JP2020514249A - レスベラトロールのシリル化誘導体および神経変性疾患、神経疾患、または炎症性疾患におけるその使用 - Google Patents
レスベラトロールのシリル化誘導体および神経変性疾患、神経疾患、または炎症性疾患におけるその使用 Download PDFInfo
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- HSTZMXCBWJGKHG-CUYWLFDKSA-N trans-piceid Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-CUYWLFDKSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910052722 tritium Chemical group 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
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Abstract
Description
R4、R5、およびR6は、直鎖もしくは分岐のC1-C6アルキル、またはフェニル基の中から独立して選択され、R7は直鎖または分岐のC1-C12アルキルであるが、
ただし、R1、R2、およびR3の少なくとも1つがSiR4R5R6基である化合物を、
炎症性疾患、神経疾患、または神経変性疾患の治療または予防のための薬剤の製造に使用することに関する。
から選択される。
R4、R5、およびR6は、直鎖もしくは分岐のC1-C6アルキル、またはフェニル基の中から独立して選択され、R7は直鎖または分岐のC1-C12アルキルであるが、
ただし、R1、R2、およびR3の少なくとも1つがSiR4R5R6基であり、かつ以下の化合物:
-(E)-(5-(4-(トリメチルシリルオキシ)スチリル)-1,3-フェニレン)ビス(オキシ)ビス(トリメチルシラン)、
-(E)-4-(3,5-ビス(トリイソプロピルシリルオキシ)スチリル)フェノール、
-(E)-3-(tert-ブチルジメチルシリルオキシ)-5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)フェノール、
-(E)-4-(3,5-ビス(tert-ブチルジメチルシリルオキシ)スチリル)フェノール、
-(E)-3-(tert-ブチルジメチルシリルオキシ)-5-(4-ヒドロキシスチリル)フェノール、
-(E)-5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)ベンゼン-1,3-ジオール、
-(E)-(5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)-1,3-フェニレン)ビス(オキシ)ビス(tert-ブチルジメチルシラン)のうちの1つではない、化合物に関する。
から選択される。
レスベラトロール(1当量)とイミダゾール(2.5当量)とを、DMFと共に丸底フラスコに攪拌しながら加え(3ml/mmolのレスベラトロール)、0℃に冷却した。続いて、対応するシリルクロリド(1.4当量〜1.55当量)を2回に分け、第1回目は半分を0時間時に、第2回目は残りの半分を3時間時に滴加した。反応物を室温で全6時間攪拌した。反応混合物を濾過し、水で希釈し、酢酸エチル(3×20ml)で抽出した。混合有機相をMgSO4で乾燥し、濾過して、乾燥するまで濃縮し、シリカゲルカラムクロマトグラフィーでヘキサン/酢酸エチル混合物を用いて溶出することにより精製した。
一般的な方法に従って、レスベラトロール(830mg、3.64mmol)とtert-ブチルジメチルシリルクロリド(849.55mg、5.64mmol)とを用いて、反応混合物をヘキサン/酢酸エチルの勾配(8:1〜2:1)を用いたカラムクロマトグラフィーにより精製した後に、化合物1、化合物2、および化合物3、さらにはモノシリル化誘導体を得た。
一般的な方法に従って、レスベラトロール(816mg、3.57mmol)とトリイソプロピルシリルクロリド(1.19、5.54mmol)とを用いて、反応混合物をヘキサン/酢酸エチルの勾配(10:1〜1:1)を用いたカラムクロマトグラフィーにより精製した後に、化合物4、化合物5、および化合物6、さらにはモノシリル化誘導体を得た。
一般的な方法に従って、レスベラトロール(809mg、3.54mmol)とエチルシリルクロリド(1.19、5.49mmol)とを用いて、反応混合物をヘキサン/酢酸エチルの勾配(10:1〜1:1)を用いたカラムクロマトグラフィーにより精製した後に、化合物7、化合物8、および化合物9、さらにはモノシリル化誘導体を得た。
イソシアン酸エチル(1.5当量)とトリエチルアミン(2当量)とを、3,4'-ジチイソプロピルシリル(dithiisopropylsilyl)・レスベラトロールまたは3,5-ジチイソプロピルシリル・レスベラトロール(1当量)のジクロロメタン溶液に加えた。室温で1時間反応させた後、反応物を濃縮し、クロマトグラフィーカラムでヘキサン:酢酸エチル(2:1〜0:1)を用いて溶出することにより精製した。
攪拌しながら、不活性アルゴン雰囲気下で、3,4'-ジトリイソプロピルシリル・レスベラトロールまたは3,5-ジトリイソプロピルシリル・レスベラトロール(1当量)を無水ジクロロメタン15mLに溶解し、ペルアセチルグルコーストリフルオロアセトイミダート(1.5当量)と三フッ化ホウ素エーテラート(0.1当量)とを加えた。30分間反応させた後、トリエチルアミン5mLを加え、濃縮し、シリカゲル精製カラムに加え、ヘキサンと酢酸エチル(5:1)の混合物を用いて溶出した。得られた生成物を、ジクロロメタン、水、およびメタノール(5mL、2:1:2)の混合液に溶解し、炭酸水素ナトリウム(3当量)を加えた。グルコース単位の中のアセテート単位を脱保護した後に(24時間〜48時間)、反応物を濃縮し、カラムクロマトグラフィーでヘキサン:酢酸エチル(1:1〜1:3)を用いて溶出することにより精製した。
3,4'-O-ジトリイソプロピルシリル-5-グルコシル・レスベラトロールまたは3,5-O-ジトリイソプロピルシリル-4'-グルコシル・レスベラトロール(1当量)を、メチルtert-ブチルエーテルと、オクタン酸ビニル(3当量)と、酵素のLypozyme TL IM(登録商標)(レスベラトロール誘導体とグラム単位で同量)との混合物に溶解した。3日間反応させた後に、酵素を濾過し、酢酸エチルとメタノールとで洗浄した。溶媒を濃縮した後、それをシリカカラムのクロマトグラフィーでヘキサン:酢酸エチル(2:1〜1:3)を用いて溶出することにより精製した。
3,5-O-トリエチルシリル・レスベラトロール(9)(1当量)をtert-ブタノールに溶解し、対応する脂肪酸のビニルエステル(6当量)とNovozyme 435(登録商標)(約100mg)とを加えた。反応物を回転振盪させながら50℃で60時間反応させた。反応させた後、酵素を除去するために反応物を濾過し、少量のメタノールで洗浄した。得られた粗製物を、シリカゲルカラムクロマトグラフィーにより移動相としてヘキサンと酢酸エチルとの混合物の勾配(100:0〜1:1)を用いて精製した。
コラーゲン(100ng/ml)で前処理し、ペニシリン/ストレプトマイシンと10%不活化ウシ胎児血清とを補充したF12培地を入れたペトリ皿で、SH-SY5Y神経芽細胞腫細胞株を培養した。
RAW264.7マクロファージをP75で、ペニシリン/ストレプトマイシンおよび10%不活化ウシ胎児血清を補充した高グルコースDMEMを用いて培養した。
サイトカインの生成を測定するために、5×105個のRAW264.7マクロファージを24ウェルプレートに播種した(1つのウェルあたり0.5ml)。続いて、評価する化合物を加え(10μM)、マクロファージを、LPS(1μg/ml)を培養培地に添加することによって刺激するか、または刺激しなかった。24時間後、上清のIL-6とTNF-αのレベルを、ELISAでBD PharMingenとPrepoTechから入手した捕捉抗体およびビオチン化抗体を用いて既知のプロトコルに従って測定した。培地の亜硝酸塩の濃度を、グリース試薬を用いて確立されたプロトコルに従って測定することで、24時間時の上清のNOレベルを間接的に測定した。各測定値に対しては最小限、2つの独立した実験と、1つの実験あたり3回の反復測定とを行った。値は平均±標準偏差として表した。
本評価の目的は、神経毒ペンチレンテトラゾール(PTZ)により誘発される神経毒性モデルにおける様々なレスベラトロールの誘導体の保護効果を分析することである。実験モデルとして、ゼブラフィッシュ(Danio rerio)を用いて、受精5日後(5dpf)の幼生において化合物がアセチルコリンエステラーゼ活性(AChE)に及ぼす影響を検討した。
化合物15を、ハンチントン病のマウスモデルにおける可能性のある治療法として調べた。化合物のレスベラトロール(RES)を参照として追加した。
化合物15を、多発性硬化症のマウスモデルにおける可能性のある治療法として調べた。化合物のレスベラトロール(RES)を参照として追加した。実験的なアレルギー性脳脊髄炎モデル(EAE)を多発性硬化症の動物モデルとして使用した。
-Tween 80乳化剤を含まないビヒクル(対照EAE(T無し))
-Tween 80乳化剤を含むビヒクル(EAE-T対照)
-予防用RES(Tween 80乳化剤を含まない)(RES-PREV)
-治療用RES(Tween 80乳化剤を含まない)(RES-TERAP)
-予防用化合物15(Tween 80乳化剤を含む)(化合物15-PREV)
-治療用化合物15(Tween 80乳化剤を含む)(化合物15-TERAP)
Claims (31)
- 式(I)の化合物であって、
R4、R5、およびR6は、直鎖もしくは分岐のC1-C6アルキル、またはフェニル基の中から独立して選択され、R7は直鎖または分岐のC1-C12アルキルであるが、
ただし、R1、R2、およびR3の少なくとも1つがSiR4R5R6基である化合物の、
炎症性疾患、神経疾患、または神経変性疾患を治療または予防するための薬剤の製造への使用。 - R1およびR2がSiR4R5R6基である、請求項1に記載の化合物の使用。
- R3がHである、請求項2に記載の化合物の使用。
- R3が-NH(CO)R7である、請求項2に記載の化合物の使用。
- R3が以下の炭化水素であり、
- R1およびR3がSiR4R5R6基である、請求項1に記載の化合物の使用。
- R2がHである、請求項6に記載の化合物の使用。
- R2が-NH(CO)R7である、請求項6に記載の化合物の使用。
- R2が以下の炭化水素であり、
- R1、R2、およびR3がSiR4R5R6基である、請求項1に記載の化合物の使用。
- R4およびR5がメチルであり、R6がtert-ブチルである、請求項1から請求項10のいずれか1項に記載の化合物の使用。
- R4、R5、およびR6がエチルである、請求項1から請求項10のいずれか1項に記載の化合物の使用。
- R4、R5、およびR6がイソプロピルである、請求項1から請求項10のいずれか1項に記載の化合物の使用。
- 以下の群:
から選択される、請求項1に記載の化合物の使用。 - 神経疾患または神経変性疾患が、アルツハイマー病、パーキンソン病、ハンチントン病、多発性硬化症、筋萎縮性側索硬化症、前頭側頭型認知症、虚血、およびてんかんから選択される、請求項1から請求項14のいずれか1項に記載の化合物の使用。
- 式(I')の化合物であって、
R4、R5、およびR6は、直鎖もしくは分岐のC1-C6アルキル、またはフェニル基から独立して選択され、R7は直鎖または分岐のC1-C12アルキルであるが、ただし、R1、R2、およびR3の少なくとも1つがSiR4R5R6基であり、かつ以下の化合物:
-(E)-(5-(4-(トリメチルシリルオキシ)スチリル)-1,3-フェニレン)ビス(オキシ)ビス(トリメチルシラン)、
-(E)-4-(3,5-ビス(トリイソプロピルシリルオキシ)スチリル)フェノール、
-(E)-3-(tert-ブチルジメチルシリルオキシ)-5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)フェノール、
-(E)-3-(tert-ブチルジメチルシリルオキシ)-5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)フェノール、
-(E)-3-(tert-ブチルジメチルシリルオキシ)-5-(4-ヒドロキシスチリル)フェノール、
-(E)-5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)ベンゼン-1,3-ジオール、
-(E)-(5-(4-(tert-ブチルジメチルシリルオキシ)スチリル)-1,3-フェニレン)ビス(オキシ)ビス(tert-ブチルジメチルシラン)のうちの1つではない、化合物。 - R1およびR2がSiR4R5R6基である、請求項16に記載の化合物。
- R3がHである、請求項17に記載の化合物。
- R3が-NH(CO)R7である、請求項17に記載の化合物。
- R3が以下の炭化水素であり、
- R1およびR3がSiR4R5R6基である、請求項16に記載の化合物。
- R2がHである、請求項21に記載の化合物。
- R2が-NH(CO)R7である、請求項21に記載の化合物。
- R2が以下の炭化水素であり、
- R1、R2、およびR3がSiR4R5R6基である、請求項16に記載の化合物。
- R4およびR5がメチルであり、R6がtert-ブチルである、請求項16から請求項25のいずれか1項に記載の化合物。
- R4、R5、およびR6がエチルである、請求項16から請求項25のいずれか1項に記載の化合物。
- R4、R5、およびR6がイソプロピルである、請求項16から請求項25のいずれか1項に記載の化合物。
- 以下の群:
から選択される、請求項16に記載の式(I')で表される化合物。 - 請求項16から請求項29のいずれか1項に記載の式(I')で表される化合物の薬剤の製造への使用。
- 請求項16から請求項29のいずれか1項に記載の式(I')で表される化合物を含む、医薬組成物。
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