JPH04308562A - Bisguanide derivative and disinfectant containing the same derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having high sterilizing effects and useful as a disinfectant for human bodies, medical instruments, etc. CONSTITUTION:A compound, e.g. 1,1'-[1,3-cyclohexanebis(methylene)]-bis[5-(4- chlorophenyl)biguanide]dihydrochloride expressed by formula I (R is phenyl which can be substituted with halogen, lower alkyl, etc., phenyl-lower alkyl which can be substituted with halogen on the phenyl ring or alkyl; A is lower alkylene). The aforementioned compound expressed by formula I is obtained by reacting a 1,1'-1,3-cyclohexanebis(alkylene)-bis(3-cyanoguanidine) expressed by formula II with an amine expressed by the formula 2RNH2. The amine is used in a molar amount of about 2 times based on the compound expressed by formula II. The compound expressed by formula I in an amount of 0.5-20wt.% is contained in a solution for external use such as a cleaning agent, etc.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel bisbiguanide derivative, and more particularly to a bisbiguanide derivative that can be used as a disinfectant for the human body, medical instruments, and the like.

0002

BACKGROUND OF THE INVENTION It is known that various guanidine derivatives have bactericidal properties, and British Patent No. 1,095,902 discloses bisbiguanide derivatives of the 1,4-dimethylenecyclohexane type.

0003

SUMMARY OF THE INVENTION An object of the present invention is to provide a bisbiguanide derivative or a salt thereof having higher activity than conventional bisbiguanide derivatives.

0004

[Means and effects for solving the problems] The bisbiguanide derivative of the present invention for achieving the above object has the general formula:

[0005]

[Case 2]

(In the formula, R is a halogen atom as a substituent,
A phenyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkylthio group; a phenyl lower alkyl group that may have a halogen atom as a substituent on the phenyl ring; group or an alkyl group, and A represents a lower alkylene group. ) or a salt thereof.

Such bisbiguanide derivatives of the present invention (
I) or a salt thereof has higher bactericidal or bacteriostatic action than conventionally known bisbiguanides. Therefore, the disinfectant of the present invention contains the bisbiguanide derivative represented by the above general formula (I) or a salt thereof as an active ingredient. Examples of the halogen atom in the present invention include chlorine, bromine, iodine, and fluorine.

Examples of the lower alkyl group include methyl,
Examples include straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-amyl, and n-hexyl groups. Examples of the halogen-substituted lower alkyl group include monochloromethyl, monobromomethyl, monofluoromethyl, monoiodomethyl, dichloromethyl, dibromomethyl, difluoromethyl, diiodomethyl, trichloromethyl, tribromomethyl, trifluoromethyl, triiodomethyl, 3-chloropropyl, 3-fluoropropyl, 2,3-dichloropropyl,
1 to 3 groups such as 3,3,3-trichloropropyl, 3-chloro-2-methylpropyl, 4-chlorobutyl, 4-fluorobutyl, 5-chloropentyl, 6-chlorohexyl, 6-fluorohexyl group, etc. Examples include halogen-substituted lower alkyl groups having 1 to 6 carbon atoms and substituted with halogen atoms.

Examples of lower alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-
Examples include lower alkylthio groups having a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as butylthio, n-amylthio, and n-hexylthio groups. Examples of phenyl lower alkyl groups that may have a halogen atom as a substituent on the phenyl ring include benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl group, benzhydryl, trityl, 4-chlorophenylmethyl,
3-chlorophenylmethyl, 2-chlorophenylmethyl, 3,4-dichlorophenylmethyl, 4-fluorophenylmethyl, 3,4-difluorophenylmethyl, 4-
Phenyl lower alkyl having 1 to 3 phenyl groups that may have 1 to 3 halogen atoms and having 1 to 6 carbon atoms in the alkyl moiety, such as chlorophenylethyl and 3,4-dichlorophenylethyl groups The basics are given.

Examples of the alkyl group used as the substituent R include straight chain or branched alkyl groups having 6 to 16 carbon atoms, specifically n-hexyl, n-
heptyl, n-octyl, n-nonyl, n-decyl, n
-undecyl, n-tetradecyl, n-hexadecyl,
Examples include 2-ethyl-1-hexyl, 2-ethyl-1-heptyl, 2-heptyl, 2-octyl, and 1,1,3,3-tetramethylbutyl groups.

Examples of lower alkylene groups include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, 1-methyl-1-trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene, Examples include alkylene groups having 1 to 6 carbon atoms such as hexamethylene groups. Specific examples of the bisbiguanide derivative (I) of the present invention are shown in the following table.

0012

[Table 1]

[0013]

[Table 2]

Bisbiguanide derivative (I) of the present invention
Since is a basic compound, it can react with organic or inorganic acids to form the corresponding acid addition salt. Examples of acids that form such salts include formic acid, acetic acid, butyric acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, and citric acid. Acid, glycolic acid, gluconic acid, sugar acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.

Acid addition salts can be prepared by directly mixing an acid and a base, by dissolving one or both of them in advance in a solvent such as water, or by dissolving and mixing the acid and base in a solvent. It is manufactured by employing conventional salt formation methods such as. After the reaction, the acid addition salt obtained is filtered if it is insoluble or sparingly soluble in the reaction medium, and recovered by evaporating the reaction medium if it is soluble in the reaction medium.

Such acid addition salts exhibit high bactericidal or bacteriostatic effects by themselves, and are also useful for purifying and isolating free bases. It is also preferred that the acid addition salt is pharmaceutically acceptable. Further, the bisbiguanide derivative (I) of the present invention may form a stable coordination compound with a metal salt. Such coordination compounds also exhibit excellent bactericidal effects. The coordination compound is a derivative thereof or an acid addition salt thereof in a predetermined amount of a metal salt, preferably V, Cr, Mn.
, Co, Ni, Cu, Zn, Pd, Re, Os, and other heavy metal salts.

Next, a method for producing the bisbiguanide derivative of the present invention will be explained. First manufacturing method

[0018]

[Chemical formula 3]

(In the formula, A and R are the same as above.) As shown in the above reaction formula, the bisbiguanide derivative (I) of the present invention has a 1,1' compound represented by the general formula (II).
-1,3-cyclohexanebis(alkylene)
-bis(3-cyanoguanidine) with the general formula (II
I) It can be obtained by reacting with the amine represented by: At this time, amine (III) is used in an amount of about twice the molar amount of compound (II). Also, amine (III)
may be in the form of a suitable acid addition salt such as a hydrochloride.

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

The starting material represented by the above general formula (II) can be produced, for example, by the following reaction scheme.

[0022]

[C4]

(In the formula, M represents an alkali metal, and A
is the same as above. ) That is, a diamine represented by general formula (IV) or its acid addition salt (hydrochloride, etc.) is reacted with an alkali metal salt (V) of dicyanamide (e.g., sodium dicyanamide, potassium dicyanamide, etc.) in an inert solvent. You can get it. Second manufacturing method

[0024]

[C5]

(In the formula, A and R are the same as above.) As shown in the above reaction formula, a bisbiguanide derivative (
I) is a process in which a diamine represented by general formula (VI) or an acid addition salt thereof (hydrochloride, etc.) and a cyanoguanidine compound represented by general formula (VII) are mixed in the presence or absence of an inert solvent. It can be obtained by reacting with The reaction takes place under heat. The cyanoguanidine compound (VII) is used in a molar ratio of about twice that of the diamine (VI).

Bisbiguanide derivative (I) of the present invention
Or its salts have higher antibacterial activity (sterilizing or bacteriostatic action) than conventionally known bisbiguanide derivatives, and some also have antiviral activity. Furthermore, the bisbiguanide derivative (I) or a salt thereof of the present invention has a broad antibacterial spectrum, is excellent in immediate action, stability, safety, etc., and has the effect that its activity lasts for a long time. In addition, it is non-irritating, odorless and soluble in water.

[0027] Therefore, the bisbiguanide derivative (I) or a salt thereof of the present invention is useful as an active ingredient of a disinfectant for the human body, medical instruments, etc. The disinfectant of the present invention is used in the form of a solution, dispersion, or suspension in which a predetermined amount of the bisbiguanide derivative (I) or a salt thereof is dissolved, dispersed, or suspended in water or an organic solvent. Typical examples include external liquid preparations such as cleaning agents. In this case, the amount of bisbiguanide derivative (I) or its salt added is usually 0.5 to 20% by weight based on the total amount.
The degree is appropriate.

[0028] Furthermore, the bisbiguanide derivatives of the present invention (
I) or its salts can be used in various cosmetics, such as various creams, lotions, powders, bean paste, makeup, toothpaste, shampoos, soaps, depilatory agents, bleaching agents, hair coloring agents, hair styling agents, and bath preparations. , nail polish, antiperspirants, deodorants, aerosol cosmetics, infant cosmetics, and the like.

When producing cosmetics, a predetermined amount of the bisbiguanide derivative (I) or its salt is dissolved, dispersed or suspended in water, other solvents, or various cosmetic base materials together with other ingredients. Manufactured. The amount added to cosmetics is usually about 0.05 to 1% by weight based on the total amount.

[0030]

EXAMPLES Next, the bisbiguanide derivative of the present invention and the disinfectant containing this derivative will be explained in detail with reference to Examples. Note that the present invention is not limited only to these examples. Example 1 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(4-chlorophenyl) biguanide]
Preparation of dihydrochloride 1,3-di(aminomethyl)cyclohexane dihydrochloride 3
3g (0.15 mol) and sodium dicyanamide 26
g (0.3 mol) in butanol at a temperature of 140°C for 12 hours to obtain 51.3 g of 1,1'-[1,3-cyclohexanebis(methylene)]-bis(3-cyanoguanidine). I got it.

5.52 g (0.02 mol) of this product and 6.56 g (0.04 mol) of p-chloroaniline hydrochloride
and β-oxyethyl ether (product name: Cellosolve)
refluxed at 140° C. for 3 hours to react, yielding 4.3 g of product. This product was purified by recrystallization with a mixed solvent of water and ethanol to obtain the title compound. White ridge-like crystals, mp. 245-248°C NMR (CDCl3+DMSO-d6) δ: 1.1
~1.9 (m, 8H), 2.8~3.5 (m
, 6H), 6.95 (bs), 7.37 (
dd, 4H, J=9 Hz), 7.90 (bs)
Example 2 1,1'-[1,3-cyclohexane bis(methylene)
]-bis[5-(4-iodophenyl) biguanide]
Production of dihydrochloride In place of p-chloroaniline hydrochloride in Example 1, p
The title compound was obtained in the same manner as in Example 1, except that -iodoaniline hydrochloride was used in the same molar amount (yield: 5.1 g). White ridge-like crystals, mp. 259-261°C Example 3 1,1'-[1,3-cyclohexane bis(methylene)
]-bis[5-(4-bromophenyl) biguanide]
Preparation of dihydrochloride The title compound was obtained in the same manner as in Example 1, except that p-bromoaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride (yield: 4.7 g). White ridge-like crystals, mp. 265-267°C Example 4 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(2,4-dichlorophenyl)biguanide] dihydrochloride Production of Example 1 except that 2,4-dichloroaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride. The title compound was obtained in the same manner (yield: 5.7 g). White ridge-like crystals, mp. 261-265°C Example 5 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(2,4-difluorophenyl)biguanide]biguanide dihydrochloride Production Example 1 except that p-chloroaniline hydrochloride was replaced with 2,4-difluoroaniline hydrochloride in the same molar amount. The title compound was obtained in the same manner as (yield: 4.1 g). White ridge-like crystals, mp. 212-215°C Example 6 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(4-t-butylphenyl)biguanide] Preparation of dihydrochloride Example 1 except that p-chloroaniline hydrochloride was replaced with p-t-butylaniline hydrochloride in the same molar amount. The title compound was obtained in the same manner as (yield: 3.6 g). White ridge-like crystals, mp. 194-197°C Example 7 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(3,4-dimethylphenyl)biguanide]dihydrochloride Production Example 1 except that 3,4-dimethylaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride. The title compound was obtained in the same manner as (yield: 3.8 g). Slight yellow edge-like crystals, mp. 162-166°C Example 8 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(4-ethylthiophenyl)biguanide] Preparation of the title in the same manner as in Example 1 except that p-ethylthioaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride. A compound was obtained (yield: 5.4 g). mp. 110-113°C Example 9 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(3-trifluoromethylphenyl)biguanide] Preparation of dihydrochloride Example 1 except that p-trifluoromethylaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride.
The title compound was obtained in the same manner as (yield: 2.5 g). White ridge-like crystals, mp. 240-242°C Example 10 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(2-ethylhexyl) biguanide]
Production The title compound was obtained in the same manner as in Example 1, except that p-(2-ethylhexyl)aniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride (yield: 4.6 g). White ridge-like crystals, mp. 105-107°C Example 11 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(3,4-dichlorobenzyl)biguanide] dihydrochloride Production Example except that 3,4-dichlorobenzylamine hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride 1
The title compound was obtained in the same manner as (yield: 5.3 g). White ridge-like crystals, mp. 231-233°C Example 12 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis[5-(3,4-dichlorophenyl)biguanide] dihydrochloride Production of Example 1 except that 3,4-dichloroaniline hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride. The title compound was obtained in the same manner (yield: 3.7 g). White ridge-like crystals, mp. 259-261°C Example 13 1,1'-[1,3-cyclohexane bis(methylene)
]-Bis(5-benzylbiguanide) dihydrochloride The title compound was obtained in the same manner as in Example 1, except that benzylamine hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride (yield: 5.9g). White ridge-like crystals, mp. 208-211°C Example 14 1,1'-[1,3-cyclohexane bis(methylene)
]-bis(5-(4-chlorobenzyl) biguanide)
Preparation of dihydrochloride The title compound was obtained in the same manner as in Example 1, except that 4-chlorobenzylamine hydrochloride was used in the same molar amount in place of p-chloroaniline hydrochloride (yield: 4.4 g). White ridge-like crystals, mp. 204-207°C Disinfectant formulation example 1 Gluconate of Example 1
5g nonionic surfactant
3.75g (polyoxyethylene phenyl ether) Distilled water for injection
Appropriate amount Total amount
Prescription example 2 of 100ml disinfectant Gluconate of Example 1
0.5g nonionic surfactant
0.375g (polyoxyethylene phenyl ether) ethanol

83ml distilled water for injection

Appropriate amount whole
amount
100 ml <Antibacterial activity test> In order to examine the bactericidal or bacteriostatic effect on various bacteria for the compounds obtained in each example, the minimum inhibitory concentration (MIC) was determined by the agar dilution plate method [CHEMOTHERAP
Y, 22, 1126-1128 (1974)]. In addition, a similar test was conducted using Hibitene as a control drug. These results are shown in Tables 3 and 4.

[0032] The number of various bacteria is 1 x 106 bacteria/ml (
O. D. 600 mμ, 0.07 to 0.16).

[0033]

[Table 3]

[0034]

[Table 4]

[0035]

[Effects of the Invention] As described above, the bisbiguanide derivative (I) or its salt of the present invention has high bactericidal or bacteriostatic activity, and therefore can be suitably used as a disinfectant for the human body, skin, etc. effective.

Claims (2)

[Claims] Claim 1: General formula: [Formula 1] (wherein R is a substituent containing 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, and a lower alkylthio group) A bisbiguanide derivative or a salt thereof, represented by a phenyl group that may have a phenyl group, a phenyl lower alkyl group or an alkyl group that may have a halogen atom as a substituent on the phenyl ring, and A represents a lower alkylene group. . 2. A disinfectant containing the bisbiguanide derivative or its salt according to claim 1 as an active ingredient.