JP2016511282A - ヤクチ(益智(alpiniaeoxyphyllaefructus))およびその全合成から単離される新規な抗神経変性天然化合物 - Google Patents
ヤクチ(益智(alpiniaeoxyphyllaefructus))およびその全合成から単離される新規な抗神経変性天然化合物 Download PDFInfo
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- JP2016511282A JP2016511282A JP2015562522A JP2015562522A JP2016511282A JP 2016511282 A JP2016511282 A JP 2016511282A JP 2015562522 A JP2015562522 A JP 2015562522A JP 2015562522 A JP2015562522 A JP 2015562522A JP 2016511282 A JP2016511282 A JP 2016511282A
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- compound
- methylphenyl
- hydroxy
- methylhexanoic acid
- methyloxy
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- C07C59/40—Unsaturated compounds
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
Description
R1およびR3は各々、H、非置換または置換アルキル、シクロアルキル、アルケニル、アルキニル、アリル、ヘテロアリル、カルボキシ、アルキルオキシ、ヒドロキシル、アミノ、ニトロ、アルキルチオ、アシル、シアノ、アシルアミノ、ハロおよびエステルからなる群から選択する。またR2およびR4は各々、H、非置換または置換アルキル、シクロアルキル、アリル、ヘテロアリル、アルキルオキシ、アシル、アシルアミノおよびハロからなる群から選択する。
図2Aおよび図2Bは、6−OHDA誘発性PC12細胞損傷への、化合物1の効果を示す。「##」はコントロール群と比較してp<0.01。「**」はビヒクル群と比較してp<0.01。
1. 化合物1の物理化学的性質
実施例2:ヤクチから化合物1を単離する方法
実施例3:ヤクチから化合物2および3を単離する方法
実施例4:化合物1、4、5の合成方法
1)1-(2-メトキシ‐5-メチルフェニル)-2-メチルプロパン-1-ワン(l-(2-methoxy-5-methylphenyl)-2-methypropan-l-one)(b)の合成
5.38 (brs, 2H), 6.76 (d, = 8.4 Hz, 1H), 6.85 (s, 1H), 6.97 (d, = 8.4 Hz, 1H)
実施例5 MPP+ 誘発性CGNs損傷を防ぐ効果を検討
実施例6:6-OHDA誘発性ニューロン損傷からPC12を保護する効果を検討
実施例7:MPTP誘発性DAニューロン損傷を弱める効果を検討。
実施例8:MPTPに誘発され、ゼブラフィッシュ幼虫の全移動距離が減少することを弱める効果を検討
実施例9:化合物1およびクリシンの神経保護に対する相乗効果を検討
実施例10:MPTP投与マウスに対する化合物1の神経保護効果を検討
An, L., S. Guan等(2006年)、PC12セル内のMPP+誘発性神経毒性に対するヤクチからのプロトカテク酸、Food and chemical toxicology 44(3): 436-443
ゼブラフィッシュ胚を作成するときのN−カドヘリンの構造および分配:異所性発現の形態形成への影響、Dev Dyn 201(2): 121-136
Cheng, Y., G. He 等 (2008年)、MPTP神経毒性に対するバイカレインの神経保護効果、Neurosci Lett 441(1): 16-20
Du, Y., K. R. Bales 等 (1997年)、培養された小脳顆粒神経細胞のグルタメート媒介アポトーシスは、システインプロテアーゼのカスパーゼ3の活性を要する。Proceedings of the National Academy of Sciences 94(21): 11657-11662
Graziose, R., M. A. Lila 等 (2010年)、漢方薬と現代の創薬技術を融合して、新規な薬品および機能性食品を発見する、Curr Drug Discov Technol 7(1): 2-12
Im, H. I., W. S. Joo 等 (2005年)、バイカレインがマウス内の6-ヒドロキシドーパミン誘発性ドーパミン作動性機能性障害および脂質過酸化を防ぐ、J Pharmacol Sci 98(2): 185-189
Lee, D. H., C. S. Kim 等 (2011年)、アスタキサンチンは、インビボおよびインビトロでMPTP/MPP+誘発性ミトコンドリア機能性障害およびROS製造から守る、Food Chem Toxicol 49(1 ):271-280
Lee, H. J., Y. H. Noh 等 (2005年)、バイカレインがSH-SY5Yセル内の6-ヒドロキシドーパミン誘発性神経毒性を弱毒化する、Eur J Cell Biol 84(11): 897-905
Levites Y., O. Weinreb 等 (2001年) 緑茶ポリフェノール(-)-エピガロカテキン‐3-ガラート がN-メチル-4-フェニル- 1、2、3、6-テトラヒドロピリジン-誘発性ドーパミン作動性神経変性を防止する、J Neurochem 78(5): 1073-1082
Li, W., M. Mak 等 (2009年)、新規な抗アルツハイマーの二量体ビス(7)コグニチン:マルチターゲットを介した神経保護の細胞構造および分子構造、Neurotherapeutics 6(1): 187-201
Lin, M. T. およびM. F. Beal (2006年)、神経変性疾患のミトコンドリア機能性障害および酸化的ストレス、Nature 443(7113): 787-795
Mandel, S., T. Amit 等 (2007年)、アルツハイマー疾患における鉄調整不全:多様式の脳浸透性鉄キレート剤であって、神経保護‐神経レスキューを示し、且つ、アミロイド前駆体タンパク質加工の抑制活動を有する治療薬、Prog Neurobiol 82(6): 348-360
Mu, X., G. He 等 (2009年)、バイカレインが、インビボおよびインビトロで6-ヒドロキシドーパミン誘発性実験的パーキンソニズムにおいて、神経保護効果を示す、Pharmacol Biochem Behav 92(4): 642-648
Mu, X., G. R. He, 等 (2011年)、バイカレインが、C57BL/6マウスのMPTPにより誘発されたニューロン障害から脳を守る、Pharmacol Biochem Behav 98(2): 286-291
Yang, M., J. Sun 等(2009年)、質量分析および液体クロマトグラフィーを用いた漢方薬の植物学分析、Journal of Chromatography A 1216(11): 2045-2062
Zhang, X., G. F. Shi等(2011年)、老化マウスの脾臓および肝臓抗酸化システムに対する、ヤクチ由来のプロトカテク酸のアンチエイジング効果、Cell Biochemistry and Function 29(4): 342-347
Zhang, Z. J., L. C. V. Cheang 等 (2012年)、ヤクチのエタノール性抽出物は、インビトロの6-ヒドロキシドーパミン誘発性損傷およびゼブラフィッシュ内のドーパミン作動性ニューロヤクチのエタノール性抽出物を保護する、Cellular and molecular neurobiology 32(1): 27-40
Claims (31)
- R1およびR3は各々、非置換または置換された(C1−C3)アルキルで、且つ、R2およびR4はHである請求項1に記載の化合物。
- 前記化合物が単離精製された((R)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)である請求項1に記載の化合物。
- 前記化合物が((S)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)または(4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)である請求項1に記載の化合物。
- 請求項1に記載の前記化合物を有する組成物および薬学的に許容される塩または担体。
- 請求項1に記載の化合物を、神経障害を防ぐために用いる使用。
- 請求項1に記載の化合物を、神経変性疾患の治療に用いる使用。
- 前記神経変性疾患がパーキンソン病である請求項7に記載の使用。
- パーキンソン病の治療方法または神経障害もしくは神経細胞損失の予防方法であって、
請求項1に記載の前記化合物を必要な場所に届ける工程を有する方法。 - ヒト患者の神経変性疾患を治療する方法であって、
治療的有効量の請求項1に記載の化合物およびクリシンを患者に投与する工程を有し、
神経保護のために、前記化合物と前記クリシンが相乗効果を示す方法。 - (4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)およびその立体異性体を調整する方法であって、
a) 1‐(2‐メトキシ‐5‐メチルフェニル)‐2‐メチルプロパン‐1‐ワンを得るために、4‐メチルアニソールとイソブチリルクロリドを反応させる工程、
b) エチル‐(2E)‐3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンテ‐2‐エノアートを得るために、前記1‐(2‐メトキシ‐5‐メチルフェニル)‐2‐メチルプロパン‐1‐ワンとホスホノ酢酸トリエチルを反応させる工程、
c) エチル‐3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐ペンテン酸メチルを得るために、エチル‐(2E)‐3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンテ‐2‐エノアートとPd/Cをエタノール中、H2雰囲気下で反応させる工程、
d) 3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンタン‐1‐オールを得るために、前記エチル‐3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐ペンテン酸メチルおよびLAHをTHF中で反応させる工程、
e) 3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンチルメチルスルホン酸を得るために、前記3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンタン‐1‐オールおよびMsClを反応させる工程、
f) 4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐4‐メチルヘキサンニトリルを得るために、前記3‐(2‐メチルオキシ‐5‐メチルフェニル)‐4‐メチルペンチル‐メチルスルホン酸およびNaCNをDMF中で反応させる工程、
g) 4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐5‐メチルヘキサンアミドを得るために、前記4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐5‐メチルヘキサンニトリルの懸濁液およびK2CO3とH2O2とをDMSO中で反応させる工程、
h) 4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐5‐メチルヘキサン酸を得るために、前記4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐5‐メチルヘキサンアミドおよびNaOHを反応させる工程、
i) 4‐(2‐ヒドロキシ‐5‐メチルフェニル) ‐5‐メチルヘキサン酸を得るために、前記4‐(2‐メチルオキシ‐5‐メチルフェニル) ‐5‐メチルヘキサン酸およびHBrを反応させる工程、
j) 前記立体異性体を得るために、前記4‐(2‐ヒドロキシ‐5‐メチルフェニル) ‐5‐メチルヘキサン酸をキラル前駆体−HPLCにより分離する工程、
を有し、前記立体異性体が、((S)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)または((R)4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)である方法。 - R1およびR3は各々、非置換または置換された(C1‐C3)アルキルで、且つ、R2およびR4はHである、請求項12に記載の化合物。
- 前記化合物が、単離精製された((4S)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)または((4R)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)である請求項12に記載の化合物。
- 請求項12に記載の化合物を有する組成物および薬学的に許容される塩または担体。
- 請求項12に記載の化合物を、神経障害を防ぐために用いる使用。
- 請求項12に記載の化合物を、神経変性疾患を治療するために用いる使用。
- 前記神経変性疾患がパーキンソン病である請求項17に記載の使用。
- パーキンソン病の治療方法または神経障害もしくは神経細胞損失の予防方法であって、請求項12に記載の前記化合物を必要な場所に届ける工程を有する方法。
- ヤクチから分離精製した化合物を調整する方法であって、
a) ヤクチのサンプルを水性アルコール溶液により低圧、熱還流の下抽出し、溶媒を除去して粗抽出液を得る工程、
b) 工程(a)の前記粗抽出液をエタノールにより再構成し、エタノール抽出液を得る工程、
c) 前記エタノール抽出液をシリカゲルに取り入れ、エタノールを除去してシリカゲル抽出物を得る工程、
d) 前記シリカゲル抽出物を順に、有機溶媒により低圧、熱還流の下、抽出し、生体活性切片を得る工程、
e) 前記生体活性切片を分別し、極性が高くなる溶媒混合液により溶出し、第1生体活性画分を得る工程、
f) 工程(e)の前記第1生体活性画分を精製し、前記化合物を得る工程
を有し、
前記化合物は、(R)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)、(4S)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)および((4R)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)からなる群から選択する方法。 - 請求項20に記載の方法であって、工程f)がさらに
g)工程(e)の前記第1生体活性画分を分画し、極性が高くなる溶媒混合液により溶出し、第2生体活性画分を得る工程、
h)前記第2生体活性画分をイソクラティック溶出により精製し((R)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)を得る工程、
を有する方法。 - 請求項20に記載の方法であって、工程f)がさらに、イソクラティック溶出で、分取高速液体クロマトグラフィーにより、前記工程e)の第1生体活性画分を精製し、化合物((4S)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)および前記((4R)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)を得る方法。
- 工程a)の前記水性アルコール溶液が、95%エタノールを有する請求項20に記載の方法。
- 工程d)で順次使用される前記有機溶媒は、石油、酢酸エチル、エタノールである請求項20に記載の方法。
- 工程e)で使用される前記溶媒混合液は、クロロホルム/メタノール混合液である請求項20に記載の方法。
- 工程e)の前記極性が高くなるクロロホルム/メタノールが、100:0から4:1である請求項25に記載の方法。
- 工程g)で使用される前記溶媒混合液は、クロロホルム/メタノール混合液である請求項21に記載の方法。
- 工程g)の前記極性が高くなるクロロホルム/メタノールが、100:0から49:1である請求項27に記載の方法。
- 工程h)の前記精製および溶出を、セファデックスLH−20を充填用具として用いてゲル濾過カラムクロマトグラフィーにより行う、請求項21に記載の方法。
- (R)‐4‐(2‐ヒドロキシ‐5‐メチルフェニル)‐5‐メチルヘキサン酸)のイソクラティック溶出のために、工程h)でメタノールを使用する請求項21に記載の方法。
- ((4S)‐4-(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)および((4R)‐4‐(3‐ヒドロキシ‐3‐メチル‐6‐オキソシクロヘックス‐1‐エニル)‐5‐メチルヘキサン酸)のイソクラティック溶出のために、工程f)で25%アセトニトリルを使用する請求項22に記載の方法。
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