JP5759000B2 - 肝疾患治療の薬物の製造におけるジインドリルメタン及びその前駆体並びにその誘導体の応用 - Google Patents
肝疾患治療の薬物の製造におけるジインドリルメタン及びその前駆体並びにその誘導体の応用 Download PDFInfo
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- JP5759000B2 JP5759000B2 JP2013524335A JP2013524335A JP5759000B2 JP 5759000 B2 JP5759000 B2 JP 5759000B2 JP 2013524335 A JP2013524335 A JP 2013524335A JP 2013524335 A JP2013524335 A JP 2013524335A JP 5759000 B2 JP5759000 B2 JP 5759000B2
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- Prior art keywords
- diindolylmethane
- indole
- derivatives
- methanol
- carbon atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
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- A—HUMAN NECESSITIES
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Description
本発明は生物医学技術分野に属し、具体的には、ウイルス性肝炎、アルコール性肝炎、薬物誘発性肝炎、脂肪肝、肝線維化又は肝硬変を治療する薬物の製造における、3,3’−ジインドリルメタン及びインドール−3−メタノール及びその誘導化合物の応用に関する。
肝線維化は、肝臓内にびまん性細胞外マトリックス(特にコラーゲン)が過剰に沈着することである。それは単独の疾患ではなく、多くの慢性肝疾患は肝線維化を引き起こす。その病因は大体、感染性(慢性B型肝炎、C型肝炎、D型ウイルス性肝炎、住血吸虫症など)、先天性代謝異常(肝変性、ヘモクロマトーシス、α1−アンチトリプシン欠乏症)、化学代謝障害(慢性アルコール性肝疾患、慢性薬物誘発性肝疾患)、自己免疫性肝炎、原発性胆汁性肝多発性硬化症及び原発性硬化性胆管炎に分けることができる。その臨床症状は主に疲労、脱力感、食欲不振、消化不良、出血などを含む。そして、治癒期間が遅れると、更に発がんに至る可能性がある。肝線維化治療について、以前は主にグルココルチコイドステロイド、コルヒチン、インターフェロンなどに集中していた。しかし、伝統的な治療の目標は非特異的であり、副作用が大きく、薬物投与停止後に再発し易く、コストが高いなど欠点がある。
本発明で解決する必要がある問題は、人体を有効に保護し、フリーラジカルの損傷を防ぎ、肝線維化発作を防止することができる小分子薬を公開することである。具体的に、インドール−3−-メタノールとジインドリルメタン及び誘導化合物や水溶液注射剤の肝線維化治療効果に関わる。
1.チオアセトアミド(thioacetamide、TAA)のリン酸塩緩衝液を使用し、ICRマウスに腹腔内注射を行い、TAA型肝線維化モデルを構築する。
2.TAA型肝線維化モデルを構築しながら、インドール−3−メタノール、ジインドリルメタン及びその誘導化合物をコーン油に溶解して胃内注入し、肝線維化を治療する。
3.TAA、インドール−3−メタノール、ジインドリルメタン及びその誘導化合物を毎週2回投与する。4週間投与した後、マウスを殺して肝臓を取り出し、それぞれヒドロキシプロリンの測定及びアラニンアミノトランスフェラーゼの測定を行う。
1.チオアセトアミド(thioacetamide、TAA)のリン酸塩緩衝液を使用し、ICRマウスに腹腔内注射を行い、TAA型肝線維化モデルを構築する。
2.TAA型肝線維化モデルを構築しながら、調合済みのインドール−3−メタノール、ジインドリルメタン及びその誘導化合物の水溶性注射製剤を注射し、肝線維化を治療する。
3.TAA、インドール−3−メタノール、ジインドリルメタン及びその誘導化合物を毎週2回投与する。4週間投与した後、マウスを殺して肝臓を取り出し、それぞれヒドロキシプロリンの測定及びアラニンアミノトランスフェラーゼの測定を行う。
1.インドール−3−メタノールとジインドリルメタン及びその誘導化合物の製造
インドール類誘導体(例えば、5−メトキシ、5−クロロ、5−ブロモ、5−フルオロ、5’−メチル、5−ニトロ、N−メチル、及び2−メチルインドール)は、商業購入を通じて取得することができる(南京鋭馬精細化学工業有限公司)。代替されたインドール−3−アセトアルデヒド生成物は、適当なアルコール(例えば、メタノールや水素化ホウ素ナトリウム)の使用を通じて、そのアルデヒド基を還元し、I3Cの置換誘導体を取得する。氷塩浴を通じて、2.9mlジメチルホルムアミドを0℃に冷却してから、ゆっくり(30分以上)と0.86ml塩化ホスホリルを加えた。8.6mmolインドール類誘導体を1.0mlのジメチルホルムアミドに溶解してから、冷却済みの塩化ホスホリル溶液にゆっくり(10分以上)と加えた。澄ました黄色溶液が淡黄色のり状物質になるまで、形成した懸濁液を37℃で60〜90分間加熱した。次に、のり状物質に1mlの氷水を加え、3.75gのKOHを含む水溶液10mlをゆっくり(30分以上)と加えた。この混合物を沸点まで加熱した後に冷却した。濾過して、インドール−3−アセトアルデヒド誘導体を取得し、水で洗って、空気に乾燥した。取得した生成物は13C誘導体の製造に使用される。
I3C、DIM及びメトキシDIMをコーン油で溶解し、2.0mg/ml貯蔵液に調合して準備した。文献報道の方法通り、マウスTAA型肝線維化モデルを構築した。即ち、雄性ICRマウス40匹、体重16−18gを取って、マウスをランダムに4組、即ちTAAモデル群、I3C治療群、DIM治療群、5−メトキシDIM治療群に分けた。各群のマウスの腹腔にTAAのリン酸塩緩衝液(200mg/kg)を注射し、毎週二回投与した。モデル構築した週に治療を開始した。I3C治療群、DIM治療群及び5−メトキシDIM治療群では、20mg/kgで薬剤を胃内注入した。TAAモデル群は、相応の量のコーン油を与えた。毎週二回投与した。モデル構築の4週間後、マウスを殺して病変肝組織を採取し、ヒドロキシプロリンの測定及びアラニンアミノトランスフェラーゼの測定を行った。
病変肝組織を採取し、ホモジネートの上清を取って、アルカリ加水分解法によりヒドロキシプロリン含量を測定した。
(2)肝臓アラニンアミノトランスフェラーゼ結果
マウス血清を採取し、アラニンアミノトランスフェラーゼ含量を測定した。
*P≦0.005を表す。
I3C、DIMI、メトキシDIM用シクロデキストリンと生理食塩水を1.0mg/kgの貯蔵液に調合して必要に備える。マウスTAA肝線維化モデルの構築は実施例1を参照。モデル構築当日、マウスをランダムに4組、即ち、TAAモデル群、I3C治療群、DIM治療群、5−メトキシDIM治療群に分けた。モデル構築の週に治療を開始し、I3C治療群、DIM治療群、5−メトキシDIM治療群には20mg/kgで注射し、TAAモデル群には同等量の生理食塩水を投与し、毎週二回投与した。モデル構築の4週間後、マウスを殺して病変肝組織を採取し、ヒドロキシプロリン測定及びアラニンアミノトランスフェラーゼ測定を行った。ヒドロキシプロリンの測定方法及びアラニンアミノトランスフェラーゼの測定方法は実施例1を参照。
*P≦0.005を表す。
Claims (5)
- 肝線維化を治療する薬物の製造における、3,3’−ジインドリルメタン及びその誘導体の使用であり、小分子化合物3,3’−ジインドリルメタン及びその誘導体の構造は下記通り:
式中、R1、R2、R4、R5、R6、R7、R1’、R2’、R4’、R5’、R6’及びR7’は、水素原子、ハロゲン、ニトロ基、又は主鎖長が1〜10炭素原子である直鎖若しくは分岐アルキル若しくはアルコキシ基である。 - 直鎖又は分岐アルキル又はアルコキシ基の主鎖長が1〜5炭素原子である、請求項1記載の使用。
- ハロゲンは塩素、臭素又はフッ素である、請求項1記載の使用。
- 小分子化合物3,3’−ジインドリルメタン及びその誘導体は次のいずれかである、請求項1記載の使用:5,5’−ジクロロ−ジインドリルメタン、5,5’−ジブロモ−ジインドリルメタン、5,5’−ジフルオロ−ジインドリルメタン、5,5’−ジメチル−ジインドリルメタン、5,5’−ジエチル−ジインドリルメタン、5,5’−ジプロピル−ジインドリルメタン、5,5’−ジブチル−ジインドリルメタン、5,5’−ジペンチル−ジインドリルメタン、5,5’−ジメトキシ−ジインドリルメタン、5,5’−ジエトキシ−ジインドリルメタン、5,5’−ジプロポキシ−ジインドリルメタン、5,5’−ジブトキシ−ジインドリルメタン、5,5’−ジペンチルオキシ−ジインドリルメタン、N,N’−ジメチル−ジインドリルメタン、N,N’−ジエチル−ジインドリルメタン、N,N’−ジプロピル−ジインドリルメタン、N,N’−ジブチル−ジインドリルメタン、N,N’−ジペンチル−ジインドリルメタン、2,2’−ジメチル−ジインドリルメタン、2,2’−ジエチル−ジインドリルメタン、2,2’−ジプロピル−ジインドリルメタン、2,2’−ジブチル−ジインドリルメタン、又は2,2’−ジペンチル−ジインドリルメタン。
- 適用される薬物担体は、コーン油、ジメチルスルホキシド、シクロデキストリン、又はゼラチンカプセルである、請求項1記載の使用。
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