WO2006117995A1

WO2006117995A1 - Therapeutic agent for loss of scalp hair

Info

Publication number: WO2006117995A1
Application number: PCT/JP2006/307814
Authority: WO
Inventors: Kazumi Ogata; Chikanori Katano
Original assignee: Iwaki & Co., Ltd.; Oga Research, Incorporated
Priority date: 2005-04-28
Filing date: 2006-04-13
Publication date: 2006-11-09
Also published as: JP2008174453A

Abstract

A therapeutic agent for loss of scalp hair comprising a lipoic acid or a lipoic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient: (1) wherein R represents an OH group, an O-alkyl group, an N-linked amine, an N-linked amino acid or an N-linked peptide; and A represents a single bond or a metal M.

Description

Specification

Hair loss treatment

Technical field

[0001] The present invention relates to a treatment for hair loss comprising lipoic acid or a lipoic acid derivative, a method for treating hair loss by administering a compound thereof, and a method for producing a therapeutic agent for hair loss. It relates to the use of compounds.

Background art

[0002] Lipoic acid (also known as a-lipoic acid, thiotate or 6,8 dithiooctanoate) is a coenzyme present in mitochondria, and its reduced form includes oxidized dartathione and oxidized vitamin C. Has the effect of regenerating to reduced form. However, the reduced form of lipoic acid is very unstable in the air and quickly oxidizes to return to lipoic acid. Therefore, when it can come into contact with air (oxygen), it remains as a reduced form. I can't leave it!

[0003] First, the present inventor uses a derivative of lipoic acid and an amino acid as a reduced form (that is, a dihydro form in which an SS bond is cleaved), and chelates the metal to stabilize the reduced form. Successful and thus obtained compounds, ie, (6,8-dimercaptootatanyl) amino acid metal chelate compounds, have an antioxidant action, a free radical inhibitory action, a melanin production inhibitory action, and an elastase inhibitory action. Furthermore, it has also been found in an international application that it has a therapeutic Z-removing effect on spots, freckles, and moles (see Patent Document 1). The present inventor further added a metal chelate compound of 6,8-dimercaptooctanoic acid (and its derivatives with alcohols, amino acids, amines and peptides) to remove melanin such as stains, freckles, and moles. Is found in international applications (see Patent Document 2).

[0004] On the other hand, with regard to hair loss, the male hormone (testosterone) is transformed into 5a-dihydrotestosterone (5a-DHT) by the reducing action of an enzyme called 5a reductase present in the hair papilla and sebaceous glands. There is a known mechanism that 5a-DHT suppresses the division of hair matrix cells, and there is a theory that this causes hair loss. The theory that excessive secretion of sebum in the scalp promotes hair loss, that is, sebum on the scalp is air and light. It is oxidized by exposure to lipids, producing lipid peroxides and fatty acids, which also cause bacterial contamination, causing scalp and hair roots to become inflamed, which prevents seborrheic alopecia, which prevents hair matrix cells from dividing. There is also a theory that causes hair loss. It is possible that the processes indicated by these theories may occur simultaneously, and the synergistic action is thought to accelerate hair loss.

[0005] On the other hand, as a hair growth promoter, since minoxidil is a known hypotensive agent in recent years, there is a drawback in that it requires sufficient care for people with low blood pressure. Propecia, known as an internal medicine, is a novel drug that potently inhibits testosterone 5 reductase activity and promotes hair growth, but has a steroid skeleton and antagonizes similar to testosterone. Therefore, side effects related to sexual function have been reported, and as long as this is seen, human use is a problem.

Thus, there is a need for safer drugs for treating hair loss. Patent Document 1: WO2002 / 076935

Patent Document 1: WO2004 / 024139

Disclosure of the invention

Problems to be solved by the invention

[0006] Based on the above background, the present invention first aims to provide means for suppressing hair loss from the viewpoint of preventing hair loss from promoting hair growth. And For this purpose, the present inventor conducted research to find a substance that suppresses hair loss, and as a result, lipoic acid and its derivatives and their salts have the effect of inhibiting testosterone 5a reductase, The present invention has been completed through further investigations, which have been found to be effective in preventing hair loss.

Means for solving the problem

[0007] That is, the present invention provides the following.

1. The following formula 1,

[0008] [Chemical 1]

(Wherein R represents an OH group, an O alkyl group, an N-bonded amine, an N-bonded amino acid or an N-bonded peptide, and A represents a single bond or a metal M). A therapeutic agent for hair loss comprising a lipoic acid or lipoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The therapeutic agent for hair loss according to 1 above, wherein R is an O-lower alkyl group.

3. The therapeutic agent for hair loss according to 1 above, wherein R is an N-bonded amine.

4. The therapeutic agent for hair loss according to 1 above, wherein R is an N-linked amino acid.

5. The therapeutic agent for hair loss according to 1 above, wherein R is a N-bonded dipeptide.

6. The agent for treating hair loss according to 3 above, wherein the active ingredient is selected from the group consisting of lipoic acid amide, N lipoyl-2-aminoethanol, N-riboyl isopropylamine, N-riboyl melatonin and N-riboyl 2-aminoviridine.

7. The active ingredient is 6,8-dimercaptooctanoic acid amide metal chelate, N- (6,8-dimercaptootatanyl) 2 aminoethanol metal chelate, N- (6,8 dimercaptootatanyl) isopropylamine metal Chelate, N- (6,8-dimercaptootatanyl) melatonin metal chelate and N- (6,8 dimercaptootatanyl) 2 aminobilidine metal chelate The above 3 hair loss treatment

8. The therapeutic agent for hair loss according to the above 4, wherein the amino acid is selected from the group power of α-amino acid, ω amino acid, and special amino acid power.

9. The active ingredient is Ν— (6,8-dimercaptootatanyl) -a-amino acid metal chelate, N— (6,8-dimercaptootathanyl) ω amino acid metal chelate and Ν— ( 6,

8—Dimercapto otatanyl) The hair loss treatment agent according to 8 above, wherein a group power that also has a special amino acid metal chelate compound strength is selected.

10. The active ingredient is Ν reboylglycine, リボ reboylalanine, リポ lipoyl threonine, リポ lipoyl serine, Ν reboylaspartic acid, Ν reboyl glutamic acid, Ν -Riboylphenylalanine, N-riboylmethionine, N-riboylnorleucine, N-riboylleucine, N-riboylcystine, N-riboylproline, N-riboylhydride xyproline, N-riboylhistidine, N-riboylhydroxytryptophan, N-ri 8. The hair loss treatment agent according to 8 above, wherein the group power consisting of boiled-silamine and N lipoyllysine is also selected.

11. The active ingredient is N lipoyl-3-aminopropionic acid, N lipoyl-4-aminobutyric acid, N-riboyl-6-aminohexanoic acid, N-riboyl-4-transaminomethyl-1-cyclohexanecarboxylic acid, N-riboyl mono 8. The hair loss treatment agent according to 8 above, which is selected from the group consisting of 2-aminoethanesulfonic acid, N lipoylsulfuric acid and N lipoylanthral acid.

12. The active ingredient is N— (6,8 dimercaptootatanyl) glycine metal chelate, N- (6,8-dimercaptootatanyl) alanin metal chelate, N— (6,8-dimercaptootatanyl) ) Threonine metal chelate, N— (6,8-dimercaptootatanyl) serine metal chelate, N— (6,8-dimercaptootatanyl) aspartate metal chelate, N— (6,8— Dimercaptootatanyl) glutamic acid metal chelate, N— (6,8-dimercaptooctanoyl) ferroalanine metal chelate, N— (6,8-dimercaptootatanyl) methionine metal chelate, N— (6, 8—Dimercaptootatanyl) norleucine metal chelate, N— (6,8-dimercaptootatanyl) cystine metal chelate, N— (6,8-dimethylcaptootatanyl) hydroxypro Metal chelate, N— (6,8-dimercaptootatanyl) histidine metal chelate, N— (6,8-dimercaptootathanyl) -5—hydroxytryptophan metal chelate, N— (6,8— 9. The hair loss treatment according to 9 above, wherein dimercaptootatanyl) pesilamine metal chelate and N— (6,8-dimercaptootatanyl) lysine metal chelate compound are also selected. Agent.

13. The active ingredient is N— (6,8 dimercaptootatanyl) 3 aminopropionic acid metal chelate, N— (6,8 dimercaptootatanyl) -4-aminobutyric acid metal chelate, N— (6,8-dimercaptootathanyl) 6-aminohexanoic acid metal chelate, N— (6,8 dimercaptootathanyl) 4 transaminomethyl 1 cyclohexanecarboxylic acid metal chelate, N— ( 6, 8 Dimercaptootatanyl) 2 Aminoethanesulfonic acid Selected from the group consisting of metal chelates, N— (6,8-dimercaptootatanyl) sulfuric acid metal chelates and N— (6,8-dimercaptootatanyl) anthral acid metal chelates 9. The hair loss treatment agent according to 9 above.

14. The therapeutic agent for hair loss as described in 5 above, wherein the active ingredient is selected from the group force that also has N-riboylparasylglycine and N-lipoylreo-leuglycine power.

15. The active ingredient is N- (6,8-dimercaptootatanyl) aspatiruglycine metal chelate and N- (6,8-dimercaptootatanyl) threoglycine metal chelate 5. The hair loss treatment agent according to 5 above, wherein a group strength that can be combined is selected.

16. Metallic hair S sub-10, 1, 2, 3, 4, 5, 7, 8, 9, 12, 13 and 15!

17. The therapeutic agent for hair loss according to any one of 1 to 16, which is an external preparation for skin.

18. The hair loss treatment agent according to 17 above, which is a hair styling agent or a hair wash.

[0010] The present invention also provides a method for preventing human hair loss and a therapeutic agent for hair loss comprising applying an effective amount of the active ingredient defined in 1 to 16 above to the human scalp surface. Also provided is the use of an active ingredient as defined in 1-16 above for the manufacture.

The invention's effect

[0011] The hair loss treatment agent of the present invention exhibits an excellent therapeutic effect on human hair loss.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] A method for synthesizing lipoic acid and a lipoic acid derivative contained in the therapeutic agent for scalp hair loss of the present invention is described below.

[0013] [Chemical 2]

[Wherein, R is as defined above. ]

[0015] The present inventors reduced lipoic acid or lipoic acid amide with zinc and acetic acid (or hydrochloric acid), respectively, as a lipoic acid derivative, to obtain a 6,8-dimercaptooctanoic acid zinc chelate and 6, 8 —Dimercaptooctanoic acid zinc chelate compound was synthesized. Further, 6,8-dimercaptooctanoic acid ethyl ester dumbbell chelate was obtained by reducing lipoic acid ethyl ester in the same manner. In addition, N— (6,8-dimercaptootatanyl) amine zinc chelate, N— (6,8-dimercaptootatanyl) amino acid zinc chelate or N— (6,8-dimercaptoocta) (Neyl) peptide zinc chelate is prepared by first dissolving lipoic acid in chloroform or acetonitrile to couple amines, amino acids or peptides by mixed acid anhydride method using chloroethyl carbonate in the presence of triethylamine. N-riboylamines, N-riboylamino acids or N-riboyl peptides were obtained. In addition, when these are reduced with zinc and acetic acid (or hydrochloric acid) to obtain each zinc chelate compound, and further converted into an alkali salt, the free acid is dissolved or suspended in water and placed in water. After neutralizing with an acid-alkali solution, the solution is concentrated and then concentrated, and an alcohol is added, and the precipitated crystals are collected by filtration to obtain an alkali salt of each zinc chelate compound in high yield.

[0016] As the metal of the metal chelate compound of the present invention, zinc, cobalt, iron, germanium, and selenium are listed. Of these, zinc is preferable.

In the present invention, regarding the substituent R, as the “lower alkyl”, those having 1 to 6 carbon atoms are preferred, those having 1 to 4 carbon atoms are more preferred, and those having 1 to 3 carbon atoms are particularly preferred. preferable.

[0018] Examples of the pharmacologically acceptable salt of the present compound include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt. Any salt can be appropriately used for the purpose of the present invention as long as it is a pharmacologically acceptable salt.

[0019] The reduced form of lipoic acid or lipoic acid derivative, ie, 6,8-dimercaptooctanoic acid or its derivative, is chelated with a force metal that is very unstable in air, such as zinc. As a result, it becomes a six-membered ring and becomes a stable compound with good crystallinity. Furthermore, these compounds are excellent compounds that have a strong reducing action and radical inhibiting action, and that have no safety problems. [0020] In animal safety studies of this compound, for example, N— (6,8 dimercaptootatanyl) L histidine sodium zinc chelate compound, oral acute toxicity is 2gZkg or more, and 10% aqueous solution As a result of conducting an application for quasi-drugs such as dermal administration, no problems were found.

[0021] The use of the hair loss preventing agent of the present invention is simple and the effect is remarkable. That is, lipoic acid or a lipoic acid derivative may be applied to the scalp, for example, mixed with a hairdressing agent. When observing the healing effect, the hair loss of the scalp, which had been removed by shampooing until now, was stopped by applying this compound, about 0.3% aqueous solution for about 1 month, and in particular, the case of remarkable cases Even if the hair near the coated area was pulled lightly, no hair loss was observed, and the hair roots were long and persistent, thus showing a healing effect.

[0022] The present compound, for example, N- (6,8 dimercaptootatanyl) -L-histidine sodium. Zinc chelate or 6,8-dimercaptooctanoic acid monoethanolamine. When a tonic containing 3 (wZv)% is applied to a subject once or twice a day for 1 month, hair loss is extremely reduced, and a satisfactory effect is obtained. No wrinkle phenomenon was observed, and a significant scalp hair removal healing effect was shown.

[0023] The present compound can also be used in the form of a hair styling agent (hair artic, hair liquid, hair gel, aqueous spray, etc.) and a hair shampoo (shampoo, rinse, etc.).

[0024] The concentration of the present compound used is, for example, in the case of aqueous tonic and aqueous spray, usually 0.001 to 5 (wZv)%, preferably 0.01 to L 0 (wZv)%. In the case of hair gel, it is usually from 0.001 to 5 (wZw)%, preferably from 0.01 to: L 0 (wZw)%, and also from shampoo, rinse, etc., preferably from 0.001 to 0.5 (wZv)%.

[0025] In addition, the therapeutic agent for hair loss of the present invention usually includes other ingredients used for hair nourishing agents, hair restoration agents, hair growth agents, as well as excipients, pigments, fragrances, ultraviolet absorbers, gelling agents, You may mix | blend antioxidant, surfactant, a stabilizer, antiseptic | preservative, etc. suitably.

[0026] The therapeutic agent for scalp hair loss of the present invention may contain one or more of the compounds according to the purpose and necessity as appropriate.

Example

[0027] Next, the present invention will be described in more detail with reference to reference examples, test examples, and examples. It is not intended that the invention be limited by these examples.

[0028] Reference Example 1: 6, 8 Sodium dimercaptooctanoate / zinc chelate compound

DL-a-lipoic acid 6.2g was dissolved in methanol 70mL, zinc powder 3.Og and 1N-hydrochloric acid 40mL were added, and it stirred at 50 degreeC for 1 hour. Next, zinc in the end reaction was filtered off, and the filtrate was concentrated under reduced pressure, and water was added to this, and the precipitated white crystals were collected by filtration. This was suspended in 150 mL of water, dissolved in 2N sodium hydroxide to a pH of about 9, the insoluble matter was filtered off, the filtrate was concentrated, ethanol was added to this, and the precipitated white crystals were collected by filtration. Recrystallization from water Z ethanol Nore force, mp. 300 ° C or more, 6. Og was obtained. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2). Also, instead of sodium hydroxide, using monoethanolamine, 6, 8 Dimercaptooctanoic acid 'zinc chelate. Monoethanolamine salt mp. 1 37-139. C, 8.5 g was obtained.

[0029] Reference Example 2: 6, 8 Ethyl dimercaptooctanoate 'Zinc chelate compound

DL-a-Ethyl lipoic acid 3.5g was dissolved in 60mL of tetrahydric furan, and 2.Og of zinc powder and 40mL of 70% acetic acid aqueous solution were added to it and stirred at 50 ° C for 2 hours. The filtrate was concentrated, and water was added to the filtrate. The precipitated white crystals were collected by filtration, recrystallized from acetic acid Z water, and gradually decomposed from around 290 ° C. Got. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2)

[0030] Reference Example 3: 6, 8 Dimercaptooctanoic acid amide 'Zinc chelate compound

DL-a-lipoic acid amide 4.2g was dissolved in tetrahydride furan 70mL, and zinc powder 2.5g and 50% acetic acid aqueous solution 30mL were added to this and stirred at 50 ° C for 2 hours to distill off the solvent. Thereafter, the precipitated crystals containing zinc were collected by filtration, washed with water and ethanol, and recrystallized from acetic acid Z water to obtain mp. 257-259 ° C., white crystals, 4.5 g. TLC, Rf = 0.80 (n-butanol: acetic acid: water = 4: 1: 2)

[0031] Reference Example 4: N— (6, 8 Dimercaptootatanyl) glycine sodium 'zinc chelate compound

DL-a Lipoic acid 4.2g and glycine 1.9g were used for N-a-riboylglycine sodium (mp. 218-220 ° C) and the target compound, mp. 3.9 g of white crystals were obtained. TLC, Rf = 0.64 (black mouth form: methanol: water = 5: 4: 1). [0032] Reference Example 5: N— (6, 8 Dimercaptootatanyl) monosodium aspartate 'Zinc chelate compound

DL-a Lipoic acid 4.2g and L-aspartic acid 2.9g, N-a-riboylaspartate sodium (mp. 300 ° C or more), the target compound, mp. 4.2 g of crystals were obtained. TLC, Rf = 0.53 (black mouth form: methanol: water = 5: 4: 1).

[0033] Reference Example 6: N— (6,8 Dimercaptootatanyl) methionine sodium 'zinc chelate compound

DL-a Lipoic acid 4.2g and L-methionine 3.5g, N-a-riboylmethionine (mp. 108-109 ° C), target compound, mp. White crystals decomposed from around 260 ° C 2. 8g was obtained. TLC, Rf = 0.82 (n-butanol: acetic acid: water = 4: 1: 2).

[0034] Reference Example 7: N— (6, 8 Dimercaptootatanyl) cystine 'zinc chelate compound

Using DL-a-lipoic acid 4.2g and L cysteine 2.6g, N-a-riboylcystine sodium (mp. Decomposes force near 150 ° C), then target compound, mp. Near 280 ° C. White crystals 4. lg were obtained. TLC, Rf = 0.71 (black mouth form: methanol: water = 5: 4: 1).

[0035] Reference Example 8: N— (6, 8 Dimercaptootatanyl) ferro-lanalanine sodium 'zinc chelate compound

Using DL-a-lipoic acid 4.2g and L-ferallanine 3.5g, through N-a-lipo-ferallanin (mp.154-156 ° C), the target compound, mp. Around 270 ° C Yielded 3.9 g of decomposed white crystals. TLC, Rf = 0.82 (n-butanol: acetic acid: water = 4: 1: 2

) o

[0036] Reference Example 9: N— (6,8 Dimercaptootatanyl) 4 Sodium aminoaminobutyrate 'Zinc chelate compound

Using DL-a-lipoic acid 4.2g and 4-aminobutyric acid 2.3g, N-a-riboyl-4-aminobutyric acid (mp. Decomposes force near 235 ° C), the target compound, mp. 297 ° From around C, 5.2 g of decomposed white crystals were obtained. TLC, Rf = 0.70 (black mouth form: methanol: water = 5: 4: 1). [0037] Reference Example 10: N— (6,8 dimercaptootatanyl) 6 sodium aminohexanoate 'zinc chelate compound

DL-a-Lipoic acid 4.2g and 6-amino hexanoic acid 3.Og, Na-a-lipoyl 6-amino hexanoic acid sodium (mp. 200-202 ° C), the target compound, mp Decomposed white crystals from around 295 ° C 2. Og was obtained. TLC, Rf = 0.84 (black mouth form: methanol: water = 5: 4: 1).

[0038] Reference Example 11: N— (6, 8 Dimercaptootatanyl) sodium anthralate 'zinc chelate compound

Using DL-a-lipoic acid 4.2g and anthrallic acid 2.9g, N-a-lipoyl anthroleate sodium (mp. 300 ° C or higher), the target compound, mp. 290 ° C Dissolved white crystals 2. lg were obtained from the vicinity. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2).

[0039] Reference Example 12: N— (6,8 Dimercaptootatanyl) 2 Sodium Aminoethanesulfonate 'Zinc Chelate Compound

Using DL-a-lipoic acid 6.2g and 2aminoethanesulfonic acid 4.5g, N-α-riboylaminoethanesulfonic acid sodium (mp. 235-237 ° C), the target compound, mp. Decomposed white crystals (4.5 g) were obtained from around 293 ° C. TLC, Rf = 0.51 (n-butanol: acetic acid: water = 4: 1: 2).

[0040] Reference Example 13: N— (6, 8 Dimercaptootatanyl) hydroxyproline sodium / lead chelate compound

From 4.2 g of DL-α lipoic acid and 2.8 g of L-4 hydroxyproline, the target compound, mp. TLC, Rf = 0.66 (n-butanol: acetic acid: water = 4: 1: 2).

[0041] Reference Example 14: N— (6,8 dimercaptootatanyl) histidine sodium 'zinc chelate compound

DL-α-lipoic acid 4.2 g and L histidine 3.4 g were used to obtain the desired compound, mp. 300 ° C. or more, and 5.8 g of white crystals. TLC, Rf = 0.39 (n-butanol: acetic acid: water = 4: 1: 2).

[0042] Reference Example 15: N— (6,8 dimercaptootatanyl) sodium glutamate 'zinc chelate compound — 4.2 g of α-lipoic acid and 3.5 g of gnoretamic acid were obtained, and mp. 300 ° C. or more and 5.7 g of white crystals were obtained. TLC, Rf = 0.74 (n-butanol: acetic acid: water = 4: 1: 2)

[0043] Reference Example 16: N— (6, 8 dimercaptootatanyl) threonine sodium zinc 'chelate compound

DL-α-lipoic acid (4.2 g) and L-threonine (2.6 g) were mixed with the objective compound, mp. TLC, Rf = 0.73 (n-butanol: acetic acid: water = 4: 1: 2).

[0044] Reference Example 17: N— (6,8 dimercaptootatanyl) alanine sodium zinc ′ chelate compound

DL-α-lipoic acid 4.2 g and L-alanin 2. lg force and other compounds were decomposed from mp. Around 290 ° C to obtain 5.4 g of white crystals. TLC, Rf = 0.78 (n-butanol: acetic acid: water = 4: 1: 2).

[0045] Reference Example 18: N— (6,8 Dimercaptootatanyl) serine sodium 'zinc chelate compound

DI ^ -. Α-lipoic acid 4. 2g your J beauty Serin 2.4g force et al purpose I spoon product, mp 285 ^Q C I dimensions near the power et al gradually decomposition, to obtain a white crystal 5. Og. TLC, Rf = 0.64 (n-butanol: acetic acid: water = 4: 1: 2).

[0046] Reference Example 19: N— (6,8 Dimercaptootatanyl) norleucine sodium 'zinc chelate compound

DL-a Lipoic acid 4.2g and L-norleucine 3. Og to obtain N-a-riboylnorleucine (mp. 120-121 ° C), gradually decomposed from the target compound, mp. White crystals 5. lg were obtained. TLC, Rf = 0.90 (n-butanol: acetic acid: water = 4: 1: 2).

[0047] Reference Example 20: N— (6, 8 dimercaptootatanyl) 5-hydroxytryptophanium thorium zinc chelate compound

DL-α-lipoic acid 4.2 g and L-5 hydroxytryptophan 5. Og force and target compound, mp. TLC, Rf = 0.81 (n-butanol: acetic acid: water = 4: 1: 2).

[0048] Reference Example 21: N— (6, 8 Dimercaptootatanyl) persilamine sodium Compounds

DL-α-lipoic acid 4.2 g and D penicillamine 3.5 g force, compound, mp. White crystals gradually decomposed from around 280 ° C. 6. Og was obtained. TLC, Rf = 0.80 (n-butanol: acetic acid: water = 4: 1: 2).

[0049] Reference Example 22: N— (6,8 dimercaptootatanyl) 3 sodium aminoaminopropionate 'zinc chelate compound

DL-a Lipoic acid 4.2g and j8-end lanine 2. Og strength and target compound, mp. TLC, Rf = 0.83 (n-butanol: acetic acid: water = 4: 1: 2).

[0050] Reference Example 23: N— (6,8 dimercaptootatanyl) -4 transaminomethyl-1 sodium cyclohexanecarboxylate. Zinc chelate compound

The target compound was gradually decomposed from DL-a lipoic acid (4.2 g) and 4-transaminomethylcyclohexanecarboxylic acid (3.5 g), and mp. TLC, Rf = 0.81 (n-butanol: acetic acid: water = 4: 1: 2).

[0051] Reference Example 24: N— (6,8 dimercaptootatanyl) sodium sulfarate 'zinc chelate compound

—Hypolipoic acid (4.2 g) and snolephaninolic acid (3.8 g). The desired compound, mp. 300 ° C. or more, and white crystals (5.4 g) were obtained. TLC, Rf = 0.57 (n-butanol: acetic acid: water = 4: 1: 2)

[0052] Reference Example 25 N— (6,8 Dimercaptootatanyl) isopropylamine 'zinc chelate compound

DL—α-Lipoic acid 4.2 g and triethylamine 2.4 g were dissolved in 50 mL of acetonitrile and cooled to −5 ° C. with stirring. To this, 2.4 g of chloroethyl carbonate was gradually added dropwise. Then, 1.5 g of isopropylamine dissolved in 30 mL of acetonitrile was rapidly added, and the mixture was further stirred for 30 minutes, returned to room temperature, and stirred for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue and the mixture was cooled. The precipitated pale yellow crystals were collected by filtration, dissolved in 60 mL of tetrahydrate-furan (THF), dissolved in 20 mL of 50% acetic acid aqueous solution and zinc. After adding 2.0 g of powder and stirring at 50 ° C for 2 hours, zinc in the powder was filtered off and the filtrate was concentrated. . Water was added to the residue, and the precipitated white crystals were collected by filtration and recrystallized from THFZ acetic acid Z water to obtain mp. 271-273 ° C., target compound 5. Og. TLC, Rf = 0.89 (n-butanol: acetic acid: water = 4: 1: 2).

[0053] Reference Example 26: N— (6,8 dimercaptootatanyl) 2 aminoethanol 'zinc chelate compound

By using 4.2 g of DL-α-lipoic acid and 1.5 g of monoethanolamine, 4.2 g of the target compound, mp. TLC, Rf = 0.77 (n-butanol: acetic acid: water = 4: 1: 2)

[0054] Reference Example 27: N— (6,8 dimercaptootatanyl) melatonin 'zinc chelate compound

DL-α Lipoic acid 4.2 g and melatonin 4. Og were used to obtain the desired compound, mp. 210-212 ° C, 6.5 g of white crystals. TLC, Rf = 0.84 (n-butanol: acetic acid: water = 4: 1: 2

) o

[0055] Reference Example 28: N— (6,8 dimercaptootatanyl) 2 aminoviridine 'zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 2.2 g of 2 aminoviridine, the target compound, mp. 2 43-245 ° C., 5.3 g of white crystals was obtained. TLC, Rf = 0.87 (n-butanol: acetic acid: water = 4: 1: 2).

[0056] Reference Example 29: N— (6,8 Dimercaptootatanyl) anthral-ethyl ethoxide 'zinc chelate compound

Using 4.2 g of DL-α-lipoic acid and 3.6 g of anthra-ethyl ethylate, white crystals (recrystallized from THF acetic acid monohydrate), mp. . TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2).

[0057] Reference Example 30: N ^E — (6, 8 Dimercaptootatanyl) lysine 'zinc chelate compound

DL-a-Lipoic acid 4.2g, triethylamine 2.4g and chloroethyl carbonate 2.4g were mixed in 50mL of acetonitrile with cooling to a mixed acid anhydride, and this was mixed with L lysine 3.lg, copper sulfate (pentahydrate) 5) and sodium hydroxide 2. Add a solution of Og dissolved in 60mL of water to allow the reaction, and precipitate the copper salt of N ^E- (a-riboyl) lysine by filtration and wash with water and methanol. After that, suspend it in a 70% acetic acid solution and place the copper sulfide with hydrogen sulfide. The filtrate was concentrated, and methanol was added to the residue, and the precipitated pale yellow crystals were collected by filtration, mp. 254-255. C, 3.5 g was obtained.

[0058] Next, this was dissolved in a 60% aqueous acetic acid solution, and zinc powder 2. Og was added, stirred at 50 ° C for 3 hours, and the zinc was filtered off and concentrated. Methanol was added thereto. The precipitated white crystals were collected by filtration to obtain 3.4 g of the objective compound gradually decomposed from around mp. TLC, Rf = 0.47

(n-butanol: acetic acid: water = 4: 1: 2).

[0059] Reference Example 31: N— (6,8 Dimercaptootatanyl) vastylglycine dynatrium 'Zinc chelate compound

DL-α-Lipoic acid 2. lg and L-parasityl glycine 2.lg. The product gradually decomposed from around 270 ° C to obtain 3.lg of white crystals. TLC, Rf = 0.54 (n-butanol: acetic acid: water = 4: 1: 2).

[0060] Reference Example 32: N— (dimercaptootatanyl) throle-glycine sodium 'zinc chelate compound

Using DL-α-lipoic acid 2. lg and L-suleol-glycine 2. lg, the target compound, mp. Was gradually decomposed from around 260 ° C. to obtain 2.6 g of pale yellowish white crystals. TLC, Rf = 0.60 (n-butanol: acetic acid: water = 4: 1: 2).

[0061] Example 1: Evaluation of testosterone 5α reductase activity inhibitory action

[Test sample]

Test sample 1: Lipoic acid (molecular weight 206. 33)

Test sample 2: N-a-riboylaminoethanesulfonic acid sodium salt (molecular weight 335. 45) (compound of Reference Example 12)

Test sample 3: 6,8-dimercaptooctanoic acid 'zinc monoethanolamine salt (molecular weight 3 32. 79) (compound of reference example 1)

Test sample 4: N— (6,8-dimercaptootatanyl) —L histidine 'zinc sodium (molecular weight 430.84) (compound of reference example 14)

[0062] [Test method]

4.2 mg / mL test step prepared with propylene glycol in a V-bottom test tube with a lid. Ron 20 μL, 825 L of 5 mmol / mL Tris—HC1 buffer (pH 7.13) containing Img / mL NADPH was mixed. Add 80 L of test sample and S-9 * ¹ 75 L prepared with ethanol, 50% ethanol or purified water, and mix again at 37 ° C for 30 minutes. To stop the reaction. This was centrifuged (1,600 × g, 10 minutes), and the methylene chloride layer was analyzed by gas chromatography under the following conditions. A blank test was conducted in the same manner.

Note l) S-9: Rat liver testosterone 5a reductase. The testosterone conversion rate is about 70% at 37 ° C and 30 minutes under the above test conditions.

[0063] Gas chromatographic analysis of 3 m androstanediol, dihydrotestosterone (DHT) and testosterone standard methylene chloride solution was performed in advance in the same manner. The amount of the compound per area was calculated, and the concentrations per peak area of 3α-androstanediol, dihydrotestosterone (DHT), and testosterone after the reaction with S-9 were determined (Formula 1). Then, the conversion rate of the test sample was calculated according to Equation 2. Based on this conversion rate, the testosterone 5 a-reductase activity inhibitory action was determined according to Equation 3.

[0064] (Formula 1) Concentration (%) = Test Sample Peak Area X Standard Product Concentration Z Standard Product Peak Area

(Expression 2) Conversion rate (%) = (A + B) Z (A + B + C)

In addition,

Α: 3 α Androstanediol concentration

Β: Concentration of dihydrotestosterone (DHT)

C: Testosterone concentration

(Formula 3) Testosterone 5 a—reductase activity inhibition rate (%) = (1 -E / D) X 100

In addition,

D: Conversion rate in blank test

E: Conversion rate with addition of test sample

[0065] [Gas chromatography conditions]

Equipment used: Shimadzu GC-7A

Column: DB—1701 (θ. 53mm X 30m, film thickness. O ^ m) Column Z injection temperature: 240 ° C / 300 ° C

Detector: FID

Carrier gas: Nitrogen gas

[0066] [Results and Discussion]

The results are shown in the following table.

[0067] [Table 1]

Testosterone 5 Reductase activity inhibitory action

[0068] As shown in the table, test sample 1 (lipoic acid), test sample 2 (N-a-riboylaminoethanesulfonic acid Na), test sample 3 (6,8-dimercaptooctanoic acid zinc monoethanol) (Ammine salt) showed a very strong testosterone 5 a-reductase activity inhibitory action. In addition, test sample 4 (N- (6,8-dimercaptootatanyl) L histidine zinc sodium) showed a tendency that the testosterone 5a reductase activity inhibitory effect increased as the concentration decreased.

[0069] Test example: Evaluation of hair loss inhibitory action

For males aged 60-60 years, who are daily experiencing hair loss, the preparation of Formulation Example 1 was toniced once a day after washing the hair, and evaluated one month later. The results are shown in the following table.

[0070] [Table 2]

Table 2. Evaluation of hair loss inhibition

As shown in the table, a decrease in hair loss was observed in 4 out of 5 (80%), of which 2 The decrease was significant. This result indicates that lipoic acid and lipoic acid derivatives have a therapeutic effect on hair loss (suppression of hair loss).

[0072] Formulation Example 1 Hair Nick

Compound of Reference Example 14 0.3 g

Canoleboxyvininole polymer 0.lg

Glycerin 3.5g

Ethanore 5mL

Methyl p-oxybenzoate 0.02 g

p-Oxypropyl benzoate 0. Olg

Monoethanolamine .... Adjust to pH 8.5 by adding appropriate amount.

All sterilized purified water lOOmL

[0073] Formulation Example 2 Hair Nick

Compound of Reference Example 1 0.3g

β Ammonium glycyrrhetinate 0.lg

Pantotenino Reano Conoret 0.2 g

Nicotinamide 0.2 g

Carboxybule polymer sodium '··· 0.lg

Propylene glycolate 3. Og

1—Menthol Nore 0. 05g

Methyl p-oxybenzoate 0.02 g

p-Oxypropyl benzoate 0. Olg

All sterilized purified water lOOmL

[0074] Formulation Example 3 Hair Nick

Compound of Reference Example 14 0.3 g

Tocopherol, ascorbic acid phosphate

Dieste / Le Potassium 0. 05g

Allantoin 0.2 g

Pyridoxine hydrochloride 0.3 g Hinokichionore 0. 05g

Propylene glycolate 3. Og

Polyoxyethylene cetyl ether 0.5g

Carboxybule polymer sodium '· · · 0.05 g

Methyl p-oxybenzoate 0.05 g

p-Oxypropyl benzoate 0.02 g

Ethanore 5mL

All sterilized purified water lOOmL

Industrial applicability

The hair loss treatment agent containing the compound of the present invention exhibits an excellent hair loss inhibitory effect and has high utility as a hair loss treatment agent.

Claims

Claim [1] The following formula (1),

[Chemical 1]

(In the formula, R represents an OH group, an O alkyl group, an N-bonded amine, an N-bonded amino acid or an N-bonded peptide, and A represents a single bond or a metal M). A therapeutic agent for hair loss comprising the lipoic acid or lipoic acid derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient.

[2] The therapeutic agent for hair loss according to claim 1, wherein R is an O-lower alkyl group.

[3] The therapeutic agent for hair loss according to claim 1, wherein R is an N-bonded amine.

[4] The therapeutic agent for hair loss according to claim 1, wherein R is an N-linked amino acid.

[5] The therapeutic agent for hair loss according to claim 1, wherein R is a N-bonded dipeptide.

[6] The active ingredient is selected from the group consisting of lipoic acid amide, N-riboyl-2-aminoethanol, N-riboylisopropylpyramine, N-riboylmelatonin and N-riboyl-2-aminoviridine. A treatment for hair loss.

[7] The active ingredient is 6,8-dimercaptooctanoic acid metal chelate, N— (6,8-dimercaptootatanyl) 2 aminoethanol metal chelate, N- (6,8 dimercaptootatanyl) Isopropylamine metal chelates, N- (6,8-dimercaptootatanyl) melatonin metal chelates and N- (6,8 dimercaptootatanyl) 2 aminoviridine metal chelates The therapeutic agent for hair loss according to claim 3, which is selected.

[8] The therapeutic agent for hair loss according to claim 4, wherein the amino acid is selected from the group power of a-amino acid, ω-amino acid, and special amino acid power.

[9] The active ingredient is Ν— (6,8-dimercaptootatanyl)-a-amino acid metal chelate, N- (6,8-dimercaptootathanyl) ω amino acid metal chelate and Ν— ( 6, 8

The therapeutic agent for hair loss according to claim 8, wherein a group strength that is also a special amino acid metal chelate compound is selected.

[10] The active ingredient is N-riboylglycine, N-riboylalanine, N-lipoylthreonine, N-lipoylserine, N-riboylspartate, N-riboylglutamate, N-riboylphenylalanine, N-riboylmethionine, N Group power consisting of riboyl norleucine, N lipoylleucine, N riboylcystine, N riboylproline, N riboylhydroxyproline, N riboylhistidine, N riboylhydroxytryptophan, N lipoylpe-silamine and N lipoyllysine The therapeutic agent for hair loss according to claim 8, wherein

[11] The active ingredient is N-riboyl-3-aminopropionic acid, N-riboyl-4-aminobutyric acid, N-riboyl-6-aminohexanoic acid, N-riboyl-4-transaminomethyl-1-cyclohexanecarboxylic acid, N lipoyl The therapeutic agent for hair loss according to claim 8, which is selected from the group consisting of 2-aminoethanesulfonic acid, N-riboylsulfuric acid and N-lipoylanthral acid.

[12] The active ingredient is N— (6,8 dimercaptootatanyl) glycine metal chelate, N— (6,8-dimercaptootatanyl) alanine metal chelate, N— (6,8-di) Mercaptooctaneyl) threonine metal chelate, N— (6,8-dimercaptootatanyl) serine metal chelate, N— (6,8-dimercaptootatanyl) aspartate metal chelate, N— ( 6,8-dimercaptootatanyl) glutamic acid metal chelate, N— (6,8-dimercaptooctanoyl) ferrolanine metal chelate, N— (6,8-dimercaptootatanyl) methionine metal chelate, N- (6,8-Dimercaptootatanyl) norleucine metal chelate, N— (6,8-dimercaptootatanyl) cystine metal chelate, N— (6,8-dimercaptootatanyl) Hydroxyproline Metal chelates, N— (6,8-Dimercaptooctaylol) histidine metal chelates, N— (6,8—Dimercaptootatanol) 5—Hide mouth Xyltryptophan metal chelates, N— (6,8— 10. The group power consisting of dimercaptootatanyl) per-silamine metal chelate and N— (6,8-dimercaptootatanyl) lysine metal chelate compound is also selected. A treatment for hair loss.

[13] The active ingredient is N— (6,8 dimercaptootatanyl) 3 aminopropionate metal chelate, N— (6,8-dimercaptootatanyl) -4-aminobutyric acid metal chelate, N — (6,8-Dimercaptootatanyl) 6-Aminohexanoic acid metal chelate, N— (6,8-di Mercaptootatanyl) -4 transaminomethyl-1-cyclohexanecarboxylic acid metal chelate, N- (6,8 dimercaptootatanyl) 2 aminoethanesulfonic acid metal chelate, N- (6,8— The hair loss according to claim 9, wherein a group force comprising dimercaptootatanyl) sulfuric acid metal chelate and N- (6,8-dimercaptootatanyl) anthral acid metal chelate is also selected. Therapeutic agent.

[14] The therapeutic agent for hair loss according to claim 5, wherein the active ingredient is selected to be a group force that also has N-riboylparasylglycine and N-lipoylthreo-glycine power.

[15] The active ingredient is N— (6,8-dimercaptootatanyl) aspatiruglycine metal chelate and N— (6,8-dimercaptootathanyl) throle-glycine metal chelate compound The therapeutic agent for hair loss according to claim 5, which is selected from a group force consisting of things.

[16] The therapeutic agent for hair loss according to claim 1, 2, 3, 4, 5, 7, 8, 9, 12, 13 and 15, wherein the metallic strength is S.

[17] The therapeutic agent for hair loss according to any one of claims 1 to 16, which is an external preparation for skin.

[18] The hair loss treatment agent according to claim 17, which is a hair styling agent or a hair wash.

[19] The following equation (1),

[Chemical 2]

(In the formula, R represents an OH group, an O alkyl group, an N-bonded amine, an N-bonded amino acid or an N-bonded peptide, and A represents a single bond or a metal M). A method for preventing human hair loss comprising applying an effective amount of lipoic acid or a lipoic acid derivative or a pharmaceutically acceptable salt thereof represented by the above to the surface of the human scalp

[20] The method for preventing human hair loss according to claim 19, wherein R is an O-lower alkyl group.

21. The method for preventing human hair loss according to claim 19, wherein R is an N-bonded amine.

[22] The method for preventing human hair loss according to claim 19, wherein R is an N-linked amino acid.

[23] The method for preventing human hair loss according to claim 19, wherein R is an N-linked dipeptide.

24. The group of claim 21, wherein the active ingredient is selected from the group consisting of lipoic acid amide, N lipoyl-2-aminoethanol, N-riboylisopropylpyramine, N-riboylmelatonin and N-riboyl-2-aminoviridine. How to prevent human hair loss.

[25] The active ingredient is 6,8 dimercaptooctanoic acid amide metal chelate, N- (6,8 dimercaptootatanyl) 2 aminoethanol metal chelate, N- (6,8 dimercaptootatanyl) isopropylamine Metal chelates, N- (6,8-dimercaptootatanyl) melatonin metal chelates and N- (6,8 dimercaptootatanyl) 2 aminoviridine metal chelate compounds The method for preventing human hair loss according to claim 21, wherein the method is for preventing hair loss.

26. The method for preventing human hair loss according to claim 22, wherein the amino acid is selected from a group of a-amino acids, ω-amino acids, and a group power that also has special amino acid strength.

[27] The active ingredient is Ν— (6,8 dimercaptootatanyl) -a—amino acid metal chelate,

N- (6, 8—Dimercaptootatanyl) ω amino acid metal chelate and Ν— (6, 8

27. The method for preventing human hair loss according to claim 26, wherein a group force that also has a special amino acid metal chelate compound strength is selected.

[28] The active ingredient is Ν reboylglycine, リボ reboylalanine, リポ lipoyl threonine, Ν lipoyl serine, リボ riboyl spartate, リボ reboyl glutamic acid, Ν reboyl phenylalanine, リボ reboyl methionine, Ν Select a group force consisting of riboylnorleucine, リポ lipoylleucine, リボ riboylcystine, Νriboylproline, Νriboylhydroxyproline, Νriboylhistidine, Νriboylhydroxytryptophan, Νlipoyl-perisilamine, and リポ lipollysine The method for preventing human hair loss of human hair according to claim 26.

[29] The active ingredient is: Ν Riboyl-1 3aminopropionic acid, リボ Riboyl-1 4-aminobutyric acid, リボ Riboyl-1-6 aminohexanoic acid, リボ Riboyl-1 4-transaminomethyl-1-cyclohexanecarboxylic acid, リポ Lipoyl 27. The method for preventing human hair loss according to claim 26, wherein the group power is selected from 2-aminoethanesulfonic acid, Ν reboylsulfuric acid, and リポ lipoylanthral acid.

[30] The active ingredient is Ν— (6,8-dimercaptootatanyl) glycine metal chelate, Ν— (6 , 8-dimercaptootatanyl) alanine metal chelate, N— (6,8-dimercaptooctayl) threonine metal chelate, N- (6,8-dimercaptootatanyl) serine metal chelate, N- (6,8-dimercaptootatanyl) aspartic acid metal chelate, N- (6,8-dimercaptootatanyl) glutamic acid metal chelate, N- (6,8-dimercaptooctanoyl) felualanine Metal chelates, N— (6,8-dimercaptootatanyl) methionine metal chelates, N- (6,8-dimercaptootatanyl) norleucine metal chelates, N— (6,8-dimercaptoota) Tanyl) Cysteine metal chelate, N— (6,8-Dimercaptootatanyl) Hydroxyproline metal chelate, N— (6,8—Dimercaptooctanol) Histidine metal chelate, N— (6,8 —Dimercaptootatanyl) 5—Hide mouth Xyltryptophan metal chelate, N— (6,8-Dimercaptootatanyl) persilamine metal chelate and N— (6,8—Dimercaptootatanyl) 28. The method for preventing human hair loss according to claim 27, wherein a group strength comprising a lysine metal chelate compound is also selected.

[31] The active ingredient is N— (6,8 dimercaptootatanyl) 3 aminopropionate metal chelate, N— (6,8-dimercaptootatanyl) -4-aminobutyric acid metal chelate, N — (6,8-Dimercaptootatanyl) 6-Aminohexanoic acid metal chelate, N— (6,8-Dimercaptootatanyl) -4 transaminomethyl-1-cyclohexanecarboxylic acid metal Chelate, N— (6,8 Dimercaptootatanyl) 2 Aminoethanesulfonic acid metal chelate, N— (6,8-Dimercaptootathanyl) sulfuric acid metal chelate and N − (6, 8 28. The method for preventing human hair loss according to claim 27, wherein a group strength comprising a dimercaptootatanyl) anthral acid metal chelate is also selected.

[32] The method for preventing human hair loss according to claim 23, wherein the active ingredient is selected to be a group force comprising N-riboylparasylglycine and N-lipoylthreoglycine.

[33] The active ingredient is N— (6,8-dimercaptootatanyl) aspatirylglycine metal chelate and N— (6,8-dimercaptootathanyl) throle-glycine metal chelate 24. The method for preventing human hair loss of human hair according to claim 23, wherein the group power comprising a compound is selected.

[34] Metallic force of claim 19, 20, 21, 22, 23, 25, 26, 27, 30, 31 and 33, which is S zinc! How to prevent human hair loss.

[35] The following formula (1) for producing a hair loss treatment agent, [Chemical 3]

(In the formula, R represents an OH group, an O alkyl group, an N-bonded amine, an N-bonded amino acid or an N-bonded peptide, and A represents a single bond or a metal M). Use of an active ingredient which is lipoic acid or a lipoic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof.

[36] The use of claim 35, wherein R is an O lower alkyl group.

[37] The use of claim 35, wherein R is an N-linked amine.

[38] The use of claim 35, wherein R is an N-linked amino acid.

[39] Use according to claim 35, wherein R is an N-linked dipeptide.

40. The group of claim 37, wherein the active ingredient is selected from the group consisting of lipoic acid amide, N lipoyl-2-aminoethanol, N-riboylisopropylpyramine, N-riboylmelatonin and N-riboyl-2-aminoviridine. use.

[41] The active ingredient is 6,8 dimercaptooctanoic acid amide metal chelate, N- (6,8 dimercaptootatanyl) 2 aminoethanol metal chelate, N- (6,8 dimercaptootatanyl) isopropylamine Metal chelates, N- (6,8-dimercaptootatanyl) melatonin metal chelates and N- (6,8 dimercaptootatanyl) 2 aminoviridine metal chelate compounds Use of claim 37, wherein

[42] The use according to claim 38, wherein the amino acid is an α-amino acid, an ω-amino acid, or a group force including a special amino acid force.

[43] The active ingredient is Ν— (6,8-dimercaptootatanyl)-a-amino acid metal chelate, N- (6,8-dimercaptootathanyl) ω amino acid metal chelate and Ν— ( 6, 8

43. Use according to claim 42, wherein a group force that also comprises a special amino acid metal chelate compound is selected.

[44] The active ingredient is Νriboylglycine, リボ riboylalanine, リポ lipoylthreonine, リポ lipoylserine, リボ riboylspartate, Νriboylglutamate, Νli Boiled phenylalanine, N-riboylmethionine, N-riboylnorleucine, N-lipoylleucine, N-riboylcystine, N-riboylproline, N-riboylhydroxyproline, N-riboylhistidine, N-riboylhydroxytryptophan, N-lipoyl Use according to claim 42, wherein a group power consisting of persilamine and N lipoyllysine is also selected.

[45] The active ingredient is N-riboyl-1-3-aminopropionic acid, N-riboyl-4-aminobutyric acid, N-riboyl-6-aminohexanoic acid, N-riboyl-4-transaminomethyl-1-cyclohexanecarboxylic acid, 43. Use according to claim 42, wherein the group power is selected from N lipoyl 2-aminoethanesulfonic acid, N reboyl sulfaric acid and N lipoyl anthralic acid.

[46] The active ingredient is N- (6,8 dimercaptootatanyl) glycine metal chelate, N (6,8-dimercaptootatanyl) alanine metal chelate, N- (6,8-dimercapto Octanol) threonine metal chelate, N— (6,8-dimercaptootatanyl) serine metal chelate, N— (6,8-dimercaptootatanyl) aspartate metal chelate, N— (6 , 8-dimercaptootatanyl) glutamic acid metal chelate, N— (6,8-dimercaptooctanoyl) ferrolanine metal chelate, N— (6,8-dimercaptootatanyl) methionine metal chelate, N -(6,8-dimercaptootatanyl) norleucine metal chelate, N- (6,8-dimercaptootatanyl) cysteine metal chelate, N- (6,8-dimercaptootatanyl) hydroxy Proline gold Genus chelate, N— (6,8-dimercaptooctaylol) histidine metal chelate, N— (6,8—dimercaptootatanyl) 5—hydride xytryptophan metal chelate, N— (6,8— 45. Use according to claim 43, wherein a group strength consisting of dimercaptootatanyl) pe-silamine metal chelates and N- (6,8-dimercaptootatanyl) lysine metal chelates is also selected. .

[47] The active ingredient is N— (6,8-dimercaptootatanyl) 3-aminoaminopropionate metal chelate, N— (6,8-dimercaptootatanyl) -4-aminobutyric acid metal chelate N- (6,8-dimercaptootatanyl) 6-aminohexanoic acid metal chelate, N- (6,8-dimercaptootatanyl) -4 transaminomethyl-1-cyclohexanecarboxylic acid Metal chelates, N— (6,8 Dimercaptootatanyl) 2 Aminoethanesulfonic acid metal Chelate, N- (6,8-Dimercaptootatanyl) sulfuric acid metal chelate and N

44. Use according to claim 43, wherein a group force consisting of (6,8-dimercaptootatanyl) anthral metal chelate is also selected.

[48] The use according to claim 39, wherein the active ingredient is selected to be a group force that also has N-riboylparasylglycine and N-lipoylthreoglycine power.

[49] The active ingredient is N— (6,8-dimercaptootatanyl) aspatiruglycine metal chelate and N— (6,8-dimercaptootatanyl) throle-glycine metal chelation 40. Use according to claim 39, wherein the group power is a compound.

[50] Use of any of claims 35, 36, 37, 38, 39, 41, 42, 43, 46, 47 and 49, which is metallic strength S zinc.