JP2610524B2 - Hair restorer - Google Patents
Hair restorerInfo
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- JP2610524B2 JP2610524B2 JP27355489A JP27355489A JP2610524B2 JP 2610524 B2 JP2610524 B2 JP 2610524B2 JP 27355489 A JP27355489 A JP 27355489A JP 27355489 A JP27355489 A JP 27355489A JP 2610524 B2 JP2610524 B2 JP 2610524B2
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は育毛剤に関し、更に詳細には、フタリド誘導
体を有効成分として含有する育毛剤に関する。Description: TECHNICAL FIELD The present invention relates to a hair restorer, and more particularly, to a hair restorer containing a phthalide derivative as an active ingredient.
男性型脱毛症、円形脱毛症などの多くの脱毛症は、未
だその発症メカニズムの詳細が不明である。従来、その
治療には経験的に、血行促進剤、免疫抑制剤、代謝亢進
剤、ビタミン剤、抗男性ホルモン剤等が用いられてい
る。Many alopecia, such as androgenetic alopecia and alopecia areata, the details of the mechanism of their development are still unknown. Conventionally, a blood circulation promoter, an immunosuppressant, a metabolic enhancer, a vitamin, an antiandrogen, and the like have been empirically used for the treatment.
しかしながら、これらの薬剤は、症状や個人によって
は効果がない場合が多いだけでなく、その効果も未だ満
足できるものではなかった。However, these drugs are not only ineffective in many cases depending on the symptoms and individuals, but their effects have not been satisfactory.
従って、症状や個人にかかわらず、多くの脱毛症に有
効な育毛剤の開発が望まれていた。Therefore, development of a hair restorer effective for many alopecia has been desired regardless of symptoms and individuals.
斯かる実情において、本発明者らは、多くの化合物の
育毛作用について鋭意研究を行った結果、後記一般式
(I)で表わされるフタリド誘導体が強い育毛作用を有
することを見出し、本発明を完成した。Under such circumstances, the present inventors have conducted intensive studies on the hair-growth effects of many compounds, and as a result, have found that the phthalide derivative represented by the following general formula (I) has a strong hair-growth effect, and completed the present invention. did.
すなわち、本発明は、一般式(I) (式中、R1は炭素数3〜16の直鎖もしくは分岐アルキル
基または炭素数3〜4の直鎖もしくは分岐アルコキシ基
を示し、R2は水素原子、ヒドロキシ基またはメトキシ基
を示す) で表わされるフタリド誘導体を含有することを特徴とす
る育毛剤を提供するものである。That is, the present invention provides a compound represented by the general formula (I): Wherein R 1 represents a straight-chain or branched alkyl group having 3 to 16 carbon atoms or a straight-chain or branched alkoxy group having 3 to 4 carbon atoms, and R 2 represents a hydrogen atom, a hydroxy group or a methoxy group. It is intended to provide a hair restorer characterized by containing the phthalide derivative represented by the formula (1).
本発明で用いられるフタリド誘導体は、一般式(I)
で表わされるが、式中、R1のうち炭素数3〜16の直鎖ア
ルキル基としては、例えばプロピル、ブチル、ペンチ
ル、ヘキシル、ヘプチル、オクチル、デシル、ドデシ
ル、ヘキサデシル基が挙げられ、分岐アルキル基として
は、例えばイソプロピル、イソブチル、イソアミルなど
が挙げられ、また炭素数3〜4の直鎖もしくは分岐アル
コキシ基としては、例えばイソプロポキシ、プロポキ
シ、ブトキシ基などが挙げられる。The phthalide derivative used in the present invention has the general formula (I)
In the formula, examples of the linear alkyl group having 3 to 16 carbon atoms in R 1 include propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, and hexadecyl groups. Examples of the group include isopropyl, isobutyl, and isoamyl. Examples of the linear or branched alkoxy group having 3 to 4 carbon atoms include an isopropoxy, propoxy, and butoxy group.
これらのフタリド誘導体(I)は、天然または合成さ
れたものの何れでも良く、例えばセリ科植物からエタノ
ール等の有機溶媒または熱水により抽出されるもののほ
か、例えば次の方法により合成することができる。These phthalide derivatives (I) may be either natural or synthetic ones. For example, besides those extracted from an organic solvent such as ethanol or hot water from a Umbelliferae plant, they can be synthesized, for example, by the following method.
(1) 無水フタル酸と酸無水物との反応 (式中、R3は炭素数2〜15の直鎖もしくは分岐アルキル
基を示す) すなわち、無水フタル酸と種々の酸無水物とを加熱反
応せしめてアルキリデンフタリドとし、次いでこれを水
素添加することによりフタリド誘導体(II)が得られ
る。(1) Reaction of phthalic anhydride with acid anhydride (Wherein, R 3 represents a linear or branched alkyl group having 2 to 15 carbon atoms) That is, phthalic anhydride and various acid anhydrides are heated and reacted to form an alkylidenephthalide, which is then hydrogenated. Thereby, a phthalide derivative (II) is obtained.
(2) フタルアルデヒド酸とアルキル金属との反応 (式中、R4は炭素数3〜16の直鎖もしくは分岐アルキル
基を示し、Mは金属原子、金属ハライド等を示す) すなわち、フタルアルデヒド酸とアルキル金属、例え
ばグリニャール試薬などを無水条件下に反応させること
により、フタリド誘導体(III)が得られる。(2) Reaction of phthalaldehyde acid with alkyl metal (In the formula, R 4 represents a straight-chain or branched alkyl group having 3 to 16 carbon atoms, and M represents a metal atom, a metal halide, or the like.) That is, phthalaldehyde acid and an alkyl metal, such as a Grignard reagent, are reacted under anhydrous conditions. To give the phthalide derivative (III).
(3) フタルアルデヒド酸とアルコールとの反応 (式中、R5は炭素数3〜4の直鎖もしくは分岐アルキル
基を示す) すなわち、フタルアルデヒド酸とアルコールとを加熱
反応させることにより、フタリド誘導体(IV)が得られ
る。(3) Reaction of phthalaldehyde acid with alcohol (In the formula, R 5 represents a linear or branched alkyl group having 3 to 4 carbon atoms.) That is, a phthalide derivative (IV) is obtained by causing a phthalaldehyde acid and an alcohol to react with heat.
(4) 安息香酸誘導体のo−位アルキル化(J.Org.Ch
em.,49,737(1984),特開昭63−83080号、同63−83081
号) (式中、R6は炭素数3〜16の直鎖もしくは分岐アルキル
基を示し、R7はアルキル基を示す) すなわち、安息香酸アミド誘導体に、ブチルリチウム
などの塩基を作用させ、これとアルデヒドを反応させた
後、加水分解することによりフタリド誘導体(V)が得
られる。(4) O-Alkylation of benzoic acid derivatives (J. Org. Ch.
em., 49 , 737 (1984), JP-A-63-83080 and JP-A-63-83081.
issue) (In the formula, R 6 represents a linear or branched alkyl group having 3 to 16 carbon atoms, and R 7 represents an alkyl group.) That is, a base such as butyl lithium is allowed to act on a benzoic acid amide derivative, and this is reacted with an aldehyde After reacting, the phthalide derivative (V) is obtained by hydrolysis.
(式中、R6は前記と同じ意味を有する) すなわち、4−メトキシフタリドに、三臭化ホウ素、
三フッ化ホウ素などのルイス酸を作用させることにより
フタリド誘導体(VI)が得られる。これらフタリド誘導
体は、単独または二種以上を組合わせて用いることがで
き、全組成中に0.01〜10重量%(以下、単に%で示
す)、好ましくは0.1〜5%配合される。 (Wherein, R 6 has the same meaning as described above). That is, 4-methoxyphthalide has boron tribromide,
The phthalide derivative (VI) is obtained by the action of a Lewis acid such as boron trifluoride. These phthalide derivatives can be used alone or in combination of two or more, and are blended in the entire composition in an amount of 0.01 to 10% by weight (hereinafter simply referred to as%), preferably 0.1 to 5%.
本発明の育毛剤には、有効成分として上記必須成分の
ほか、通常用いられる養毛薬効剤、例えば抗炎症剤、細
胞賦活剤、皮脂分泌抑制剤、末梢血管拡張剤、アミノ酸
類、ビタミン類等を必要に応じて適宜配合することもで
きる。In the hair restorer of the present invention, in addition to the above-mentioned essential ingredients as active ingredients, commonly used hair restorer active agents such as anti-inflammatory agents, cell activators, sebum secretion inhibitors, peripheral vasodilators, amino acids, vitamins and the like Can be appropriately compounded as needed.
また、本発明の育毛剤は、外用剤として用いられるも
のであればその剤形は特に制限されないが、特に軟膏、
ローション、トニック、スプレー、懸濁液、乳剤などの
塗布剤とするのが好ましい。これらの製剤は通常の方法
により製造することができ、前記有効成分以外に、蒸留
水;エタノール等の低級アルコール類;セタノール等の
高級アルコール類;ポリエチレングリコール、プロピレ
ングリコール等の多価アルコール類;カルボキシメルセ
ルロース、ヒドロキシプロピルセルロース等のセルロー
ス類;動物性、植物性および合成油脂成分;ワセリン、
ロウ、シリコーン、界面活性剤などを本発明の効果を損
なわない範囲で配合することができる。Further, the hair restorer of the present invention is not particularly limited in its dosage form as long as it is used as an external preparation, especially ointment,
It is preferable to use a coating agent such as lotion, tonic, spray, suspension, emulsion and the like. These preparations can be produced by a usual method. In addition to the above-mentioned active ingredients, distilled water; lower alcohols such as ethanol; higher alcohols such as cetanol; polyhydric alcohols such as polyethylene glycol and propylene glycol; Celluloses such as mercellulose and hydroxypropylcellulose; animal, vegetable and synthetic fats and oils components;
A wax, silicone, a surfactant and the like can be blended within a range that does not impair the effects of the present invention.
次に、参考例および実施例を挙げて本発明を更に説明
する。Next, the present invention will be further described with reference to Reference Examples and Examples.
参考例1 3−ブチルフタリドの合成: 無水フタル酸(60.0g,0.41mol)、無水吉草酸(79.3
g,0.4mol)および酢酸ナトリウム(21.0g,0.26mol)の
混合物を170℃に加熱すると、CO2の発泡と共に反応が進
行する。7時間後、減圧蒸留によりブチリデンフタリド
を41.7g(0.22mol)得た。収率55%。このブチリデンフ
タリドをエタノールに溶かし、5%パラジウム−炭素2.
0g(5%)を加えて、水素圧40atmで水添を行う。2時
間後、濾過により触媒を除去する。減圧蒸留により、3
−ブチルフタリドを得た。収率55%。Reference Example 1 Synthesis of 3-butylphthalide: phthalic anhydride (60.0 g, 0.41 mol), valeric anhydride (79.3
g, 0.4 mol) and sodium acetate (21.0 g, 0.26 mol) is heated to 170 ° C. and the reaction proceeds with CO 2 bubbling. After 7 hours, 41.7 g (0.22 mol) of butylidenephthalide was obtained by distillation under reduced pressure. 55% yield. This butylidenephthalide is dissolved in ethanol and 5% palladium-carbon 2.
0 g (5%) is added, and hydrogenation is performed at a hydrogen pressure of 40 atm. After 2 hours, the catalyst is removed by filtration. By vacuum distillation, 3
-Butylphthalide was obtained. 55% yield.
b.p. 111−114℃/0.05mmHg1 H−NMR(270MHz,CDCl3,TMS) δ:0.80−0.95(3H,t,J=5.9Hz),1.25−1.60(4H,m),
1.65−2.20(2H,m),5.45−5.50(1H,q,J=4.0Hz),7.4
5−7.9(4H,m) IR(NaCl,cm-1) 3000(s),2950(s),2900(m),1780(s),1640
(m),1490(m) 参考例2 3−ペンチルフタリドの合成: 参考例1と同様にして3−ペンチルフタリドを得た。
収率29%。1 H−NMR(60MHz,CDCl3,TMS) δ:8.10−7.25(4H,m),5.45(1H,dd,J=4.0Hz,6.0H
z),2.30−1.10(8H,m),0.80(3H,t) 参考例3 3−イソアミルフタリドの合成: 窒素ガス雰囲気下、乾燥テトラヒドロフラン(THF)
中、臭化イソアミル(15.1g,100mmol)、金属マグネシ
ウム(2.2g,90mg原子)より、臭化イソアミルマグネシ
ウムを調製した、このグリニャール(Grignard)溶液中
に、室温下、o−フタルアルデヒド酸(6.0g,40mmol)/
THFを徐々に滴下する。THF還流下2時間、更に室温下12
時間熟成後、加水分解さらに酸処理を行った。シリカゲ
ルクロマトグラフィー(ヘキサン/酢酸エチル=20/1)
により精製し、3−イソアミルフタリドを得た。収率38
%。1 H−NMR(270MHz,CDCl3,TMS) δ:0.8(3H,d,J=2.9Hz),0.9(3H,d,J=2.9Hz),1.30
−2.10(5H,m),5.5(1H,dd,J=7.7Hz,4.0Hz),7.5−7.
9(4H,m) IR(NaCl,cm-1) 2950(s),2900(m),1780(s),1620(w),1490
(m) 参考例4 3−オクチルフタリドの合成: 臭化−n−オクチル、金属マグネシウムより調製した
臭化−n−オクチルマグネシムを用い、参考例3と同様
にして3−オクチルフタリドを得た。収率38%。1 H−NMR(60MHz,CDCl3,TMS) δ:0.7−1.0(3H,m),1.0−2.3(14H,m),1.3−2.1(5
H,m),5.3−5.6(1H,m),7.8−8.0(4H,m) IR(NaCl,cm-1) 2950(s),2900(m),1780(s),1620(w),1480
(m) 参考例5 3−ヘキシルフタリドの合成: 参考例3と同様にして3−ヘキシルフタリドを得た。
収率51%。1 H−NMR(200MHz,CDCl3,TMS) δ:0.88(3H,t,J=6.49Hz),2.2−1.1(10H,m),5.47
(1H,dd,J=4.05Hz),7.44(1H,d,J=7.4Hz),7.52(1
H,t,J=7.34Hz),7.67(1H,dt,J=1.01Hz,7.4Hz),7.89
(1H,d,J=7.6Hz) IR(NaCl,cm-1) 2950(m),2880(m),1780(s),1620(w),1480
(m),1300(m),1070(m) 参考例6 3−ヘプチルフタリドの合成: 参考例1と同様にして、カプリル酸無水物(71.4g,26
4mmol)、無水フタル酸(30.0g,203mmol)、酢酸ナトリ
ウム(12.5g,152mmol)より、3−ヘプチリデンフタリ
ドを合成した後、水添し、3−ヘプチルフタリドを得
た。収率27%。1 H−NMR(60MHz,CDCl3,TMS) δ:8.0−7.2(4H,m),5.6−5.3(1H,m),2.3−1.7(2H,
m),1.7−1.0(8H,m),1.0−0.7(3H,m) 参考例7 3−デシルフタリドの合成: 参考例3と同様にして3−デシルフタリドを合成し
た。収率35%。bp 111-114 ° C / 0.05mmHg 1 H-NMR (270MHz, CDCl 3 , TMS) δ: 0.80-0.95 (3H, t, J = 5.9Hz), 1.25-1.60 (4H, m),
1.65-2.20 (2H, m), 5.45-5.50 (1H, q, J = 4.0Hz), 7.4
5-7.9 (4H, m) IR (NaCl, cm -1 ) 3000 (s), 2950 (s), 2900 (m), 1780 (s), 1640
(M), 1490 (m) Reference Example 2 Synthesis of 3-pentylphthalide: In the same manner as in Reference Example 1, 3-pentylphthalide was obtained.
Yield 29%. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 8.10-7.25 (4H, m), 5.45 (1H, dd, J = 4.0Hz, 6.0H
z), 2.30-1.10 (8H, m), 0.80 (3H, t) Reference Example 3 Synthesis of 3-isoamylphthalide: Dry tetrahydrofuran (THF) under a nitrogen gas atmosphere
In the medium, isoamyl magnesium bromide was prepared from isoamyl bromide (15.1 g, 100 mmol) and magnesium metal (2.2 g, 90 mg atom). In this Grignard solution, o-phthalaldehyde acid (6.0 g, 40mmol) /
THF is slowly added dropwise. 2 hours under reflux with THF
After aging for a time, hydrolysis and acid treatment were performed. Silica gel chromatography (hexane / ethyl acetate = 20/1)
To give 3-isoamylphthalide. Yield 38
%. 1 H-NMR (270 MHz, CDCl 3 , TMS) δ: 0.8 (3H, d, J = 2.9 Hz), 0.9 (3H, d, J = 2.9 Hz), 1.30
−2.10 (5H, m), 5.5 (1H, dd, J = 7.7Hz, 4.0Hz), 7.5−7.
9 (4H, m) IR (NaCl, cm -1 ) 2950 (s), 2900 (m), 1780 (s), 1620 (w), 1490
(M) Reference Example 4 Synthesis of 3-octylphthalide: Using 3-n-octyl bromide and magnesium n-octylmagnesium prepared from magnesium metal, 3-octylphthalide was obtained in the same manner as in Reference Example 3. Was. Yield 38%. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 0.7-1.0 (3H, m), 1.0-2.3 (14H, m), 1.3-2.1 (5
H, m), 5.3-5.6 (1H, m), 7.8-8.0 (4H, m) IR (NaCl, cm- 1 ) 2950 (s), 2900 (m), 1780 (s), 1620 (w), 1480
(M) Reference Example 5 Synthesis of 3-hexylphthalide: In the same manner as in Reference Example 3, 3-hexylphthalide was obtained.
Yield 51%. 1 H-NMR (200 MHz, CDCl 3 , TMS) δ: 0.88 (3H, t, J = 6.49 Hz), 2.2-1.1 (10H, m), 5.47
(1H, dd, J = 4.05Hz), 7.44 (1H, d, J = 7.4Hz), 7.52 (1
H, t, J = 7.34 Hz), 7.67 (1H, dt, J = 1.01 Hz, 7.4 Hz), 7.89
(1H, d, J = 7.6Hz) IR (NaCl, cm -1 ) 2950 (m), 2880 (m), 1780 (s), 1620 (w), 1480
(M), 1300 (m), 1070 (m) Reference Example 6 Synthesis of 3-heptylphthalide: In the same manner as in Reference Example 1, caprylic anhydride (71.4 g, 26
After synthesizing 3-heptylidenephthalide from 4 mmol), phthalic anhydride (30.0 g, 203 mmol) and sodium acetate (12.5 g, 152 mmol), hydrogenation was performed to obtain 3-heptylphthalide. Yield 27%. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 8.0-7.2 (4H, m), 5.6-5.3 (1H, m), 2.3-1.7 (2H,
m), 1.7-1.0 (8H, m), 1.0-0.7 (3H, m) Reference Example 7 Synthesis of 3-decylphthalide: In the same manner as in Reference Example 3, 3-decylphthalide was synthesized. 35% yield.
m.pp. 39.5−40.9℃1 H−NMR(60MHz,CDCl3,TMS) δ:8.0−7.2(4H,m),5.6−5.2(1H,m),2.2−0.6(21
H,m) IR(KBr,cm-1) 2950(s),2900(m),1780(s),1620(w),1490
(m),1080(m) 参考例8 3−ドデシルフタリドの合成: 参考例3と同様にして3−ドデシルフタリドを得た。
収率31%。m.pp. 39.5-40.9 ° C 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 8.0-7.2 (4H, m), 5.6-5.2 (1H, m), 2.2-0.6 (21
H, m) IR (KBr, cm -1 ) 2950 (s), 2900 (m), 1780 (s), 1620 (w), 1490
(M), 1080 (m) Reference Example 8 Synthesis of 3-dodecylphthalide: In the same manner as in Reference Example 3, 3-dodecylphthalide was obtained.
Yield 31%.
m.p. 52.8−53.3℃1 H−NMR(60MHz,CDCl3,TMS) δ:8.0−7.2(4H,m),5.6−5.2(1H,m),2.0−0.7(25
H,m) IR(KBr,cm-1) 2980(s),2900(m),1780(s),1630(w),1620
(w),1480(m),1080(m) 参考例9 3−ヘキサデシルフタリドの合成: 臭化ヘキサデシルと金属マグネシウムより臭化ヘキサ
デシルマグネシウムを調製し、参考例3と同様にして3
−ヘキサデシルフタリドを得た。収率15.4%。1 H−NMR(270MHz,CDCl3,TMS) δ:7.91(1H,d,J=7.69Hz),7.69−7.51(2H,m),7.45
(1H,d,J=6.59Hz),5.51−5.48(1H,m),2.04−1.76
(1H,m),1.57−0.92(28H,m),0.90(3H,t,J=6.22H
z) IR(KBr,cm-1) 2950(s),2900(m),1770(s),1630(w),1490
(m),1100(m) 参考例10 3−イソプロポキシフタリドの合成: o−フタルアルデヒド酸(6.0g,40mmol)、イソプロ
ピルアルコール(4.8g,80.0mmol)の混合物を100℃、6
時間反応させ、3−イソプロポキシフタリドを得た。収
率75.0%。mp 52.8-53.3 ° C. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 8.0-7.2 (4H, m), 5.6-5.2 (1H, m), 2.0-0.7 (25
H, m) IR (KBr, cm -1 ) 2980 (s), 2900 (m), 1780 (s), 1630 (w), 1620
(W), 1480 (m), 1080 (m) Reference Example 9 Synthesis of 3-hexadecylphthalide: Hexadecylmagnesium bromide was prepared from hexadecyl bromide and magnesium metal, and was prepared in the same manner as in Reference Example 3.
-Hexadecylphthalide was obtained. Yield 15.4%. 1 H-NMR (270 MHz, CDCl 3 , TMS) δ: 7.91 (1H, d, J = 7.69 Hz), 7.69-7.51 (2H, m), 7.45
(1H, d, J = 6.59 Hz), 5.51-5.48 (1H, m), 2.04-1.76
(1H, m), 1.57−0.92 (28H, m), 0.90 (3H, t, J = 6.22H
z) IR (KBr, cm -1 ) 2950 (s), 2900 (m), 1770 (s), 1630 (w), 1490
(M), 1100 (m) Reference Example 10 Synthesis of 3-isopropoxyphthalide: A mixture of o-phthalaldehyde acid (6.0 g, 40 mmol) and isopropyl alcohol (4.8 g, 80.0 mmol) was heated at 100 ° C. for 6 hours.
The reaction was carried out for an hour to obtain 3-isopropoxyphthalide. Yield 75.0%.
m.p. 65.3−66.7℃1 H−NMR(60MHz,CDCl3,TMS) δ:1.3(3H,d,J=6.0Hz),1.4(3H,d,J=6.0Hz),4.2
(1H,qu,J=6.0Hz),6.4(1H,s),7.4−8.0(4H,m) IR(KBr,cm-1) 3000(m),2950(m),1770(s),1620(w),1480
(m),1360(m),1300(m) 参考例11 3−プロポキシフタリドの合成: イソプロピルアルコールの代わりにプロピルアルコー
ルを用いる以外は参考例10と同様にして3−プロポキシ
フタリドを得た。収率72%。1 H−NMR(60MHz,CDCl3,TMS) δ:0.9(3H,t,J=7.0Hz),1.7(2H,q,J=7.0Hz),4.0−
3.6(2H,m),6.3(1H,s),8.0−7.3(4H,m) IR(KBr,cm-1) 3000(m),2950(m),2900(m),1780(s),1630
(w),1480(m),1300(m),1080(m) 参考例12 3−ブトキシフタリドの合成: イソプロピルアルコールの代わりにブチルアルコール
を用いる以外は参考例10と同様にして3−ブトキシフタ
リドを得た。収率87%。1 H−NMR(270MHz,CDCl3,TMS) δ:7.86(1H,d,J=8.06Hz),7.70(1H,d,J=7.33Hz),
7.61−7.57(2H,m),3.93−3.77(2H,m),1.69−1.61
(2H,m),1.45−1.37(2H,m),0.93(3H,t,J=7.33Hz) 参考例13 4−メトキシ−3−ブチルフタリドの合成: 乾燥THF40ml、n−ブチルリチウム/n−ヘキサン14ml
(22.0mmol)、テトラメチルエチレンジアミン(2.56g,
22.0mmol)を混和し、−68℃に冷却し、N,N−ジエチル
−3−メトキシ安息香酸アミド(4.15g,20.0mmol)/THF
を徐々に加え、30分後に、白色結晶を得た。臭化マグネ
シウム・エーテル(11.0g,42.6mmol)を加え反応させた
後、1−ペンタナール(3.5g,40.0mmol)を−78℃で反
応させた。酸加水分解、クロロホルム抽出後、減圧蒸留
により、4−メトキシ−3−ブチルフタリドを得た。収
率22%。mp 65.3-66.7 ° C. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 1.3 (3H, d, J = 6.0 Hz), 1.4 (3H, d, J = 6.0 Hz), 4.2
(1H, qu, J = 6.0Hz), 6.4 (1H, s), 7.4-8.0 (4H, m) IR (KBr, cm -1 ) 3000 (m), 2950 (m), 1770 (s), 1620 (W), 1480
(M), 1360 (m), 1300 (m) Reference Example 11 Synthesis of 3-propoxyphthalide: A 3-propoxyphthalide was obtained in the same manner as in Reference Example 10 except that propyl alcohol was used instead of isopropyl alcohol. . Yield 72%. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 0.9 (3H, t, J = 7.0 Hz), 1.7 (2H, q, J = 7.0 Hz), 4.0-
3.6 (2H, m), 6.3 (1H, s), 8.0-7.3 (4H, m) IR (KBr, cm -1 ) 3000 (m), 2950 (m), 2900 (m), 1780 (s), 1630
(W), 1480 (m), 1300 (m), 1080 (m) Reference Example 12 Synthesis of 3-butoxyphthalide: The procedure of Reference Example 10 was repeated except that butyl alcohol was used instead of isopropyl alcohol. The phthalide was obtained. 87% yield. 1 H-NMR (270 MHz, CDCl 3 , TMS) δ: 7.86 (1 H, d, J = 8.06 Hz), 7.70 (1 H, d, J = 7.33 Hz),
7.61-7.57 (2H, m), 3.93-3.77 (2H, m), 1.69-1.61
(2H, m), 1.45-1.37 (2H, m), 0.93 (3H, t, J = 7.33 Hz) Reference Example 13 Synthesis of 4-methoxy-3-butylphthalide: dry THF 40 ml, n-butyllithium / n-hexane 14ml
(22.0 mmol), tetramethylethylenediamine (2.56 g,
22.0 mmol), cooled to −68 ° C., and N, N-diethyl-3-methoxybenzoic acid amide (4.15 g, 20.0 mmol) / THF
Was gradually added, and after 30 minutes, white crystals were obtained. After adding and reacting magnesium bromide ether (11.0 g, 42.6 mmol), 1-pentanal (3.5 g, 40.0 mmol) was reacted at -78 ° C. After acid hydrolysis and chloroform extraction, 4-methoxy-3-butylphthalide was obtained by distillation under reduced pressure. Yield 22%.
m.p. 44.3−45.3℃1 H−NMR(270MHz,CDCl3,TMS) δ:0.89(3H,t,J=6.96Hz),1.5−1.2(4H,m),1.8−1.
6(1H,m),2.35−2.20(1H,m),5.5(1H,dd,J=7.69Hz,
2.93Hz),7.09(1H,t,J=4.4Hz),7.5−7.4(2H,m) IR(KBr,cm-1) 3000(m),2960(m),2900(w),1780(s),1630
(m),1520(m),1300(s),1060(s) 参考例14 4−メトキシ−3−ヘプチルフタリドの合
成: 窒素ガス雰囲気下、乾燥THF中、m−アニス酸(15.2
g,100mmol)と塩化チオニル(36.3g,305mmol)から、m
−アニシルクロリドを得た。2−アミノ−2−メチル−
1−プロパノール(17.8g,200mmol)と、このm−アニ
シルクロリドを反応させ、更に塩化チオニルを作用さ
せ、2−(3−メトキシフェニル)−4,4−ジメチルオ
キサゾリン塩酸塩を得た。次に、n−ブチルリチウム/n
−ヘキサン(1.6N,20.6ml)と反応させ、更に、オクタ
ナール(7.7g,60mmol)を加え、反応後、反応物を6N HC
l中、120℃で処理し、4−メトキシ−3−ヘプチルフタ
リドを得た。収率48%。mp 44.3-45.3 ° C 1 H-NMR (270 MHz, CDCl 3 , TMS) δ: 0.89 (3H, t, J = 6.96 Hz), 1.5-1.2 (4H, m), 1.8-1.
6 (1H, m), 2.35-2.20 (1H, m), 5.5 (1H, dd, J = 7.69Hz,
2.93Hz), 7.09 (1H, t, J = 4.4Hz), 7.5-7.4 (2H, m) IR (KBr, cm- 1 ) 3000 (m), 2960 (m), 2900 (w), 1780 (s) ), 1630
(M), 1520 (m), 1300 (s), 1060 (s) Reference Example 14 Synthesis of 4-methoxy-3-heptylphthalide: m-anisic acid (15.2) in dry THF under a nitrogen gas atmosphere
g, 100 mmol) and thionyl chloride (36.3 g, 305 mmol), m
-Anisyl chloride was obtained. 2-amino-2-methyl-
This m-anisyl chloride was reacted with 1-propanol (17.8 g, 200 mmol) and further reacted with thionyl chloride to obtain 2- (3-methoxyphenyl) -4,4-dimethyloxazoline hydrochloride. Next, n-butyllithium / n
-Hexane (1.6 N, 20.6 ml), and octanal (7.7 g, 60 mmol) was further added.
Treatment at 120 ° C. in 1 l gave 4-methoxy-3-heptylphthalide. 48% yield.
m.p. 63.9−64.5℃1 H−NMR(60MHz,CDCl3,TMS) δ:1.0−0.6(3H,m),2.3−1.0(12H,m),3.9(3H,m),
5.6−5.3(1H,m),7.1(1H,t,J=4Hz),7.5(2H,J=4H
z) IR(KBr,cm-1) 2950(m),2900(w),1780(s),1640(w),1520
(m),1300(s),1060(m) 参考例15 4−メトキシ−3−デシルフタリドの合成: 参考例14と同様にして4−メトキシ−3−デシルフタ
リドを得た。収率99.3%。mp 63.9-64.5 ° C. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 1.0-0.6 (3H, m), 2.3-1.0 (12H, m), 3.9 (3H, m),
5.6−5.3 (1H, m), 7.1 (1H, t, J = 4Hz), 7.5 (2H, J = 4H
z) IR (KBr, cm -1 ) 2950 (m), 2900 (w), 1780 (s), 1640 (w), 1520
(M), 1300 (s), 1060 (m) Reference Example 15 Synthesis of 4-methoxy-3-decylphthalide: In the same manner as in Reference Example 14, 4-methoxy-3-decylphthalide was obtained. 99.3% yield.
m.p. 57.8−60.7℃1 H−NMR(200MHz,CDCl3,TMS) δ:0.88(3H,t,J=6.2Hz),1.5−1.1(18H,m),5.55(1
H,dd,J=3.1Hz,7.8Hz),7.00(1H,d,J=7.7Hz),7.37
(1H,t,J=7.6Hz),7.47(1H,d,J=7.1Hz) IR(KBr,cm-1) 2950(m),2900(w),1790(s),1640(w),1520
(s),1500(s),1295(s),1060(m) 参考例16 4−ヒドロキシ−3−ブチルフタリドの合
成: 窒素ガス雰囲気下、参考例13で合成した4−メトキシ
−3−ブチルフタリドと三臭化ホウ素/塩化メチレン
(9ml,1N)を作用させ、4−ヒドロキシ−3−ブチルフ
タリドを得た。収率63%。mp 57.8-60.7 ° C. 1 H-NMR (200 MHz, CDCl 3 , TMS) δ: 0.88 (3H, t, J = 6.2 Hz), 1.5-1.1 (18H, m), 5.55 (1
H, dd, J = 3.1Hz, 7.8Hz), 7.00 (1H, d, J = 7.7Hz), 7.37
(1H, t, J = 7.6Hz), 7.47 (1H, d, J = 7.1Hz) IR (KBr, cm -1 ) 2950 (m), 2900 (w), 1790 (s), 1640 (w), 1520
(S), 1500 (s), 1295 (s), 1060 (m) Reference Example 16 Synthesis of 4-hydroxy-3-butylphthalide: 4-methoxy-3-butylphthalide synthesized in Reference Example 13 under a nitrogen gas atmosphere. By reacting with boron tribromide / methylene chloride (9 ml, 1N), 4-hydroxy-3-butylphthalide was obtained. 63% yield.
m.p. 162.5−164℃1 H−NMR(60MHz,CDCl3,TMS) δ:0.9(3H,t,J=5Hz),2.3−1.2(6H,m),2.9(1H,b
s),5.6(1H,dd,J=8.4Hz),7.5−7.1(3H,m) IR(KBr,cm-1) 3240(br),2980(w),2880(w),1730(s),1620
(m),1510(m),1480(m),1300(m),1100(w) 参考例17 4−ヒドロキシ−3−ヘプチルフタリドの合
成: 参考例14で合成した4−メトキシ−3−ヘプチルフタ
リドと三臭化ホウ素を用い、参考例16と同様にして4−
ヒドロキシ−3−ヘプチルフタリドを得た。収率74%。1 H−NMR(60MHz,CDCl3,TMS) δ:0.9(3H,t,J=5Hz),2.3−1.2(6H,m),2.8(1H,b
s),5.6−5.3(1H,m),7.5−7.0(3H,m) IR(KBr,cm-1) 3250(br),2980(w),2950(m),2900(m),1740
(s),1630(m),1480(m),1300(s),1110(m) 参考例18 4−ヒドロキシ−3−デシルフタリドの合
成: 参考例15で合成した4−メトキシ−3−デシルフタリ
ドと三臭化ホウ素を用い、参考例16と同様にして4−ヒ
ドロキシ−3−デシルフタリドを得た。収率62%。mp 162.5-164 ° C. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 0.9 (3 H, t, J = 5 Hz), 2.3-1.2 (6 H, m), 2.9 (1 H, b
s), 5.6 (1H, dd, J = 8.4Hz), 7.5-7.1 (3H, m) IR (KBr, cm- 1 ) 3240 (br), 2980 (w), 2880 (w), 1730 (s) , 1620
(M), 1510 (m), 1480 (m), 1300 (m), 1100 (w) Reference Example 17 Synthesis of 4-hydroxy-3-heptylphthalide: 4-methoxy-3-synthesized in Reference Example 14 Using heptyl phthalide and boron tribromide, 4-
Hydroxy-3-heptylphthalide was obtained. 74% yield. 1 H-NMR (60 MHz, CDCl 3 , TMS) δ: 0.9 (3 H, t, J = 5 Hz), 2.3-1.2 (6 H, m), 2.8 (1 H, b
s), 5.6-5.3 (1H, m), 7.5-7.0 (3H, m) IR (KBr, cm- 1 ) 3250 (br), 2980 (w), 2950 (m), 2900 (m), 1740
(S), 1630 (m), 1480 (m), 1300 (s), 1110 (m) Reference Example 18 Synthesis of 4-hydroxy-3-decylphthalide: 4-methoxy-3-decylphthalide synthesized in Reference Example 15 4-Hydroxy-3-decylphthalide was obtained in the same manner as in Reference Example 16 using boron tribromide. Yield 62%.
m.p. 155.6−157.1℃ IR(KBr,cm-1) 3250(br),2950(m),2900(w),1740(s),1640
(m),1500(m),1310(m),1120(m) 実施例1 参考例1〜18で合成した各種フタリド誘導体を、50%
エタノール水に1%で溶解または懸濁させ、育毛剤を調
製した。それぞれの育毛剤を本発明品1〜18と称する。mp 155.6-157.1 ° C IR (KBr, cm -1 ) 3250 (br), 2950 (m), 2900 (w), 1740 (s), 1640
(M), 1500 (m), 1310 (m), 1120 (m) Example 1 50% of various phthalide derivatives synthesized in Reference Examples 1 to 18
A hair restorer was prepared by dissolving or suspending at 1% in ethanol water. Each hair restorer is referred to as "Products 1 to 18" of the present invention.
試験例1 本発明品1〜18の育毛剤を用い、C3Hマウス背部毛に
於ける養毛・育毛効果について評価した。すなわち、休
止期にある生後7週目のマウス(雄)の背部毛を皮膚に
傷をつけない様に電気バリカン、電気カミソリを用いて
剃毛した(2×4cm2)。これらのマウスを20匹ずつの群
に分け、翌日から、本発明品1〜18の試料を各々の群
に、1匹当り、1日20μ、週5回背後皮膚に塗布し、
これを1ケ月間続けた。また、対照群として、50%エタ
ノール水を用い、同様の実験を行った。試料塗布開始翌
日より剃毛部を写真に撮り、印画紙上で剃毛部に対する
毛の再生の認められた面積の割合(%)を求め、その増
加速度を調べた。表1に15日目と24日目の結果を示し
た。Test Example 1 Using the hair restorers of the products 1 to 18 of the present invention, hair growth and hair growth effects on C3H mouse back hair were evaluated. That is, the back hair of a 7-week-old mouse (male) in the telogen period was shaved (2 × 4 cm 2 ) using an electric clipper and an electric razor so as not to damage the skin. These mice were divided into groups of 20 each, and from the next day, samples of the present invention 1 to 18 were applied to each group on the back skin 5 times a week, 20 μ per day per mouse,
This was continued for one month. Similar experiments were performed using 50% ethanol water as a control group. From the day after the start of the sample application, the shaved portion was photographed, and the ratio (%) of the area of the shaved portion where hair regeneration was observed on the photographic paper was determined, and the rate of increase was examined. Table 1 shows the results on days 15 and 24.
表1の結果から明らかなように、本発明の育毛剤塗布
群での毛の再生速度は、対照群に比べ有意に速かった。
特に参考例4で合成した3−オクチルフタリドと参考例
17で合成した4−ヒドロキシ−3−ヘプチルフタリドは
他のフタリド類に比べ育毛活性が強かった。また、これ
らの育毛剤を塗布されたマウスはすべて健康で、塗布部
位の皮膚には紅斑や落屑等の皮疹も認められなかった。 As is clear from the results in Table 1, the hair regeneration rate in the group to which the hair restorer of the present invention was applied was significantly higher than that in the control group.
In particular, 3-octylphthalide synthesized in Reference Example 4 and Reference Example
4-Hydroxy-3-heptylphthalide synthesized in 17 had stronger hair growth activity than other phthalides. All the mice to which these hair restorers were applied were healthy, and no rash such as erythema or desquamation was observed on the skin at the application site.
実施例2 参考例4で合成した3−オクチルフタリドと参考例17
で合成した4−ヒドロキシ−3−ヘプチルフタリドを、
表2に示す組成のヘアートニック基剤に有効成分として
それぞれ0.2%配合し、育毛剤を調製した。Example 2 3-octylphthalide synthesized in Reference Example 4 and Reference Example 17
4-hydroxy-3-heptylphthalide synthesized in
Hair tonics were prepared by mixing 0.2% each as an active ingredient with a hair tonic base having the composition shown in Table 2.
これらの育毛剤について、育毛効果を評価した。すな
わち、日頃抜け毛の多いことで悩んでいる31から40歳ま
での男性52名を対象とし、頭部正中線より左右に分け、
一方を育毛剤、残る一方をヘアートニック基剤を塗布す
る部位とし、連日使用させた。試験開始0日、1ケ月、
3ケ月、6ケ月目に頭頂部周囲の正中線より、3cmはな
れた3ケ所の7×7mm2の面積のトリコグラムを測定し、
休止期毛率および毛群中の成長期毛の本数を求めた。結
果を表3および表4に示す。 These hair restorers were evaluated for hair restore effect. In other words, targeting 52 men from 31 to 40 years old who are worried about daily hair loss, divided left and right from the head midline,
One was used as a site for applying a hair tonic and the other was applied as a hair tonic base, and used daily. On the first day of the test, one month,
At 3 months and 6 months, the tricogram of the area of 3 × 7mm 2 at 3 places separated from the median line around the crown by 3cm was measured.
The percentage of telogen hair and the number of anagen hairs in the hair group were determined. The results are shown in Tables 3 and 4.
表3および表4の結果から明らかなように、処理期間
1ケ月では、本発明の育毛剤とヘアートニック基剤の塗
布部位には変化を認めなかったが、3ケ月、6ケ月目で
はそれぞれ育毛剤の塗布部位において、休止期毛率の減
少が認められた。また、毛群中の成長期毛の本数におい
ても、それぞれの育毛剤塗布部位で1本の成長期毛より
なる毛群の割合が減少し、これに反比例するように、3
本および4本以上の成長期毛よりなる毛群の割合が増加
しており、本発明の育毛剤処理部での毛の密度の増加が
認められた。 As is clear from the results in Tables 3 and 4, no change was observed in the application site of the hair growth agent of the present invention and the hair tonic base in the treatment period of one month, but the hair growth was observed in the third and sixth months, respectively. At the site where the agent was applied, a decrease in the telogen rate was observed. Also, in the number of anagen hairs in the hair group, the proportion of the anagen hair group consisting of one anagen hair at each hair growth agent application site decreased.
The proportion of the hair group consisting of the hair and four or more anagen hairs increased, and an increase in the density of the hair in the hair restorative treatment section of the present invention was observed.
本発明の育毛剤は、優れた育毛効果を有し、症状や個
人にかかわらず、多くの脱毛症に有効なものである。The hair restorer of the present invention has an excellent hair restorer effect and is effective for many alopecia irrespective of symptoms or individuals.
Claims (1)
基または炭素数3〜4の直鎖もしくは分岐アルコキシ基
を示し、R2は水素原子、ヒドロキシ基またはメトキシ基
を示す) で表わされるフタリド誘導体を含有することを特徴とす
る育毛剤。(1) Wherein R 1 represents a straight-chain or branched alkyl group having 3 to 16 carbon atoms or a straight-chain or branched alkoxy group having 3 to 4 carbon atoms, and R 2 represents a hydrogen atom, a hydroxy group or a methoxy group. A hair restorer comprising the phthalide derivative represented.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27355489A JP2610524B2 (en) | 1989-10-20 | 1989-10-20 | Hair restorer |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27355489A JP2610524B2 (en) | 1989-10-20 | 1989-10-20 | Hair restorer |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH03135907A JPH03135907A (en) | 1991-06-10 |
JP2610524B2 true JP2610524B2 (en) | 1997-05-14 |
Family
ID=17529429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP27355489A Expired - Fee Related JP2610524B2 (en) | 1989-10-20 | 1989-10-20 | Hair restorer |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2610524B2 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0818955B2 (en) * | 1993-06-14 | 1996-02-28 | 花王株式会社 | Hair nourishment |
JPH0818956B2 (en) * | 1993-06-14 | 1996-02-28 | 花王株式会社 | Hair nourishment |
KR20010103107A (en) * | 2001-10-08 | 2001-11-23 | 이혜복 | Agent for hair growth and restoration containing mucous ingredients from tideland as a main component |
JP4713134B2 (en) * | 2004-11-26 | 2011-06-29 | 高砂香料工業株式会社 | Process for producing optically active alkylphthalides |
US10682335B2 (en) * | 2014-07-28 | 2020-06-16 | Everfront Biotech Inc. | Use of butylidenephthalide (Bdph), method of using the same, and method for preparing pharmaceutical composition containing the same |
CN105310896B (en) * | 2014-07-28 | 2020-07-03 | 易珈生技股份有限公司 | Method for promoting hair growth and composition used therefor |
TWI564031B (en) * | 2014-11-07 | 2017-01-01 | 白金淩 | Nanoparticulate composition having butylidenephthalide, preparation process and pharmaceutical use thereof |
US10543191B2 (en) * | 2017-01-25 | 2020-01-28 | Ejia Biotechnology Co., Ltd. | Use of butylidenephthalide (Bdph), method of using the same, and method for preparing pharmaceutical composition containing the same |
-
1989
- 1989-10-20 JP JP27355489A patent/JP2610524B2/en not_active Expired - Fee Related
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