External preparation for skin containing a depigmentation agent

Abstract: An external preparation for skin including one or more than two types of tranexamic acid derivatives represented by the following general formula (A). GENERAL FORMULA (A) (In the formula (A), R₁, R₂ and R₃ represents hydrogen atoms or substituents and at least one of these is the substituent.) The external preparation for skin including the derivatives have excellent depigmentation effect as well as skin care effect.

Description: FIELD OF THE INVENTION The present invention relates to an external preparation for skin, and more particularly to a remarkably improved skin depigmentation agent thereof. BACKGROUND ART Although the mechanisms of pigmentation such as melasma, chloasma and the like in the skin are not fully understood, it is believed that a melanin pigment is formed and abnormally deposited in the skin due to hormone abnormalities and UV light irritation caused by sunlight. The above-mentioned pigmentation is generally treated by administering substances suppressing the formation of melanin. For example, Vitamin C is administered in a large amount; glutathione or a similar compound is injected; or L-ascorbic acid, kojic acid, cysteine, or a similar compound is applied to localized areas in the form of an ointment, cream, or lotion. In the United States and Europe, hydroquinone preparations are used as pharmaceuticals. The depigmentation effects of the above-mentioned compounds, except for hydroquinone, are very weak. Furthermore, although the depigmentation effects of hydroquinone on the skin are apparently recognized, the use of hydroquinone on the skin is generally limited due to its contact allergenicity. Documents Database WPI, Week 9237, Derwent Publications Ltd., London, GB, AN=92-304633 and Patent Abstracts of Japan, vol. 13, no. 308, (C-617), 14/7/89 disclose tranexamic acid derivates in an external skin agent. DISCLOSURE OF THE INVENTION Accordingly, it is an object of the present invention to eliminate the above-described problems of the prior art and to provide an external preparation for skin which has excellent depigmentation effect and high safety. As a result of studies undertaken by the present inventors so as to attain this aim, it has been found that certain types of tranexamic acid derivatives had suppression effect of melanine generation and excellent depigmentation effect to improve the depigmentation in the skin and skin trouble. The present invention has been achieved on the basies of this findings. In general terms, the present invention relates to an external preparation for skin including at least one tranexamic acid derivative represented by the following general formula (A). The particular compounds used in the present invention comprise nine groups. Compound Groups 1 to 9 are respectively defined in claims 1 to 9. COMPOUND GROUP 1 It is possible to synthesize the amide derivatives and the salt of tranexamic acid according to the present invention by the method described in, for example, Acta Pharm. Suecica, 7 , 441 (1970), J. Med. Chem., 15 , 247 (1972). Namely, the amino group of the tranexamic acid is protected by the suitable protecting group such as, for example, benzyloxycarbonyl group. After that, an amine ingredient reacts to the protected derivatives or a reactive protested derivatives thereof. As a result, a amide derivatives of the protected tranexamic acid can be obtained. As examples of the reactive protected derivatives, acyl halides such as acid chloride and bromides, or mixed acid anhydrides can be cited. After the reaction, the amide derivatives of tranexamic acid can be synthesized by removing the protecting group by, for example, the catalytic reduction. The above-described compound can be in forms of an inorganic acid salts such as salt of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid or an organic acid salts such as salt of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and p-toluene sulfonic acid. As preferable examples of the compound group 1; Trans-4-aminomethylcyclohexanecarboxamide, Trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-n-hexyl-trans-4-aminomethylcyclohexanecarboxamide, N-n-hexyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-n-heptyl-trans-4-aminomethylcyclchexanecarboxamide, N-n-heptyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-n-butyl-trans-4-aminomethylcyclohexanecarboxamide, N-n-butyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-n-propyl-trans-4-aminomethylcyclohexanecarboxamide, N-cyclohexyl-trans-4-aminomethylcyclohexanecarboxamide, N-cyclohexyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N,N-dicyclohexyl-trans 4-aminomethylcyclohexanecarboxamide, N,N-dicyclohexyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N,N-diethyl-trans-4-aminomethylcyclohexanecarboxamide, N,N-diethyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-benzyl-trans-4-aminomethylcyclohexanecarboxamide, N-benzyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-(4'-methoxyphenyl) trans-4-aminomethylcyclohexanecarboxamide, N-(4'-methoxyphenyl)-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-(4'-ethoxy phenyl)-trans-4-aminomethylcyclohexanecarboxamide, N-(4'-ethoxy phenyl)-trans-4-aminomethylcyclohexanecarboxamide hydrochloride N-(2'-methyl phenyl)-trans-4-aminomethylcyclohexanecarboxamide, N-(2'-methyl phenyl)-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-(3'-methyl phenyl)-trans-4-aminomethylcyclohexanecarboxamide N-(3'-methyl phenyl)-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-(4'-chlorophenyl)-trans-4-aminomethylcyclohexanecarboxamide, N-(4'-chlorophenyl)-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, are cited. COMPOUND GROUP 2 It is possible to synthesize the amide derivatives and the salt of the tranexamic acid according to the present invention by the method described in, for example, J.Med.Chem., 15 , 247(1972), JAPANESE PATENT LAID OPEN No.48-68541, JAPANESE PATENT LAID OPEN No.53-148536 or JAPANESE PATENT LAID OPEN No.57-59847. The above-described compound can be in forms of an inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt and calcium salt or organic salts such as monoethanolamine, diethanolamine and triethanolamine. As preferable examples of the compounds; Trans-4-acetylaminomethylcyclohexanecarboxylic acid, Trans-4-trifluoroacetylaminomethylcyclohexanecarboxylic acid, Trans-4-propionylaminomethylcyclohexanecarboxylic acid, Trans-4-butyrylaminomethylcyclohexanecarboxylic acid, Trans-4-isobutyrylaminomethylcyclohexanecarboxylic acid, Trans-4-valerylaminomethylcyclohexancarboxylic acid, Trans-4-isovalerylaminomethylcyclohexanecarboxylic acid, Trans-4-pivaloylaminomethylcyclohexanecarboxylic acid, Trans-4-pentanoylaminomethylcyclohexanecarboxylic acid, Trans-4-hexanoylaminomethylcyclohexanecarboxylic acid, Trans-4-(2-hexenoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-nonylaminomethylcyclohexanecarboxylic acid, Trans-4-(9-tetradecenoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-decanoylaminomethylcyclohexanecarboxylic acid, Trans-4-palmitoylaminomethylcyclohexanecarboxylic acid, Trans-4-stearoylaminomethylcyclohexanecarboxylic acid, Trans-4-oleoylaminomethylcyclohexanecarboxylic acid, Trans-4-linoleoylaminomethylcyclohexanecarboxylic acid, Trans-4-linolenoylaminomethylcyclohexanecarboxylic acid, Trans-4-(2,4,6-octatrienoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-(trans-4'-n-pentylcyclohexylcarbonylaminomethyl)cyclohexane carboxylic acid, Trans-4-(trans-4-isobutylcyclohexylcarbonylaminomethyl)cyclohexanecarboxylic acid, Trans-4-benzoylaminomethylcyclohexanecarboxylic acid, Trans-4-(3',4'-dimethoxycinnamoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4',5'-trimethoxybenzoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2'-aminobenzoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2'-amino-5'-bromobenzoylaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3'-pyridylcarbonylaminomethyl)cyclohexanecarboxylic acid, are cited. COMPOUND GROUP 3 It is possible to synthesize the derivatives and the salt of the tranexamic acid according to the present invention by the method described in, for example, JAPANESE PATENT LAID OPEN No.57-59847. Namely the compounds can be synthesized by, for example, (1) Acyl chloride method, (2) Mixed anhydride method, and (3) Activated ester method. The above-described compounds can be in forms of an inorganic acid salt such as salt of hydrochloric acid, sulfuric acid phosphoric acid and hydrobromic acid or an organic acid salt such as salt of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid and methanesulfonic acid, and p-toluene sulfonic acid, an inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt, and calcium salt or organic salt such as monoethanolamine, diethanolamine and triethanolamine. As preferable examples of the compounds; L-glycyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-seryl-trans-4-aminomethylcyclohexanecarboxylic acid, L-threonyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-cysteinyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-tyrosyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-asparaginyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-glutaminyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-alanyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-valyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-leucyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-isoleucyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-prolyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-phenylalanyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-tryptophanyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-methionyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-α-aspartyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-α-glutamyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-lysyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-arginyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-histidyl-trans-4-aminomethylcyclohexanecarboxylic acid, L-ornithyl-trans-4-aminomethylcyclohexanecarboxylic acid, are cited. COMPOUND GROUP 4 It is possible to synthesize the derivatives and the salt of the tranexamic acid according to the present invention by the method described in, for example, J.Med.Chem.,15,247(1972). The above-described compounds can be in forms of an inorganic acid salt such as salt of hydrochloric acid, sulfuric acid hydrobromic acid, and phosphoric acid, or an organic acid salt such as salt of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid, or inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt, and calcium salt or organic salts such as monoethanolamine, diethanolamine and triethanolamine. As preferable examples of the compounds; Trans-4-methylaminomethylcyclohexanecarboxylic acid, Trans-4-methylaminomethylcyclohexanecarboxylic acid hydrochloride, Trans-4-ethylaminomethylcyclohexanecarboxylic acid, Trans-4-ethylaminomethylcyclohexanecarboxylic acid hydrochloride, Trans-4-dimethylaminomethylcyclohexanecarboxylic acid, Trans-4-dimethylaminomethylcyclohexanecarboxylic acid hydrochloride, Trans-4-diethylaminomethylcyclohexanecarboxylic acid, Trans-4-diethylaminomethylcyclohexanecarboxylic acid hydrochloride, Trans-4-diisobutylaminomethylcyclohexanecarboxylic acid, Trans-4-diisobutylaminomethylcyclohexanecarboxylic acid hydrochloride, are cited. COMPOUND GROUP 5 As examples of the R of the compound group 5; a lower alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, n-heptyl group, isoheptyl group or 2-ethyl hexyl group are cited. As examples of the R 1 of the compound group 5; an alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, n-pentyl group, isopentyl group, n-hexyl group, isohexyl group, n-heptyl group, isoheptyl group, 2-ethyl hexyl group; an cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group are cited. It is possible to synthesize the derivatives and the salt of tranexamic acid according to the present invention by method described in, for example, J.Med.Chem.,15,247(1972) and JAPANESE PATENT LAID OPEN No.57-59852. The above-described compounds can be in forms of an inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt, and calcium salt or organic salts such as monoethanolamine, diethanolamine and triethanolamine. As preferable examples of the compounds; Trans-4-ureidomethylcyclohexanecarboxylic acid, Trans-4-(N'-ethylureidomethyl)cyclohexanecarboxylic acid, Trans-4-(N'-n-butylureidomethyl)cyclohexanecarboxylic acid, Trans-4-(N'-ethoxycarbonylmethylureidomethyl)cyclohexanecarboxylic acid, Trans-4-(N'-cyclohexylureidomethyl)cyclohexanecarboxylic acid, Trans-4-(N'-phenylureidomethyl)cyclohexanecarboxylic acid, Trans-4-(N'-2'-chlorophenylureidomethyl)cyclohexanecarboxylic acid, are cited. COMPOUND GROUP 6 As an example of the R of the compound group 6; a normal chain alkyl group such as methyl group, ethyl group, propyl group, butyl group, heptyl group and hexyl group, a branched chain alkyl group such as isopropyl group, isobutyl group, isopentyl group, octane-2-yl group, heptane-2-yl group, or a cyclic alkyl group such as cyclopentyl group, cyclohexyl group, an aralkyl group such as benzyl group, and pyridyl methyl group, are cited. It is possible to synthesize the cyclohexanecarboxylic acid derivatives and the salt according to the present invention by the method described in, for example, JAPANESE PATENT LAID OPEN No.57-126461. The above-described compounds can be in forms of an inorganic acid salt such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid or an organic acid salt such as salts of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid, or an inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt and calcium salt or organic salts such as monoethanolamine, diethanolamine and triethanolamine. As preferable examples of the compounds; Methyl trans-4-guanidinomethylcyclohexanecarboxylate, Ethyl trans-4-guanidinomethylcyclohexanecarboxylate, Propyl trans-4-guanidinomethylcyclohexanecarboxylate, Butyl trans-4-guanidinomethylcyclohexanecarboxylate, Heptyl trans-4-guanidinomethylcyclohexanecarboxylate Isopropyl trans-4-guanidinomethylcyclohexanecarboxylate, Isobutyl trans-4-guanidinomethylcyclohexanecarboxylate, Octan-2-yl trans-4-guanidinomethylcyclohexanecarboxylate, Heptan-2-yl-trans-4-guanidinomethylcyclohexanecarboxylate, Cyclopentyl trans-4-guanidinomethylcyclohexanecarboxylate, Cyclohexyl trans-4-guanidinomethylcyclohexanecarboxylate, Benzyl trans-4-guanidinomethylcyclohexanecarboxylate, 4'-pyridylmethyl trans-4-guanidinomethylcyclohexanecarboxylate, are cited. COMPOUND GROUP 7 As examples of the R of the compound group 7, methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, and t-butyl group are cited. It is possible to synthesize the trans-4-guanidinomethyl cyclohexanecarboxylic acid derivatives and the salt according to the present invention by the method described in, for example, JAPANESE PATENT LAID OPEN No.57-21360, JAPANESE PATENT LAID OPEN No.57-48960. The above-described compounds can be in forms of an inorganic acid salt such as salts of hydrochloric acid, sulfuric acid. phosphoric acid, and hydrobromic acid or an organic acid salt such as salts of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid. citric acid, methanesulfonic acid and p-toluene sulfonic acid. As a preferable example of the compounds; Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenoxycarbonyl phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonyl phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-benzyloxycarbonyl phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzyloxycarbonyl phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-carboxyphenylester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethoxy carbonyl phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-methoxycarbonylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxymethylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-t-butyloxycarbonylmethylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2-carboxyethyl)phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2-ethoxycarbonyl ethyl)phenyl ester, are cited. COMPOUND GROUP 8 As examples of the R 1 , R 2 and R 3 of the compound group 8; lower alkyl group such as methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, t-butyl group; lower alkoxy group such as methoxy group, ethoxy group, propoxy group and butoxy group; alkanoyl group such as acetyl group, propionyl group, butyryl group; halogen atom such as chlorine atom, bromine atom, iodine atom, fluorine atom; are cited. It is possible to synthesize the trans-4-guandinomethylcyclohexanecarboxylic acid derivatives and the salt according to the present invention by the method described in, for example, JAPANESE PATENT LAID OPEN No.57-16856, JAPANESE PATENT LAID OPEN No.57-122059, JAPANESE PATENT LAID OPEN No.57-122061, and JAPANESE PATENT LAID OPEN No.57-122062. The above-described compounds can be in forms of an inorganic acid salt such as salt of hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, or an organic acid salt such as salt of acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and p-toluene sulfonic acid. As preferable examples of the compounds; Trans-4-guanidinomethylcyclohexanecarboxylic acid phenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-methylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-methoxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-methoxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-ethoxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-acetylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-acetylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-chlorophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-chlorophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-bromophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-iodinephenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 3',4'-dichlorophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2',4',6'- trichlorophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-trifluoromethylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-nitrophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-acetoaminophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-sulfamoylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzoylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenoxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-benzyloxyphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-formylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-formylphenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-cyanophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-cyanophenyl ester, Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-isopropyl-4'-chloro-5'-methylphenyl ester, are cited. COMPOUND GROUP 9 As an example of the A of the compound group 9, pyridyl group such as 2-pyridyl group, 3-pyridyl group, 4-pyridyl group are cited. As an example of the X 3 , halogen atom such as chlorine atom, bromine atom, iodine atom, fluorine atom are cited. It is possible to synthesize the cyclohexanecarboxylic acid derivatives and the salt according to the present invention by the method described in, for example, JAPANESE PATENT PUBLISH No.63-12055, JAPANESE PATENT PUBLISH No.63-46736, JAPANESE PATENT LAID OPEN No.57-116035, and JAPANESE PATENT LAID OPEN No.57-140714. As preferable examples of the compounds; Trans-4-benzylideneaminomethylcyclohexanecarboxylic acid, Trans-4-(2'-nitrobenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3'-nitrobenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(4'-nitrobenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2'-hydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3'-hydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(4'-hydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2'-methoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3'-methoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(4'-methoxybenzylideneaminomethyl) cyclohexanecarboxylic acid, Trans-4-(3'-carboxy-4'-hydroxy-benzylidene-aminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4',5'-trimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4',5' trihydroxybenzylidenaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4'-dimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',3'-dimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',4'-dimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',5'-dimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',5'-dimethoxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4'-dihydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',3'-dihydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',4'-dihydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2',5'-dihydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',5'-dihydroxybenzylideneaminomethyl)cycloyyhexanecarboxylic acid, Trans-4-(4'-chlorobenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(2'-chlorobenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3'-trifluoromethylbenzylideneaminomethyl)cyclohexane carboxylic acid, Trans-4-(3'-pyridylmethylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(4'-pyridylmethylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(4'-isopropenylbenzylideneaminomethyl)cyclohexanecarboxylic acid, Trans-4-(3',4'-dihydroxybenzylideneaminomethyl)cyclohexanecarboxylic acid ethyl ester, are cited. The external preparation for skin according to the present invention contains one or more than two types of the derivatives of tranexamic acid. The content of the derivatives is from 0.001 to 20 weight % in the total amount of external preparation, and more preferably from 0.01 to 7 weight %. If the content is less than 0.001 weight %, it is difficult to obtain the depigmentation effect and the skin care effect. Also, even if the content is more than 20 weight %, the further improvement might not be obtained. It is possible to add other ingredients which can be generally used for an external preparation for skin such as cosmetics and the medical supplies to the external preparation for skin according to the present invention. For example, it is possible to add oil, an ultraviolet ray absorbant, an antioxidant, a surface-active agent, a moisture agent, a perfume, water, alcohol, a thickener, a color agent, a skin nutrition agent (tocopherol acetate, pantothenyl ethyl ether, salt of glycyrrhizic acid). [EXAMPLE] The composition of the present invention is explained in detail by the following examples. It should be noted that the present invention is not limited by these examples. The content is expressed by weight %. The examination methods which were carried out in these examples are explained before the description of the examples. COMPOUND GROUP 1 (1) DEPIGMENTATION EFFECT [Preparation of Sample] Lotions were prepared by the following formula, using each sample. Namely, the alcohol phase and aqueous phase according to the following formula were prepared respectively, and both phases were mixed and dissolved according to an ordinary method. (Alcohol phase) Weight % 95% ethyl alcohol 25.0 Polyoxyethylene (25 moles) hydrogenated castor oil ether 2.0 Antioxidant and antiseptic q.s. Perfume q.s. Composition (TABLE 1) (Aqueous phase) 1.0 Glycerol 5.0 Sodium hexametaphosphate q.s. Ion exchanged water balance [Examination Method] 10 subjects for each group were disposed under sunlight in summer for 4 hours (2 hours × 2 days). The lotion were applied to the skin of medial brachia for once in each morning and evening from 5 days after the day exposed to the sun light for 8 weeks. After the application period, depression effect to the pigmentation which was caused by the sun light irradiation were examined and evaluated the degree based on the following standard. [Standard] o ○ : The number of the subjects who judged the result was "extremely effective" or "effective" were equal to or more than 80 % ○ : The number of the subjects who judged the result was "extremely effective" or "effective" were from 50 % to 80% ▵ : The number of the subjects who judged the result was "extremely effective" or "effective" were from 30 to 50% X : The number of the subjects who judged the result was "extremely effective" or "effective" were less than 30% The result is shown in TABLE 1. COMPOUND DEPIGMENTAION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 1 N-n-hexyl-trans-4-aminomethyl cyclohexanecarboxamide hydrochloride o ○ EXAMPLE 2 Trans-4-aminomethylcyclohexane carboxamide o ○ EXAMPLE 3 N-(p-methoxy)phenyl-trans-4-aminomethylcyclohexanecarboxamide o ○ As is clear from the TABLE 1, the external preparation for skin according to the example 1 to 3 could suppress deposition of melanic pigment and suntan. (2) SKIN CARE EFFECT The external preparation for skin according to the example 1 to 3 were applied to left halves of faces of subjects, and the preparation according to the comparison 1 was applied to right halves of the faces of subjects after washing the face is every morning and night for two weeks. One group of subjects included 10 women and 3 group of subjects were examined. The results of the examination were evaluated the degree based on the following standard for moisturising effect, texture of skin surface, and maintenance of moisturising effect. [Standard] o ○ : The number of the subjects who judged the result was "extremely effective" or "effective" were equal to or more than 80 % ○ : The number of the subjects who judged the result was "extremely effective" or "effective" were from 50% to 80% ▵ : The number of the subjects who judged the result was "extremely effective" or "effective" were from 30% to 50% X : The number of the subjects who judged the result was "extremely effective" or "effective" were less than 30% The result is shown in TABLE 2. Moistursing effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 1 o ○ o ○ o ○ EXAMPLE 2 o ○ o ○ o ○ EXAMPLE 3 o ○ o ○ o ○ As is clear from the TABLE 2, the external preparation for skin according to the example 1 to 3 had excellent skin care effect. EXAMPLE 4 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine monostearate 3.0 Propylene glycol 10.0 Trans-4-aminomethylcyclohexanecarboxamide 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The propylene glycol and caustic potash were added to the ion exchanged water, dissolved and heated to 70 °C (Aqueous phase). The other ingredients were mixed, heated, melted and kept 70 °C (Oil phase). The oil phase was added to the aqueous phase gradually. After finishig the adding, the temparature was kept and complete a reaction. The system was uniformly emulsified with the homomixer and cooled to 30 °C under stirring condition. EXAMPLE 5 CREAM weight % Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) sorbitan monostearate 1.5 Propylene glycol 10.0 N-n-hexyl trans-4-aminomethylcyclohexanecarboxamide hydrochloride 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The propylene glycol was added to the ion exchanged water, dissolved and heated to 70 °C (Aqueous phase). The other ingredients were mixed, heated, melted and kept 70 °C (Oil phase). The oil phase was added to the aqueous phase and preemulsified. The system was uniformly emulsified with the homomixer and cooled to 30 °C under stirring condition. EXAMPLE 6 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerine monostearate 2.0 Propylene glycol 5.0 N-n-propyl trans-4-aminomethylcyclohexanecarboxamide 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The propylene glycol was added to the ion exchanged water, dissolved and heated to 70 °C (Aqueous phase). The other ingredients were mixed, heated, melted and kept 70 °C (Oil phase). The oil phase was added to the aqueous phase and preemulsified. The system was uniformly emulsified with the homomixer and cooled to 30 °C under stirring condition. EXAMPLE 7 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 N-benzyl trans-4-aminomethylcyclohexanecarboxamide 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The carboxyvinyl polymer was dissolved in a part of the ion exchanged water (A phase). The polyethylene glycol 1500 and the triethanolamine were added to the other part of ion exchanged water , dissolved, heated and kept at 70 °C (aqueous phase). The other agents were mixed, heated, melted and kept at 70°C (Oil phase). The oil phase was added to the aqueous phase and preemulsified. The system was uniformly emulsified with the homomixer and cooled to 30 °C under stirring condition. EXAMPLE 8 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 N-(p-methoxy)phenyl trans-4-aminomethylcyclohexanecarboxamide 1.0 Trans-4-aminomethylcyclohexanecarboxamide hydrochloride 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogen sulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The oil phase agents were dissolved at 70°C. The aqueous phase agents were dissolved at 70°C. The oil phase was added to the aqueous phase and the system was uniformly emulsified with the homomixer and cooled to 30 °C with a heat exchanger. EXAMPLE 9 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleylalcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 N,N-diethyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride 1.0 N-1-naphthyl-trans-4-aminomethylcyclohexanecarboxamide 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The carboxyvinyl polymer was uniformly dissolved in the ion exchanged water. The N,N-diethyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride, N-1-naphthyl-trans-4-aminomethylcyclohexanecarboxamide, polyoxyethylene (50 moles) oleyl alcohol ether were dissolved in the 95% ethanol. The ethanol phase was added to the aqueous phase and the other ingredients were added. The system was neutralized and thicked by the caustic soda and L-arginine. EXAMPLE 10 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethylether 0.1 Trans 4-aminomethylcyclohexanecarboxamide hydrochloride 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The A phase, B phase and C phase were uniformly dissolved, respectively. The A phase was dissolved in the C phase, the B phase was added and the system was packed. EXAMPLE 11 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) N-n-butyl-trans-4-aminomethylcyclohexanecarboxamide hydrochloride 1.0 Trans-4-aminomethylcyclohexanecarboxamide hydrochloride 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The A phase, B phase and C phase were uniformly dissolved, respectively. The B phase was dissolved in the A phase, and the C phase was added and the system was packed. The external preparation for skin according to the example 4 to 11 had excellent depigmentation effect as well as skin care effects. COMPOUND GROUP 2 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 2 was examined according to the method described above. The result is shown in TABLE 3. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 12 Trans-4-(trans-4'-isobutylcyclohexylcarbonylaminomethyl) cyclohexanecarboxylic acid o ○ EXAMPLE 13 Sodium trans-4-oleoylaminomethylcyclohexane carboxylic acid o ○ EXAMPLE 14 Trans-4-(3',4'-dimethoxycinnamoylaminomethyl) cyclohexanecarboxylic acid o ○ As is clear from the TABLE 3, the external preparation for skin according to the example 12 to 14 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 2 was examined according to the method described above. The result is shown in TABLE 4. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 12 o ○ o ○ o ○ EXAMPLE 13 o ○ o ○ o ○ EXAMPLE 14 o ○ o ○ o ○ As is clear from the TABLE 4, the external preparation for skin according to the example 12 to 14 had excellent skin care effect. EXAMPLE 15 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Trans-4-acetylaminomethylcyclohexanecarboxylic acid 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 16 CREAM weight % Stearic acid 6.0 Sorbitane monostearate 2.0 Polyoxyethylene (20 moles) sorbitanemonostearate 1.5 Propylene glycol 10.0 Trans-4-palmitoylaminomethylcyclohexanecarboxylic acid 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogensulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 17 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecylalcohol 6.0 Polyoxyethylene (25 moles) cetylalcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 Trans-4-(2'-aminobenzoylaminomethyl) cyclohexanecarboxylic acid 0.005 Perfume q.s. Sodium hydrogensulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 18 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-benzoylaminomethylcyclohexanecarboxylic acid 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 19 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-(3',4',5'-trimethoxybenzoylaminomethyl) cyclohexanecarboxylic acid 1.0 Trans-4-decanoylaminomethylcyclohexanecarboxylic acid 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 20 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleylalcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-trifluoroacetylcyclohexanecarboxylic acid 1.0 Sodium trans-4-linoleylaminomethylcyclohexanecarboxylic acid 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 21 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethylether 0.1 Trans-4-(3'-pyridylcarbonylaminomethyl)cyclohexane carboxylic acid 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 22 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Sodium trans-4-(2',4',6'-octatrienoylaminomethyl)cyclohexane carboxylic acid 1.0 Trans-4-trifluoroacetylaminomethylcyclohexane carboxylic acid 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 3 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 3 was examined according to the method described above. The result is shown in TABLE 5. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 23 L-alanyl-trans-4-aminomethyl cyclohexanecarboxylic acid o ○ EXAMPLE 24 L-valyl-aminomethylcyclohexane carboxylic acid o ○ EXAMPLE 25 L-threonyl-trans-4-aminomethyl cyclohexanecarboxylic acid o ○ As is clear from the TABLE 5, the external preparation for skin according to the example 23 to 25 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 3 was examined according to the method described above. The result is shown in TABLE 6. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 23 o ○ o ○ o ○ EXAMPLE 24 o ○ o ○ o ○ EXAMPLE 25 o ○ o ○ o ○ As is clear from the TABLE 6, the external preparation for skin according to the example 23 to 25 had execllent skin care effect. EXAMPLE 26 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine monostearate 3.0 Propylene glycol 10.0 L-leucyl-trans-4-aminomethylcyclohexanecarboxylic acid 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 27 CREAM weight % Stearic acid 6.0 Sorbitane monostearate 2.0 Polyoxyethylene (20 moles) sorbitanemonostearate 1.5 Propylene glycol 10.0 L-alanyl-trans-4-aminomethylcyclohexanecarboxylic axid 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 28 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetylalcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 L-valyl-trans-4-aminomethylcyclohexanecarboxylic axid 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 29 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 L-glycyl-trans-4-aminomethylcyclohexanecarboxylic acid 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 30 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 L-phenylalanyl-trans-4-aminomethylcyclohexane carboxylic acid 1.0 L-isoleucyl-trans-4-aminomethylcyclohexane carboxylic acid hydrochloride 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogen sulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 31 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleylalcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 L-seryl-trans-4-aminomethylcyclohexane carboxylic acid hydrochloride 1.0 L-tyrosyl-trans-4-aminomethylcyclohexanecarboxylic acid 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 32 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 L-lysyl-trans-4-aminomethylcyclohexanecarboxylic acid 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 33 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) L-asparaginyl-trans-4-aminomethylcyclohexane carboxylic acid 1.0 L-glutamyl-trans-4-aminomethylcyclohexanecarboxylic acid 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 4 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 4 was examined according to the method described above. The result is shown in TABLE 7. COMPOUND DEPIGMENTATIONE EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 34 Trans-4-ethylaminomethyl cyclohexanecarboxylic acid hydrochloride o ○ EXAMPLE 35 Trans-4-diethylaminomethylcyclohexane carboxylic acid o ○ EXAMPLE 36 Trans-4-diisobutylaminomethyl cyclohexanecarboxylic acid hydrochloride o ○ As is clear from the TABLE 7, the external preparation for skin according to the example 34 to 36 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 4 was examined according to the method described above. The result is shown in TABLE 8. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 34 o ○ o ○ o ○ EXAMPLE 35 o ○ o ○ o ○ EXAMPLE 36 o ○ o ○ o ○ As is clear from the TABLE 8, the external preparation for skin according to the example 34 to 36 had excellent skin care effect. EXAMPLE 37 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Trans-4-methylaminomethylcyclohexanecarboxylic acid hydrochloride 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 38 CREAM weight % Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) sorbitan monostearate 1.5 Propylene glycol 10.0 Trans-4-methylaminomethylcyclohexanecarboxylic acid 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 39 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 Trans-4-ethylaminomethylcyclohexanecarboxylic acid 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 40 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-dimethylaminomethylcyclohexanecarboxylic acid 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 41 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-diethylaminomethylcyclohexane carboxylic acid hydrochloride 1.0 Trans-4-ethylaminomethylcyclohexanecarboxylic acid 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 42 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-methylaminomethylcyclohexane carboxylic acid hydrochloride 1.0 Trans-4-dimethylaminomethylcyclohexane carboxylic acid 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 43 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Trans-4-diethylaminomethylcyclohexanecarboxylic acid hydrochloride 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 44 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Trans-4-dimethylaminomethylcyclohexane carboxylic acid hydrochloride 1.0 Trans-4-diethylaminomethylcyclohexane carboxylic acid hydrochloride 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 5 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 5 was examined according to the method described above. The result is shown in TABLE 9. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 45 Trans-4-ureidomethyl cyclohexanecarboxylic acid o ○ EXAMPLE 46 Trans-4-(N'-ethylureidomethyl) cyclohexane carboxylic acid o ○ EXAMPLE 47 Trans-4-(N'-cyclohexylureidomethyl) cyclohexanecarboxylic acid o ○ As is clear from the TABLE 9, the external preparation for skin according to the example 45 to 47 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 5 was examined according to the method described above. The result is shown in TABLE 10. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 45 o ○ o ○ o ○ EXAMPLE 46 o ○ o ○ o ○ EXAMPLE 47 o ○ o ○ o ○ As is clear from the TABLE 10, the external preparation for skin according to the example 45 to 47 had exellent skin care effect. EXAMPLE 48 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Trans-4-(N'-n-butylureidomethyl)cyclohexane carboxylic acid 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 49 CREAM weight % Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) sorbitan monostearate 1.5 Propylene glycol 10.0 Trans-4-(N'-ethoxycarbonylmethylureidomethyl) cyclohexanecarboxylic acid 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 50 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerine monostearate 2.0 Propylene glycol 5.0 Trans-4-(N'-phenylureidomethyl) cyclohexanecarboxylic acid 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 51 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-(N'-2'-chlorophenylureidomethyl) cyclohexanecarboxylic acid 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 52 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-ureidomethylcyclohexanecarboxylic acid 1.0 Trans-4-(N'-ethylureidomethyl)cyclohexanecarboxylic acid 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogen sulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 53 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-(N'-n-butylureidomethyl)cyclohexane carboxylic acid 1.0 Trans-4-(N'-ethoxycarbonylmethylureidomethyl) cyclohexanecarboxylic acid 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 54 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Trans-4-(N'-cyclohexylureidomethyl)cyclohexane carboxylic acid 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 55 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Trans-4-(N'-phenylureidomethyl) cyclohexanecarboxylic acid 1.0 Trans-4-(N'-2'-chlorophenylureidomethyl)cyclohexane carboxylic acid 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 6 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 6 was examined according to the method described above. The result is shown in TABLE 11. COMPOUN DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 56 Trans-4-guanidinomethyl cyclohexanecarboxylicacid o ○ EXAMPLE 57 Ethyltrans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride o ○ EXAMPLE 58 Octane-2-yl-trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride o ○ As is clear from the TABLE 11, the external preparation for skin according to the example 56 to 58 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 6 was examined according to the method described above. The result is shown in TABLE 12. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 56 o ○ o ○ o ○ EXAMPLE 57 o ○ o ○ o ○ EXAMPLE 58 o ○ o ○ o ○ As is clear from the TABLE 12, the external preparation for skin according to the example 56 to 58 had exellent skin care effect. EXAMPLE 59 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Benzyltrans-4-guanidinomethylcyclohexane carboxylate hydrochoride 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 60 CREAM weight % Stearic acid 6.0 Sorbitane monostearate 2.0 Polyoxyethylene (20 moles) sorbitanemonostearate 1.5 Propylene glycol 10.0 4'-pyridylmethyltrans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogensulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 61 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 Cyclohexyl trans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 62 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 63 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Ethyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride 1.0 Benzyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 64 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Octan-2-yl-trans-4-guanidinomethylcyclohexane carboxylate hydrochloride 1.0 Cyclohexyltrans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 65 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Ethyltrans-4-guanidinomethylcyclohexane carboxylate hydrochloride 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 66 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Ethyltrans-4-guanidinomethyl cyclohexanecarboxylate hydrochloride 1.0 Trans-4-guanidinomethylcyclohexane carboxylic acid hydrochloride 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 7 (1) DEPIGMENTATION The depigmentation effect of the compound group 7 was examined according to the method described above. The result is shown in TABLE 13. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 67 Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-carboxyphenyl ester hydrochloride o ○ EXAMPLE 68 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonylphenylester hydrochloride o ○ EXAMPLE 69 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethoxycarbonylphenylester hydrochloride o ○ As is clear from the TABLE 13, the external preparation for skin according to the example 67 to 69 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 7 was examined according to the method described above. The result is shown in TABLE 14. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 67 o ○ o ○ o ○ EXAMPLE 68 o ○ o ○ o ○ EXAMPLE 69 o ○ o ○ o ○ As is clear from the TABLE 14, the external preparation for skin according to the example 67 to 69 had exellent skin care effect. EXAMPLE 70 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine monostearate 3.0 Propylene glycol 10.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-benzyloxycarbonylphenylester hydrochloride 20.0 Caustic potash 0.2 Sodium hydrogen sulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 71 CREAM weight % Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) sorbitan monostearate 1.5 Propylene glycol 10.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2-carboxyethyl)phenylester hydrochloride 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 72 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerine monostearate 2.0 Propylene glycol 5.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2-ethoxycarbonyl ethyl) phenylester hydrochloride 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 73 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxymethylphenylester hydrochloride 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 74 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzyloxycarbonylphenylester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 3'-methoxycarbonylphenylester hydrochloride 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogen sulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 75 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-t-butyloxycarbonylmethylphenyl ester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-carboxyphenylester hydrochloride 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 76 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethoxycarbonylphenylester hydrochloride 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 dipropyleneglycol 10.0 Sodium hydrogen sulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 77 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonylphenylester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-(2-carboxyethyl)phenylester hydrochloride 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 8 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 8 was examined according to the method described above. The result is shown in TABLE 15. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 78 Trans-4-guanidinomethylcyclohexanecarboxylic acid phenyl ester hydrochloride o ○ EXAMPLE 79 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethylphenylester hydrochloride o ○ EXAMPLE 80 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-methoxyphenylester hydrochloride o ○ As is clear from the TABLE 15, the external preparation for skin according to the example 78 to 80 could also suppress deposition of melanoic pigment and suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 8 was examined according to the method described above. The result is shown in TABLE 16. moisturising effect texture of skin surface maintenance of moisturising effect COMPARISON 1 X X X EXAMPLE 78 o ○ o ○ o ○ EXAMPLE 79 o ○ o ○ o ○ EXAMPLE 80 o ○ o ○ o ○ As is clear from the TABLE 16, the external preparation for skin according to the example 78 to 80 had exellent skin care effect. EXAMPLE 81 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-acetylphenylester hydrochloride 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 82 CREAM weight % Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 moles) sorbitan monostearate 1.5 Propylene glycol 10.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenylphenylester hydrochloride 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 83 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-chlorophenylester hydrochloride 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 84 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-acetoaminophenylester hydrochloride 10.0 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 85 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monooleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-sulfamoylphenyl ester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzoylphenyl ester hydrochloride 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogen sulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 86 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-phenoxyphenylester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-formylphenylester hydrochloride 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 87 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-cyanophenylester hydrochloride 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 Dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 88 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-ethylphenylester hydrochloride 1.0 Trans-4-guanidinomethylcyclohexanecarboxylic acid 3',4'-dichlorophenylester hydrochloride 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. COMPOUND GROUP 9 (1) DEPIGMENTATION EFFECT The depigmentation effect of the compound group 9 was examined according to the method described above. The result is shown in TABLE 17. COMPOUND DEPIGMENTATION EFFECT COMPARISON 1 NONE X COMPARISON 2 HYDROQUINONE ▵ EXAMPLE 89 Trans-4-benzylideneaminomethyl cyclohexanecarboxylic acid o ○ EXAMPLE 90 Trans-4-(3',4'-dihydroxybenzylideneaminomethyl) cyclohexanecarboxylic acid o ○ EXAMPLE 91 Trans-4-(4'-nitrobenzylideneaminomethyl) cyclohexanecarboxylic acid o ○ As is clear from the TABLE 17, the external preparation for skin according to the example 89 to 91 could also suppress deposition of melanoic pigment and supress suntan. (2) SKIN CARE EFFECT The skin care effect of the compound group 9 was examined according to the method described above. The result is shown in TABLE 18. drying of skin wrinkle drying of skin in morning COMPARISON 1 X X X EXAMPLE 89 o ○ o ○ o ○ EXAMPLE 90 o ○ o ○ o ○ EXAMPLE 91 o ○ o ○ o ○ As is clear from the TABLE 18, the external preparation for skin according to the example 89 to 91 had exellent skin care effect. EXAMPLE 92 CREAM weight % Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerine mono stearate 3.0 Propylene glycol 10.0 Trans-4-(3',4',5'-trimethoxybenzylideneaminomethyl) cyclohexanecarboxylic acid 20.0 Caustic potash 0.2 Sodium hydrogensulfite 0.01 Antiseptic q.s. Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 4. EXAMPLE 93 CREAM weight % Stearic acid 6.0 Sorbitane monostearate 2.0 Polyoxyethylene (20 moles) sorbitanemonostearate 1.5 Propylene glycol 10.0 Trans-4-(3'-pyridylmethylideneaminomethyl) cyclohexanecarboxylic acid 7.0 Glycerine trioctanoate 10.0 Squalene 5.0 Sodium hydrogensulfite 0.01 Ethylparaben 0.3 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 5. EXAMPLE 94 CREAM weight % Stearyl alcohol 7.0 Stearic acid 2.0 Hydrogenated lanoline 2.0 Squalane 5.0 2-octyldodecyl alcohol 6.0 Polyoxyethylene (25 moles) cetyl alcohol ether 3.0 Glycerinemonostearate 2.0 Propylene glycol 5.0 Trans-4-(4'-isopropenylbenzylideneaminomethyl) cyclohexanecarboxylic acid 0.005 Perfume q.s. Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 6. EXAMPLE 95 MILKY LOTION weight % Stearic acid 2.5 Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 moles) monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Trans-4-(3',4'-dimethoxybenzylideneaminomethyl) cyclohexanecarboxylic acid 10.0 Sodium hydrogensulfite 0.01 Ethylparaben 0.3 Carboxyvinyl polymer 0.05 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 7. EXAMPLE 96 MILKY LOTION weight % (Oil phase) Stearyl alcohol 1.5 Squalene 2.0 Petrolatum 2.5 Deodorized liquid lanoline 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerine monoleate 2.0 Polyoxyethylene (60 moles) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethylparaben 0.2 Butylparaben 0.1 Trans-4-(4'-chlorobenzylideneaminomethyl) cyclohexanecarboxylic acid 1.0 Trans-4-(2'-methoxybenzylideneaminomethyl) cyclohexanecarboxylic acid 1.0 Perfume q.s. (Aqueous phase) Sodium hydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 8. EXAMPLE 97 JELLY weight % 95% ethyl alcohol 10.0 Dipropyleneglycol 15.0 Polyoxyethylene (50 moles) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda 0.15 L-arginine 0.1 Trans-4-(2'-hydroxybenzylideneaminomethyl) cyclohexanecarboxylic acid 1.0 Trans-4-(3'-trifluoromethylbenzylideneaminomethyl) cyclohexanecarboxylic acid 1.0 4-hydroxybenzoic acid methylester 0.2 Perfume q.s. Ion exchanged water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 9. EXAMPLE 98 LOTION weight % (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 moles) octyldodecanol 1.0 4-hydroxybenzoic acid methylester 0.15 Pantothenyl ethyl ether 0.1 Trans-4-(3'-carboxy-4'-hydroxybenzylideneaminomethyl) cyclohexanecarboxylic acid 0.05 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0 dipropyleneglycol 10.0 Sodium hydrogensulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 10. EXAMPLE 99 PACK weight% (A phase) Dipropyleneglycol 5.0 Polyoxyethylene (60 moles) hydrogenated castor oil 5.0 (B phase) Trans-4-(2'-nitrobenzylideneaminomethyl) cyclohexanecarboxylic acid 1.0 Trans-4-(3',4'-dihydroxybenzylideneaminomethyl) cyclohexanecarboxylic acid ethyl ester 1.0 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (C phase) Sodium hydrogensulfite 0.03 Polyvinyl alcohol (saponification degree 90, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water balance (Manufacturing method) The preparation with respect to the present example was prepared by the same method described in the explanation of example 11. As is clear from the above-described examples, the external preparations for skin including derivatives of tranexamic acid have excellent whitening effect as well as skin care effect.

Claims: An external preparation for skin including at least one tranexamic acid derivative of formula (A) wherein R 2 and R 3 are H; and R 1 is NR 4 R 5 , wherein R 4 and R 5 are the same or different and are H, C 1-18 alkyl, C 5-8 cycloalkyl, benzyl, or phenyl having 0 to 3 substituents selected from lower alkyl, lower alkoxy, OH, amino and halogen; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH or lower alkoxy; R 2 is H; and R 3 is R 6 CO wherein R 6 is alkyl, cycloalkyl, alkenyl, cycloalkenyl, pyridyl, CF 3 , phenyl substituted by 0 or more substituents selected from OH, alkoxy, amino and halogen, or 2-phenylethenyl in which the phenyl group is substituted by 0 to 3 OH or lower alkoxy substituents; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH; R 2 is H; and R 3 is an amino-acid residue; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH; R 2 is C 1-4 alkyl; and R 3 is H or C 1-4 alkyl; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH or lower alkoxy; R 2 is H; and R 3 is R 7 HNCO wherein R 7 is H, alkyl, cycloalkyl, aryl, aralkyl or -(CH 2 ) n COOR 8 wherein R 8 is H or lower alkyl and n = 1-8; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH, alkoxy, cycloalkoxy or aralkoxy; R 2 is H; and R 3 is HN=C(NH 2 )-; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is phenoxy substituted by -(CH 2 ) 0-2 COOR 9 wherein R 9 is H, lower alkyl, benzyl or phenyl; R 2 is H; and R 3 is HN=C(NH 2 )-; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is phenoxy substituted by 0 to 3 substituents selected from lower alkyl, lower alkoxy, alkanoyl, phenyl, halogen, trihalomethyl, nitro, acetoamino, carbamoyl, sulfamoyl, benzoyl, phenoxy, benzyloxy, formyl and cyano; R 2 is H; and R 3 is HN=C(NH 2 )-; or a salt thereof. An external preparation for skin including at least one tranexamic acid derivative of the formula shown in claim 1, wherein R 1 is OH, ONa or C 1-4 alkoxy; and R 2 and R 3 together are R 10 R 11 C= wherein R 10 is pyridyl, isopropenylphenyl, or phenyl substituted by 0 to 2 OH or methoxy groups and optionally also by OH, methoxy, halogen, nitro, CF 3 , carboxyl or and R 11 is H or C 1-10 alkyl; or a salt thereof. A cosmetic method for the treatment of skin, which comprises the topical administration of a preparation according to any preceding claim. Use of one or more derivatives as defined in any of claims 1 to 9, for the manufacture of the preparation for use in therapeutic treatment of the skin.

Inventors: AKIYAMA NAOE, KITAMURA KENJI, MORIKAWA YOSHIHIRO, OHNUMA MANAMI, SUETSUGU MASARU, YAMASE YUKI, AKIYAMA, NAOE, KITAMURA, KENJI, MORIKAWA, YOSHIHIRO, OHNUMA, MANAMI, SUETSUGU, MASARU, YAMASE, YUKI, Akiyama, Naoe, c/o Shiseido Res. Center, Kitamura, Kenji, c/o Shiseido Res. Center, Morikawa, Yoshihiro, c/o Shiseido Res. Center, Ohnuma, Manami, c/o Shiseido Res. Center, Suetsugu, Masaru, c/o Shiseido Res. Center, YAMASE, YUKI, C/O SHISEIDO RES. CENTER
Applicants: SHISEIDO CO LTD, SHISEIDO COMPANY LIMITED
Application year: 1993
Main classification: A61K7
IPC codes: A61K8, A61Q19