Biguanide derivatives, manufacturing method thereof, and disinfectants containing the derivatives

Abstract: The invention presents a biguanide derivative or its salt expressed by a formula: (where R¹ and R² are as defined in Specification), or formula: (where A and R³ is as defined in specification). This biguanide derivative or its salt is preferably used as the effective amount of a disinfectant for humans, animals, medical appliances, etc.

Description: The invention relates to novel biguanide derivatives used in disinfection of humans, animals, medical appliances, and others, a method of manufacturing the same, and disinfectants containing such derivatives. It is known that various guanidine derivatives possess bactericidal actions, and biguanide derivatives of 1,4-dimethylene cyclohexane type are disclosed in the British Patent Specification No. 1,095,902. US patent US-3183230 reveals haloaralkyl biguanides such as N 1 , N 5 -di(4-chlorobenzyl)-biguanide. The compounds are conveniently prepared by reaction of approximately equal molar quantities of the appropriately substituted dicyanamide with an acid salt of the appropriate amine. French patent application FR-A-2100M discloses alkoxy propylbiguanides. These biguanides are indicated to have antimicrobial activity and in particular N 1 -lauroxypropyl derivates of the biguanide are studied. SUMMARY OF THE INVENTION It is a primary object of this invention to present novel biguanide derivatives or their salts possessing a higher activity than the conventional biguanide derivatives or their salts, and disinfectants containing such derivatives or their salts. To achieve the above object, a monobiguanide derivative of the invention is a biguanide derivative or its salt, expressed by a general formula: (where R 1 represents 3,4-dichlorobenzyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, benzyl group or 4-chlorobenzyl group, and R 2 represents octyl group, 3,4-dichlorobenzyl group, dodecyl 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-dimethylphenyl group, 3,4-methylenedioxyphenyl group, 4-t-butylphenyl group, 4-ethylthiophenyl group, 1,1,3,3-tetramethylbutyl group, hexyl group, 3-diethylaminopropyl group, (2-diethylamino)-ethyl group, 3-(di-n-butylamino)propyl group, cyclohexylmethyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, 4-acetylaminophenyl group, 3,4-methylenedioxybenzyl group, or isobutyl group,), and the derivative being N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -octyl-biguanide, N 1 -benzyl-N 5 -dodecyl-biguanide, N 1 -benzyl-N 5 -decyl-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-bromophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-iodophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,4-dichiorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dichiorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,3,4-trichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dimethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-t-butylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(n-decyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(1,1,3,3-tetramethylbutyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -hexyl-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3-diethylaminopropyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[(2-diethylamino)-ethyl)]-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[3-(di-n-butylamino)propyl]-biguanide, N 1 -(4-chlorophenyl)-N 5 -cyclohexylmethyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-chlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(2,4-dichlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-acetylaminophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(4-chlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -decyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -dodecyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -isobutyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -hexyl-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -decyl-biguanide. The biguanide derivatives listed above of formula (1) and salts thereof of the invention possess a higher bactericidal action or anti-bacterial action than a known biguanide. Therefore, the disinfectant of the invention contains a biguanide derivative as listed above or a salt thereof as an active ingredient. In the following explanation, the compound expressed by the general formula (1) is called a monobiguanide derivative. DETAILED DESCRIPTION OF THE INVENTION The monobiguanide derivative expressed by Formula (1) or its salt of the invention is specifically represented in the Examples hereinafter. The monobiguanide derivative (1) of the invention is a basic compound, and forms a corresponding acid-addition salt by reacting with an organic acid or an inorganic acid. Acids for forming such salt may include, for example, formic acid, acetic acid, lactic acid, butyric acid, isobutyric acid, α-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinic monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, gluconic acid, saccharic 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 and carbonic acid, and are not particularly limited. Besides, the ratio of monobiguanide derivative and acid for forming acid-addition salt is not particularly limited, and salts of various ratios may be used such as 1:1, 1:2, or the like. The acid-addition salt is manufactured in an ordinary salt forming method, such as direct mixing of acid and base, dissolving one or both in solvent such as water and mixing, and charging acid or base in solvent to dissolve and mix. After reaction, the obtained acid-addition salt is filtered if insoluble or hardly soluble in reaction medium, or recovered by evaporating the reaction medium if soluble in the reaction medium. Such acid-addition salt itself exhibits a high bactericidal effect or antibacterial effect, and is also useful for refining or isolation of free base. Meanwhile, the acid-addition salt is preferred to be acceptable pharmaceutically. The monobiguanide derivative (1) of this invention may also form a stable coordination compound with a metal salt. Such coordination compound also presents a bactericidal effect. The coordination compound is obtained by reaction of its derivative or its acid-adition salt with a specified quantity of metal salt, preferably a heavy metal salt such as V, Cr, Mn, Co, Ni, Cu, Zn, Pd, Re and Os. Next is explained a manufacturing method of the monobiguanide derivative (1) of the invention. (where R 1 and R 2 are same as defined above.) As shown in the reaction formula above, the monobiguanide derivative (1) of the invention is obtained by reaction of the amine expressed by Formula (a) with N 1 -cyanoguanidine compound expressed by Formula (b). At this time, the amine (a) is used in about equimolecular amounts of the compound (b). The amine (a) may be used in a form of proper acid-addition salt such as hydrochloric acid salt. The both components (a) and (b) are caused to react by heating in the presence or absence of inert solvent, such as 2-ethoxyethanol, 2-methoxyethanol and o-dichlorobenzene. If the product is an acid-addition salt, it may be changed into a form of free base by causing an alkali such as sodium hydroxide to act thereon, or may be changed into other acid-addition salt by ion exchange or other process. The starting material expressed by Formula (b) may be manufactured, for example, in the following reaction formula. (where M represents an alkali metal, and R 2 is same as defined above.) That is, the amine expressed by Formula (c) or its acid-addition salt (hydrochloride, etc.) is caused to react with the alkali metal salt (d) of dicyanamide (for example, sodium dicyanamide, potassium dicyanamide) in an inert solvent to obtain the material. The monobiguanide derivative (1) of this invention may be also manufactured in the following reaction formula. (where R 1 and R 2 represent the same as above.) This reaction is performed nearly in the same condition as in the above reaction. The biguanide derivative (1) of this invention and its salts possess higher antibacterial activities (bactericidal action or antibacterial action) as compared with the hitherto known biguanide derivatives, and some of them also possess antiviral activity. Furthermore, the biguanide derivatives of the invention and their salts possess a broad antibacterial spectrum, and are also excellent in rapidity of action, stability, safety and others, and their activities last for a long time. In addition, they are stimulation-free, odor-free, and soluble also in water. In particular, the compounds in Examples 1 to 4 mentioned below and their salts are particularly excellent in these features, and above all the compound of Example 1 and its salt are excellent in, including the above features, broad antibacterial spectrum, high short-time bactericidal activity, long-lasting drug effect, no problem in color, odor and taste, low toxicity, and the like. The salt of the compound of this invention is excellent in various points, including the above features, such as high solubility, low stimulation and toxicity, high stability, and the like. Therefore, the biguanide derivatives of this invention and their salts are useful as active ingredient for disinfectants for humans, animals, and medical appliances. The disinfectant of this invention is used in a form of solution, dispersion or suspension by dissolving, dispersing or suspending a specified amount of the biguanide derivatives or their salts in water or organic solvent. Typical examples are eye-drop, nose-drop, gargle, detergent, cleaning agent, and other external application liquids. In these cases, the content of the biguanide derivatives or their salts may be usually about 0.01 to 20 % by weight of the total amount. Besides, the biguanide derivatives of this invention and their salts may be contained in various cosmetics, such as creams, lotions, powders, colors, makeups, toothpaste, shampoo, soap, depilatories, bleaches, hair-dyes, hair tonics, bath additives, manicure, antiperspiration agent, deodorant, aerosol cosmetics, and baby cosmetics, and the like. Cosmetics are manufactured by dissolving, dispersing or suspending the specified amount of the biguanide derivatives or their salts, together with other ingredients, in water, other solvent, or various cosmetic bases, The content of the biguanide derivative or their salts in the cosmetic is usually about 0.001 to 1 % by weight of the total amount. EXAMPLES Referring to examples, the biguanide derivative of this invention and the disinfectant containing the derivative are explained in detail below. Example 1 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide hydrochloride To 20 g of N 1 -cyano-N 3 -octyl-guanidine and 20.2 g of 3,4-dichlorobenzylamine hydrochloride, 200 ml of mesitylene was added, which was heated and refluxed for 1.5 hours. Returning to room temperature after reaction, mesitylene was removed. To the residue, 200 ml of 10% ethanol aqueous solution was added, which was heated, and stirred for 3 hours at room temperature to be solidified. It was filtered off, and washed with 10% ethanol solution, water and isopropylether in turn, and 28.1 g of rough product was obtained. It was recrystallized in ethyl acetate, and 22.1 g of the captioned compound was obtained. White edged crystals mp. 177∼179°C Elemental analysis C 17 H 28 Cℓ 3 N 5 C H N Calcd. 49.95 6.90 17.13 Found 49.67 7.18 17.01 Example 2 Preparation of N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide hydrochloride To 20 g of N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine and 13.5 g of 4-chloroaniline hydrochloride, 200 ml of water was added, which was heated and refluxed for 2 hours. When cooled gradually after reaction, crystals was precipiated. After filtering the crystals, by drying the crystals obtained by heat treatment in 200 ml of ethyl acetate, 21.8 g of the captioned compound was obtained. White edged crystals mp. 238∼240°C Elemental analysis C 15 H 15 Cℓ 4 N 5 C H N Calcd. 44.25 3.71 17.20 Found 44.19 3.66 17.17 Example 3 Preparation of N 1 -(3,4-dichlorophenyl)-N 5 -octylbiguanide hydrochloride In the same procedure as in Example 1 except that 3,4-dichlorobenzylamine hydrochloride was replaced by the equimolecular amount of 3,4-dichloroaniline hydrochloride, 28.2 g of the captioned compound was obtained. White edged crystals mp. 176∼177°C Elemental analysis C 16 H 26 Cℓ 3 N 5 C H N Calcd. 48.68 6.64 17.74 Found 48.52 6.50 17.77 Example 4 Preparation of N 1 -benzyl-N 5 -dodecyl-biguanide hydrochloride To 20 g of N 1 -cyano-N 3 -benzyl-guanidine and 25.4 g of dodecylamine hydrochloride, 200 ml of mesitylene was added, which was heated and refluxed for 2 hours. After reaction, by the same operation as in Example 1, 23.7 g of the captioned compound was obtained. White edged crystals mp. 135∼137°C Elemental analysis C 21 H 38 CℓN 5 C H N Calcd. 63.69 9.67 17.68 Found 63.47 9.41 17.73 Example 5 Preparation of N 1 -benzyl-N 5 -decyl-biguanide hydrochloride In the same manner as in Example 4 except that dodecylamine hydrochloride was replaced by the equimolecular amount of decylamine hydrochloride, 20.3 g of the captioned compound was obtained. White edged crystals mp. 133∼135°C Elemental analysis C 19 H 34 CℓN 5 C H N Calcd. 62.02 9.31 19.03 Found 62.29 9.57 18.91 Example 6 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(3-trifluoromethylphenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 3-trifluoromethylaniline hydrochloride, 23.2 g of the captioned compound was obtained. White edged crystals mp. 185∼188°C Elemental analysis C 16 H 15 Cℓ 3 F 3 N 5 C H N Calcd. 43.61 3.43 15.89 Found 43.57 3.24 16.10 Example 7 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(4-bromophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 4-bromoaniline hydrochloride, 21.6 g of the captioned compound was obtained. White edged crystals mp. 223∼225°C Elemental analysis C 15 H 15 BrCℓ 3 N 5 C H N Calcd. 39.90 3.35 15.51 Found 40.34 3.16 15.82 Example 8 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(4-iodophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 4-iodoaniline hydrochloride, 22.6 g of the captioned compound was obtained. White edged crystals mp. 215∼217°C Elemental analysis C 15 H 15 Cℓ 3 IN 5 C H N Calcd. 36.14 3.03 14.05 Found 36.25 2.80 14.21 Example 9 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(2,4-dichlorophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 2,4-dichloroaniline hydrochloride, 20.4 g of the captioned compound was obtained. White edged crystals mp. 217∼220°C Elemental analysis C 15 H 15 Cℓ 5 N 5 C H N Calcd. 40.80 3.20 15.86 Found 41.25 2.93 15.79 Example 10 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 3,4-dichloroaniline hydrochloride, 21.7 g of the captioned compound was obtained. White edged crystals mp. 205∼208°C Elemental analysis C 15 H 14 Cℓ 5 N 5 C H N Calcd. 40.80 3.20 15.86 Found 41.03 2.94 15.94 Example 11 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(2,3,4-trichlorophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 2,3,4-trichloroaniline hydrochloride, 23.2 g of the captioned compound was obtained. White edged crystals mp. 227∼228°C Elemental analysis C 15 H 13 Cℓ 6 N 5 C H N Calcd. 37.85 2.75 14.71 Found 38.09 2.55 14.81 Example 12 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dimethylphenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 3,4-dimethylaniline hydrochloride, 20.3 g of the captioned compound was obtained. White edged crystals mp. 190∼191°C Elemental analysis C 17 H 20 Cℓ 3 N 5 C H N Calcd. 50.95 5.03 17.48 Found 50.66 4.78 17.56 Example 13 Preparation of N 1 -(3,4-dichlorobenzyl)- N 5 -(3,4-methylenedioxyphenyl)-biguanide hydrochloride In tie same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 3,4-methylenedioxyaniline hydrochloride, 25.7 g of the captioned compound was obtained. White edged crystals mp. 204∼206°C Elemental analysis C 16 H 16 Cℓ 3 N 5 O 2 C H N Calcd. 46.12 3.87 16.81 Found 45.83 3.69 16.97 Example 14 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(4-t-butylphenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 4-t-butylaniline hydrochloride, 22.5 g of the captioned compound was obtained. White edged crystals mp. 228∼230°C Elemental analysis C 19 H 24 Cℓ 3 N 5 C H N Calcd. 53.22 5.64 16.33 Found 52.93 5.38 16.16 Example 15 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(4-ethyl-thiophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that 4-chloroaniline hydrochloride was replaced by the equimolecular amount of 4-ethylthioaniline hydrochloride, 20.7 g of the captioned compound was obtained. White edged crystals mp. 199∼200°C Elemental analysis C 17 H 20 Cℓ 3 N 5 S C H N Calcd. 47.18 4.66 16.18 Found 47.12 4.46 16.04 Example 16 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(n-decyl)-biguanide hydrochloride In the same manner as in Example 1 except that N 1 -cyano-N 3 -octyl-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(n-decyl)-guanidine, 24.5 g of the captioned compound was obtained. White edged crystals mp. 135∼137°C Elemental analysis C 19 H 32 Cℓ 3 N 5 C H N Calcd. 52.24 7.38 16.03 Found 52.08 7.12 16.31 Example 17 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(1,1,3,3-tetramethylbutyl)-biguanide hydrochloride In the same manner as in Example 1 except that N 1 -cyano-N 3 -oxtyl-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(1,1,3,3-tetrabutyl)-guanidine, 23.1 g of the captioned compound was obtained. White edged crystals mp. 196∼198°C Elemental analysis C 17 H 28 Cℓ 3 N 5 C H N Calcd. 49.95 6.90 17.13 Found 49.78 6.81 17.01 Example 18 Preparation of N 1 -(3,4-dichlorobenzyl)- N 5 -hexyl-biguanide hydrochloride In the same manner as in Example 1 except that N 1 -cyano-N 3 -octyl-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -hexyl guanidine, 19.7 g of the captioned compound was obtained. White edged crystals mp. 155∼157°C Elemental analysis C 15 H 24 Cℓ 3 N 5 C H N Calcd. 47.32 6.35 18.39 Found 47.21 6.17 18.50 Example 21 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -(3-diethylaminopropyl)-biguanide A rough product was obtained in the same manner as in Example 1 except that N 1 -cyano-N 3 -octyl-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(3-diethylaminopropyl)-guanidine. The product was dissolved in 100 ml of methanol, and an equimolecular amount of 1N sodium hydroxide was added, which was concentrated at reduced pressure, and the residue was recrystallized in isopropanol, and 16.7 of the captioned compound was obtained. White edged crystals mp. 156∼158°C Elemental analysis C 16 H 26 Cℓ 2 N 6 C H N Calcd. 51.48 7.02 22.51 Found 51.21 6.83 22.76 In the following Examples 24 and 26, using proper starting materials, the individual compounds were prepared in the same manner as in Example 1. Example 24 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -[(2-diethylamino)-ethyl]-biguanide White edged crystals mp. 137∼140°C Elemental analysis C 15 H 24 Cℓ 2 N 6 C H N Calcd. 50.14 6.73 23.39 Found 50.01 6.48 23.15 Example 26 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -[3-(di-n- butylamino)propyl]-biguanide dihydrochloride White edged crystals mp. 122∼124°C Elemental analysis C 20 H 36 Cℓ 4 N 6 C H N Calcd. 47.82 7.22 16.73 Found 47.72 7.01 16.65 Example 27 Preparation of N 1 -(4-chlorophenyl)-N 5 -cyclohexylmethyl-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -cyclohexylmethyl-guanidine, 20.4 g of the captioned compound was obtained. White edged crystals mp. 240∼241°C Elemental analysis C 15 H 23 Cℓ 2 N 5 C H N Calcd. 52.33 6.73 20.34 Found 52.24 6.61 20.48 Example 28 Preparation of N 1 -(4-chlorophenyl)-N 5 -(3-trifluoromethylphenyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(3-trifluoromethylphenyl)-guanidine, 22.7 g of the captioned compound was obtained. White edged crystals mp. 213∼215°C Elemental analysis C 15 H 14 Cℓ 2 F 3 N 5 C H N Calcd. 45.93 3.60 17.86 Found 46.03 3.55 18.04 Example 29 Preparation of N 1 -(4-chlorophenyl)-N 5 -(4-ethylthiophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(4-ethylthiophenyl)-guanidine, 20.76 g of the captioned compound was obtained. White edged crystals mp. 243∼245°C Elemental analysis C 16 H 19 Cℓ 2 N 5 S C H N Calcd. 50.00 4.98 18.22 Found 50.04 4.82 18.10 Example 30 Preparation of N 1 -(4-chlorophenyl)-N 5 -(4-chlorobenzyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(4-chlorobenzyl)-guanidine, 21.6 g of the captioned compound was obtained. White edged crystals mp. 225∼227°C Elemental analysis C 15 H 16 Cℓ 3 N 5 C H N Calcd. 48.34 4.33 18.79 Found 48.32 4.19 18.86 Example 31 Preparation of N 1 -(4-chlorophenyl)-N 5 -(2,4-dichlorobenzyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(2,4-dichlorobenzyl)-guanidine, 20.1 g of the captioned compound was ob- White edged crystals mp. 234∼236°C Elemental analysis C 15 H 15 Cℓ 4 N 5 C H N Calcd. 44.25 3.71 17.20 Found 44.42 3.50 16.95 Example 32 Preparation of N 1 -(4-chlorophenyl)-N 5 - (4-acetylaminophenyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(4-acetylaminophenyl)-guanidine, 18.6 g of the captioned compound was obtained. White edged crystals mp. 253∼255°C Elemental analysis C 16 H 18 Cℓ 2 N 6 O C H N Calcd. 50.40 4.76 22.04 Found 50.63 4.51 21.92 Example 33 Preparation of N 1 -(4-chlorophenyl)-N 5 - (3,4-methylenedioxyphenyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(3,4-methylenedioxypehnyl)-guanidine, 19.7 g of the captioned compound was obtained. White edged crystals mp. 237∼239°C Elemental analysis C 15 H 15 Cℓ 2 N 5 O 2 C H N Calcd. 48.93 4.11 8.69 Found 48.76 3.95 8.47 Example 34 Preparation of N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide hydrochloride In the same manner as in Example 2 except that N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine was replaced by the equimolecular amount of N 1 -cyano-N 3 -(3,4-methylenedioxybenzyl)-guanidine, 22.4 g of the captioned compound was obtained. White edged crystals mp. 231∼233°C Elemental analysis C 16 H 17 Cℓ 2 N 5 O 2 C H N Calcd. 50.27 4.48 18.32 Found 50.44 4.29 18.31 Example 35 Preparation of N 1 -(4-chlorobenzyl)-N 5 -octyl-biguanide hydrochloride In the same manner as in Example 1 except that 3,4-dichlorobenzylamine hydrochloride was replaced by the equimolecular amount of 2,4-chlorobenzylamine hydrochloride, 21.3 g of the captioned compound was obtained. White edged crystals mp. 156∼158°C Elemental analysis C 17 H 29 Cℓ 2 N 5 C H N Calcd. 54.54 7.81 18.71 Found 54.76 7.68 18.69 Example 36 (Reference) Preparation of N 1 -(4-chlorobenzyl)-N 5 -(4-chlorobenzyl)-biguanide hydrochloride Using 20.85 g of N 1 -cyano-N 5 -(4-chlorobenzyl)-guanidine and 17.8 g of 4-chlorobenzylamine hydrochloride, 21.4 g of the captioned compound was obtained by operating the same manner as in Example 1. White edged crystals mp. 200∼202°C Elemental analysis C 16 H 18 Cℓ 3 N 5 C H N Calcd. 49.69 4.69 18.11 Found 49.62 4.61 18.37 Example 37 Preparation of N 1 -(4-chlorobenzyl)-N 5 -decyl-biguanide hydrochloride In the same manner as in Reference Example 36 except that 4-chlorobenzylamine hydrochloride was replaced by the equimolecular amount of decylamine hydrochloride, 24.3 g of the captioned compound was obtained. White edged crystals mp. 161∼163°C Elemental analysis C 19 H 33 Cℓ 2 N 5 C H N Calcd. 56.71 8.27 17.40 Found 56.60 8.12 17.63 Example 38 Preparation of N 1 -(4-chlorobenzyl)-N 5 -dodecyl-biguanide hydrochloride In the same manner as in Reference Example 36 except that 4-chlorobenzylamine hydrochloride was replaced by the equimolecular amount of dodecylamine hydrochloride, 22.3 g of the captioned compound was obtained. White edged crystals mp. 158∼160°C Elemental analysis C 21 H 37 Cℓ 2 N 5 C H N Calcd. 58.59 8.66 16.27 Found 58.41 8.53 16.55 Example 39 Preparation of N 1 -(4-chlorobenzyl)-N 5 -isobutyl-biguanide hydrochloride In the same manner as in Reference Example 36 except that 4-chlorobenzylamine hydrochloride was replaced by the equimolecular amount of isobutylamine hydrochloride, 18.7 g of the captioned compound was obtained. White edged crystals mp. 219∼221°C Elemental analysis C 13 H 21 Cℓ 2 N 5 C H N Calcd. 49.06 6.65 22.01 Found 48.87 6.52 22.23 Example 40 Preparation of N 1 -(4-chlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide hydrochloride In the same manner as in Reference Example 36 except that 4-chlorobenzylamine hydrochloride was replaced by the equimolecular amount of 3,4-dichloraniline hydrochloride, 21.7 g of the captioned compound was obtained. White edged crystals mp. 183∼185°C Elemental analysis C 15 H 15 Cℓ 4 N 5 C H N Calcd. 44.25 3.71 17.20 Found 44.37 3.66 17.42 Example 41 Preparation of N 1 -(3,4-dichlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide hydrochloride Using 21.5 g of N 1 -cyano-N 3 -(3,4-dichlorophenyl)-guanidine and 18.8 g of 3,4-methylenedioxybenzylamine hydrochloride, 27.3 g of the captioned compound was obtained by operating the same manner as in Example 1. White edged crystals mp. 175∼177°C Elemental analysis C 16 H 16 Cℓ 3 N 5 O 2 C H N Calcd. 46.12 3.87 16.81 Found 46.01 3.76 16.97 Example 42 Preparation of N 1 -(3,4-dichlorophenyl)-N 5 - hexyl -biguanide hydrochloride In the same manner as in Example 41 except that 3,4-methylenedioxybenzylamine hydrochloride was replaced by the equimolecular amount of hexylamine hydrochloride, 22.3 g of the captioned compound was obtained. White edged crystals mp. 154∼156°C Elemental analysis C 14 H 22 Cℓ 3 N 5 C H N Calcd. 45.85 6.05 19.10 Found 45.66 6.17 19.03 Example 43 Preparation of N 1 -(3,4-dichlorophenyl)-N 5 - decyl -biguanide hydrochloride In the same manner as in Example 41 except that 3,4-methylenedioxybenzylamine hydrochloride was replaced by the equimolecular amount of decylamine hydrochloride, 24.2 g of the captioned compound was obtained. White edged crystals mp. 131∼133°C Elemental analysis C 18 H 30 Cℓ 3 N 5 C H N Calcd. 51.13 7.15 6.56 Found 51.02 7.32 16.37 Example 44 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide lactate Dissolving 20 g of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide hydrochloride in 200 ml of methanol, 24.5 ml of 5N NaOH was added, and the solvent was distilled away. The residual white solid was washed with water, suspended in 200 ml of water off, and 13 g of lactic acid was added, and dissolved by heating. Chilled in ice, precipitating crystals were filtered, and 12.14 g of the captioned compound was obtained. White edged crystals mp. 45∼46°C Example 45 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide glycolate The captioned compound was obtained in the same manner as in Example 44 except that lactic acid was replaced by glycolic acid. White edged crystals mp. 109∼110°C Example 46 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide monomethanesulfonate The captioned compound was obtained in the smae manner as in Example 44 except that lactic acid was replaced by methanesulfonic acid. White edged crystals mp. 174∼176°C Example 47 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide hydrobromade The captioned compound was obtained in the same manner as in Example 44 except that lactic acid was replaced by 47% hydrobromic acid. White edged crystals mp. 120∼121°C Example 48 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide phosphate The captioned compound was obtained in the same manner as in Example 44 except that lactic acid was replaced by phosphoric acid. White edged crystals mp. 96∼98°C Example 49 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide dimethanesulfonate Dissolving 25 g of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide hydrochloride in 250 ml of methanol, 30.6 ml of 5N NaOH was added, and the solvent was distilled away. The residual white solid was washed with water, and dissolved in 500 ml of acetone, and 14.7 g of methanesulfonic acid was added. The precipitating crystals were filtered off, and by recrystallizing from ethanol-ether, 25.8 g of the captioned compound was obtained. White edged crystals mp. 171∼172°C Elemental analysis C 17 H 27 N 5 Cℓ 2 ·2CH 3 SO 3 H C H N Calcd. 40.42 6.25 12.41 Found 40.40 6.55 12.31 Reference Example Preparation of N 1 -(3,4-dichlorobenzyl)-N 3 -cyanoguanidine Putting 63.7 g (300 mM) of 3,4-dichlorobenzylamine hydrochloride and 30.9 g (1.1 eq.) of sodium dicyanamide in 950 ml (15 V) of acetonitrile, the mixture was heated and refluxed for 3.5 hours. Distilling away the solvent, 600 ml of water was added to the residue (white solid) to disperse and wash. Obtained crystals were filtered off, and dispersed and washed in 600 ml of dichloromethane. Since residue of amine was recognized, the crystals were dispersed and washed again in 600 ml of water and 500 ml of dichloromethane. Crystals were filtered off, and dried overnight at 60 °C, and 57.7 g (78.9%) of the captioned compound was obtained. White crystals mp. 173°C Elemental analysis C 9 H 8 Cℓ 2 N 4 C H N Calcd. 44.47 3.32 23.05 Found 44.32 3.08 23.30 Example 50 Preparation of N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide dihydrochloride Suspending 10.0 g (41.1 mM) of N 1 -(3,4-dichlorobenzyl)-N 3 -cyanoguanidine and 5.31 g (1.0 eq.) of n-octylamine in 100 ml of xylene, 3.5 ml (1.1 eq.) of concentrated hydrochloric acid was added and stirred for several minutes. The reaction was continued for 8 hours in reflux by using Dean-Stark trap. Distilling away the solvent, and by ethanol coboiling, xylene was removed. The residue was dissolved in 40 ml of 70% acetonitrile, and 6.8 ml (2.0 eq.) of concentrated hydrochloric acid was added. Further adding 90 ml of 70% acetonitrile, the mixture was recrystallized. Obtained cystals were filtered off, dried overnight at 60 °C, and 14.3 g (78.2%) of white crystal-line product was obtained. The obtained rough crystals were recrytallized twice with 70% acetonitrile (6 to 7 V), and 7.16 g (50.1%) of the captioned compound was obtained. mp. 176∼178°C Elemental analysis C 17 H 29 Cℓ 4 N 5 C H N Calcd. 45.86 6.56 15.73 Found 45.54 6.66 15.79 Meanwhile, when the produced material (dihydrochloride) was recrystallized in a solvent of high water content (such as CH 3 CN, ethanol), it was converted into the same monohydrochloride as obtained in Example 1. Prescription 1 of disinfectant Monobiguanide derivative of Example 1 5 g Nonionic surface active agent (Polyoxyethylene phenylether) 3.75 g Distilled water for injection proper Whole volume 100 ml Prescription 2 of disinfectant Monobiguanide derivative of Example 1 0.5 g Nonionic surface active agent (Polyoxyethylene phenylether) 0.375 g Ethanol 83 ml Distilled water for injection proper Whole volume 100 ml [Antibacterial activity test] In order to test the antibacterial action of the compounds obtained in the examples in various organisms, the minimum inhibitory concentration (MIC) was determined according to the standard method of Japan Society of Chemotherapy. The culture medium for sensitivity disc was used (Chemotherapy, vol. 29, No. 1, 76-79, 1981). As the control drug, gluconic chlorohexydine (tradename "Hibiten" commercially available from Sumitomo Pharmaceutical) was used and tested similarly. The results are shown in Table 1. The inoculum size was adjusted to 1 x 10 6 cells/ml (0.07 to 0.16 at O.D. 600 nm). [Bactericidal activity test] As to the compounds obtained in Examples 1 and 2, the bactericidal activity at room temperature (25 °C) was measured by treating in a short time by reference to the phenol coefficient measurement method. (1) Culture medium For prior culture of test organism, Mueller Hinton Broth (DIFCD) was used. As growth culture medium of surviving cells in the test solution after bactericidal treatment, SCDLP culture medium inactivated by disinfectant was used ("Daigo" commercially available from Nippon Seiyaku). (2) Test method The compound obtained in each examples was dissolved in distilled water, and adjusted to a double concentration of the test concentration, and after aseptic filtering, the solution was diluted in steps of 1/2 in a range of specified test concentration, and 50 µl was dispensed in 96-well microplate. On the other hand, the test organism undergoing the prior culture for 16 hours twice was adjusted to 10 8 cells/ml with sterilized distilled water in order to eliminate the effects of culture medium (0.3 at O.D. 660 nm), and diluted to 1/100 with 5 ml or 10 ml of sterilized distilled water to obtain 10 6 cells/ml, and into 50 µl of the test solution in the microplate, an equivalent 50 µl was injected and mixed. After the lapse of 1 minute and 3 minutes, 5 µl of the test solution was taken out from the microplate, and was suspended in 150 µl of inactivated culture medium, and was cultivated for 16 to 18 hours at 37 °C. The survival of organisms in the test solution was judged by the turbidity, and the minimum bactericidal concentration in lapse of 1 minute and 3 minutes was determined. The result is shown in Table 2. Strain Minimum Bactericidal Concentration µg/mℓ (10 6 cells/mℓ) Example 1 Example 2 Control agent 1 min. 3 min. 1 min. 3 min. 1 min. 3 min. S. aureus FDA 209P 12.5 3.13 500 100 >1000 25 S. aureus MRSA 57 6.25 ≦1.56 200 25 >1000 50 E. coli NIHJ JC-2 3.13 ≦1.56 25 6.25 12.5 6.25 K. pneumoniae NCTC 9632 3.13 3.13 12.5 12.5 3.13 ≦1.56 S. marcescens IFO 12648 6.25 ≦1.56 25 6.25 12.5 6.25 A. calcoaceticus Ac-54 3.13 3.13 12.5 6.25 6.25 6.25 P. aeruginosa ATCC 10145 3.13 3.13 12.5 6.25 12.5 6.25 P. cepacia 2315-C0010 200 50 200 50 >1000 >1000 Thus, the monobiguanide derivative (1) of the invention or its salt possesses a high bactericidal action and antibacterial action, and hence it may be preferably used as the disinfectant for the human or animal skin or the like.

Claims: Claims for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, MC, NL, PT, SE A biguanide derivative selected from: N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide, N 1 -(3,4-dichloropbenyl)-N 5 -octyl-biguanide, N 1 -benzyl-N 5 -dodecyl-biguanide, N 1 -benzyl-N 5 -decyl-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-bromopbenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-iodophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,3,4-trichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dimethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-t-butylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(n-decyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(1,1,3,3-tetramethylbutyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5- hexyl-biguanide, N 1 -(3,4-dicblorobenzyl)-N 5 -(3-diethylaminopropyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[(2-diethylamino)-ethyl]-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[3-(di-n-butylamino)propyl]-biguanide, N 1 -(4-chlorophenyl)-N 5 -cyclohexylmethyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-chlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(2,4-dichlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-acetylaminophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(4-chlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -decyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -dodecyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -isobutyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -(3,4-dichloropbenyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -hexyl-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -decyl-biguanide and salts thereof. A biguanide derivative selected from: N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide N 1 -(3,4-dichloropbenyl)-N 5 -octyl-biguanide, and N 1 -benzyl-N 5 -dodecyl-biguanide, and salts thereof. N 1 -(3,4-Dichlorobenzyl)-N 5 -octyl-biguanide or its salt. The biguanide derivative according to claim 3, in the form of its hydrochloride, lactate, glucolate, monomethanesulphonate, hydrobromide, phosphate, dimethanesulphonate or dihydrochloride salt. N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide or its salt. A process for preparing a biguanide derivative or its salt according to claim 1, which comprises; (I) reacting an amine or its salt expressed by a general formula: R 1 -NH 2 where R 1 represents 3,4-dichlorobenzyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, benzyl group or 4-chlorobenzyl group with N 1 -cyanoguanidine compound expressed by a general formula: where R 2 represents octyl group, 3,4-dichlorobenzyl group, dodecyl group, decyl group, 3-trifluoromethylphenyl group, 4-bromphenyl group, 4-iodophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 2,3,4-trichlorophenyl group, 3,4-dimethylphenyl group, 3,4-methylenedioxyphenyl group, 4-t-butylphenyl group, 4-ethylthiophenyl group, 1,1,3,3-tetramethylbutyl group, hexyl group, 3-diethylaminopropyl group, (2-diethylamino)-ethyl group, 3-(di-n-butylamino)propyl group, cyclohexylmethyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, 4-acetylaminophenyl group, 3,4-methylenedioxybenzyl group, or isobutyl group, to obtain biguanide derivative expressed by a general formula: (where R 1 and R 2 are same as defined above) or its salt; (II) reacting or N 5 -cyanoguanidine compound expressed by a general formula: (wherein R 1 is same as defined above), with an amine or its salt expressed by general a formula: R 2 -NH 2 (wherein R 2 is same as defined above) to obtain biguanide derivative expressed by the above formula (1) or its salt; The process according to claim 6 comprising (III) reacting N 1 -cyano-N 3 -octyl-guanidine with 3,4-dichlorobenzylamine or its acid-addition salt, or reacting N 1 -(3,4-dichlorobenzyl)-N 3 -cyano-guanidine with octylamine or its acid-addition salt to obtain N 1 -(3,4-dichlorobenzyl)-N 5 -octyl biguanide or its salt; The process according to claim 6 comprising (IV) reacting N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine with 4-chloroaniline or its acid-addition salt, or reacting N 1 -(4-chlorophenyl)-N 3 -cyano-guanidine with 3,4-dichlorobenzylamine or its acid-addition salt, to obtain N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide or its salt. A disinfectant composition comprising an effective amount of a biguanide derivative or its salt according to any of claims 1 to 5 and a carrier. Use of biguanide derivative or its salt according to any of claims 1 to 5 for manufacture of a disinfectant for humans, animals or medical appliances. Claims for the following Contracting States : ES, GR A process for preparing a biguanide derivative or its salt selected from N 1 -(3,4-dichlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -octyl-biguanide, N 1 -benzyl-N 5 -dodecyl-biguanide, N 1 -benzyl-N 5 -decyl-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-bromophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-iodophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(2,3,4-trichlorophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-dimethylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-t-butylphenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(n-decyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(1,1,3,3-tetramethylbutyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -hexyl-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -(3-diethylaminopropyl)-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[(2-diethylamino)-ethyl]-biguanide, N 1 -(3,4-dichlorobenzyl)-N 5 -[3-(di-n-butylamino)propyl]-biguanide, N 1 -(4-chlorophenyl)-N 5 -cyclohexylmethyl-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3-trifluoromethylphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-ethylthiophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-chlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(2,4-dichlorobenzyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(4-acetylaminophenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxyphenyl)-biguanide, N 1 -(4-chlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(4-chlorobenzyl)-N 5 -octyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -decyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -dodecyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -isobutyl-biguanide, N 1 -(4-chlorobenzyl)-N 5 -(3,4-dichlorophenyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -(3,4-methylenedioxybenzyl)-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -hexyl-biguanide, N 1 -(3,4-dichlorophenyl)-N 5 -decyl-biguanide, and salts thereof, which comprises: (I) reacting an amine or its salt expressed by a general formula: R 1 -NH 2 wherein R 1 represents 3,4-dichlorobenzyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, benzyl group or 4-chlorobenzyl group with N 1 -cyanoguanidine compound expressed by a general formula: wherein R 2 represents octyl group, 3,4-dichlorobenzyl group, dodecyl group, decyl group, 3-trifluoromethylphenyl group, 4-bromphenyl group, 4-iodophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 2,3,4-trichlorophenyl group, 3,4-dimethylphenyl group, 3,4-methylenedioxyphenyl group, 4-t-butylphenyl group, 4-ethylthiophenyl group, 1,1,3,3-tetramethylbutyl group, hexyl group, 3-diethylaminopropyl group, (2-diethylamino)ethyl group, 3-(di-n-butylamino)propyl group, cyclohexylmethyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, 4-acetylaminophenyl group, 3,4-methylenedioxybenzyl group or isobutyl group, to obtain biguanide derivative expressed by a general formula: (where R 1 and R 2 are the same as defined above), or its salt; (II) reacting a N 5 -cyanoguanidine compound expressed by a general formula: (wherein R 1 is the same as defined above), with an amine or its salt expressed by a general formula: R 2 ―NH 2 (wherein R 2 is the same as defined above), to obtain biguanide derivative expressed by the above formula (1) or its salt. The process according to claim 1 comprising (III) reacting N 1 -cyano-N 3 -octyl-guanidine with 3,4-dichlorobenzylamine or its acid-addition salt, or reacting N 1 -(3,4-dichlorobenzyl)-N 3 -cyano-guanidine with octylamine or its acid-addition salt to obtain N 1 -(3,4-dichlorobenzyl)-N 5 -octyl biguanide or its salt. The process according to claim 1 comprising (IV) reacting N 1 -cyano-N 3 -(3,4-dichlorobenzyl)-guanidine with 4-chloroaniline or its acid-addition salt, or reacting N 1 -(4-chlorophenyl)-N 3 -cyano-guanidine with 3,4-dichlorobenzylamine or its acid-addition salt to obtain N 1 -(4-chlorophenyl)-N 5 -(3,4-dichlorobenzyl)-biguanide or its salt.

Inventors: HIGUCHI YUKIO, ISHIKAWA HIROSHI, TAMAOKA HISASHI, TSUBOUCHI HIDETSUGU, YASUMURA KOICHI, HIGUCHI, YUKIO, ISHIKAWA, HIROSHI, TAMAOKA, HISASHI, TSUBOUCHI, HIDETSUGU, YASUMURA, KOICHI
Applicants: OTSUKA PHARMA CO LTD, OTSUKA PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: C07C279
IPC codes: C07C279