamino) ethyl 4-chlorophenylacetate and octylbromide 3 .8
6 g and 10 ml of ethyl acetate were added, and the mixture was heated under reflux for 3 days. After completion of the reaction, when the temperature was returned to room temperature, crystals were precipitated, so this was collected by filtration and washed with ethyl acetate. It was dried at 60 ° C. under reduced pressure to obtain 5.91 g of the title compound. Colorless scaly crystals, melting point = 122-125 ° C.

[0032]

Example 2 Preparation of N-2- (3,4-dichlorophenylacetoxy) ethyl-N, N-dimethyl-decylammonium bromide 2- (N, N-dimethylamino) ethyl 3,4-dichlorophenylacetate 1.38 g And 1.22 g of decyl bromide were added to 10 ml of ethyl acetate, and the mixture was heated under reflux for 3 days. After completion of the reaction, when the temperature was returned to room temperature, crystals were precipitated, so this was collected by filtration and washed with ethyl acetate. 4 under reduced pressure
After drying at 0 ° C, 1.12 g of the title compound was obtained. Colorless plate crystals, melting point = 131-132 ° C

[0033]

Example 3 Preparation of N-2- (4-methoxyphenylacetoxy) ethyl-N, N-dimethyl-dodecylammonium bromide 2- (N, N-dimethylamino) ethyl 4-methoxyphenylacetate 4.93 g and dodecyl Bromide 1.
37 g and 10 ml of ethyl acetate were added, and the mixture was heated under reflux for 3 days. After the reaction was completed, when the temperature was returned to room temperature, crystals were precipitated.
This was collected by filtration and washed with ethyl acetate. 60 ° C under reduced pressure
After drying in, 2.13 g of the title compound was obtained. Slightly yellow prism crystal, melting point = 78 to 79 ° C.

[0034]

Example 4 Preparation of N-2- (3-phenylpropoxy) ethyl-N, N-dimethyl-tetradecylammonium bromide 1.11 g of 2- (N, N-dimethylamino) ethyl 3-phenylpropionate and tetra Decyl bromide 1.
53 g and 10 ml of ethyl acetate were added, and the mixture was heated under reflux for 3 days. After the reaction was completed, when the temperature was returned to room temperature, crystals were precipitated.
This was collected by filtration and washed with ethyl acetate. 60 ° C under reduced pressure
After drying in a vacuum, 1.97 g of the title compound was obtained. Colorless needles, melting point = 103-107 ° C

[0035]

Examples 5 to 20 In the same manner as in Examples 1 to 4, each compound shown in Table 1 below was obtained using appropriate starting materials. First
In the table, the yield, melting point (° C.) and crystal form of each compound obtained are shown together.

[0036]

[Table 1]

[0037]

[Table 2]

Next, prescription examples of the disinfectant of the present invention containing the compound of the present invention obtained in each of the above Examples as an active ingredient will be given.

[0039]

[Formulation Example 1] Compound of the present invention obtained in Example 1 5 g Nonionic surfactant 3.75 g (Polyoxyethylene nonylphenyl ether) Distilled water for injection Appropriate amount 100 ml The above components are mixed to disinfect the present invention. The drug was prepared.

[0040]

Formulation Example 2 Compound of the present invention obtained in Example 5 0.5 g Nonionic surfactant 0.375 g (Polyoxyethylene nonylphenyl ether) Ethanol 83 ml Distilled water for injection Appropriate amount 100 ml Mixing the above components The disinfectant of the present invention was prepared.

The antibacterial activity test conducted on the compound of the present invention will be described below.

[0042]

[Antibacterial activity test example 1] Regarding the compounds obtained in each example, room temperature (25 ° C) was used with reference to the phenol coefficient measurement method.
The bactericidal activity of the disinfectant was measured in a short time.

As the medium to be used, Mueller Hinton Broth (manufactured by Difco) was used for pre-culturing the test bacteria, and as a growth medium for surviving bacteria in the test solution after the sterilization treatment, SCDLP which was a disinfectant inactivating medium was used. The medium "Daigo" (Nippon Pharmaceutical Co., Ltd.) was used.

The test solution is adjusted to a concentration twice the test concentration with distilled water, sterile filtered, and then diluted 1/2 in the desired test concentration range, and 50 μl is dispensed to a 96-well microplate. 1
The test bacterium obtained by repeating the preculture for 6 hours twice was adjusted to 10 ⁸ cells / ml with sterilized distilled water (0.3 at OD660 nm) in order to remove the influence of the medium, and further 5 ml or 10
Dilute 1/100 with ml of sterile distilled water to give 10 ⁶ cells / m
l, and 50 μl of the test solution in the microplate was mixed with an equal volume of 5
Inject and mix 0 μl. Test time (10 seconds, 30 seconds, 1
Minutes, 3 minutes, 5 minutes), 5 μl of test bacteria was added to 150 μl
And incubate at 37 ° C. for 16 to 18 hours. Determine the minimum bactericidal concentration by determining the life and death of bacteria in the test solution by turbidity [Aiko Nakano, Test method of bactericidal efficacy of disinfectant, antibacterial and antifungal, vol.11, No.12, 685-692 (1983) reference].

Benzalkonium chloride and chlorhexidine gluconate were used as control agents.

Table 2 shows the results of obtaining the minimum bactericidal concentration when the above-mentioned bacteria were used as test bacteria and treated for 3 minutes as described above.

[Test Bacterial Name] 1 ... Staphylococcus aureus
aureus) FDA209P 2 ... Staphylococcus aureus
aureus) MRSA 57 (clinical isolate) 3 ... Escherichia coli NI
HJ JC-24 ... Klebsiella pneumon
iae) NCTC9632 5 ... Serratia marcescens
e) IFO 12648 6 ... Pseudomonas aeru
ginosa) ATCC 10145 7 ... Pseudomonas cepacia
) 2315-C0010 (Clinical isolate) 8 ... Acinetobacco calcoaceticus (Acinetobac)
ter calcoaceticus) Ac-54

[0048]

[Table 3]

From the above table, it is clear that the aminoester compound salts of the present invention are all useful as excellent disinfectants.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location A61K 31/215 ADZ 8413-4C A61L 2/18 7108-4C

Claims (2)

[Claims] 1. A general formula: [Wherein R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is an alkyl group having 1 to 19 carbon atoms, and R ⁴ is a halogen atom and a lower alkoxy group as a substituent on the phenyl ring. A phenyl lower alkyl group which may have 1 to 3 groups selected from the group, A represents a lower alkylene group, and X ⁻ represents an anionic group. ] The aminoester compound salt represented by these. 2. A disinfectant containing the aminoester compound salt according to claim 1 as an active ingredient.