JP6872195B2 - コラーゲン産生抑制剤 - Google Patents
コラーゲン産生抑制剤 Download PDFInfo
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- JP6872195B2 JP6872195B2 JP2017547621A JP2017547621A JP6872195B2 JP 6872195 B2 JP6872195 B2 JP 6872195B2 JP 2017547621 A JP2017547621 A JP 2017547621A JP 2017547621 A JP2017547621 A JP 2017547621A JP 6872195 B2 JP6872195 B2 JP 6872195B2
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- skin
- collagen production
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
[1]式(1);
式(2);
で表される化合物、並びにそれらの塩(以下、「本件化合物類」ということがある)から選択される1種又は2種以上を含有することを特徴とするコラーゲン産生抑制剤。
[2]式(1)で表される化合物が、以下の式(1’)であることを特徴とする上記[1]に記載のコラーゲン産生抑制剤。
[3]式(2)で表される化合物が、以下の式(2’)であることを特徴とする上記[1]に記載のコラーゲン産生抑制剤。
[4]式(1)で表される化合物が、以下の式(1−1)であることを特徴とする上記[1]に記載のコラーゲン産生抑制剤。
式(2);
で表される化合物、並びにそれらの塩から選択される1種又は2種以上を含有することを特徴とする皮膚線維化疾患の予防又は治療剤。
[7]式(1)で表される化合物が、以下の式(1’)であることを特徴とする上記[6]に記載の予防又は治療剤。
[8]式(2)で表される化合物が、以下の式(2’)であることを特徴とする上記[6]に記載の予防又は治療剤。
[9]式(1)で表される化合物が、以下の式(1−1)であることを特徴とする上記[6]に記載の予防又は治療剤。
本件化合物類に含まれる化合物は、以下の式(1)又は式(2)で表される化合物である。
式(1)及び式(2)で表される化合物は、公知の有機化学反応を用いる有機合成手法によって得ることができる。
式(1)で表される化合物は、以下に示すように式(3)で表されるカルボン酸化合物と式(4)で表されるインドール誘導体とをマイケル反応させることにより得ることができる。
式(2)で表される化合物は、式(6)で表される5−ヒドロキシ−3−インドール酢酸誘導体を出発原料として、合成することができる。具体的には、式(6)で表される5−ヒドロキシ−3−インドール酢酸を、メタノールやエタノール、プロパノール、イソプロパノール等のアルコール中、酸性条件下で反応させることにより、式(7)で表されるエステル体へと誘導する。
次に、上記エステル体と式(8)で表されるハロゲン化合物とを塩基の存在下反応させることで、式(9)で表される化合物を合成できる。上記の塩基としては、水素化ナトリウムや、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムといったアルカリ金属の炭酸塩が挙げられる。
続いて、式(9)で表される化合物のエステル部分を加水分解することにより、式(2)で表される化合物が合成される。
上記式(8)中、Xは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子を表す。
上記式(6)、式(7)、式(8)、式(9)におけるR3、R4、m3、m4は、式(2)におけるR3、R4、m3、m4と同じ定義である。
本件化合物類がコラーゲン産生抑制作用を有することを確認するために、強皮症由来皮膚線維芽細胞を用い、コラーゲン産生量を指標とした解析を行った。なお、強皮症由来皮膚線維芽細胞(東京女子医大の川口教授より分与)は、100U/mLペニシリン(GIBCO社製)、100μg/mLストレプトマイシン(GIBCO社製)、10%ウシ胎児血清(FBS)(GIBCO社製)を含むRPMI1640(GIBCO社製)培養液(以下、「RPMI1640培養液」という)中で5%CO2/20%O2、37℃条件下で培養・維持した。
また、本件化合物#1及び#2は、それぞれ特許文献4に記載の化合物#5(本件化合物#1)及び#35(本件化合物#2)の合成方法にしたがって合成した。
12穴細胞培養プレートに1ウエルあたり3×106個の強皮症由来皮膚線維芽細胞を撒いた後24時間培養し、本件化合物#1又は#2を1、10、又は100μMとなるようにRPMI1640培養液に添加した(図1及び2の「−TGFβ1」参照)。本件化合物1又は#2の添加の際、リコンビナントヒトTGF−β1(Transforming Growth Factor-β1)(Roche社製)を、10ng/mLとなるようにRPMI1640培養液に添加し、コラーゲン産生量を促進させた条件下での実験も行った(図1及び2の「+TGFβ1」参照)。48時間及び72時間培養後、培養液中に産生されたコラーゲン産生量を、ヒトI型コラーゲンELISA定量キット(ACEL社製)を用いて測定した。また、コントロールとして化合物及びTGF−β1非存在下で培養した細胞(図1及び2中の「−TGFβ1のDMSO」)や、化合物非存在下でかつTGF−β1存在下で培養した細胞(図1及び2中の「+TGFβ1のDMSO」)を用いた。なお、図1の「−TGFβ1」は、TGF−β1非存在下の細胞培養を48時間行った結果を示し、「+TGFβ1」は、TGF−β1存在下の細胞培養を72時間行ったときの結果を示す。
強皮症由来皮膚線維芽細胞を、TGF−β1の非存在下及び存在下のいずれの条件下で培養したときも、本件化合物#1又は#2を加えることによりその濃度依存的にコラーゲン産生を抑制することが明らかとなった(図1及び2参照)。この結果は、本件化合物類(本件化合物#1及び#2)は、TGF−β1の有無にかかわらず、皮膚におけるコラーゲン産生や、皮膚におけるコラーゲンの過剰な蓄積を抑制する効果を有することを示すとともに、皮膚線維化の予防又は抑制や、強皮症等の皮膚線維化疾患の予防又は治療に有用であることを示している。
本件化合物類はコラーゲン産生抑制作用を有することが確認されたので、コラーゲン産生増加が原因として生じる皮膚線維化疾患の治療効果の有無について、アトピー性皮膚炎モデルマウスを用いて解析を行った。
雌BALB/Cマウスの両耳介表裏に、それぞれ0.15%ジニトロクロロベンゼン(DNCB)溶液を25μLずつ(計100μL)塗布し、かかる塗布処理を隔日にさらに4回(計5回)行うことにより、DNCB感作アトピー性皮膚炎モデルマウスを調製した。2週間後に、かかるモデルマウスに再度DNCBを塗布し、アトピー性皮膚炎を惹起させた。かかる惹起当日の1時間前と、惹起2〜10日前のそれぞれの日に、本件化合物#1又は#2溶液を、マウスの両耳介表裏に、それぞれ25μLずつ(計100μL[計10、100、又は1000μM])塗布した。アトピー性皮膚炎の惹起から1時間、6時間、及び24時間後に、耳介膨張を計測した(図3参照)。なお、陽性コントロールとして、アトピー性皮膚炎モデルマウスに、アトピー性皮膚炎に対する塗布剤である0.1%タクロリムス(FK506)含有エタノール溶液を塗布した実験を行い(図中の「FK506」)、また、陰性コントロールとして、正常マウスに生理食塩水を塗布した場合の実験(図中の「vehicle」)と、アトピー性皮膚炎モデルマウスに、生理食塩水を塗布した場合の実験(図中の「control」)を行った。
アトピー性皮膚炎の惹起から少なくとも6〜24時間後において、本件化合物#1又は#2を投与すると、耳介膨張の有意な抑制効果が認められた。この結果は、本件化合物類(本件化合物#1及び#2)は、アトピー性皮膚炎の予防又は治療に有用であることを示している。
本件化合物類が、アトピー性皮膚炎の予防又は治療効果を有することが確認されたので、アトピー性皮膚炎以外の皮膚線維化疾患である乾癬の治療効果の有無について、乾癬モデルマウスを用いて解析を行った。
雌BALB/Cマウスの両耳介表裏に、それぞれベセルナクリーム5%(イミキモド12.5mg/クリーム250mg;持田製薬社製)を塗布し、かかる塗布処理を隔日にさらに4回(計5回)行うことにより、イミキモド感作乾癬モデルマウスを調製した。2週間後に、かかるモデルマウスに再度ベセルナクリーム5%を塗布し、乾癬を惹起させた。かかる惹起当日の1時間前と、惹起2〜10日前のそれぞれの日に、本件化合物#1又は#2溶液を、マウスの両耳介表裏に、それぞれ25μLずつ(計100μL[計10、100、又は1000μM])塗布した。乾癬の惹起から12及び14日後に、耳介膨張を計測した(図4参照)。なお、陰性コントロールとして、乾癬モデルマウスに、生理食塩水を塗布した場合の実験(図中の「control」)を行った。
乾癬の惹起から少なくとも12〜14日後において、本件化合物#1又は#2を投与すると、耳介膨張の有意な抑制効果が認められ、乾癬の症状が抑制されることが確認された。この結果は、本件化合物類(本件化合物#1及び#2)は、乾癬の予防又は治療に有用であることを示している。
Claims (7)
- 皮膚線維化疾患が、アトピー性皮膚炎、乾癬、又は強皮症であることを特徴とする請求項4〜6のいずれかに記載の予防又は治療剤。
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SK12752000A3 (sk) * | 1998-02-25 | 2001-03-12 | Genetics Institute, Inc. | Inhibítory fosfolipázových enzýmov, farmaceutický prostriedok s ich obsahom a ich použitie |
DE10305089A1 (de) * | 2003-02-07 | 2004-08-26 | Merckle Gmbh | Neue heteroarylsubstituierte Acetonderivate als Hemmstoffe der Phospholiphase A2 |
CN101384256A (zh) * | 2006-02-27 | 2009-03-11 | 惠氏公司 | 用于治疗肌肉病状的pai-1抑制剂 |
JP6076597B2 (ja) * | 2008-08-09 | 2017-02-08 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 化粧品としてのインドール化合物の使用 |
CA2896437C (en) * | 2012-11-26 | 2021-01-19 | Takaaki Abe | Erythropoietin expression promoter |
JP6372817B2 (ja) * | 2014-03-27 | 2018-08-15 | 国立大学法人東北大学 | 臓器線維化抑制剤 |
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