JP2005232061A - Biocompatibility-imparting agent - Google Patents
Biocompatibility-imparting agent Download PDFInfo
- Publication number
- JP2005232061A JP2005232061A JP2004042011A JP2004042011A JP2005232061A JP 2005232061 A JP2005232061 A JP 2005232061A JP 2004042011 A JP2004042011 A JP 2004042011A JP 2004042011 A JP2004042011 A JP 2004042011A JP 2005232061 A JP2005232061 A JP 2005232061A
- Authority
- JP
- Japan
- Prior art keywords
- mmol
- dodecyloxy
- benzamide
- added
- biocompatibility
- 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.)
- Granted
Links
Landscapes
- Materials For Medical Uses (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polyethers (AREA)
Abstract
Description
本発明は、新規なベンズアミド誘導体に関するものである。さらに詳しくは、生体適合性付与剤等として使用可能なベンズアミド誘導体に関するものである。 The present invention relates to a novel benzamide derivative. More specifically, the present invention relates to a benzamide derivative that can be used as a biocompatibility imparting agent or the like.
医療用材料には、様々な観点からの生体適合性が求められている。その代表的なものとして、細胞に異物認識され難く、蛋白質との相互作用が弱い表面、また、その反対に、蛋白質との相互作用が強く、細胞が接着しやすい表面が挙げられる。
我々はこれまでに、式（２）で示される化合物（ただし、式中で、ＲはＯ（ＣＨ2）nＣＨ3またはＨを、ｍは１から５までの整数を、ｎは１１から１７までの整数を表す。）を合成し、得られた化合物は疎水性表面に固定化可能であり、化合物が固定化された表面は蛋白質との相互作用が弱いことを示した（特許文献１参照）。
We have heretofore obtained a compound represented by the formula (2) (wherein R represents O (CH 2 ) n CH 3 or H, m represents an integer of 1 to 5, and n represents 11 to 17). The obtained compound can be immobilized on a hydrophobic surface, and the surface on which the compound is immobilized showed weak interaction with proteins (see Patent Document 1). ).
また、式（３）で示される化合物（ただし、式中で、ＲはＯ（ＣＨ2）nＣＨ3またはＨを、ｍは２から６までの整数を、ｎは１１から１７までの整数を表す。）を合成し、得られた化合物は疎水性表面に固定化可能であり、化合物が固定化された表面は細胞接着能が高いことを示した（特許文献２参照）。
しかし、式（２）で示される化合物は、生体成分との接触によりエステル結合が加水分解され易いという問題点があった。また、式（３）で示される化合物は、式（２）で示される化合物と混合して細胞接着能を制御して用いようとする場合、化合物の長さや疎水性が不具合を生じる可能性があった。
従って、生体による異物反応が少なく、かつ、容易に加水分解されない生体適合性付与剤、および、その生体適合性付与剤と混合して使用することが可能で、かつ、細胞接着性を有する生体適合性付与剤が求められていた。
Therefore, the biocompatibility imparting agent which is less susceptible to foreign body reaction by the living body and is not easily hydrolyzed, and can be used by mixing with the biocompatibility imparting agent and has bioadhesive properties with cell adhesion. A sex imparting agent has been demanded.
本発明の目的は、生体による異物反応が少なく、かつ、容易に加水分解されない生体適合性付与剤、および、その生体適合性付与剤と混合して使用することが可能で、かつ、細胞接着性を有する生体適合性付与剤、および、それらの生体適合性付与剤を使用した生体適合性材料を提供することにある。 An object of the present invention is to provide a biocompatibility imparting agent that hardly causes foreign body reaction by a living body and is not easily hydrolyzed, and can be used by being mixed with the biocompatibility imparting agent, and has cell adhesiveness. And a biocompatible material using these biocompatibility-imparting agents.
上記課題を鋭意検討した結果、本発明者らは、エチレングリコールのオリゴマーまたはポリマーの一端をアミノ基に変換し、長鎖アルキルオキシ基を有する安息香酸誘導体とアミド結合することによって得られる加水分解に安定な化合物が蛋白質との相互作用が弱いこと、および、エチレングリコールのオリゴマーまたはポリマーの両末端をアミノ基に変換し、長鎖アルキルオキシ基を有する安息香酸誘導体とアミド結合することによって得られる加水分解に安定な化合物が蛋白質との相互作用が強いことを見出して、本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have succeeded in hydrolysis obtained by converting one end of an ethylene glycol oligomer or polymer into an amino group and amide bonding with a benzoic acid derivative having a long-chain alkyloxy group. Stable compounds have weak interactions with proteins, and hydrolyzates obtained by converting both ends of ethylene glycol oligomers or polymers to amino groups and amide bonds with benzoic acid derivatives having long-chain alkyloxy groups. The inventors found that a compound that is stable to degradation has a strong interaction with a protein, and completed the present invention.
すなわち、本発明は、式（１）で示されるベンズアミド誘導体、および、式（１）で示される化合物を有効成分とする生体適合性付与剤、および、式（１）で示される化合物を有効成分とする生体適合性材料を提供するものである。
式（１）で示される化合物は、例えば、エチレングリコールのオリゴマーまたはポリマーの一端を、まず、トシル化して、次いで、トシル基をヨウ素に置換し、さらに、フタルイミドに変換した化合物をヒドラジンで脱保護して得られるエチレングリコールのオリゴマーまたはポリマーの一端がアミノ基に置換された化合物、あるいは、エチレングリコールのオリゴマーまたはポリマーの両端を同様に変換して得られるエチレングリコールのオリゴマーまたはポリマーの両端がアミノ基に置換された化合物を、長鎖のアルキル基がエーテル結合した３，５−ジヒドロキシ安息香酸あるいは３，４，５−トリヒドロキシ安息香酸（バイオオーガニック・アンド・メディシナル・ケミストリー（Bioorg. Med. Chem.）２００２年、１０巻、ｐ．４０１３−４０２２）と、ジシクロヘキシルカルボジイミドや１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド等の適当な縮合剤を用いて縮合することによって得られる。
式（１）で示される化合物を、例えば、エタノール、プロパノール等の溶媒に溶解させ、プラスチックディッシュ、細胞培養容器、中空糸等、様々な形状を持った疎水性表面に接触させることによって固定化することにより、生体適合性材料が得られる。
以下に、本発明をさらに詳細に説明するが、本発明は以下の記述に限定されるものではない。
In the compound represented by the formula (1), for example, one end of an ethylene glycol oligomer or polymer is first tosylated, then the tosyl group is substituted with iodine, and the compound converted to phthalimide is further deprotected with hydrazine. A compound in which one end of an ethylene glycol oligomer or polymer obtained by substitution is replaced with an amino group, or both ends of an ethylene glycol oligomer or polymer obtained by similarly converting both ends of an ethylene glycol oligomer or polymer are amino groups. The compound substituted with 3,5-dihydroxybenzoic acid or 3,4,5-trihydroxybenzoic acid (Bioorganic and Medicinal Chemistry (Bioorg. Med. Chem. ) 2002, 10 volumes, p.4013 And 4022), obtained by condensing using dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) suitable condensing agent such as carbodiimide.
The compound represented by the formula (1) is dissolved in, for example, a solvent such as ethanol or propanol, and immobilized by bringing it into contact with hydrophobic surfaces having various shapes such as plastic dishes, cell culture vessels, and hollow fibers. As a result, a biocompatible material is obtained.
The present invention will be described in more detail below, but the present invention is not limited to the following description.
（Ｎ−（８−ヒドロキシ−３，６−ジオキサオクチル）−３，５−ビス（ドデシロキシ）ベンズアミドの合成）
３,５−ビス（ドデシロキシ）安息香酸（1.24g, 2.53mmol）をジクロロメタン（100ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（0.58g, 3.03mmol）と１−ヒドロキシベンゾトリアゾール水和物（0.41g, 3.03mmol）を加え、室温で１時間撹拌した。その後、８−アミノ−３,６−ジオキサオクタノール（0.45g, 3.03mmol）を加え、室温で１時間撹拌した。反応終了後、反応液をクロロホルムで抽出した後、有機層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝13：1）により精製し、目的物（1.40g, 89%）を得た。
1H-NMR (CDCl3, 600MHz) δ 6.92 (d, 2H, J = 2.1 Hz)、6.82 (s, 1H)、6.56 (s, 1H)、3.96 (t, 4H, J = 6.5 Hz)、3.72〜3.61 (m, 12H)、1.77 (m, 4H)、1.43 (m, 4H)、1.26 (m, 32H)、0.88 (t, 6H, J = 6.5 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m/z 645 ([M+Na]+)。
(Synthesis of N- (8-hydroxy-3,6-dioxaoctyl) -3,5-bis (dodecyloxy) benzamide)
3,5-bis (dodecyloxy) benzoic acid (1.24 g, 2.53 mmol) was dissolved in dichloromethane (100 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.58 g, 3.03 mmol) was dissolved. 1-Hydroxybenzotriazole hydrate (0.41 g, 3.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 8-amino-3,6-dioxaoctanol (0.45 g, 3.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 13: 1) to obtain the desired product (1.40 g, 89%).
1 H-NMR (CDCl 3 , 600 MHz) δ 6.92 (d, 2H, J = 2.1 Hz), 6.82 (s, 1H), 6.56 (s, 1H), 3.96 (t, 4H, J = 6.5 Hz), 3.72 ~ 3.61 (m, 12H), 1.77 (m, 4H), 1.43 (m, 4H), 1.26 (m, 32H), 0.88 (t, 6H, J = 6.5 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m / z 645 ([M + Na] + ).
（Ｎ−（８−アミノ−３，６−ジオキサオクチル）−３，５−ビス（ドデシロキシ）ベンズアミドの合成）
３,５−ビス（ドデシロキシ）安息香酸（0.50g, 1.02mmol）をジクロロメタン（20ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（0.23g, 1.22mmol）と１−ヒドロキシベンゾトリアゾール水和物（0.17g, 1.22mmol）を加え、室温で１時間撹拌した。その後、１,８−ジアミノ−３,６−ジオキサオクタン（0.24ml, 2.04mmol）を加え、室温で２時間撹拌した。反応終了後、反応液をクロロホルムで抽出した後、有機層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝5：1）により精製し、目的物（0.25g, 39%）を得た。
1H-NMR (CDCl3, 600MHz) δ 6.91 (s, 2H)、6.54 (d, 1H, J = 2.1Hz)、3.94 (t, 4H, J = 7.2 Hz)、3.68 (m, 12H)、3.11 (s, 2H)、1.74 (m, 4H)、1.41 (m, 4H)、1.26 (m, 32H)、0.88 (t, 6H, J = 7.2 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m/z 622 ([M+H]+)。
(Synthesis of N- (8-amino-3,6-dioxaoctyl) -3,5-bis (dodecyloxy) benzamide)
3,5-bis (dodecyloxy) benzoic acid (0.50 g, 1.02 mmol) was dissolved in dichloromethane (20 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.22 mmol) was added. 1-Hydroxybenzotriazole hydrate (0.17 g, 1.22 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, 1,8-diamino-3,6-dioxaoctane (0.24 ml, 2.04 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain the desired product (0.25 g, 39%).
1 H-NMR (CDCl 3 , 600 MHz) δ 6.91 (s, 2H), 6.54 (d, 1H, J = 2.1 Hz), 3.94 (t, 4H, J = 7.2 Hz), 3.68 (m, 12H), 3.11. (s, 2H), 1.74 (m, 4H), 1.41 (m, 4H), 1.26 (m, 32H), 0.88 (t, 6H, J = 7.2 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m / z 622 ([M + H] + ).
（Ｎ−（８−ヒドロキシ−３，６−ジオキサオクチル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（4.60g, 6.81mmol）をジクロロメタン（100ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（1.69g, 8.86 mmol）、１−ヒドロキシベンゾトリアゾール（1.19g, 8.86mmol）を加え、室温で１時間攪拌した。その後、８−アミノ−３，６−ジオキサオクタノール（2.99g, 20.1mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）により精製し、目的物(4.99g, 6.19mmol, 91%)を得た。
1H-NMR ( CDCl3, 600 MHz ) δ7.02 ( 2H, s ), 6.68 ( 1H, s ), 4.01 ( 4H, t, J = 6.19 Hz ), 3.98 ( 2H, t, J = 6.19 Hz ), 3.71-3.65 (10H, m), 3.64 (2H, t, J = 4.1 Hz), 1.80 (4H, quint, J = 6.9 Hz ), 1.73 (2H, quint, J = 6.9 Hz), 1.46 (6H, m), 1.33-1.24 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m/z 806.84 ([M+H]+)。
(Synthesis of N- (8-hydroxy-3,6-dioxaoctyl) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (4.60 g, 6.81 mmol) was dissolved in dichloromethane (100 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.69 g, 8.86 mmol) was dissolved. ), 1-hydroxybenzotriazole (1.19 g, 8.86 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 8-amino-3,6-dioxaoctanol (2.99 g, 20.1 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (4.99 g, 6.19 mmol, 91%).
1 H-NMR (CDCl 3 , 600 MHz) δ7.02 (2H, s), 6.68 (1H, s), 4.01 (4H, t, J = 6.19 Hz), 3.98 (2H, t, J = 6.19 Hz) , 3.71-3.65 (10H, m), 3.64 (2H, t, J = 4.1 Hz), 1.80 (4H, quint, J = 6.9 Hz), 1.73 (2H, quint, J = 6.9 Hz), 1.46 (6H, m), 1.33-1.24 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m / z 806.84 ([M + H] + ).
（Ｎ−（８−アミノ−３，６−ジオキサオクチル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（1.10 g, 1.63 mmol）をジクロロメタン（100 ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（0.381 g, 1.96 mmol）、１−ヒドロキシベンゾトリアゾール（0.261g, 1.96mmol）を加え、室温で１時間撹拌した。その後、１，８−ジアミノ−３，６−ジオキサオクタン（1.21g, 8.15 mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）により精製し、目的物（922mg, 1.14mmol, 70%）を得た。
1H-NMR (CDCl3, 600MHz ) δ6.99 (2H, s ), 6.72 (1H, brs ), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz), 3.66 (8H, m ), 3.50 (2H, t, J = 5.5 Hz ), 2.84 (2H, t, J = 5.5 Hz), 1.80 (4H, quint, J = 6.8 Hz), 1.73 (2H, quint, J = 6.8 Hz ), 1.34−1.26 ( 54H, m ), 0.88 (9H, t , J = 6.8 Hz ).
MALDI-TOFMS (Dithranol) m/z 806.08 ([M+H]+)。
(Synthesis of N- (8-amino-3,6-dioxaoctyl) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (1.10 g, 1.63 mmol) was dissolved in dichloromethane (100 ml) to give 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.381 g, 1.96). mmol) and 1-hydroxybenzotriazole (0.261 g, 1.96 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 1,8-diamino-3,6-dioxaoctane (1.21 g, 8.15 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (922 mg, 1.14 mmol, 70%).
1 H-NMR (CDCl 3 , 600 MHz) δ6.99 (2H, s), 6.72 (1H, brs), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz), 3.66 (8H, m), 3.50 (2H, t, J = 5.5 Hz), 2.84 (2H, t, J = 5.5 Hz), 1.80 (4H, quint, J = 6.8 Hz), 1.73 (2H, quint, J = 6.8 Hz), 1.34−1.26 (54H, m), 0.88 (9H, t, J = 6.8 Hz).
MALDI-TOFMS (Dithranol) m / z 806.08 ([M + H] + ).
（Ｎ−（１７−ヒドロキシ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，５−ビス（ドデシロキシ）ベンズアミドの合成）
３,５−ビス（ドデシロキシ）安息香酸（0.29g, 0.59mmol）をジクロロメタン（30ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（0.14g, 0.71mmol）と１−ヒドロキシベンゾトリアゾール水和物（0.09g, 0.71mmol）を加え、室温で１時間撹拌した。その後、１７−アミノ−３,６,９,１２,１５−ペンタオキサヘプタデカノール（0.20g, 0.71mmol）を加え、室温で１時間撹拌した。反応終了後、反応液をクロロホルムで抽出した後、有機層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝50：1−20：1−10：1）により精製し、目的物（0.15g, 32%）を得た。
1H-NMR (CDCl3, 600MHz) δ6.91 (d, 2H, J = 2.8 Hz)、6.55 (t, 1H, J = 2.8 Hz)、3.96 (t, 4H, J = 6.5 Hz)、3.71-3.58 (m, 24H)、1.76 (m, 4H)、1.43 (m, 4H)、1.34-1.26 (m, 32H)、0.88 (t, 6H, J = 6.9 Hz)、
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m/z 755 ([M+H]+)。
(Synthesis of N- (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) -3,5-bis (dodecyloxy) benzamide)
3,5-bis (dodecyloxy) benzoic acid (0.29 g, 0.59 mmol) was dissolved in dichloromethane (30 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.14 g, 0.71 mmol) was added. 1-Hydroxybenzotriazole hydrate (0.09 g, 0.71 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, 17-amino-3,6,9,12,15-pentaoxaheptadecanol (0.20 g, 0.71 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1-20: 1-10: 1) to obtain the desired product (0.15 g, 32%).
1 H-NMR (CDCl 3 , 600 MHz) δ6.91 (d, 2H, J = 2.8 Hz), 6.55 (t, 1H, J = 2.8 Hz), 3.96 (t, 4H, J = 6.5 Hz), 3.71- 3.58 (m, 24H), 1.76 (m, 4H), 1.43 (m, 4H), 1.34-1.26 (m, 32H), 0.88 (t, 6H, J = 6.9 Hz),
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m / z 755 ([M + H] + ).
（Ｎ−（１７−アミノ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，５−ビス（ドデシロキシ）ベンズアミドの合成）
３,５−ビス（ドデシロキシ）安息香酸（0.58g, 1.19mmol）をジクロロメタン（30ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（0.29g, 1.55mmol）と１−ヒドロキシベンゾトリアゾール水和物（0.21g, 1.55mmol）を加え、室温で１時間撹拌した。その後、１,１７−ジアミノ−３,６,９,１２,１５−ペンタオキサヘプタデカン（2.33g, 3.09mmol）を加え、室温で３時間撹拌した。反応終了後、反応液をクロロホルムで抽出した後、有機層を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで脱水した。ろ過した後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝9：1）により精製し、目的物（0.33g, 37%）を得た。
1H-NMR (CD3OD, 600MHz) δ6.96 (d, 2H, J = 2.1Hz)、6.62 (t, 1H, J = 2.1Hz)、3.99 (t, 4H, J = 6.5 Hz)、3.70 (t, 2H, J = 5.2 Hz)、3.62 (m, 20H)、3.56 (t, 2H, J = 5.5 Hz)、3.09 (t, 2H, J = 5.2 Hz)、1.77 (m, 4H)、1.48 (m, 4H)、1.34 (m, 32H)、0.89 (t, 6H, J = 7.2 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m/z 754 ([M+H]+)。
(Synthesis of N- (17-amino-3,6,9,12,15-pentaoxaheptadecyl) -3,5-bis (dodecyloxy) benzamide)
3,5-bis (dodecyloxy) benzoic acid (0.58 g, 1.19 mmol) was dissolved in dichloromethane (30 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 1.55 mmol) was added. 1-Hydroxybenzotriazole hydrate (0.21 g, 1.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 1,17-diamino-3,6,9,12,15-pentaoxaheptadecane (2.33 g, 3.09 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the desired product (0.33 g, 37%).
1 H-NMR (CD 3 OD, 600 MHz) δ6.96 (d, 2H, J = 2.1 Hz), 6.62 (t, 1H, J = 2.1 Hz), 3.99 (t, 4H, J = 6.5 Hz), 3.70 (t, 2H, J = 5.2 Hz), 3.62 (m, 20H), 3.56 (t, 2H, J = 5.5 Hz), 3.09 (t, 2H, J = 5.2 Hz), 1.77 (m, 4H), 1.48 (m, 4H), 1.34 (m, 32H), 0.89 (t, 6H, J = 7.2 Hz).
MALDI-TOFMS (2,5-Dihydroxybenzoic acid) m / z 754 ([M + H] + ).
（Ｎ−（１７−ヒドロキシ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（360mg, 0.533mmol）をジクロロメタン（100ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（99.3mg, 0.518 mmol）、１−ヒドロキシベンゾトリアゾール（86.5mg, 0.640mmol）を加え、室温で１時間撹拌した。その後、１７−アミノ−３，６，９，１２，１５−ペンタオキサヘプタデカノール（150mg, 0.533mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）で精製し、目的物（356mg, 0.379mmol, 72%）を得た。
1H-NMR (CDCl3, 600 MHz ) δ7.01 (2H, s), 6.89 (1H, brs), 4.01(4H t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz), 3.70−3.60 (22H, m ), 3.54 (2H, t, J = 3.4 Hz), 2.92 (1H, brs), 1.80 (4H, quint, J = 6.8 Hz ), 1.74 (2H, quint, J = 6.8 Hz ), 1.45 (6H, m ), 1.34−1.24 (48H, m), 0.88 (9H, t , J = 6.9 Hz ).
MALDI-TOFMS (Dithranol) m/z 939.00 ([M+H]+)。
(Synthesis of N- (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (360 mg, 0.533 mmol) was dissolved in dichloromethane (100 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (99.3 mg, 0.518 mmol) 1-hydroxybenzotriazole (86.5 mg, 0.640 mmol) was added and stirred at room temperature for 1 hour. Thereafter, 17-amino-3,6,9,12,15-pentaoxaheptadecanol (150 mg, 0.533 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (356 mg, 0.379 mmol, 72%).
1 H-NMR (CDCl 3 , 600 MHz) δ7.01 (2H, s), 6.89 (1H, brs), 4.01 (4H t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz), 3.70−3.60 (22H, m), 3.54 (2H, t, J = 3.4 Hz), 2.92 (1H, brs), 1.80 (4H, quint, J = 6.8 Hz), 1.74 (2H, quint, J = 6.8 Hz ), 1.45 (6H, m), 1.34−1.24 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m / z 939.00 ([M + H] + ).
（Ｎ−（１７−アミノ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（250mg, 0.371mmol）をジクロロメタン（20ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（84.4mg, 0.440mmol）、１−ヒドロキシベンゾトリアゾール（60.0mg, 0.440mmol）を加え、室温で１時間撹拌した。その後、１，１７−ジアミノ−３，６，９，１２，１５−ペンタオキサヘプタデカン（415mg, 1.48mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）により精製し、目的物（184mg, 0.196mmol, 53%）を得た。
1H-NMR ( CDCl3, 600 MHz ) δ7.01 (2H, s), 6.99 (1H, brs), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, J = 6.5 Hz ), 3.75−3.60 (22H, m ), 3.49 (2H, t, J = 5.1 Hz ), 2.84 (2H, t, J = 5.1 Hz ), 1.80 (4H, quint, J = 6.8 Hz ), 1.73 (2H, quint, J = 6.8 Hz), 1.29 (6H, m) 1.28−1.26 (48H, m), 0.88 (9H, t , J = 7.2 Hz ).
MALDI-TOFMS (Dithranol) m/z 938.85 ([M+H]+)。
(Synthesis of N- (17-amino-3,6,9,12,15-pentaoxaheptadecyl) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (250 mg, 0.371 mmol) was dissolved in dichloromethane (20 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (84.4 mg, 0.440 mmol) , 1-hydroxybenzotriazole (60.0 mg, 0.440 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, 1,17-diamino-3,6,9,12,15-pentaoxaheptadecane (415 mg, 1.48 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (184 mg, 0.196 mmol, 53%).
1 H-NMR (CDCl 3 , 600 MHz) δ7.01 (2H, s), 6.99 (1H, brs), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, J = 6.5 Hz), 3.75 −3.60 (22H, m), 3.49 (2H, t, J = 5.1 Hz), 2.84 (2H, t, J = 5.1 Hz), 1.80 (4H, quint, J = 6.8 Hz), 1.73 (2H, quint, J = 6.8 Hz), 1.29 (6H, m) 1.28−1.26 (48H, m), 0.88 (9H, t, J = 7.2 Hz).
MALDI-TOFMS (Dithranol) m / z 938.85 ([M + H] + ).
（Ｎ−（ヒドロキシＰＥＧ４００）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（1.55g, 2.30mmol）をジクロロメタン（100ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（651mg, 3.40mmol）、１−ヒドロキシベンゾトリアゾール（464 mg, 3.40mmol）を加え、室温で１時間撹拌した。その後、アミノＰＥＧ４００（2.84g, 7.10mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）で精製し、目的物（2.13g, 2.01mmol, 87%）を得た。
1H-NMR ( CDCl3, 600 MHz ) δ6.99 (2H, s), 6.71 (1H, brs), 4.01 (4H t, J = 6.5 Hz), 3.98 (2H t, J = 6.5 Hz), 3.72−3.58 (m), 1.80 (4H, quint, J = 6.8 Hz), 1.72 (2H, quint, J = 6.8 Hz), 1.46 (6H, m), 1.35-1.26 (48H, m), 0.88 (9H, t , J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m/z 938.83, 1026.84, 1070.82, 1114.78, 1158.82, 1204.21([M+H]+)。
(Synthesis of N- (hydroxyPEG400) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (1.55 g, 2.30 mmol) was dissolved in dichloromethane (100 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (651 mg, 3.40 mmol) , 1-hydroxybenzotriazole (464 mg, 3.40 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, aminoPEG400 (2.84 g, 7.10 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (2.13 g, 2.01 mmol, 87%).
1 H-NMR (CDCl 3 , 600 MHz) δ6.99 (2H, s), 6.71 (1H, brs), 4.01 (4H t, J = 6.5 Hz), 3.98 (2H t, J = 6.5 Hz), 3.72 −3.58 (m), 1.80 (4H, quint, J = 6.8 Hz), 1.72 (2H, quint, J = 6.8 Hz), 1.46 (6H, m), 1.35-1.26 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m / z 938.83, 1026.84, 1070.82, 1114.78, 1158.82, 1204.21 ([M + H] + ).
（Ｎ−（ヒドロキシＰＥＧ１０００）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（780mg, 1.16mmol）をジクロロメタン（100ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（345mg, 1.80mmol）、１−ヒドロキシベンゾトリアゾール（243mg, 1.80mmol）を加え、室温で１時間撹拌した。その後、アミノＰＥＧ１０００（4.04g, 4.00mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１）により精製し、目的物（1.41g, 0.851 mmol, 73%）を得た。
1H-NMR ( CDCl3, 600 MHz ) δ6.99 (2H, s), 6.69 (1H, brs), 4.01 (4H t, J = 6.5 Hz), 3.98 (2H t, J = 6.5 Hz), 3.72-3.61 (m), 2.60 (1H, brs), 1.80 (4H, quint, J = 6.8 Hz), 1.74 ( 2H, quint, J = 6.8 Hz), 1.46 (6H, quint, J = 6.8 Hz), 1.35-1.26 (48H, m), 0.88 (9H, t , J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m/z 1554.50, 1599.56, 1643.80, 1688.79, 1731.48, 1774.53, 1818.58, 1863.68 ([M+H]+)。
(Synthesis of N- (hydroxyPEG1000) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-tris (dodecyloxy) benzoic acid (780 mg, 1.16 mmol) was dissolved in dichloromethane (100 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (345 mg, 1.80 mmol), 1-Hydroxybenzotriazole (243 mg, 1.80 mmol) was added and stirred at room temperature for 1 hour. Thereafter, aminoPEG 1000 (4.04 g, 4.00 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (1.41 g, 0.851 mmol, 73%).
1 H-NMR (CDCl 3 , 600 MHz) δ6.99 (2H, s), 6.69 (1H, brs), 4.01 (4H t, J = 6.5 Hz), 3.98 (2H t, J = 6.5 Hz), 3.72 -3.61 (m), 2.60 (1H, brs), 1.80 (4H, quint, J = 6.8 Hz), 1.74 (2H, quint, J = 6.8 Hz), 1.46 (6H, quint, J = 6.8 Hz), 1.35 -1.26 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m / z 1554.50, 1599.56, 1643.80, 1688.79, 1731.48, 1774.53, 1818.58, 1863.68 ([M + H] + ).
（Ｎ−（アミノＰＥＧ１０００）−３，４，５−トリス（ドデシロキシ）ベンズアミドの合成）
３，４，５−トリス（ドデシロキシ）安息香酸（1.60 g, 2.37 mmol）をジクロロメタン（100 ml）に溶解し、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（736mg, 38.4mmol）、１−ヒドロキシベンゾトリアゾール（519mg, 38.4mmol）を加え、室温で１時間攪拌した。その後、ジアミノＰＥＧ１０００（8.29g, 8.31mmol）を加え、室温でさらに１時間撹拌した。反応溶液は飽和重曹水、飽和食塩水で順次洗浄し、有機層を無水硫酸ナトリウムで脱水した。乾燥剤をろ別し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝50：1）により精製し、目的物（373mg, 0.231mmol, 9%）を得た。
1H-NMR ( CDCl3, 600 MHz ) δ 7.00 (2H, s), 6.73 (1H, brs), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz ), 3.72-3.58 (m), 3.23 (2H, brs ), 1.80 (4H, quint, J = 6.8 Hz ), 1.72 (2H, quint, J = 6.8 Hz ), 1.46 (6H, quint, J = 6.8 Hz ), 1.35-1.26 (48H, m), 0.88 (9H, t , J = 6.9 Hz ).
MALDI-TOFMS (Dithranol) m/z 1333.30, 1377.25, 1422.30, 1466.25, 1509.25, 1553.20, 1598.20, 1642.23, 1686.18 ([M+H]+)。
(Synthesis of N- (aminoPEG1000) -3,4,5-tris (dodecyloxy) benzamide)
3,4,5-Tris (dodecyloxy) benzoic acid (1.60 g, 2.37 mmol) was dissolved in dichloromethane (100 ml) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (736 mg, 38.4 mmol) was dissolved. ), 1-hydroxybenzotriazole (519 mg, 38.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, diaminoPEG 1000 (8.29 g, 8.31 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the desired product (373 mg, 0.231 mmol, 9%).
1 H-NMR (CDCl 3 , 600 MHz) δ 7.00 (2H, s), 6.73 (1H, brs), 4.01 (4H, t, J = 6.5 Hz), 3.98 (2H, t, J = 6.5 Hz), 3.72-3.58 (m), 3.23 (2H, brs), 1.80 (4H, quint, J = 6.8 Hz), 1.72 (2H, quint, J = 6.8 Hz), 1.46 (6H, quint, J = 6.8 Hz), 1.35-1.26 (48H, m), 0.88 (9H, t, J = 6.9 Hz).
MALDI-TOFMS (Dithranol) m / z 1333.30, 1377.25, 1422.30, 1466.25, 1509.25, 1553.20, 1598.20, 1642.23, 1686.18 ([M + H] + ).
（ベンズアミド誘導体と蛋白質との相互作用解析）
ベンズアミド誘導体と蛋白質との相互作用は、分子間相互作用解析装置であるＩＡｓｙｓ ｐｌｕｓ（Ａｆｆｉｎｉｔｙ Ｓｅｎｓｏｒｓ社製）を用いて解析した。
ＩＡｓｙｓ ｐｌｕｓの疎水性キュベットを、界面活性剤水溶液、バッファー、イソプロパノールで洗浄の後、各ベンズアミド誘導体の１ｍＭ溶液（クロロホルム：メタノール：イソプロパノール＝１：３：１６）６０μｌを添加して固定化を行った。このキュベットを、バッファー、塩酸水溶液、水酸化ナトリウム水溶液、バッファーで洗浄の後、１ｍｇ／ｍｌの濃度のウシ血清アルブミン（ＢＳＡ）溶液５０μｌを添加して５分間放置、さらに、バッファーに置換して３分放置して、ＢＳＡの吸着量を求めた。
(Interaction analysis between benzamide derivatives and proteins)
The interaction between the benzamide derivative and the protein was analyzed using IAsys plus (Affinity Sensors), which is an intermolecular interaction analyzer.
The hydrophobic cuvette of IAsys plus was washed with an aqueous surfactant solution, a buffer, and isopropanol, and then immobilized by adding 60 μl of a 1 mM solution of each benzamide derivative (chloroform: methanol: isopropanol = 1: 3: 16). . The cuvette was washed with a buffer, hydrochloric acid aqueous solution, sodium hydroxide aqueous solution and buffer, 50 μl of a bovine serum albumin (BSA) solution having a concentration of 1 mg / ml was added and left for 5 minutes. The amount of BSA adsorbed was determined by standing for a minute.
Ｎ−（８−ヒドロキシ−３，６−ジオキサオクチル）−３，５−ビス（ドデシロキシ）ベンズアミドの固定化量は７７８．２Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は３０．２Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（８−アミノ−３，６−ジオキサオクチル）−３，５−ビス（ドデシロキシ）ベンズアミドの固定化量は７４３．２Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は３１９．１Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（８−ヒドロキシ−３，６−ジオキサオクチル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの固定化量は７９１．８Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は７．１Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（８−アミノ−３，６−ジオキサオクチル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの固定化量は８７１．９Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は４３２．６Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（１７−ヒドロキシ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，５−ビス（ドデシロキシ）ベンズアミドの固定化量は８０９．５Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は０．０Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（１７−アミノ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，５−ビス（ドデシロキシ）ベンズアミドの固定化量は７４８．６Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は３０９．７Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（１７−ヒドロキシ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの固定化量は７６０．２Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は８．８Ａｒｃ ｓｅｃｏｎｄｓだった。
Ｎ−（１７−アミノ−３，６，９，１２，１５−ペンタオキサヘプタデシル）−３，４，５−トリス（ドデシロキシ）ベンズアミドの固定化量は８１１．５Ａｒｃ ｓｅｃｏｎｄｓ、ＢＡＳの吸着量は３７１．４Ａｒｃ ｓｅｃｏｎｄｓだった。
The amount of N- (8-hydroxy-3,6-dioxaoctyl) -3,5-bis (dodecyloxy) benzamide immobilized was 778.2 Arc seconds, and the amount of BAS adsorbed was 30.2 Arc seconds.
The amount of N- (8-amino-3,6-dioxaoctyl) -3,5-bis (dodecyloxy) benzamide immobilized was 743.2 Arc seconds, and the amount of BAS adsorbed was 319.1 Arc seconds.
The amount of N- (8-hydroxy-3,6-dioxaoctyl) -3,4,5-tris (dodecyloxy) benzamide immobilized was 791.8 Arc seconds, and the amount of BAS adsorbed was 7.1 Arc seconds.
The amount of N- (8-amino-3,6-dioxaoctyl) -3,4,5-tris (dodecyloxy) benzamide immobilized was 871.9 Arc seconds, and the amount of BAS adsorbed was 432.6 Arc seconds.
The amount of N- (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) -3,5-bis (dodecyloxy) benzamide immobilized was 809.5 Arc seconds, and the amount of BAS adsorbed was 0.0Arc. It was seconds.
The amount of N- (17-amino-3,6,9,12,15-pentaoxaheptadecyl) -3,5-bis (dodecyloxy) benzamide immobilized was 748.6 Arc seconds, and the amount of BAS adsorbed was 309.7 Arc. It was seconds.
The amount of N- (17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl) -3,4,5-tris (dodecyloxy) benzamide immobilized was 760.2 Arc seconds, and the amount of BAS adsorbed was 8. .8 Arc seconds.
The amount of N- (17-amino-3,6,9,12,15-pentaoxaheptadecyl) -3,4,5-tris (dodecyloxy) benzamide immobilized was 811.5 Arc seconds, and the amount of BAS adsorbed was 371. .4 Arc seconds.
本発明は、生体適合性付与剤および生体適合性材料を与えるものであり、医療用材料、細胞培養材料、医療用機器等への利用が可能である。 The present invention provides a biocompatible imparting agent and a biocompatible material, and can be used for medical materials, cell culture materials, medical devices, and the like.
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004042011A JP4526832B2 (en) | 2004-02-18 | 2004-02-18 | Biocompatibility imparting agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004042011A JP4526832B2 (en) | 2004-02-18 | 2004-02-18 | Biocompatibility imparting agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005232061A true JP2005232061A (en) | 2005-09-02 |
| JP4526832B2 JP4526832B2 (en) | 2010-08-18 |
Family
ID=35015382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004042011A Expired - Fee Related JP4526832B2 (en) | 2004-02-18 | 2004-02-18 | Biocompatibility imparting agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4526832B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007217551A (en) * | 2006-02-16 | 2007-08-30 | Noguchi Inst | Biocompatible hydrogel |
| JP2007269768A (en) * | 2006-03-07 | 2007-10-18 | Noguchi Inst | Method for purifying sugar-chain-binding substance |
| JP2008074720A (en) * | 2006-09-19 | 2008-04-03 | Noguchi Inst | Gm3 sugar chain probe |
| WO2009035003A1 (en) * | 2007-09-10 | 2009-03-19 | The Noguchi Institute | Benzamide derivative, hydrogelling agent, and hydrogel |
| JP2010059323A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Double chain hydrogelling agent |
| JP2010059324A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Transparent hydrogelling agent |
| JP2010059109A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Asymmetric hydrogelling agent |
| WO2010098320A1 (en) | 2009-02-24 | 2010-09-02 | 学校法人立命館 | Dual-terminal amide hydrogelling agent |
| WO2018020034A1 (en) * | 2016-07-29 | 2018-02-01 | Vectura Limited | Polymer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001122889A (en) * | 1999-10-26 | 2001-05-08 | Noguchi Inst | Glycolipid analog compound |
| JP2002030091A (en) * | 2000-07-13 | 2002-01-29 | Noguchi Inst | Double chain glycolipide analog |
| JP2002265427A (en) * | 2001-03-06 | 2002-09-18 | Noguchi Inst | Cell-adhesive compound |
| JP2003252835A (en) * | 2002-03-04 | 2003-09-10 | Noguchi Inst | Oligoethylene glycol lipid |
| JP2005232278A (en) * | 2004-02-18 | 2005-09-02 | Noguchi Inst | Gellant for preparing mold |
-
2004
- 2004-02-18 JP JP2004042011A patent/JP4526832B2/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001122889A (en) * | 1999-10-26 | 2001-05-08 | Noguchi Inst | Glycolipid analog compound |
| JP2002030091A (en) * | 2000-07-13 | 2002-01-29 | Noguchi Inst | Double chain glycolipide analog |
| JP2002265427A (en) * | 2001-03-06 | 2002-09-18 | Noguchi Inst | Cell-adhesive compound |
| JP2003252835A (en) * | 2002-03-04 | 2003-09-10 | Noguchi Inst | Oligoethylene glycol lipid |
| JP2005232278A (en) * | 2004-02-18 | 2005-09-02 | Noguchi Inst | Gellant for preparing mold |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007217551A (en) * | 2006-02-16 | 2007-08-30 | Noguchi Inst | Biocompatible hydrogel |
| JP2007269768A (en) * | 2006-03-07 | 2007-10-18 | Noguchi Inst | Method for purifying sugar-chain-binding substance |
| JP2008074720A (en) * | 2006-09-19 | 2008-04-03 | Noguchi Inst | Gm3 sugar chain probe |
| WO2009035003A1 (en) * | 2007-09-10 | 2009-03-19 | The Noguchi Institute | Benzamide derivative, hydrogelling agent, and hydrogel |
| JP2010059323A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Double chain hydrogelling agent |
| JP2010059324A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Transparent hydrogelling agent |
| JP2010059109A (en) * | 2008-09-04 | 2010-03-18 | Ritsumeikan | Asymmetric hydrogelling agent |
| WO2010098320A1 (en) | 2009-02-24 | 2010-09-02 | 学校法人立命館 | Dual-terminal amide hydrogelling agent |
| CN102317253A (en) * | 2009-02-24 | 2012-01-11 | 学校法人立命馆 | Both-end acid amide type hydrogel adhesive |
| US8633022B2 (en) | 2009-02-24 | 2014-01-21 | The Ritsumeikan Trust | Dual-terminal amide hydrogelling agent |
| JP5604714B2 (en) * | 2009-02-24 | 2014-10-15 | 学校法人立命館 | Double-ended amide-type hydrogelator |
| WO2018020034A1 (en) * | 2016-07-29 | 2018-02-01 | Vectura Limited | Polymer |
| US11583587B2 (en) | 2016-07-29 | 2023-02-21 | Vectura Limited | Polymer |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4526832B2 (en) | 2010-08-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4526832B2 (en) | Biocompatibility imparting agent | |
| WO2006088248A1 (en) | Polyoxyalkylene derivative | |
| CN102264697B (en) | Pyrroline-carboxy-Methionin that biosynthesizing produces and protein modified by the locus specificity of pyrroline-carboxy-Methionin and pyrrolysine residue chemical derivatization | |
| Stevens et al. | Potent and selective indolomorphinan antagonists of the kappa-opioid receptor | |
| BRPI0607248A2 (en) | conjugate of a polypeptide and an oligosaccharide, pharmaceutical composition, use of the conjugate, and process for the preparation of a conjugate | |
| EP2654794A1 (en) | Materials and methods for conjugating a water soluble fatty acid derivative to a protein | |
| JP2008525491A5 (en) | ||
| JP2000513375A (en) | Fibrinogen receptor antagonist prodrug | |
| JP4947512B2 (en) | Biocompatible hydrogel | |
| US20110097302A1 (en) | Il-1ra-polymer conjugates | |
| Boyer et al. | Synthesis of α, α‐Difluoro‐β‐amino Esters or gem‐Difluoro‐β‐lactams as Potential Metallocarboxypeptidase Inhibitors | |
| Thorstensson et al. | Synthesis of novel thrombin inhibitors. Use of ring-closing metathesis reactions for synthesis of P2 cyclopentene-and cyclohexenedicarboxylic acid derivatives | |
| US5098996A (en) | Process for introducing fluorine into biologically active materials | |
| CN100364660C (en) | Low density lipoprotein adsorption material for treating hyperlipoproteinemia | |
| JPS5936686A (en) | Organogermanium compound having both hydrophilic nature and lipophilic nature and its preparation | |
| CA2709881A1 (en) | Methods of peptide modification | |
| Loaiza et al. | Click chemistry based solid phase supported synthesis of dopaminergic phenylacetylenes | |
| JP5282200B2 (en) | Transparent hydrogelator | |
| JP2005232278A (en) | Gellant for preparing mold | |
| JP5352810B2 (en) | Asymmetric hydrogelator | |
| TW201201845A (en) | Bifunctional compound with monomeric sugars and N2S2 ligands, method for preparing and the use thereof | |
| JPWO2013115334A1 (en) | Separating agent and method for producing the same | |
| JPWO2016060096A1 (en) | Phosphorylcholine group-containing compound and phosphorylcholine complex | |
| JP5343282B2 (en) | Double-chain hydrogelator | |
| JP2003252835A (en) | Oligoethylene glycol lipid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20061207 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100310 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100315 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100510 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100601 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100602 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130611 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130611 Year of fee payment: 3 |
|
| S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130611 Year of fee payment: 3 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |