JP2008174453A - Therapeutic agent for scalp alopecia - Google Patents
Therapeutic agent for scalp alopecia Download PDFInfo
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- JP2008174453A JP2008174453A JP2005160423A JP2005160423A JP2008174453A JP 2008174453 A JP2008174453 A JP 2008174453A JP 2005160423 A JP2005160423 A JP 2005160423A JP 2005160423 A JP2005160423 A JP 2005160423A JP 2008174453 A JP2008174453 A JP 2008174453A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4986—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with sulfur as the only hetero atom
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- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
- C07D339/02—Five-membered rings
- C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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Abstract
Description
本発明は、リポ酸またはリポ酸誘導体を含有してなる新規かつ有用な頭皮脱毛治療剤に関する。 The present invention relates to a novel and useful scalp hair removal therapeutic agent comprising lipoic acid or a lipoic acid derivative.
リポ酸（α−リポ酸）はミトコンドリア中に存在する補酵素であり、その還元体は酸化型のグルタチオンやビタミンＣを還元型に再生させる作用がある。しかし、空気中では非常に不安定で酸化されてリポ酸に戻る。 Lipoic acid (α-lipoic acid) is a coenzyme present in mitochondria, and its reductant has an action of regenerating oxidized glutathione and vitamin C into a reduced form. However, it is very unstable in air and is oxidized to return to lipoic acid.
本発明者はリポ酸またはリポ酸誘導体の還元体に金属でキレート化させて安定化させた化合物、すなわち、６，８−ジメルカプトオクタン酸金属キレート化合物またはその誘導体に抗酸化作用、フリーラジカル抑制作用、並びにメラニン産生抑制作用など、更にしみ、そばかす、黒子など治療除去作用を発明し特許出願中である。 The present inventor has antioxidation and free radical suppression to a compound obtained by chelating with a metal a reduced form of lipoic acid or lipoic acid derivative and stabilized, ie, 6,8-dimercaptooctanoic acid metal chelate compound or derivative thereof. Invented anti-bacterial and anti-melanin production effects such as blemishes, freckles, and moles.
本発明者は研究を重ねた結果、リポ酸またはリポ酸誘導体およびそれらの薬理学的に許容できる塩に頭皮の脱毛を阻害する効果を見出し、本発明を完成させた。 As a result of repeated researches, the present inventors have found that lipoic acid or lipoic acid derivatives and their pharmacologically acceptable salts have an effect of inhibiting hair loss of the scalp, thereby completing the present invention.
すなわち、頭皮の脱毛は男性ホルモン（テストステロン）が毛乳頭や皮脂腺に存在する５α−リダクターゼという酵素の還元作用で５α−ジヒドロテストステロン（５α−ＤＨＴ）に変化し、この５α−ＤＨＴが毛母細胞の細胞分裂を抑制するというメカニズムが知られている。また、頭皮は皮脂分泌の過剰が脱毛を促進している学説つまり、頭皮上の皮脂は空気や光で酸化され、過酸化脂質や脂肪酸並びに細菌汚染も絡み、頭皮や毛根が炎症を起こし、この炎症で毛母が細胞分裂できなくなる脂漏性脱毛症が考えられ、両理論が同時に起きる可能性も充分考えられ相乗作用によって脱毛の進行を早めていると考えられている。 That is, the hair loss of the scalp is changed to 5α-dihydrotestosterone (5α-DHT) by reducing action of an enzyme called 5α-reductase present in the hair papilla or sebaceous gland, and the male hormone (testosterone) is changed to 5α-DHT. A mechanism for suppressing cell division is known. In addition, the theory of scalp is that excessive sebum secretion promotes hair loss, that is, sebum on the scalp is oxidized by air and light, lipid peroxide, fatty acids and bacterial contamination are also involved, and the scalp and hair roots are inflamed. It is thought that seborrheic alopecia, in which the hair matrix is unable to divide due to inflammation, and the possibility that both theories occur at the same time, is considered to accelerate the progress of hair loss by synergistic action.
上記文献には、新規、Ｎ−（６，８−ジメルカプトオクノイル）アミノ酸金属キレート化合物に抗酸化作用、フリーラジカル抑制作用、メラニン産生抑制作用、エラスターゼ抑制作用が記載されている。 The above document describes a novel N- (6,8-dimercaptoocnoyl) amino acid metal chelate compound having an antioxidant action, a free radical inhibitory action, a melanin production inhibitory action, and an elastase inhibitory action.
上記文献には、６，８−ジメルカプトオクタン酸金属キレート化合物またはその誘導体にしみ、そばかす、黒子などのメラニン消去作用が記載されている。 In the above document, 6,8-dimercaptooctanoic acid metal chelate compound or a derivative thereof is described, and melanin erasing action such as freckles and kuroko is described.
本発明は、リポ酸またはリポ酸誘導体およびそれらの薬理学的に許容できる塩を含有してなる頭皮脱毛治療剤を提供する。 The present invention provides a therapeutic agent for scalp hair loss comprising lipoic acid or lipoic acid derivatives and pharmacologically acceptable salts thereof.
（１）本発明は、次の式（１）（式中、ＲはＯＨ基、Ｏ−アルキル基あるいはＮ−結合のアミン類、アミノ酸またはペプタイドを示し、Ｍは金属を示す）で表わされるリポ酸またはリポ酸誘導体、およびそれらの薬理学的に許容できる塩を含有する頭皮脱毛治療剤。 (1) The present invention relates to a lipoprotein represented by the following formula (1) (wherein R represents an OH group, an O-alkyl group or an N-linked amine, an amino acid or a peptide, and M represents a metal). A scalp hair removal therapeutic agent comprising an acid or lipoic acid derivative and a pharmacologically acceptable salt thereof.
（２）リポ酸またはリポ酸誘導体がその低級アルキルエステルまたはその金属キレートからなる群から選ばれるものである、上記（１）記載の頭皮脱毛治療剤。 (2) The scalp hair removal therapeutic agent according to (1) above, wherein the lipoic acid or lipoic acid derivative is selected from the group consisting of a lower alkyl ester or a metal chelate thereof.
（３）リポ酸誘導体がＮ−リポイルアミン類またはその金属キレート化合物からなる群から選ばれるものである、上記（１）記載の頭皮脱毛治療剤。 (3) The scalp hair removal therapeutic agent according to the above (1), wherein the lipoic acid derivative is selected from the group consisting of N-lipoylamines or metal chelate compounds thereof.
（４）リポ酸誘導体がＮ−リポイルアミノ酸またはその金属キレート化合物からなる群から選ばれるものである、上記（１）記載の頭皮脱毛治療剤。 (4) The scalp hair removal therapeutic agent according to (1) above, wherein the lipoic acid derivative is selected from the group consisting of N-lipoylamino acid or a metal chelate compound thereof.
（５）リポ酸誘導体がＮ−リポイルジペプタイドまたはその金属キレート化合物からなる群から選ばれるものである、上記（１）記載の頭皮脱毛治療剤。 (5) The scalp hair removal therapeutic agent according to the above (1), wherein the lipoic acid derivative is selected from the group consisting of N-lipoyl dipeptide or a metal chelate compound thereof.
（６）リポイルアミン類がリポ酸アミド、Ｎ−リポイル−２−アミノエタノール、Ｎ−リポイルイソプロピルアミン、Ｎ−リポイルメラトニンまたはＮ−リポイル−２−アミノピリジンからなる群から選ばれるものである、上記（３）記載の頭皮脱毛治療剤。 (6) The lipoylamine is selected from the group consisting of lipoic acid amide, N-lipoyl-2-aminoethanol, N-lipoylisopropylamine, N-lipoyl melatonin or N-lipoyl-2-aminopyridine. The scalp hair removal therapeutic agent as described in said (3).
（７）Ｎ−（６，８−ジメルカプトオクタノイル）アミン類金属キレート化合物が６，８−ジメルカプトオクタン酸アミド金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−２−アミノエタノール金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）イソプロピルアミン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）メラトニン金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）−２−アミノピリジン金属キレート化合物からなる群から選ばれるものである、上記（３）記載の頭皮脱毛治療剤。 (7) N- (6,8-dimercaptooctanoyl) amine metal chelate compound is 6,8-dimercaptooctanoic acid amide metal chelate, N- (6,8-dimercaptooctanoyl) -2-aminoethanol Metal chelates, N- (6,8-dimercaptooctanoyl) isopropylamine metal chelates, N- (6,8-dimercaptooctanoyl) melatonin metal chelates and N- (6,8-dimercaptooctanoyl) -2 -The scalp hair removal therapeutic agent according to (3), which is selected from the group consisting of aminopyridine metal chelate compounds.
（８）リポイルアミノ酸がα−アミノ酸、ω−アミノ酸、特殊アミノ酸からなる群から選ばれるものである、上記（４）記載の頭皮脱毛治療剤。 (8) The scalp hair removal therapeutic agent according to the above (4), wherein the lipoylamino acid is selected from the group consisting of α-amino acids, ω-amino acids and special amino acids.
（９）Ｎ−（６，８−ジメルカプトオクタノイル）アミノ酸金属キレート化合物がＮ−（６，８−ジメルカプトオクタノイル）−α−アミノ酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−ω−アミノ酸金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）特殊アミノ酸金属キレート化合物からなる群から選ばれるものである、上記（４）記載の頭皮脱毛治療剤。 (9) N- (6,8-dimercaptooctanoyl) amino acid metal chelate compound is N- (6,8-dimercaptooctanoyl) -α-amino acid metal chelate, N- (6,8-dimercaptooctanoyl) ) -Ω-amino acid metal chelate and N- (6,8-dimercaptooctanoyl) special amino acid metal chelate compound.
（１０）リポイル−α−アミノ酸がＮ−リポイルグリシン、Ｎ−リポイルアラニン、Ｎ−リポイルスレオニン、Ｎ−リポイルセリン、Ｎ−リポイルアスパラギン酸、Ｎ−リポイルグルタミン酸、Ｎ−リポイルフェニルアラニン、Ｎ−リポイルメチオニン、Ｎ−リポイルノルロイシン、Ｎ−リポイルロイシン、Ｎ−リポイルシステイン、Ｎ−リポイルプロリン、Ｎ−リポイルハイドロキシプロリン、Ｎ−リポイルヒスチジン、Ｎ−リポイルハイドロキシトリプトファン、Ｎ−リポイルペニシラミンおよびＮ−リポイルリジンからなる群から選ばれるものである、上記（８）記載の頭皮脱毛治療剤。 (10) Lipoyl-α-amino acid is N-lipoylglycine, N-lipoylalanine, N-lipoylthreonine, N-lipoylserine, N-lipoylaspartic acid, N-lipoylglutamic acid, N-lipoylphenylalanine, N-lipoylmethionine, N-lipoylnorleucine, N-lipoylleucine, N-lipoylcysteine, N-lipoylproline, N-lipoylhydroxyproline, N-lipoylhistidine, N-lipoylhydroxytryptophan The therapeutic agent for scalp hair loss according to (8) above, which is selected from the group consisting of N-lipoylpenicillamine and N-lipoyllysine.
（１１）Ｎ−（６，８−ジメルカプトオクタノイル）−α−アミノ酸金属キレートがＮ−（６，８−ジメルカプトオクタノイル）グリシン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）アラニン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）スレオニン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）セリン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）アスパラギン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）グルタミン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）フェニルアラニン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）メチオニン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）ノルロイシン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）システイン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）ハイドロキシプロリン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）ヒスチジン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−５−ハイドロキシトリプトファン金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）ペニシラミン金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）リジン金属キレート化合物からなる群から選ばれるものである、上記（９）記載の頭皮脱毛治療剤。 (11) N- (6,8-dimercaptooctanoyl) -α-amino acid metal chelate is N- (6,8-dimercaptooctanoyl) glycine metal chelate, N- (6,8-dimercaptooctanoyl) Alanine metal chelate, N- (6,8-dimercaptooctanoyl) threonine metal chelate, N- (6,8-dimercaptooctanoyl) serine metal chelate, N- (6,8-dimercaptooctanoyl) aspartic acid Metal chelate, N- (6,8-dimercaptooctanoyl) glutamic acid metal chelate, N- (6,8-dimercaptooctanoyl) phenylalanine metal chelate, N- (6,8-dimercaptooctanoyl) methionine metal chelate N- (6,8-dimercaptooctanoyl) norleucine metal chelate, N- (6 8-dimercaptooctanoyl) cysteine metal chelate, N- (6,8-dimercaptooctanoyl) hydroxyproline metal chelate, N- (6,8-dimercaptooctanoyl) histidine metal chelate, N- (6,8 -Dimercaptooctanoyl) -5-hydroxytryptophan metal chelate, N- (6,8-dimercaptooctanoyl) penicillamine metal chelate and N- (6,8-dimercaptooctanoyl) lysine metal chelate compound The scalp hair removal therapeutic agent according to (9), which is selected.
（１２）ω−アミノ酸および特殊アミノ酸がＮ−リポイル−３−アミノプロピオン酸、Ｎ−リポイル−４−アミノ酪酸、Ｎ−リポイル−６−アミノヘキサン酸、Ｎ−リポイル−４−トランスアミノメチル−１−シクロヘキサンカルボン酸、Ｎ−リポイル−２−アミノエタンスルホン酸、Ｎ−リポイルスルファニル酸およびＮ−リポイルアントラニル酸からなる群から選ばれるものである、上記（８）記載の頭皮脱毛治療剤。 (12) The ω-amino acid and the special amino acid are N-lipoyl-3-aminopropionic acid, N-lipoyl-4-aminobutyric acid, N-lipoyl-6-aminohexanoic acid, N-lipoyl-4-transaminomethyl-1 -The scalp hair removal therapeutic agent according to (8) above, which is selected from the group consisting of cyclohexanecarboxylic acid, N-lipoyl-2-aminoethanesulfonic acid, N-lipoylsulfanilic acid and N-lipoylanthranilic acid.
（１３）Ｎ−（６，８−ジメルカプトオクタノイル）−ω−アミノ酸金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）特殊アミノ酸金属キレート化合物がＮ−（６，８−ジメルカプトオクタノイル）−３−アミノプロピオン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−４−アミノ酪酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−６−アミノヘキサン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−４−トランスアミノメチル−１−シクロヘキサンカルボン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）−２−アミノエタンスルホン酸金属キレート、Ｎ−（６，８−ジメルカプトオクタノイル）スルファニル酸金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）アントラニル酸金属キレートからなる群から選ばれるものである、上記（９）記載の頭皮脱毛治療剤。 (13) N- (6,8-dimercaptooctanoyl) -ω-amino acid metal chelate and N- (6,8-dimercaptooctanoyl) special amino acid metal chelate compound are N- (6,8-dimercaptoocta Noyl) -3-aminopropionic acid metal chelate, N- (6,8-dimercaptooctanoyl) -4-aminobutyric acid metal chelate, N- (6,8-dimercaptooctanoyl) -6-aminohexanoic acid metal Chelate, N- (6,8-dimercaptooctanoyl) -4-transaminomethyl-1-cyclohexanecarboxylic acid metal chelate, N- (6,8-dimercaptooctanoyl) -2-aminoethanesulfonic acid metal chelate N- (6,8-dimercaptooctanoyl) sulfanilic acid metal chelate and N- (6,8-dimercapto Kutanoiru) are those selected from the group consisting of anthranilic acid metal chelate, scalp hair loss treatment agent according to (9) described.
（１４）ジペプタイドがＮ−リポイルアスパラチイルグリシンおよびＮ−リポイルスレオニルグリシンからなる群から選ばれるものである、上記（５）記載の頭皮脱毛治療剤。 (14) The scalp hair removal therapeutic agent according to (5) above, wherein the dipeptide is selected from the group consisting of N-lipoyl asparathyl glycine and N-lipoyl threonyl glycine.
（１５）Ｎ−（６，８−ジメルカプトオクタノイル）ジペプタイド金属キレート化合物がＮ−（６，８−ジメルカプトオクタノイル）アスパラチイルグリシン金属キレートおよびＮ−（６，８−ジメルカプトオクタノイル）スレオニルグリシン金属キレート化合物からなる群から選ばれるものである、上記（５）記載の頭皮脱毛治療剤。 (15) N- (6,8-dimercaptooctanoyl) dipeptide metal chelate compound is N- (6,8-dimercaptooctanoyl) aspartiylglycine metal chelate and N- (6,8-dimercaptooctanoyl) ) The scalp hair removal therapeutic agent according to (5) above, which is selected from the group consisting of a threonylglycine metal chelate compound.
（１６）金属が亜鉛である上記（１）〜（１５）記載のいずれかに記載の頭皮脱毛治療剤。 (16) The scalp hair removal therapeutic agent according to any one of (1) to (15), wherein the metal is zinc.
（１７）皮膚外用剤である上記（１）〜（１６）のいずれかに記載の頭皮脱毛治療剤。 (17) The scalp hair removal therapeutic agent according to any one of (1) to (16), which is an external preparation for skin.
（１８）化粧料である上記（１７）記載の頭皮脱毛治療剤に関する。 (18) The present invention relates to the scalp hair removal therapeutic agent according to the above (17), which is a cosmetic.
頭皮の脱毛は男性ホルモン（テストステロン）が毛乳頭や皮脂腺に存在する５α−リダクターゼという酵素の還元作用で５α−ジヒドロテストステロン（５α−ＤＨＴ）に変化し、この５α−ＤＨＴが毛母細胞の細胞分裂を抑制するというメカニズムから頭皮の脱毛につながると云われている。また、頭皮は皮脂分泌の過剰が脱毛を促進している学説もあり、頭皮の皮脂は空気中の酸素や光酸化を受けて、過酸化脂質や脂肪酸並びに細菌汚染も絡み、頭皮や毛根が炎症を起こし、毛母細胞が細胞分裂できなくなる脂漏性脱毛症も考えられている。 The hair loss of the scalp changes male hormone (testosterone) to 5α-dihydrotestosterone (5α-DHT) by the reducing action of an enzyme 5α-reductase present in the hair papilla and sebaceous glands, and this 5α-DHT is the cell division of hair matrix cells. It is said that the mechanism of suppressing hair leads to hair loss of the scalp. There is also a theory that the scalp has excessive sebum secretion that promotes hair loss, and the scalp sebum is subject to oxygen and photooxidation in the air, involving lipid peroxides, fatty acids, and bacterial contamination, and the scalp and hair roots are inflamed. Seborrheic alopecia that causes hair matrix cells to divide is also considered.
先ず、発毛を促進させるためには脱毛の流れを食い止めることが発毛に繋がると考えられる。 First, in order to promote hair growth, it is thought that stopping the flow of hair loss leads to hair growth.
そこで、本発明者らは研究を進めた結果、頭皮の脱毛を防止する効果を突き止めた。 Therefore, as a result of researches, the present inventors have found the effect of preventing scalp hair loss.
すなわち、本発明はリポ酸またはリポ酸誘導体に頭髪の脱毛を防止するテストステロン５α−リダクターゼを阻害することも含めて、本発明を完成するに至った。 That is, the present invention has been completed by inhibiting testosterone 5α-reductase, which prevents hair loss from being caused by lipoic acid or a lipoic acid derivative.
近年、発毛促進剤として、降圧剤のミノキジルが知られているが、低血圧の人には要注意の欠点がある。 In recent years, minoxidil, an antihypertensive agent, has been known as a hair growth promoter, but there is a drawback that requires attention to people with low blood pressure.
しかし、本発明は簡単で顕著である。すなわちリポ酸またはリポ酸誘導体、例えば整髪料に混ぜて塗布すればよい。治癒効果を観察すると、今まで洗髪などで脱毛していた頭皮の脱毛が本化合物、約０．３％水溶液を１ヶ月間ほど塗布することにより、脱毛が止まり、極端的に云えば、塗布した付近の頭髪を軽く引っ張っても脱毛が見られなく毛根が長くしっかりし、治癒効果が見られた。 However, the present invention is simple and remarkable. That is, it may be applied in a mixture with lipoic acid or a lipoic acid derivative such as a hair styling agent. When the healing effect was observed, the hair removal 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 extreme cases, it was applied. Even if the nearby hair was pulled lightly, no hair loss was seen and the hair root was long and firm, and a healing effect was seen.
本化合物の効果、例えば、Ｎ−（６，８−ジメルカプトオクタノイル）−Ｌ−ヒスチジンナトリウム・亜鉛キレートまたは６，８−ジメルカプトオクタン酸モノエタノールアミン・亜鉛キレート化合物０．３（ｗ／ｖ）％含有のトニックで、１日、１〜２回の塗布で、１ヶ月間塗布すれば脱毛は極端に少なくなり満足すべき効果が得られ、頭髪も白髪に変わるような現象は見られなかった。 Effects of this compound, for example, N- (6,8-dimercaptooctanoyl) -L-histidine sodium / zinc chelate or 6,8-dimercaptooctanoic acid monoethanolamine / zinc chelate compound 0.3 (w / v )% Tonic, applied once or twice a day for 1 month, hair loss will be extremely reduced, and a satisfactory effect will be obtained, and there is no phenomenon that the hair turns into gray hair It was.
このようなことから、本化合物は頭皮脱毛治癒効果があることがわかった。 From these results, it was found that this compound has a scalp hair loss healing effect.
本発明の頭皮脱毛治療剤に含有されるリポ酸の他、リポ酸誘導体の合成法を次に掲げる。 In addition to lipoic acid contained in the therapeutic agent for scalp hair loss of the present invention, a method for synthesizing a lipoic acid derivative is listed below.
（式中、Ｒは前記と同義である。） (In the formula, R is as defined above.)
本発明者らはリポ酸誘導体として、リポ酸またはリポ酸アミドを各々、亜鉛と酢酸（または塩酸）で還元して、６，８−ジメルカプトオクタン酸亜鉛キレートおよび６，８−ジメルカプトオクタン酸アミド亜鉛キレート化合物を合成した。また、６，８−ジメルカプトオクタン酸エチルエステル亜鉛キレートは、リポ酸エチルエステルを同様に還元して得た。さらに、Ｎ−（６，８−ジメルカプトオクタノイル）アミン類亜鉛キレート、Ｎ−（６，８−ジメルカプトオクタノイル）アミノ酸亜鉛キレートまたはＮ−（６，８−ジメルカプトオクタノイル）ペプタイド亜鉛キレートは、まず、リポ酸をクロロホルムまたはアセトニトリルに溶かし、トリエチルアミン存在下、クロル炭酸エチルを用いて混合酸無水物法によりアミン類、アミノ酸またはペプタイドを各々、カップリングさせ、Ｎ−リポイルアミン類、Ｎ−リポイルアミノ酸またはＮ−リポイルペプタイドを得た。また、これらを亜鉛と酢酸（または塩酸）で還元して、各々の亜鉛キレート化合物を得、さらにアルカリ塩に導く場合は、その遊離酸を水に溶解または懸濁して置き、水酸化アルカリで中和して溶かした後、濃縮し、アルコールを加えて析出する結晶を濾取すれば高収率で各々の亜鉛キレート化合物のアルカリ塩を得ることが出来る。 As a lipoic acid derivative, the present inventors reduced lipoic acid or lipoic acid amide with zinc and acetic acid (or hydrochloric acid), respectively, to obtain a 6,8-dimercaptooctanoic acid zinc chelate and 6,8-dimercaptooctanoic acid. An amidozinc chelate compound was synthesized. In addition, 6,8-dimercaptooctanoic acid ethyl ester zinc chelate was obtained by reducing lipoic acid ethyl ester in the same manner. Further, N- (6,8-dimercaptooctanoyl) amine zinc chelate, N- (6,8-dimercaptooctanoyl) amino acid zinc chelate or N- (6,8-dimercaptooctanoyl) peptide zinc chelate First, lipoic acid is dissolved in chloroform or acetonitrile, and amines, amino acids or peptides are respectively coupled by a mixed acid anhydride method using ethyl chlorocarbonate in the presence of triethylamine, and N-lipoylamines, N-lipoides are coupled. Yle amino acid or N-lipoyl peptide was obtained. In addition, when these are reduced with zinc and acetic acid (or hydrochloric acid) to obtain each zinc chelate compound and further led to an alkali salt, the free acid is dissolved or suspended in water and placed in an alkali hydroxide. After adding and dissolving, if concentrated, adding alcohol and collecting precipitated crystals by filtration, alkali salts of each zinc chelate compound can be obtained in high yield.
本願の金属キレート化合物の金属としては、亜鉛、コバルト、鉄、ゲルマニウムが掲げられるが、このうち、亜鉛が好ましい。 Examples of the metal of the metal chelate compound of the present application include zinc, cobalt, iron, and germanium. Among these, zinc is preferable.
本化合物の薬理学的に許容できる塩としては、ナトリウム塩やカリウム塩などのアルカリ金属塩およびカルシウム塩やマグネシウム塩などのアルカリ土類金属塩が挙げられるが、これら以外の塩であっても薬理学的に許容できる塩であればいずれのものであっても本発明の目的のため適宜に用いることが出来る。 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 that is physically acceptable can be used as appropriate for the purposes of the present invention.
リポ酸またはリポ酸誘導体の還元体、すなわち、６，８−ジメルカプトオクタン酸またはその誘導体は空気中で非常に不安定であるが、金属、例えば亜鉛でこれをキレート化させると六員環となり結晶性の良い安定な化合物となる。更に、還元作用並びにラジカル抑制作用も強く、また安全性面に問題ない優れた化合物である。 Lipoic acid or a reduced form of lipoic acid derivative, ie, 6,8-dimercaptooctanoic acid or its derivative, is very unstable in air, but when chelated with a metal such as zinc, it becomes a six-membered ring. It becomes a stable compound with good crystallinity. Furthermore, it is an excellent compound that has a strong reducing action and radical suppressing action and has no problem in safety.
本化合物、例えば、Ｎ−（６，８−ジメルカプトオクタノイル）−Ｌ−ヒスチジンナトリウム亜鉛キレート化合物の動物による安全性試験では、経口急性毒性２ｇ／ｋｇ以上、および１０％水溶液の皮膚投与などによる医薬部外品申請用項目について実施した結果、全く問題なかった。 In animal safety studies of this compound, for example, N- (6,8-dimercaptooctanoyl) -L-histidine sodium zinc chelate compound, oral acute toxicity is 2 g / kg or more, and dermal administration of 10% aqueous solution, etc. As a result of conducting the quasi drug application items, there was no problem.
本化合物の使用用途は整髪剤、洗髪剤にも適用される。 The use of this compound is also applied to hair styling agents and hair washing agents.
本化合物の使用濃度は例えば、水性トニック、水性スプレーの場合、通常０．００１〜５（ｗ／ｖ）％で、好ましくは０．０１〜１．０（ｗ／ｖ）％であり、頭髪用ゲル化剤の場合は通常０．００１〜５（ｗ／ｗ）％で、好ましくは０．０１〜１．０（ｗ／ｗ）％であり、また、シャンプ−、リンスなど、好ましくは０．００１〜０．５（ｗ／ｖ）％である。 The concentration of the compound used is, for example, 0.001 to 5 (w / v)%, preferably 0.01 to 1.0 (w / v)% in the case of aqueous tonic and aqueous spray. In the case of a gelling agent, it is usually 0.001 to 5 (w / w)%, preferably 0.01 to 1.0 (w / w)%, and shampoo, rinse, etc., preferably 0. 001 to 0.5 (w / v)%.
また、通常、養毛剤、育毛剤、発毛剤に用いられる成分、並びに賦形剤、顔料、香料、紫外線吸収剤、ゲル化剤、酸化防止剤、界面活性剤、安定化剤、防腐剤など適宜配合してもよい。 In addition, components used in hair restoration agents, hair growth agents, hair growth agents, and excipients, pigments, fragrances, ultraviolet absorbers, gelling agents, antioxidants, surfactants, stabilizers, preservatives, etc. You may mix | blend.
本発明の頭皮脱毛治療剤には、目的と必要に応じて、本化合物の１種または２種以上を適宜組み合わせて含有させることも出来る。 The therapeutic agent for scalp epilation according to the present invention can contain one or more of the present compounds as appropriate in combination, depending on the purpose and necessity.
次に、参考例、試験例および実施例を挙げて本発明を説明するが、本発明の範囲に限定されない。 Next, although a reference example, a test example, and an Example are given and this invention is demonstrated, it is not limited to the scope of the present invention.
参考例１ ６，８−ジメルカプトオクタン酸ナトリウム・亜鉛キレート化合物 Reference Example 1 6,8-dimercaptooctanoic acid sodium / zinc chelate compound
ＤＬ−α−リポ酸６．２ｇをメタノール７０ｍＬに溶かし、亜鉛末３．０ｇおよび１Ｎ−塩酸４０ｍＬを加えて５０℃、１時間攪拌する。つぎに、末反応の亜鉛を濾別し、濾液を減圧下で濃縮させ、これに水を加えて析出した白色結晶を濾取する。これを水１５０ｍＬに懸濁して置き、２Ｎ−水酸化ナトリウムで約ｐＨ９として溶かし、不溶物を濾別し、濾液を濃縮させ、これにエタノールを加えて析出する白色結晶を濾取し、水／エタノールから再結晶させると、ｍｐ．３００℃以上、６．０ｇを得た。ＴＬＣ，Ｒｆ＝０．８８（ｎ−ブタノール：酢酸：水＝４：１：２）。また、水酸化ナトリウムの代わりに、モノエタノールアミンを用いて、６，８−ジメルカプトオクタン酸・亜鉛キレート．モノエタノールアミン塩ｍｐ．１３７〜１３９℃、８．５ｇを得た。 Dissolve 6.2 g of DL-α-lipoic acid in 70 mL of methanol, add 3.0 g of zinc dust and 40 mL of 1N hydrochloric acid, and stir at 50 ° C. for 1 hour. Next, the zinc in the end reaction is filtered off, the filtrate is concentrated under reduced pressure, and water is added to this, and the precipitated white crystals are 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 thereto, and the precipitated white crystals were collected by filtration. When recrystallized from ethanol, mp. More than 300 degreeC and 6.0g were obtained. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2). In addition, monoethanolamine is used instead of sodium hydroxide, and 6,8-dimercaptooctanoic acid / zinc chelate. Monoethanolamine salt mp. 137-139 degreeC and 8.5g were obtained.
参考例２ ６，８−ジメルカプトオクタン酸エチル・亜鉛キレート化合物 Reference Example 2 Ethyl 6,8-dimercaptooctanoate / zinc chelate compound
ＤＬ−α−リポ酸エチル３．５ｇをテトラハイドロフラン６０ｍＬに溶かし、これに亜鉛末２．０ｇおよび７０％酢酸水溶液４０ｍＬを加えて、５０℃で２時間攪拌した後、末反応の亜鉛を濾別し、濾液を濃縮させ、これに水を加えて析出した白色結晶を濾取し、酢酸／水から再結晶させると、ｍｐ．２９０℃付近から徐々に分解、目的化合物３．６ｇを得た。ＴＬＣ，Ｒｆ＝０．８８（ｎ−ブタノール：酢酸：水＝４：１：２） Dissolve 3.5 g of DL-α-ethyl lipoate in 60 mL of tetrahydrofuran, add 2.0 g of zinc dust and 40 mL of 70% aqueous acetic acid solution, and stir at 50 ° C. for 2 hours. Separately, the filtrate was concentrated, water was added thereto, and the precipitated white crystals were collected by filtration and recrystallized from acetic acid / water. The product was gradually decomposed from around 290 ° C. to obtain 3.6 g of the target compound. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2)
参考例３ ６，８−ジメルカプトオクタン酸アミド・亜鉛キレート化合物 Reference Example 3 6,8-dimercaptooctanoic acid amide / zinc chelate compound
ＤＬ−α−リポ酸アミド４．２ｇをテトラハイドロフラン７０ｍＬに溶かし、これに亜鉛末２．５ｇおよび５０％酢酸水溶液３０ｍＬを加えて５０℃、２時間攪拌させ、溶媒を留去させた後、析出した亜鉛混じりの結晶を濾取し、水およびエタノールで洗い、酢酸／水から再結晶させると、ｍｐ．２５７〜２５９℃、白色結晶、４．５ｇを得た。ＴＬＣ，Ｒｆ＝０．８０（ｎ−ブタノール：酢酸：水＝４：１：２） After dissolving 4.2 g of DL-α-lipoic acid amide in 70 mL of tetrahydrofuran, 2.5 g of zinc dust and 30 mL of 50% acetic acid aqueous solution were added thereto, and the mixture was stirred at 50 ° C. for 2 hours. The precipitated zinc-mixed crystals were collected by filtration, washed with water and ethanol, and recrystallized from acetic acid / water. 257-259 ° C., white crystals, 4.5 g were obtained. TLC, Rf = 0.80 (n-butanol: acetic acid: water = 4: 1: 2)
参考例４ Ｎ−（６，８−ジメルカプトオクタノイル）グリシンナトリウム・亜鉛キレート化合物 Reference Example 4 N- (6,8-dimercaptooctanoyl) glycine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびグリシン１．９ｇを用いて、Ｎ−α−リポイルグリシンナトリウム（ｍｐ．２１８〜２２０℃）を経て、目的化合物、ｍｐ．２９７℃付近から分解の白色結晶３．９ｇを得た。ＴＬＣ，Ｒｆ＝０．６４（クロロホルム：メタノール：水＝５：４：１）。 Using 4.2 g of DL-α-lipoic acid and 1.9 g of glycine, sodium N-α-lipoylglycine (mp. 218 to 220 ° C.), the target compound, mp. From around 297 ° C., 3.9 g of decomposed white crystals were obtained. TLC, Rf = 0.64 (chloroform: methanol: water = 5: 4: 1).
参考例５ Ｎ−（６，８−ジメルカプトオクタノイル）アスパラギン酸モノナトリウム・亜鉛キレート化合物 Reference Example 5 N- (6,8-dimercaptooctanoyl) aspartic acid monosodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−アスパラギン酸２．９ｇを用いて、Ｎ−α−リポイルアスパラギン酸ナトリウム（ｍｐ．３００℃以上）を経て、目的化合物、ｍｐ．２９５℃付近から分解の白色結晶４．２ｇを得た。ＴＬＣ，Ｒｆ＝０．５３（クロロホルム：メタノール：水＝５：４：１）。 Using 4.2 g of DL-α-lipoic acid and 2.9 g of L-aspartic acid, sodium N-α-lipoylaspartate (mp. 300 ° C. or higher), the target compound, mp. The decomposition | disassembly white crystal 4.2g was obtained from 295 degreeC vicinity. TLC, Rf = 0.53 (chloroform: methanol: water = 5: 4: 1).
参考例６ Ｎ−（６，８−ジメルカプトオクタノイル）メチオニンナトリウム・亜鉛キレート化合物 Reference Example 6 N- (6,8-dimercaptooctanoyl) methionine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−メチオニン３．５ｇを用いて、Ｎ−α−リポイルメチオニン（ｍｐ．１０８〜１０９℃）を経て、目的化合物、ｍｐ．２６０℃付近から分解の白色結晶２．８ｇを得た。ＴＬＣ，Ｒｆ＝０．８２（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 4.2 g of DL-α-lipoic acid and 3.5 g of L-methionine, N-α-lipoylmethionine (mp. 108-109 ° C.), the target compound, mp. From about 260 ° C., 2.8 g of decomposed white crystals were obtained. TLC, Rf = 0.82 (n-butanol: acetic acid: water = 4: 1: 2).
参考例７ Ｎ−（６，８−ジメルカプトオクタノイル）システイン・亜鉛キレート化合物 Reference Example 7 N- (6,8-dimercaptooctanoyl) cysteine / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−システイン２．６ｇを用いて、Ｎ−α−リポイルシステインナトリウム（ｍｐ．１５０℃付近から分解）を経て、目的化合物、ｍｐ．２８０℃付近から分解の白色結晶４．１ｇを得た。ＴＬＣ，Ｒｆ＝０．７１（クロロホルム：メタノール：水＝５：４：１）。 Using 4.2 g of DL-α-lipoic acid and 2.6 g of L-cysteine, sodium N-α-lipoylcysteine (decomposed from around 150 ° C.) and the target compound, mp. 4.1 g of decomposed white crystals were obtained from around 280 ° C. TLC, Rf = 0.71 (chloroform: methanol: water = 5: 4: 1).
参考例８ Ｎ−（６，８−ジメルカプトオクタノイル）フェニルアラニンナトリウム・亜鉛キレート化合物 Reference Example 8 N- (6,8-dimercaptooctanoyl) phenylalanine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−フェニルアラニン３．５ｇを用いて、Ｎ−α−リポイルフェニルアラニン（ｍｐ．１５４〜１５６℃）を経て、目的化合物、ｍｐ．２７０℃付近から分解の白色結晶３．９ｇを得た。ＴＬＣ，Ｒｆ＝０．８２（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 4.2 g of DL-α-lipoic acid and 3.5 g of L-phenylalanine, N-α-lipoylphenylalanine (mp. 154 to 156 ° C.), the target compound, mp. From about 270 ° C., 3.9 g of decomposed white crystals were obtained. TLC, Rf = 0.82 (n-butanol: acetic acid: water = 4: 1: 2).
参考例９ Ｎ−（６，８−ジメルカプトオクタノイル）−４−アミノ酪酸ナトリウム・亜鉛キレート化合物 Reference Example 9 N- (6,8-dimercaptooctanoyl) -4-aminobutyric acid sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよび４−アミノ酪酸２．３ｇを用いて、Ｎ−α−リポイル−４−アミノ酪酸（ｍｐ．２３５℃付近から分解）を経て、目的化合物、ｍｐ．２９７℃付近から分解の白色結晶５．２ｇを得た。ＴＬＣ，Ｒｆ＝０．７０（クロロホルム：メタノール：水＝５：４：１）。 Using 4.2 g of DL-α-lipoic acid and 2.3 g of 4-aminobutyric acid, N-α-lipoyl-4-aminobutyric acid (decomposed from around 235 ° C.), the target compound, mp. The decomposition | disassembly white crystal 5.2g was obtained from 297 degreeC vicinity. TLC, Rf = 0.70 (chloroform: methanol: water = 5: 4: 1).
参考例１０ Ｎ−（６，８−ジメルカプトオクタノイル）−６−アミノヘキサン酸ナトリウム・亜鉛キレート化合物 Reference Example 10 N- (6,8-dimercaptooctanoyl) -6-aminohexanoic acid sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよび６−アミノヘキサン酸３．０ｇを用いて、Ｎ−α−リポイル−６−アミノヘキサン酸ナトリウム（ｍｐ．２００〜２０２℃）を経て、目的化合物、ｍｐ．２９５℃付近から分解の白色結晶２．０ｇを得た。ＴＬＣ，Ｒｆ＝０．８４（クロロホルム：メタノール：水＝５：４：１）。 Using 4.2 g of DL-α-lipoic acid and 3.0 g of 6-aminohexanoic acid, sodium N-α-lipoyl-6-aminohexanoate (mp. 200-202 ° C.), the target compound, mp. The decomposition | disassembly white crystal 2.0g was obtained from 295 degreeC vicinity. TLC, Rf = 0.84 (chloroform: methanol: water = 5: 4: 1).
参考例１１ Ｎ−（６，８−ジメルカプトオクタノイル）アントラニル酸ナトリウム・亜鉛キレート化合物 Reference Example 11 N- (6,8-dimercaptooctanoyl) sodium anthranilate / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびアントラニル酸２．９ｇを用いて、Ｎ−α−リポイルアントラニル酸ナトリウム（ｍｐ．３００℃以上）を経て、目的化合物、ｍｐ．２９０℃付近から分解の白色結晶２．１ｇを得た。ＴＬＣ，Ｒｆ＝０．８８（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 4.2 g of DL-α-lipoic acid and 2.9 g of anthranilic acid, sodium N-α-lipoylanthranilate (mp. 300 ° C. or higher), the target compound, mp. The decomposition | disassembly white crystal 2.1g was obtained from 290 degreeC vicinity. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１２ Ｎ−（６，８−ジメルカプトオクタノイル）−２−アミノエタンスルホン酸ナトリウム・亜鉛キレート化合物 Reference Example 12 N- (6,8-dimercaptooctanoyl) -2-aminoethanesulfonic acid sodium / zinc chelate compound
ＤＬ−α−リポ酸６．２ｇおよび２−アミノエタンスルホン酸４．５ｇを用いて、Ｎ−α−リポイルアミノエタンスルホン酸ナトリウム（ｍｐ．２３５〜２３７℃）を経て、目的化合物、ｍｐ．２９３℃付近から分解の白色結晶４．５ｇを得た。ＴＬＣ，Ｒｆ＝０．５１（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 6.2 g of DL-α-lipoic acid and 4.5 g of 2-aminoethanesulfonic acid, sodium N-α-lipoylaminoethanesulfonic acid (mp. 235 to 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).
参考例１３ Ｎ−（６，８−ジメルカプトオクタノイル）ハイドロキシプロリンナトリウム・亜鉛キレート化合物 Reference Example 13 N- (6,8-dimercaptooctanoyl) hydroxyproline sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−４−ハイドロキシプロリン２．８ｇから目的化合物、ｍｐ．３００℃以上、白色結晶４．９ｇを得た。ＴＬＣ，Ｒｆ＝０．６６（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 2.8 g of L-4-hydroxyproline, the desired compound, mp. 300 degreeC or more and 4.9g of white crystals were obtained. TLC, Rf = 0.66 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１４ Ｎ−（６，８−ジメルカプトオクタノイル）ヒスチジンナトリウム・亜鉛キレート化合物 Reference Example 14 N- (6,8-dimercaptooctanoyl) histidine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−ヒスチジン３．４ｇから目的化合物、ｍｐ．３００℃以上、白色結晶５．８ｇを得た。ＴＬＣ，Ｒｆ＝０．３９（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 3.4 g of L-histidine, the desired compound, mp. 300 degreeC or more and 5.8g of white crystals were obtained. TLC, Rf = 0.39 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１５ Ｎ−（６，８−ジメルカプトオクタノイル）グルタミン酸ナトリウム・亜鉛キレート化合物 Reference Example 15 N- (6,8-dimercaptooctanoyl) glutamic acid sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−グルタミン酸３．５ｇから目的化合物、ｍｐ．３００℃以上、白色結晶５．７ｇを得た。ＴＬＣ，Ｒｆ＝０．７４（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 3.5 g of L-glutamic acid, the target compound, mp. 300 degreeC or more and 5.7g of white crystals were obtained. TLC, Rf = 0.74 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１６ Ｎ−（６，８−ジメルカプトオクタノイル）スレオニンナトリウム亜鉛・キレート化合物 Reference Example 16 N- (6,8-dimercaptooctanoyl) threonine sodium zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−スレオニン２．６ｇから目的化合物、ｍｐ．３００℃以上、白色結晶５．５ｇを得た。ＴＬＣ，Ｒｆ＝０．７３（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 2.6 g of L-threonine, the target compound, mp. More than 300 degreeC and 5.5g of white crystals were obtained. TLC, Rf = 0.73 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１７ Ｎ−（６，８−ジメルカプトオクタノイル）アラニンナトリウム亜鉛・キレート化合物 Reference Example 17 N- (6,8-dimercaptooctanoyl) alanine sodium zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−アラニン２．１ｇから目的化合物、ｍｐ．２９０℃付近から分解、白色結晶５．４ｇを得た。ＴＬＣ，Ｒｆ＝０．７８（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 2.1 g of L-alanine, the target compound, mp. Decomposition from around 290 ° C. gave 5.4 g of white crystals. TLC, Rf = 0.78 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１８ Ｎ−（６，８−ジメルカプトオクタノイル）セリンナトリウム・亜鉛キレート化合物 Reference Example 18 N- (6,8-dimercaptooctanoyl) serine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−セリン２．４ｇから目的化合物、ｍｐ．２８５℃付近から徐々に分解、白色結晶５．０ｇを得た。ＴＬＣ，Ｒｆ＝０．６４（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 2.4 g of L-serine, the target compound, mp. The product gradually decomposed from around 285 ° C. to obtain 5.0 g of white crystals. TLC, Rf = 0.64 (n-butanol: acetic acid: water = 4: 1: 2).
参考例１９ Ｎ−（６，８−ジメルカプトオクタノイル）ノルロイシンナトリウム・亜鉛キレート化合物 Reference Example 19 N- (6,8-dimercaptooctanoyl) norleucine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−ノルロイシン３．０ｇからＮ−α−リポイルノルロイシン（ｍｐ．１２０〜１２１℃）を得て、目的化合物、ｍｐ．２９５℃付近から徐々に分解、白色結晶５．１ｇを得た。ＴＬＣ，Ｒｆ＝０．９０（ｎ−ブタノール：酢酸：水＝４：１：２）。 N-α-lipoylnorleucine (mp. 120-121 ° C.) was obtained from 4.2 g of DL-α-lipoic acid and 3.0 g of L-norleucine, and the desired compound, mp. The product gradually decomposed from around 295 ° C. to obtain 5.1 g of white crystals. TLC, Rf = 0.90 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２０ Ｎ−（６，８−ジメルカプトオクタノイル）−５−ハイドロキシトリプトファンナトリウム・亜鉛キレート化合物 Reference Example 20 N- (6,8-dimercaptooctanoyl) -5-hydroxytryptophan sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＬ−５−ハイドロキシトリプトファン５．０ｇから目的化合物、ｍｐ．２９０℃付近から分解、灰白色結晶６．５ｇを得た。ＴＬＣ，Ｒｆ＝０．８１（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 5.0 g of L-5-hydroxytryptophan, the desired compound, mp. Decomposition from around 290 ° C. gave 6.5 g of grayish white crystals. TLC, Rf = 0.81 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２１ Ｎ−（６，８−ジメルカプトオクタノイル）ペニシラミンナトリウム・亜鉛キレート化合物 Reference Example 21 N- (6,8-dimercaptooctanoyl) penicillamine sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびＤ−ペニシラミン３．５ｇから目的化合物、ｍｐ．２８０℃付近から徐々に分解の白色結晶６．０ｇを得た。ＴＬＣ，Ｒｆ＝０．８０（ｎ−ブタノール：酢酸：水＝４：１：２）。 The target compound, mp., Was obtained from 4.2 g of DL-α-lipoic acid and 3.5 g of D-penicillamine. From about 280 ° C., 6.0 g of gradually decomposed white crystals was obtained. TLC, Rf = 0.80 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２２ Ｎ−（６，８−ジメルカプトオクタノイル）−３−アミノプロピオン酸ナトリウム・亜鉛キレート化合物 Reference Example 22 N- (6,8-dimercaptooctanoyl) -3-aminopropionic acid sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびβ−アラニン２．０ｇから目的化合物、ｍｐ．２９５℃付近から徐々に分解の白色結晶５．８ｇを得た。ＴＬＣ，Ｒｆ＝０．８３（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 2.0 g of β-alanine, the target compound, mp. From about 295 ° C., 5.8 g of gradually decomposed white crystals were obtained. TLC, Rf = 0.83 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２３ Ｎ−（６，８−ジメルカプトオクタノイル）−４−トランスアミノメチル−１−シクロヘキサンカルボン酸ナトリウム・亜鉛キレート化合物 Reference Example 23 N- (6,8-dimercaptooctanoyl) -4-transaminomethyl-1-cyclohexanecarboxylate sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよび４−トランスアミノメチルシクロヘキサンカルボン酸３．５ｇから目的化合物、ｍｐ．２９７℃付近から徐々に分解、白色結晶５．８ｇを得た。ＴＬＣ，Ｒｆ＝０．８１（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 3.5 g of 4-transaminomethylcyclohexanecarboxylic acid, the desired compound, mp. The product gradually decomposed from around 297 ° C. to obtain 5.8 g of white crystals. TLC, Rf = 0.81 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２４ Ｎ−（６，８−ジメルカプトオクタノイル）スルファニル酸ナトリウム・亜鉛キレート化合物 Reference Example 24 N- (6,8-dimercaptooctanoyl) sulfanilate sodium / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびスルファニル酸３．８ｇから目的化合物、ｍｐ．３００℃以上、白色結晶５．４ｇを得た。ＴＬＣ，Ｒｆ＝０．５７（ｎ−ブタノール：酢酸：水＝４：１：２）。 From 4.2 g of DL-α-lipoic acid and 3.8 g of sulfanilic acid, the desired compound, mp. 5.4 g of white crystals was obtained at 300 ° C or higher. TLC, Rf = 0.57 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２５ Ｎ−（６，８−ジメルカプトオクタノイル）イソプロピルアミン・亜鉛キレート化合物 Reference Example 25 N- (6,8-dimercaptooctanoyl) isopropylamine / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびトリエチルアミン２．４ｇをアセトニトリル５０ｍＬに溶かして攪拌下−５℃に冷却し、これにクロル炭酸エチル２．４ｇを徐々に滴下させ、滴下終了２０分後、さらに、イソプロピルアミン１．５ｇをアセトニトリル３０ｍＬに溶かしたものを速やかに加えて３０分間、さらに、室温に戻して１時間攪拌させる。これを減圧下で溶媒を留去させ、残さに水を加えて冷却させ、析出した淡黄色結晶を濾取、これをテトラハイドロフラン（ＴＨＦ）６０ｍＬに溶かし、５０％酢酸水溶液２０ｍＬおよび亜鉛末２．０ｇを加えて、５０℃、２時間攪拌させた後、末反応の亜鉛を濾別し、濾液を濃縮させる。残さに水を加えて析出した白色結晶を濾取し、ＴＨＦ／酢酸／水から再結晶させると、ｍｐ．２７１〜２７３℃、目的化合物５．０ｇを得た。ＴＬＣ，Ｒｆ＝０．８９（ｎ−ブタノール：酢酸：水＝４：１：２）。 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 ethyl chlorocarbonate was gradually added dropwise. Then, a solution of 1.5 g of isopropylamine dissolved in 30 mL of acetonitrile is quickly added, and the mixture is stirred for 30 minutes, and further returned to room temperature 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 tetrahydrofuran (THF), 20 mL of 50% acetic acid aqueous solution and zinc dust 2 After adding 0.0 g and stirring at 50 ° C. for 2 hours, zinc at the end reaction is filtered off and the filtrate is concentrated. Water was added to the residue and the precipitated white crystals were collected by filtration and recrystallized from THF / acetic acid / water. 271-273 degreeC and the target compound 5.0g were obtained. TLC, Rf = 0.89 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２６ Ｎ−（６，８−ジメルカプトオクタノイル）−２−アミノエタノール・亜鉛キレート化合物 Reference Example 26 N- (6,8-dimercaptooctanoyl) -2-aminoethanol / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびモノエタノールアミン１．５ｇを用いて目的化合物、ｍｐ．２９８℃付近から徐々に分解の白色結晶４．２ｇを得た。ＴＬＣ，Ｒｆ＝０．７７（ｎ−ブタノール：酢酸：水＝４：１：２） Using 4.2 g of DL-α-lipoic acid and 1.5 g of monoethanolamine, the target compound, mp. From about 298 ° C., 4.2 g of gradually decomposed white crystals were obtained. TLC, Rf = 0.77 (n-butanol: acetic acid: water = 4: 1: 2)
参考例２７ Ｎ−（６，８−ジメルカプトオクタノイル）メラトニン・亜鉛キレート化合物 Reference Example 27 N- (6,8-dimercaptooctanoyl) melatonin / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびメラトニン４．０を用いて、目的化合物、ｍｐ．２１０〜２１２℃、白色結晶６．５ｇを得た。ＴＬＣ，Ｒｆ＝０．８４（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 4.2 g of DL-α-lipoic acid and melatonin 4.0, the target compound, mp. 210-212 degreeC and 6.5g of white crystals were obtained. TLC, Rf = 0.84 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２８ Ｎ−（６，８−ジメルカプトオクタノイル）−２−アミノピリジン・亜鉛キレート化合物 Reference Example 28 N- (6,8-dimercaptooctanoyl) -2-aminopyridine / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよび２−アミノピリジン２．２ｇを用いて目的化合物、ｍｐ．２４３〜２４５℃、白色結晶５．３ｇを得た。ＴＬＣ，Ｒｆ＝０．８７（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 4.2 g of DL-α-lipoic acid and 2.2 g of 2-aminopyridine, the target compound, mp. 243-245 degreeC and 5.3g of white crystals were obtained. TLC, Rf = 0.87 (n-butanol: acetic acid: water = 4: 1: 2).
参考例２９ Ｎ−（６，８−ジメルカプトオクタノイル）アントラニル酸エチル・亜鉛キレート化合物 Reference Example 29 N- (6,8-dimercaptooctanoyl) anthranilate / zinc chelate compound
ＤＬ−α−リポ酸４．２ｇおよびアントラニル酸エチル３．６ｇを用いて白色結晶（ＴＨＦ−酢酸−水から再結晶）、ｍｐ．２９０℃付近から徐々に分解の目的化合物４．６ｇを得た。ＴＬＣ，Ｒｆ＝０．８８（ｎ−ブタノール：酢酸：水＝４：１：２）。 White crystals (recrystallized from THF-acetic acid-water) using 4.2 g of DL-α-lipoic acid and 3.6 g of ethyl anthranilate, mp. From about 290 ° C., 4.6 g of the objective compound for decomposition was gradually obtained. TLC, Rf = 0.88 (n-butanol: acetic acid: water = 4: 1: 2).
参考例３０ Ｎε−（６，８−ジメルカプトオクタノイル）リジン・亜鉛キレート化合物Reference Example 30 N ε - (6,8- dimercapto-octanoyl) lysine zinc chelate compound
ＤＬ−α−リポ酸４．２ｇ、トリエチルアミン２．４ｇおよびクロル炭酸エチル２．４ｇをアセトニトリル５０ｍＬ中、冷却下で混合酸無水物とし、これにＬ−リジン３．１ｇ、硫酸銅（５水和物）５．５ｇおよび水酸化ナトリウム２．０ｇを水６０ｍＬに溶かしたものを加えて反応させ、析出したＮε−（α−リポイル）リジンの銅塩を濾取し、水およびメタノールで洗った後、これを７０％の酢酸水溶液にサスペンドして置き、硫化水素で銅を硫化銅として濾別し、濾液を濃縮し、残さにメタノールを加えて析出した淡黄色の結晶を濾取、ｍｐ．２５４〜２５５℃、３．５ｇを得た。DL-α-lipoic acid (4.2 g), triethylamine (2.4 g) and ethyl chlorocarbonate (2.4 g) were mixed with 50 mL of acetonitrile under cooling to form a mixed acid anhydride. To this, 3.1 g of L-lysine and copper sulfate (pentahydrate) Product) 5.5 g and 2.0 g of sodium hydroxide dissolved in 60 mL of water were added and reacted, and the precipitated copper salt of N ε- (α-lipoyl) lysine was collected by filtration and washed with water and methanol. Thereafter, this was suspended in a 70% aqueous acetic acid solution, copper was filtered off with hydrogen sulfide as copper sulfide, the filtrate was concentrated, methanol was added to the residue, and the precipitated pale yellow crystals were collected by filtration, mp. 254-255 degreeC and 3.5g were obtained.
つぎに、これを６０％酢酸水溶液に溶かし、亜鉛末２．０ｇを加えて、５０℃、３時間攪拌し、亜鉛を濾別した後、濃縮し、これにメタノールを加えて析出した白色結晶を濾取、ｍｐ．２９５℃付近から徐々に分解の目的化合物３．４ｇを得た。ＴＬＣ，Ｒｆ＝０．４７（ｎ−ブタノール：酢酸：水＝４：１：２）。 Next, this was dissolved in a 60% aqueous acetic acid solution, 2.0 g of zinc dust was added, and the mixture was stirred at 50 ° C. for 3 hours. After filtering off the zinc, the solution was concentrated, and methanol was added to the precipitated white crystals. Filtered, mp. From about 295 ° C., 3.4 g of the objective compound gradually decomposed was obtained. TLC, Rf = 0.47 (n-butanol: acetic acid: water = 4: 1: 2).
参考例３１ Ｎ−（６，８−ジメルカプトオクタノイル）アスパラチイルグリシンジナトリウム・亜鉛キレート化合物 Reference Example 31 N- (6,8-dimercaptooctanoyl) aspartiylglycine disodium / zinc chelate compound
ＤＬ−α−リポ酸２．１ｇおよびＬ−アスパラチイルグリシン２．１ｇを用いて、同様にして、Ｎ−（α−リポイル）アスパラチイルグリシンナトリウムを径由して、目的化合物、ｍｐ．２７０℃付近から徐々に分解、白色結晶３．１ｇを得た。ＴＬＣ，Ｒｆ＝０．５４（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 2.1 g of DL-α-lipoic acid and 2.1 g of L-aspartiylglycine, the target compound, mp. The crystals gradually decomposed from around 270 ° C. to obtain 3.1 g of white crystals. TLC, Rf = 0.54 (n-butanol: acetic acid: water = 4: 1: 2).
参考例３２ Ｎ−（ジメルカプトオクタノイル）スレオニルグリシンナトリウム・亜鉛キレート化合物 Reference Example 32 N- (dimercaptooctanoyl) threonylglycine sodium / zinc chelate compound
ＤＬ−α−リポ酸２．１ｇおよびＬ−スレオニルグリシン２．１ｇを用いて、目的化合物、ｍｐ．２６０℃付近から徐々に分解、淡黄白色結晶２．６ｇを得た。ＴＬＣ，Ｒｆ＝０．６０（ｎ−ブタノール：酢酸：水＝４：１：２）。 Using 2.1 g of DL-α-lipoic acid and 2.1 g of L-threonylglycine, the target compound, mp. The product 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).
実施例１ テストステロン５α−リダクターゼ活性阻害作用の評価 Example 1 Evaluation of testosterone 5α-reductase activity inhibitory action
１．リポ酸
２．参考例１２の化合物（Ｎ−α−リポイルアミノエタンスルホン酸Ｎａ）
３．参考例１の化合物（Ｎ−６，８−ジメルカプトオクタン酸亜鉛
モノエタノールアミン塩）
４．参考例１４の化合物（Ｎ−（６，８−ジメルカプトオクタノイル）
−Ｌ−ヒスチジン亜鉛Ｎａ）1. Lipoic acid Compound of Reference Example 12 (N-α-lipoylaminoethanesulfonic acid Na)
3. Compound of Reference Example 1 (zinc N-6,8-dimercaptooctanoate
Monoethanolamine salt)
4). Compound of Reference Example 14 (N- (6,8-dimercaptooctanoyl)
-L-histidine zinc Na)
蓋付Ｖ底試験管にて、プロピレングリコールで調製した４．２ｍｇ／ｍＬテストステロン２０μＬ、１ｍｇ／ｍＬ ＮＡＤＰＨ含有５ｍｍｏｌ／ＬＴｒｉｓ−ＨＣｌ緩衝液（ｐＨ７．１３）８２５μＬを混合した。これに、エタノール、５０％エタノールもしくは精製水で調製した被験試料８０μＬおよびＳ−９７５μＬを加え再び混合し、３７℃にて３０分反応させた後、塩化メチレン １ｍＬを加え反応を停止した。これを遠心（１６００×ｇ、１０分）し、塩化メチレン層をガスクロマトグラフィー分析した。 In a V-bottom test tube with a lid, 4.2 μL of 4.2 mg / mL testosterone prepared with propylene glycol and 825 μL of 5 mmol / LTris-HCl buffer (pH 7.13) containing 1 mg / mL NADPH were mixed. To this, 80 μL of a test sample prepared with ethanol, 50% ethanol or purified water and S-975 μL were added and mixed again. After reacting at 37 ° C. for 30 minutes, 1 mL of methylene chloride was added to stop the reaction. This was centrifuged (1600 × g, 10 minutes), and the methylene chloride layer was analyzed by gas chromatography.
被験試料濃度４００（μｇ／ｍＬ）に於けるテストステロン５α−リダクターゼ 活性阻害率（％） Testosterone 5α-reductase activity inhibition rate (%) at test sample concentration 400 (μg / mL)
１．リポ酸 ７８．７
２．参考例１２の化合物
（Ｎ−α−リポイルアミノエタンスルホン酸Ｎａ） ９２．０
３．参考例１の化合物
（Ｎ−６，８−ジメルカプトオクタン酸亜鉛
モノエタノールアミン塩） １００．０
４．参考例１４の化合物
（Ｎ−（６，８−ジメルカプトオクタノイル）
−Ｌ−ヒスチジン亜鉛Ｎａ） ４２．０1. Lipoic acid 78.7
2. Compound of Reference Example 12 (N-α-lipoylaminoethanesulfonic acid Na) 92.0
3. Compound of Reference Example 1 (Zinc N-6,8-dimercaptooctanoate
Monoethanolamine salt) 100.0
4). Compound of Reference Example 14 (N- (6,8-dimercaptooctanoyl)
-L-histidine zinc Na) 42.0
上記の試験結果から、リポ酸およびリポ酸誘導体はテストステロン５α−リダクターゼ活性を強く阻害した。 From the above test results, lipoic acid and lipoic acid derivatives strongly inhibited testosterone 5α-reductase activity.
使用試験例１ 男性４０〜６０才、５名について製剤実施例１を１日、１回洗髪後トニックし、１ヶ月後評価した。
１．使用前に比べて、洗髪時に脱毛がかなり減少した ２名
２．使用前に比べて、洗髪時に脱毛が減少した ２名
３．使用前に比べて、洗髪時に脱毛が変化なし １名
４．使用前に比べて、洗髪時に脱毛が多く感じられた ０名Test Example 1 Formulation Example 1 for 5 males, 40 to 60 years old, was toniced once a day, washed one day, and evaluated one month later.
1. Compared to before use, hair loss decreased considerably during shampooing. 2. Hair loss decreased during shampooing compared to before use. No change in hair loss when shampooing compared to before use. 0 people who felt more hair loss during shampooing than before use
上記の使用試験例から、リポ酸およびリポ酸誘導体には頭皮脱毛の治療効果があると考えられる。 From the above use test examples, it is considered that lipoic acid and lipoic acid derivatives have a therapeutic effect on scalp hair loss.
製剤実施例１ ヘアートニックFormulation Example 1 Hair Nick
参考例１４の化合物 ０．３ｇ
カルボキシビニルポリマー ０．１ｇ
グリセリン ３．５ｇ
エタノール ５ｍＬ
ｐ−オキシ安息香酸メチル ０．０２ｇ
ｐ−オキシ安息香酸プロピル ０．０１ｇ
モノエタノールアミン 適量を加えてｐＨ８．５に調整
滅菌精製水 全量 １００ｍＬ0.3 g of the compound of Reference Example 14
Carboxyvinyl polymer 0.1g
Glycerin 3.5g
Ethanol 5mL
Methyl p-oxybenzoate 0.02g
0.01 g propyl p-oxybenzoate
Monoethanolamine Adjust to pH 8.5 by adding appropriate amount Sterilized purified water Total volume 100mL
製剤実施例２ ヘアートニックFormulation Example 2 Hair Nick
参考例１の化合物 ０．３ｇ
β−グリチルレチン酸アンモニウム ０．１ｇ
パントテニルアルコール ０．２ｇ
ニコチン酸アミド ０．２ｇ
カルボキシビニルポリマーナトリウム ０．１ｇ
プロピレングリコール ３．０ｇ
ｌ−メントール ０．０５ｇ
ｐ−オキシ安息香酸メチル ０．０２ｇ
ｐ−オキシ安息香酸プロピル ０．０１ｇ
滅菌精製水 全量 １００ｍＬ0.3 g of the compound of Reference Example 1
β-glycyrrhetinic acid ammonium 0.1 g
Pantothenyl alcohol 0.2g
Nicotinamide 0.2g
Carboxyvinyl polymer sodium 0.1g
Propylene glycol 3.0g
l-Menthol 0.05g
Methyl p-oxybenzoate 0.02g
0.01 g propyl p-oxybenzoate
Sterile purified water 100mL
製剤実施例３ ヘアートニックFormulation Example 3 Hair Nick
参考例１４の化合物 ０．３ｇ
トコフェロール、アスコルビン酸リン酸
ジエステルカリウム ０．０５ｇ
アラントイン ０．２ｇ
塩酸ピリドキシン ０．３ｇ
ヒノキチオール ０．０５ｇ
プロピレングリコール ３．０ｇ
ポリオキシエチレンセチルエーテル ０．５ｇ
カルボキシビニルポリマーナトリウム ０．０５ｇ
ｐ−オキシ安息香酸メチル ０．０５ｇ
ｐ−オキシ安息香酸プロピル ０．０２ｇ
エタノール ５ｍＬ
滅菌精製水 全量 １００ｍＬ0.3 g of the compound of Reference Example 14
Tocopherol, ascorbic acid phosphate
Diester potassium 0.05g
Allantoin 0.2g
0.3 g of pyridoxine hydrochloride
Hinokitiol 0.05g
Propylene glycol 3.0g
Polyoxyethylene cetyl ether 0.5g
Carboxyvinyl polymer sodium 0.05g
0.05 g methyl p-oxybenzoate
0.02 g of propyl p-oxybenzoate
Ethanol 5mL
Sterile purified water 100mL
よって、リポ酸またはリポ酸誘導体ならびにその還元体の６，８−ジメルカプトオクタン酸亜鉛キレート化合物およびその誘導体は頭皮脱毛に対して優れた治療効果を示し、頭皮脱毛治療に極めて有用である。 Therefore, lipoic acid or lipoic acid derivatives and their reduced 6,6-dimercaptooctanoic acid zinc chelate compounds and derivatives thereof have an excellent therapeutic effect on scalp hair removal and are extremely useful for scalp hair removal treatment.
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| JP2012505919A (en) * | 2008-10-17 | 2012-03-08 | インヴアスク セラピューテイックス インコーポレイテッド | A composition and method for treating renin-angiotensin aldosterone-related diseases. |
| JP2012062283A (en) * | 2010-09-16 | 2012-03-29 | Oita Univ | Anti-hair loss composition for cancer chemotherapy induced alopecia |
| WO2012080223A1 (en) | 2010-12-15 | 2012-06-21 | Sigea S.R.L. | Use of glycosaminoglycan lipoate esters in the trichology field |
| JP2014159421A (en) * | 2014-02-19 | 2014-09-04 | Salon De Rejue Co Ltd | Hair-growing composition |
| WO2016170990A1 (en) * | 2015-04-18 | 2016-10-27 | ジェイオーコスメティックス株式会社 | Tyrosinase activity inhibitor and external preparation for skin |
| EA025550B1 (en) * | 2014-08-08 | 2017-01-30 | Кыргызско-Российский Славянский Университет | Method of treating alopecia |
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| WO2008075366A2 (en) * | 2006-12-20 | 2008-06-26 | Medwell Laboratories Ltd. | Novel conjugates of polyunsaturated fatty acids with amines and therapeutic uses thereof |
| CN101786975B (en) * | 2009-01-22 | 2013-11-13 | 杭州民生药业有限公司 | Lipoamide series derivates, preparation method and pharmaceutical application thereof |
| US7928067B2 (en) | 2009-05-14 | 2011-04-19 | Ischemix Llc | Compositions and methods for treating ischemia and ischemia-reperfusion injury |
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| JPS62175417A (en) * | 1986-01-27 | 1987-08-01 | Kanebo Ltd | Hair tonic cosmetic |
| PT1294353E (en) * | 2000-06-06 | 2006-07-31 | Basf Ag | USE OF LIPOIC ACID ENANTIOMER (R) IN COSMETIC AND DERMATOLOGICAL COMPOSITIONS |
| DE60234164D1 (en) * | 2001-03-19 | 2009-12-10 | Senju Pharma Co | NEW A-LIPONIC ACID DERIVATIVE AND ITS USE |
| KR100973451B1 (en) * | 2002-09-13 | 2010-08-02 | 유겐가이샤 오가 리서치 | Melanin extinguisher |
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| JP2012505919A (en) * | 2008-10-17 | 2012-03-08 | インヴアスク セラピューテイックス インコーポレイテッド | A composition and method for treating renin-angiotensin aldosterone-related diseases. |
| JP2012062283A (en) * | 2010-09-16 | 2012-03-29 | Oita Univ | Anti-hair loss composition for cancer chemotherapy induced alopecia |
| WO2012080223A1 (en) | 2010-12-15 | 2012-06-21 | Sigea S.R.L. | Use of glycosaminoglycan lipoate esters in the trichology field |
| JP2013545774A (en) * | 2010-12-15 | 2013-12-26 | シジェア ソシエタ ア レスポンサビリタ リミタータ | Use of glycosaminoglycan lipoic acid ester in dermatology |
| KR20140040678A (en) * | 2010-12-15 | 2014-04-03 | 시제아 에스.알.엘 | Use of glycosaminoglycan lipoate esters in the trichology field |
| KR101896969B1 (en) * | 2010-12-15 | 2018-09-10 | 시제아 에스.알.엘 | Use of glycosaminoglycan lipoate esters in the trichology field |
| JP2014159421A (en) * | 2014-02-19 | 2014-09-04 | Salon De Rejue Co Ltd | Hair-growing composition |
| EA025550B1 (en) * | 2014-08-08 | 2017-01-30 | Кыргызско-Российский Славянский Университет | Method of treating alopecia |
| WO2016170990A1 (en) * | 2015-04-18 | 2016-10-27 | ジェイオーコスメティックス株式会社 | Tyrosinase activity inhibitor and external preparation for skin |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006117995A1 (en) | 2006-11-09 |
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