JP2021512094A - 新規なクリシン誘導体化合物を有効成分として含む糖尿病合併症の予防または治療用薬学組成物 - Google Patents
新規なクリシン誘導体化合物を有効成分として含む糖尿病合併症の予防または治療用薬学組成物 Download PDFInfo
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A—HUMAN NECESSITIES
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Abstract
Description
R1はC1−4アルキル、C1−6アルケニルおよび−COR3からなる群より選ばれ;
R2はH、ハロゲン、C1−4アルキルおよび−COR4からなる群より選ばれ;
R3およびR4はそれぞれ独立してC1−4アルキルである。
R1はC1−4アルキル、C1−6アルケニルおよび−COR3からなる群より選ばれ;
R2はH、ハロゲン、C1−4アルキルおよび−COR4からなる群より選ばれ;
R3およびR4はそれぞれ独立してC1−4アルキルである。
5,7−ジ−O−アセチルクリシン;
7−O−プレニルクリシン;
7−O−メトキシクリシン;および
5,7−ジ−O−メトキシクリシン。
無水酢酸(10mM)をピリジン50mL及びクリシン(10mM)を含む溶液に滴下した。室温で撹拌しながら2時間反応させた後、40℃で溶媒をロータリーエバポレーターで除去した。
無水アセトン(70mL)にクリシン(10mM)、プレニルブロミド(2.2mM)および無水K2CO3(3.7mM)を添加した後、混合物を65℃で8時間還流させた。
80mLのDMC(Dimethyl Carbonate)中に2.54gのクリシン(0.5mmol)と1.84gの1,8−ジアザビシクロ(5.4.0)ウンデカ−7−エン(1,8-Diazabicyclo(5.4.0)undec-7-ene)を混合し90℃で19時間反応を進めた。
(1)アマドリ化合物(amadori compound)形成に対するヘモグロビン−δ−グルコノラクトン分析(初期段階)
タンパク質糖化の初期段階の評価は、δ−グルコノラクトン分析法(Rahbar et al., 1999)によって決定された。簡単に言えば、37℃で7日間滅菌された暗条件の下で0.2g/L NaN3を含有するリン酸塩緩衝液(pH7.4)で新しいヒト血液(50mg/mL)をブドウ糖(144mg/mL)とともに培養した。
様々な濃度の化合物(対照群を含む)の存在下でウシ血清アルブミン(50mg/mL)をリン酸ナトリウム緩衝液(0.1M、pH7.4)中メチルグリオキサール(100mM)とともに37℃で24時間恒温培養した。
この試験はRahbar等(1999)によって記述された方法を用いてD−リボースの存在下でGKペプチドの架橋結合を阻害するサンプルの能力を評価するに使われた。GKペプチド(26.7mg/mL)をリン酸ナトリウム緩衝液(0.5M、pH7.4)中D−リボース(200mg/mL)と37℃で24時間無菌条件の下で培養した。合成された化合物を10mMおよび50mMで使われたアミノグアニジンを除いて1mMの最終濃度でモデルシステムに添加した。培養期間の終期に、蛍光強度は335nmの励起波長および460nmの放出波長で測定された。
各段階におけるクリシン誘導体の最終糖化産物の形成抑制効果は[表2]の通りである。
アマドリ化合物形成を抑制するためにクリシンとその誘導体の能力を比較した 結果、合成例1と合成例5の初期抑制活性は陽性対照群に比べてそれぞれ4.66倍、13.92倍高かった。合成例2はアマドリ化合物形成に対する最も強力な抑制活性を示したが、これはクリシンおよび陽性対照群よりも66.96倍および422.07倍も高かった。合成例2は0.0025〜0.05μg/mLで1.76〜55.13%の容量依存的阻害率を示した。
クリシンおよび誘導体の抑制活性をAGE形成に対して分析しその結果を表2に示した。AGE抑制剤アミノグアニジン(IC50=136.79μM)を陽性対照群に用い、クリシンは陽性対照群より5.48倍高い活性を示した。
表2に示されているように、合成例2および合成例5はAGE架橋結合に対して有意の抑制活性を示した。合成例2および合成例5はそれぞれ22.33および39.88μMのIC50値を示したが、陽性対照群は低いIC50値(1902.67μM)を示した。
RAW264.7細胞でクリシンおよび誘導体の細胞毒性をMTS分析キットを用いて調べた。細胞(1.6×104/ウェル)を96−ウェルプレートで培養し、サンプル(10、25および100μM)を12、24、48および72時間処理した。培養後、MTS溶液20μL/ウェルを加湿5%CO2大気で37℃で90分間培養した。EL−800ユニバーサルマイクロプレートリーダー(Universal microplate reader)(Bio-Tek Instrument Inc., Winooski,USA)を用いて490nmでの光学密度を3回測定した。治療されていないグループの細胞生存率は100%と設定された。RAW264.7細胞を4×105細胞/ウェルで12−ウェルプレートに播種(seeding)し、LPS(1μg/mL)および24時間様々な濃度のサンプルに培養した。培地中の酸化窒素(NO)濃度は、製造者が記述したグリスト試薬システムを用いて測定した。EL−800ユニバーサルマイクロプレートリーダー(Bio−Tek Instrument Inc., Winooski,USA)を用いて570nmでNOの生成を測定し亜硝酸塩標準検量線[21]と比較した。
RAW264.7細胞に対するクリシン誘導体の抗炎症効果の結果は図1の通りである。
クリシンおよび誘導体を蒸留水に溶解させ溶解度を最大化するために1時間超音波処理して37℃で培養した。超音波処理後、遠心分離(7000g、37℃、5分)で溶解されていないサンプルを除去した。上層液をメタノールで希釈し0.45μm1回用シリンジフィルター(Advantec,Dublin,CA,USA)でろ過しHPLC分析を通してサンプルの濃度を分析した。
クリシン誘導体の溶解度を比較すると[表3]の通りである。
Claims (9)
- R1は−COR3であり、R2はH、−CH3および−COCH3からなる群より選ばれ、R3はC1−4アルキルであることを特徴とする、請求項1に記載の薬学組成物。
- R1は−COCH3であることを特徴とする、請求項2に記載の薬学組成物。
- 上記化学式1の化合物が、下記化合物からなる群より選ばれることを特徴とする、請求項1に記載の薬学組成物:
7−O−アセチルクリシン;
5,7−ジ−O−アセチルクリシン;
7−O−プレニルクリシン;
7−O−メトキシクリシン;および
5,7−ジ−O−メトキシクリシン。 - 上記薬学組成物が、最終糖化産物(Advanced Glycation End products;AGE)の形成を抑制させることを特徴とする、請求項1に記載の薬学組成物。
- 上記糖尿病合併症が、糖尿病性神経障害、糖尿病性腎臓病、糖尿病性心筋梗塞、糖尿病性網膜症、糖尿病性白内障及び糖尿病性足部潰瘍からなる群より選ばれる1種以上であることを特徴とする、請求項1に記載の薬学組成物。
- 請求項1に記載の薬学組成物を含む、薬学的製剤。
- 上記薬学的製剤が、錠剤、丸剤、散剤、カプセル剤、シロップまたはエマルジョン状であることを特徴とする、請求項7に記載の薬学的製剤。
- 上記薬学的製剤が、薬学的に許容可能な担体、補強剤および賦形剤からなる群より選ばれる1種以上を更に含むことを特徴とする、請求項7に記載の薬学的製剤。
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PCT/KR2019/001158 WO2019151732A1 (ko) | 2018-01-31 | 2019-01-28 | 신규한 크리신 유도체 화합물을 유효성분으로 포함하는 당뇨합병증의 예방 또는 치료용 약학 조성물 |
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JP2015227329A (ja) * | 2014-05-09 | 2015-12-17 | サントリーホールディングス株式会社 | メトキシフラボンを含むNOX阻害剤及びNFκB阻害剤 |
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EP1435930A2 (en) * | 2001-10-15 | 2004-07-14 | National Research Council Of Canada | Anti-glycation agents for preventing age-, diabetes-, and smoking-related complications |
EP2046313A4 (en) * | 2006-07-10 | 2012-01-25 | Glucox Biotech Ab | USE OF NAPHTHOQUINONES IN THE TREATMENT AND CONTROL OF DIABETES, INSULIN RESISTANCE AND HYPERGLYCEMIA |
KR101510257B1 (ko) * | 2013-12-30 | 2015-04-09 | 한림대학교 산학협력단 | 크리신(chrysin)을 유효성분으로 하는 당뇨합병성 신세뇨관 섬유화로 인한 신장섬유증 억제용 조성물 |
KR101742096B1 (ko) * | 2016-11-22 | 2017-06-15 | 한림대학교 산학협력단 | 크리신을 함유하는 당뇨병성 망막병증 억제용 조성물 |
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2018
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2019
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- 2019-01-28 JP JP2020541647A patent/JP2021512094A/ja active Pending
- 2019-01-28 US US16/966,859 patent/US20210038562A1/en not_active Abandoned
- 2019-01-28 EP EP19747673.2A patent/EP3747435A4/en not_active Withdrawn
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JP2015227329A (ja) * | 2014-05-09 | 2015-12-17 | サントリーホールディングス株式会社 | メトキシフラボンを含むNOX阻害剤及びNFκB阻害剤 |
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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 6, JPN6022044477, 1999, pages 869 - 874, ISSN: 0005060774 * |
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 62, no. 6, JPN6022044479, 2014, pages 1344 - 1351, ISSN: 0005060775 * |
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KR20190093064A (ko) | 2019-08-08 |
EP3747435A1 (en) | 2020-12-09 |
US20210038562A1 (en) | 2021-02-11 |
KR102032739B1 (ko) | 2019-10-16 |
WO2019151732A1 (ko) | 2019-08-08 |
US20220105072A1 (en) | 2022-04-07 |
CN111655254A (zh) | 2020-09-11 |
EP3747435A4 (en) | 2021-10-13 |
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