JP2021513509A - 発毛障害の予防および処置のための組成物 - Google Patents
発毛障害の予防および処置のための組成物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
R1は、H、直線状または分枝C1〜C6アルキル、シクロアルキル、フェニル、−CH2−NH−フェニルであり;
R2は、H、直線状または分枝C1〜C6アルキル、ハロゲン、フェニルであり;
R3は、COO(C1〜C6)アルキル、CONR4R5であり、式中、R4およびR5は、個々に、HもしくはC1〜C6アルキルであるか、またはR1およびR2が一緒になって、チオフェン環と融合したC5〜C7シクロアルキルを形成する、
のイミノオキソチアゾリジン化合物の、発毛障害を処置するための美容的、非治療的使用を提供する。
R1は、H、直線状または分枝C1〜C6アルキル、シクロアルキル、フェニル、−CH2−NH−フェニルであり;
R2は、H、直線状または分枝C1〜C6アルキル、ハロゲン、フェニルであり;
R3は、COO(C1〜C6)アルキル、CONR4R5であり、式中、R4およびR5は、個々に、HもしくはC1〜C6アルキルであるか、またはR1およびR2が一緒になって、チオフェン環と融合したC5〜C7シクロアルキルを形成する、
のイミノオキソチアゾリジン誘導体を提供する。
R1は、H、直線状または分枝C1〜C6アルキル、好ましくはC1〜C3アルキル、(C3〜C6)シクロアルキル、フェニル、−CH2−NH−フェニルであり;
R2は、H、直線状または分枝C1〜C6アルキル、好ましくはC1〜C3アルキル、ハロゲン、フェニルであり;
R3は、COO(C1〜C6)アルキル、好ましくはCOO(C1〜C3)アルキル、CONR4R5であり、式中、R4およびR5は、個々に、HもしくはC1〜C6アルキル、好ましくはC1〜C3アルキルであるか、またはR1およびR2が一緒になって、チオフェン環と融合したC5〜C7シクロアルキルを形成する、
のイミノオキソチアゾリジン化合物の、発毛を促進するため、または脱毛を予防および/もしくは遅延させるための美容的/非治療的使用を提供する。
R2は、Hまたはハロゲン、好ましくはBrであり、
R3は、COOCH3またはCOOCH2CH3である。
R1はメチルであり、R2はBrであり、R3はCOOエチルであり;
R1はメチルであり、R2はHであり、R3はCOOエチルであり、
R1はHであり、R2はHであり、R3はCOOメチルであり、
R1は−CH2−NH−フェニルであり、R2はBrであり、R3はCOOエチルである。
R1は、H、直線状または分枝C1〜C6アルキル、好ましくはC1〜C3アルキル、(C3〜C6)シクロアルキル、フェニル、−CH2−NH−フェニルであり;
R2は、H、直線状または分枝C1〜C6アルキル、好ましくはC1〜C3アルキル、ハロゲン、フェニルであり;
R3は、COO(C1〜C6)アルキル、好ましくはCOO(C1〜C3)アルキル、CONR4R5であり、式中、R4およびR5は、個々に、HもしくはC1〜C6アルキル、好ましくはC1〜C3アルキルであるか、またはR1およびR2が一緒になって、チオフェン環と融合したC5〜C7シクロアルキルを形成する。
実験的証拠。
本発明の化合物の活性の証拠は、膨出幹細胞の成長および分化において重要な役割を果たすリンパ系エンハンサー結合因子1(Lef1)の発現によって提供される(International Journal of Medical Sciences 2013;10(6):738−746)。
試験した化合物は、以下であった:
C1:2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸メチルエステル
C5:2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸エチルエステル。
顕微解剖したヒトアナーゲンVI頭皮HFを、2mMのL−グルタミン(Gibco)、10ng/mlのヒドロコルチゾン(Sigma−Aldrich)、10μg/mlのインスリン(Sigma−Aldrich)および1%のペニシリン/ストレプトマイシン混合物(Gibco)を添加したWilliam’s E培地(Gibco,Life Technologies)の最少培地で5% CO2で37℃で培養して、既に記載されているように(Philpott et al.,1990;Kloepper et al.,2010;Langan et al.,2015)Williams完全培地(WCM)を作成した。24時間後に、培地を、最終濃度0.1%のDMSO(賦形剤)を含むWCMまたはC1およびC5のための最終濃度15μMの試験化合物のいずれかを含む新鮮な培地に置き換えた。qRT−PCTについては、6時間のみ処置した毛包からRNAを抽出した。
RNAはRNeasyキット(Qiagen,USA)で毛包から抽出し、製造者の指示に従ってTetro cDNA合成キット(Bioline)で逆転写した。qPCRを、QuantStudio3(Thermo Fisher)において、Axin2(Hs00610344_m1、Thermo Fisher)、Lef1(Hs01547250_m1、Thermo Fisher)、b−アクチン(Hs01060665_g1、Life Technologies)およびGapdh (Hs02758991_g1、Thermo Fisher)についてのTaqmanプローブを用いて行った。発現レベルは、デルタ−デルタCT方法で算出した。
Lef−1(遺伝子発現)
以下の表は、ビヒクル、C1およびC5で処理された微小切片化された卵胞におけるLef1(mRNA)の遺伝子発現を報告する。
本発明のイミノオキソチアゾリジン化合物、特に以下の表Iに報告されている化合物の発毛促進活性を評価することを目的とした追加の試験。
ヒト卵胞皮膚乳頭細胞(HFDPC)
ヒト卵胞皮膚乳頭細胞(HFDPC)を、Promocell (ドイツ)から購入した。
陽性対照:Way316606
陰性対照:同一の試料培養条件下での卵胞皮膚乳頭細胞における未処理細胞。
LEF1の発現は、RT−PCRで調べた。分析は、Applied Biosystemsによって供給されているTaqMan Gene Expression Assayを使用して、報告された方法(Gibson et al,1996;Heid et al,1996)に従って行った。簡単に説明すると、遺伝子特異的PCRオリゴヌクレオチドプライマー対内で、50末端にレポーター蛍光色素(FAM)および30末端にクエンチャー蛍光色素(TAMURA)で標識したオリゴヌクレオチドプローブを設計した。プローブが未変化の場合、レポーター色素放出はクエンチされた。PCRサイクルの延長局面の間、DNAポリメラーゼの核融解活性は、ハイブリダイゼーションプローブを切断し、プローブからレポーター色素を放出した。PCR増幅中に産生された蛍光強度を、反応チューブ内で直接配列検出器によりモニターした(「リアルタイム」)。コンピュータアルゴリズムでは、レポーター色素発光の量をクエンチング色素発光と比較し、ベースラインの標準偏差の10倍にシグナルが達したときの閾値サイクル数(CT)を計算し、それから、試験した種々の遺伝子から転写されたmRNAのレベルが得られた(Gibson et al,1996)。
1.細胞の活性化合物での24時間にわたる処理;
2.RNA抽出;
3.cDNAレトロ転写;
4.定量RT−PCR;
細胞(ヒト卵胞皮膚乳頭細胞)が約80%の融合に達したとき、それらをトリプシン/EDTAで回収し、12ウェルプレートに1×106細胞/mlの密度で播種した後、37℃、5%CO2(24時間)でインキュベートした。
細胞が約80%の融合に達したとき、完全な培地を除去した;細胞をPBS 1Xで1回洗浄し、ヒト卵胞皮膚乳頭細胞中で37℃、5%CO2で少なくとも24時間インキュベートした;
全RNAを単離するための単一の均質な溶液であるTri試薬(Thermo Fisher)を用いて、全RNAを細胞から抽出した。この手順は、全RNA単離のために(ChomczynskiおよびMackey,1995)によって報告された単一ステップ法の改良である。単相溶液中のグアニジンチオシアネートおよびフェノールの混合物であるTri Reagentは、組織試料の均質化または溶解時にDNA、RNA、およびタンパク質を効果的に溶解し、変性剤およびRNA分解酵素阻害剤の独特の組み合わせを含み、簡便な一段階の破壊/分離手順で使用される。
「PRIME SCRIPT RT試薬キット(Perfect Real time)(Takara)」を用いて、全RNAを抽出、定量し増幅した。
RT−PCR解析は、TaqMan線状プローブ(Applied Biosystems)を用いて設定した。これらのプローブは、qPCR適用のために最も広く使用され、公表されている検出化学である。
種々の時点の処理細胞からのcDNAを用いてRTPCRを行い、対照細胞(未処理)を2X TaqMan遺伝子発現マスターミックス10μlおよび20X TaqMan遺伝子発現アッセイ1μlに添加した。各生体試料を二連で処理し、ハウスキーピングTaqMan遺伝子発現アッセイおよび標的TaqMan遺伝子発現アッセイの両方で増幅した。また、非鋳型対照試料(NCT)を、すべての試行に含めた。
・ 95℃、30秒(Amplitaq活性化);
・ 95℃、5秒(変性)
・ 60℃、20秒(アニーリング−拡張)
Stratagene MX3000P機器によって提供されるデータは、内部ソフトウェアMXPro v.4.01によって登録された。増幅が完了した時点で、ソフトウェアは、自動的に2−ΔΔCt法を適用し、処理された試料とキャリブレーターの標的遺伝子間のCt差異を計算し、処理された試料およびキャリブレーター試料のノーマライザー遺伝子のCtsの差異によって補正する。標的およびノーマライザーのCt値は、理想的にはお互いに約10周期以内であるべきである。
24時間のインキュベーション後、試験したすべての化合物はLEF1 mRNA発現を誘導し、刺激することができた(図1)。また、陽性対照として用いたWAY316606も、このような誘導作用を発揮した。
Claims (10)
- R1は、HまたはC1〜C3アルキル、好ましくはメチルであり、
R2は、H、ハロゲン、好ましくはBrまたはC1〜C3アルキル、好ましくはCH3であり、
R3は、COO(C1〜C3)アルキル、好ましくはメチルまたはエチルエステルである、
請求項1に記載の使用。 - 前記化合物が2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸メチルエステルまたは2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸エチルエステルである、請求項1または2に記載の使用。
- 請求項1〜3のいずれか一項に記載の式(I)のイミノオキソチアゾリジン化合物および生理学的に許容可能な担体を含む組成物の、発毛を促進するための、ならびに/または脱毛を予防し、および/もしくは減少させるための美容的使用。
- 前記組成物が局部的もしくは局所的適用用または経口投与用である、請求項4に記載の使用。
- R1がHまたはC1〜C3アルキル、好ましくはメチルであり;
R2がH、ハロゲン、好ましくはBrまたはC1〜C3アルキル、好ましくはCH3であり、
R3がCOO(C1〜C3)アルキル、好ましくはメチルまたはエチルエステルである、
請求項5に記載の使用のための式(I)のイミノオキソチアゾリジン化合物。 - 前記化合物が、2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸メチルエステルまたは2−(2−(2−イミノ−4−オキソ−チアゾリジン−5−イル)−アセチルアミノ)−4,5−ジメチル−チオフェン−3−カルボン酸エチルエステルである、請求項1または2に記載の使用のための式(I)のイミノオキソチアゾリジン化合物。
- 請求項6〜8のいずれか一項に記載の使用のための式(I)のイミノオキソチアゾリジン化合物および薬学的に許容可能な担体を含む、医薬組成物。
- 前記組成物が局部的/局所的適用用または全身投与用である、請求項9に記載の使用のための医薬組成物。
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