JP5282227B2 - Both-end diamide type hydrogelator - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hydrogelling agent having a novel chemical structure and a hydrogel. <P>SOLUTION: This hydrogelling agent is a benzamide derivative represented by Formula (1) (wherein Z<SB>1</SB>and Z<SB>2</SB>each represent an amide bond of NHCO or CONH, k represents an integer of 0 to 4, m represents an integer of 1 to 100, n represents an integer of 1 to 6, and p represents an integer of 1 to 6; R<SB>1</SB>represents a 8-22C hydrocarbon group bonded through an oxygen atom; R<SB>2</SB>represents H or a 1-22C hydrocarbon group bonded through an oxygen atom; and R<SB>3</SB>represents H or a 1-22C alkoxy group, and R<SB>2</SB>and R<SB>3</SB>are not simultaneously H) produced by bonding oligomer or polymer derivatives of ethylene glycol through a plurality of amide bonds. There is also provided a hydrogel comprising the derivative as the hydrogelling agent and water. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a hydrogelator having a novel chemical structure and a hydrogel.

A low molecular gel is a gel in which solvent molecules are captured by forming a three-dimensional network by self-assembly of low molecular compounds by intermolecular forces (see, for example, Non-Patent Document 1).
Low molecular gels are expected to be applied to various fields such as separation membranes, sensors, catalysts, electronic materials, biomaterials, etc., since molecular design of low molecular compounds that form gels is possible. Patent Document 2).

  We also synthesized 3,4,5-long-chain alkyloxybenzamide derivatives having a novel structure (see Patent Document 1), and found that some of the compounds gelled organic solvents. It has been found that the gelling ability is increased by increasing the number of the nuclei (see Patent Document 2).

  However, when considering application to biomaterials, it is clear that water gelled hydrogels are preferable to organogel gels, but there are few reports of low molecular hydrogels (for example, Non-Patent Document 3). Further, when the obtained hydrogel is used as a biomaterial, it is desirable that the hydrogel itself has biocompatibility, but there has been almost no report from this viewpoint.

  We have synthesized 3,4,5-long chain alkyloxybenzamide derivatives to which oligomers or polymer derivatives of ethylene glycol have been bound so far, and these compounds are intended to impart biocompatibility to medical materials. It has been disclosed that these compounds can be used (see Patent Document 3), and that these compounds gel organic solvents (see Patent Document 4), and further, these compounds have been found to form hydrogels ( (See Patent Document 5). However, development of a hydrogelator having a new molecular structure is desired in order to optimize the properties and preparation methods of the hydrogel according to the purpose and application.

JP 2001-122889 A JP 2004-262809 A JP 2005-232061 A JP-A-2005-232278 JP 2007-217551 A

Chemical Review (Chem. Rev.), 1997, Vol. 97, p. 3133-3159 Angewante Chemie International Edition (Angew. Chem. Int. Ed.), 2000, 39, p. 2263-2266 Chemical Review (Chem. Rev.), 2004, 104, p. 1201-1217

  An object of the present invention is to provide a hydrogelator having a novel chemical structure and a hydrogel.

（式中で、Ｚ_１及びＺ_２はＮＨＣＯ又はＣＯＮＨのアミド結合を、ｋは０から４までの整数を、ｍは１から、好ましくは７から、１００までの整数を、ｎは１から、好ましくは２から、６までの整数を、ｐは１から６までの整数を表す。また、Ｒ_１は酸素を介して結合した炭素数８から２２まで、好ましくは１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を、Ｒ_３はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を表し、Ｒ_２とＲ_３は同時にＨではない。また、好ましくはＲ_１及びＲ_３は酸素原子を介して結合した炭素数１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素原子を介して結合した炭素数１から１８までの炭化水素基を表す。）

（式中で、ＸはＯＨ又はＮＨ_２を、ＺはＮＨＣＯ又はＣＯＮＨのアミド結合を、ｋは０から４までの整数を、ｍは１から、好ましくは７から、１００までの整数を、ｎは１から、好ましくは２から、６までの整数を、ｐは１から６までの整数を表す。また、Ｒ_１は酸素を介して結合した炭素数８から２２まで、好ましくは１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を、Ｒ_３はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を表し、Ｒ_２とＲ_３は同時にＨではない。また、好ましくはＲ_１及びＲ_３は酸素原子を介して結合した炭素数１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素原子を介して結合した炭素数１から１８までの炭化水素基を表す。）
すなわち、本発明は、式（１）で示されるベンズアミド誘導体、それを有効成分とするヒドロゲル化剤、そのヒドロゲル化剤と水を含んでなるヒドロゲル、式（１）及び式（２）で示されるベンズアミド誘導体の両方を有効成分として含むヒドロゲル化剤、及び、そのヒドロゲル化剤と水とを含んでなるヒドロゲルを提供する。 The present inventors have found that a benzamide derivative having a long-chain alkyloxy group formed by binding an ethylene glycol oligomer or polymer represented by the formula (2) forms a hydrogel, and has synthesized the derivative. At that time, for the purpose of confirming the structure and molecular weight of these derivatives, it was possible to find the conditions of mass spectrometry by examining the ionization conditions. As a result, it was discovered that a compound having a benzamide derivative bonded to both ends via an oligomer or polymer of ethylene glycol represented by the formula (1), which could not be found by analysis such as NMR, was completed. It came to. The compound represented by the formula (1) does not inhibit the formation of the hydrogel of the compound represented by the formula (2), and brings about a variety of new molecular structures to the benzamide derivative that forms the hydrogel. Gives a means to optimize

(Wherein Z ₁ and Z ₂ are amide bonds of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 1, preferably from 7 to 100, and n is from 1; Preferably, it represents an integer from 2 to 6, and p represents an integer from 1 to 6. In addition, R ₁ is a hydrocarbon group having 8 to 22 carbon atoms, preferably 12 to 18 carbon atoms bonded via oxygen. R ₂ represents a hydrocarbon group having 1 to 22 carbon atoms, preferably 18 bonded via H or oxygen, and R ₃ represents 1 to 22 carbon atoms bonded via H or oxygen. R ₂ and R ₃ are not H at the same time, preferably R ₁ and R ₃ are hydrocarbons having 12 to 18 carbon atoms bonded via an oxygen atom. R ₂ is H or carbon bonded via an oxygen atom Represents a hydrocarbon group having a prime number of 1 to 18.)

(Wherein X is OH or NH ₂ , Z is an amide bond of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 1, preferably 7 to 100, n Represents an integer from 1, preferably from 2 to 6, and p represents an integer from 1 to 6. R ₁ has from 8 to 22 carbon atoms bonded via oxygen, preferably from 12 to 18 R ₂ is a hydrocarbon group having 1 to 22 carbon atoms, preferably 18 carbon atoms bonded through H or oxygen, and R ₃ is a carbon atom bonded through H or oxygen. R ₂ and R ₃ are not H at the same time, and preferably R ₁ and R ₃ are bonded to each other via an oxygen atom, and represent a hydrocarbon group having a number of 1 to 22, preferably 18. the hydrocarbon group of up to, R ₂ is H, or, through an oxygen atom It represents a bond hydrocarbon group having 1 to 18 carbon atoms.)
That is, the present invention is represented by formula (1) and formula (2), a benzamide derivative represented by formula (1), a hydrogelator comprising the same as an active ingredient, a hydrogel comprising the hydrogelator and water, formula (1) and formula (2) Provided are a hydrogelator comprising both benzamide derivatives as active ingredients, and a hydrogel comprising the hydrogelator and water.

  The present invention adds a variety of new molecular structures to a rare molecular species in which a compound having an ethylene glycol oligomer or polymer as a partial structure hydrogels by molecular self-assembly.

（式中で、Ｚ_１及びＺ_２はＮＨＣＯ又はＣＯＮＨのアミド結合を、ｋは０から４までの整数を、ｍは１から、好ましくは７から、１００までの整数を、ｎは１から、好ましくは２から、６までの整数を、ｐは１から６までの整数を表す。また、Ｒ_１は酸素を介して結合した炭素数８から２２まで、好ましくは１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を、Ｒ_３はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を表し、Ｒ_２とＲ_３は同時にＨではない。また、好ましくはＲ_１及びＲ_３は酸素原子を介して結合した炭素数１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素原子を介して結合した炭酸素数１から１８までの炭化水素基を表す。） The benzamide derivative of the present invention is a compound represented by the formula (1).

(Wherein Z ₁ and Z ₂ are amide bonds of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 1, preferably from 7 to 100, and n is from 1; Preferably, it represents an integer from 2 to 6, and p represents an integer from 1 to 6. In addition, R ₁ is a hydrocarbon group having 8 to 22 carbon atoms, preferably 12 to 18 carbon atoms bonded via oxygen. R ₂ represents a hydrocarbon group having 1 to 22 carbon atoms, preferably 18 bonded via H or oxygen, and R ₃ represents 1 to 22 carbon atoms bonded via H or oxygen. R ₂ and R ₃ are not H at the same time, preferably R ₁ and R ₃ are hydrocarbons having 12 to 18 carbon atoms bonded via an oxygen atom. R ₂ is H or carbon bonded via an oxygen atom Represents a hydrocarbon group having 1 to 18 oxygen atoms.)

In addition, m is preferably 7 or more from the viewpoint of hydrogel formation near room temperature, R ₁ has 12 to 18 carbon atoms, R ₂ and R ₃ have 18 or less carbon atoms, and n is 2 or more from the viewpoint of the synthesis step. Is preferred.

The benzamide derivative represented by the formula (1) is, for example, amide-condensed between a benzoic acid derivative bonded to a hydrocarbon group via oxygen and an amine derivative having a carboxy group or amino group protected at the terminal (Japanese Patent Laid-Open No. 2004-2006). 2628091), after deprotection, it is obtained by amide condensation of an ethylene glycol oligomer or polymer amine derivative or carboxylic acid derivative. In this case, the alkyl chain length between Z ₁ or Z ₂ and the ethylene glycol oligomer or polymer can be adjusted according to the synthesis method of the ethylene glycol oligomer or polymer amine derivative or carboxylic acid derivative described below. is there. Further, when the resulting product is a mixture of a compound having a benzamide structure at both ends and a compound having a benzamide structure only at one end, depending on the raw materials or reaction conditions, a known fractionation method, if necessary, For example, it is possible to fractionate one or obtain a composition with an increased proportion of one by high-performance liquid chromatography.

  Derivatives in which both ends of the ethylene glycol oligomer or polymer are aminated are, for example, tosylated or mesylated, iodinated tosyl group or mesyl group, iodine group Obtained by conversion to phthalimide and deprotection with hydrazine. For oligomers with lengths that are not commercially available, one end of oligoethylene glycol is protected, the other end is tosylated, and condensed with oligoethylene glycol, the total length of which is required, followed by deprotection. Tosylation or mesylation, iodination of a tosyl group or mesyl group, in order, on both ends of the resulting compound (J. Org. Chem. 2004, 69, p. 639-647) , Conversion of iodine group to phthalimide, deprotection with hydrazine (Biochemistry 1980, 19, p. 4595-4600). Alternatively, a similar compound can be obtained by tosylation or mesylation followed by azidation of a tosyl group or mesyl group, followed by reduction. In particular, by mesylating an ethylene glycol oligomer or polymer, it becomes easy to obtain a compound having amino groups introduced at both ends thereof.

  Derivatives in which both ends of the ethylene glycol oligomer or polymer are carboxy groups are likewise obtained, for example, by ether formation with alcohols having terminally protected carboxy groups.

  A benzoic acid derivative having the same hydrocarbon group bonded to the 3, 4, 5 position via an oxygen atom is obtained by etherifying 3,4,5-trihydroxybenzoic acid ester and then hydrolyzing the ester. .

  A benzoic acid derivative in which the 5-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 4-position via an oxygen atom, and 3- and 4-positions are simultaneously etherified using 3,4-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, a benzoic acid derivative in which different hydrocarbon groups are bonded to the 3-position and 4-position via an oxygen atom, for example, selectively etherifies the 4-position by utilizing the difference in reactivity between the 3-position and 4-position. Subsequently, it is obtained by hydrolyzing the ester after etherification of the 3-position with a hydrocarbon group different from the 4-position.

  A benzoic acid derivative having a hydrocarbon group different from the 3rd and 4th positions through an oxygen atom at the 5th position is, for example, the 3rd and 4th positions of the 3,4,5-trihydroxybenzoic acid ester of the boronic acid derivative. Protection with selective crosslinking, etherification at the 5-position followed by deprotection of the boronic acid derivative, etherification at the 3- and 4-positions followed by hydrolysis of the ester in the same manner as above Obtained by.

  A benzoic acid derivative in which the 4-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 5-position via an oxygen atom, and 3- and 5-positions are simultaneously etherified using 3,5-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, a benzoic acid derivative having different hydrocarbon groups at the 3-position and 5-position via an oxygen atom, for example, can be obtained by reducing the equivalent of a hydrocarbonating agent during etherification and by simply converting one etherified. And the remaining hydroxyl group is etherified with a different hydrocarbonating agent and then the ester is hydrolyzed.

  A benzoic acid derivative having a hydrocarbon group different from the 3rd and 5th positions through an oxygen atom at the 4th position utilizes, for example, the difference in reactivity at the 4th position of 3,4,5-trihydroxybenzoic acid ester. First, after etherification at the 4-position, it is obtained by etherification at the 3-position and 5-position and subsequent hydrolysis of the ester in the same manner as described above.

（式中で、ＸはＯＨ又はＮＨ_２を、ＺはＮＨＣＯ又はＣＯＮＨのアミド結合を、ｋは０から４までの整数を、ｍは１から、好ましくは７から、１００までの整数を、ｎは１から、好ましくは２から、６までの整数を、ｐは１から６までの整数を表す。また、Ｒ_１は酸素を介して結合した炭素数８から２２まで、好ましくは１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を、Ｒ_３はＨ、又は、酸素を介して結合した炭素数１から２２まで、好ましくは１８までの炭化水素基を表し、Ｒ_２とＲ_３は同時にＨではない。また、好ましくは、Ｒ_１及びＲ_３は酸素原子を介して結合した炭素数１２から１８までの炭化水素基を、Ｒ_２はＨ、又は、酸素原子を介して結合した炭素数１から１８までの炭化水素基を表す。）
なお、室温付近でのヒドロゲル形成の観点からｍは７以上（より好ましくは２０以上８０以下）、Ｒ_１の炭素数は１２から１８まで、Ｒ_２とＲ_３の炭素数は１８以下が好ましく、合成工程の観点からｎは２以上が好ましい。
式（２）で示されるベンズアミド誘導体は、例えば、酸素を介して炭化水素基と結合した安息香酸誘導体と末端に保護されたカルボキシ基又はアミノ基を持つアミン誘導体をアミド縮合し（特開２００４−２６２８０９１）、脱保護の後、エチレングリコールのオリゴマー又はポリマーのアミン誘導体又はカルボン酸誘導体をアミド縮合することによって得られる。また、末端のＸとエチレングリコールのオリゴマー又はポリマーの間のアルキル鎖長、及び、Ｚとエチレングリコールのオリゴマー又はポリマーの間のアルキル鎖長は、下に記載のエチレングリコールのオリゴマー又はポリマーのアミン誘導体又はカルボン酸誘導体の合成法に準じて調整が可能である。 The benzamide derivative represented by the formula (1) can be used as a hydrogelator alone or as a mixture with the compound represented by the formula (2), for example.
In the present invention, the benzamide derivative that can be used together with the compound represented by the above formula (1) is a compound represented by the formula (2).

(Wherein X is OH or NH ₂ , Z is an amide bond of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 1, preferably 7 to 100, n Represents an integer from 1, preferably from 2 to 6, and p represents an integer from 1 to 6. R ₁ has from 8 to 22 carbon atoms bonded via oxygen, preferably from 12 to 18 R ₂ is a hydrocarbon group having 1 to 22 carbon atoms, preferably 18 carbon atoms bonded through H or oxygen, and R ₃ is a carbon atom bonded through H or oxygen. R ₂ and R ₃ are not H at the same time, and preferably R ₁ and R ₃ are from 12 carbon atoms bonded via an oxygen atom. a hydrocarbon group of up to 18, _{R 2} is through H, or an oxygen atom Te represents a hydrocarbon group of a carbon number of 1 bound to 18.)
From the viewpoint of forming a hydrogel near room temperature, m is 7 or more (more preferably 20 to 80), R ₁ has 12 to 18 carbon atoms, and R ₂ and R ₃ have 18 or less carbon atoms, From the viewpoint of the synthesis step, n is preferably 2 or more.
The benzamide derivative represented by the formula (2) is obtained by, for example, amide condensation of a benzoic acid derivative bonded to a hydrocarbon group via oxygen and an amine derivative having a protected carboxy group or amino group at the terminal (Japanese Patent Application Laid-Open No. 2004-2005). 2628091), after deprotection, it is obtained by amide condensation of an ethylene glycol oligomer or polymer amine derivative or carboxylic acid derivative. The alkyl chain length between the terminal X and the ethylene glycol oligomer or polymer, and the alkyl chain length between Z and the ethylene glycol oligomer or polymer are the amine derivatives of the ethylene glycol oligomer or polymer described below. Or it can adjust according to the synthesis method of a carboxylic acid derivative.

  Examples of ethylene glycol oligomers or polymer amine derivatives include, for example, tosylation or mesylation, iodination of tosyl group or mesyl group, iodine group phthalimide at one end or both ends of commercially available ethylene glycol oligomer or polymer. Obtained by conversion to hydrazine and deprotection. For oligomers with lengths that are not commercially available, one end of oligoethylene glycol is protected, the other end is tosylated, and condensed with oligoethylene glycol, the total length of which is required, followed by deprotection. One of the compounds (J. Org. Chem. 2004, 69, p.639-647) or both ends are sequentially tosylated or mesylated, tosyl group or mesyl. It is obtained by iodination of the group, conversion of the iodine group to phthalimide, deprotection with hydrazine (Biochemistry 1980, 19, p. 4595-4600). Alternatively, a similar compound can be obtained by tosylation or mesylation followed by azidation of a tosyl group or mesyl group, followed by reduction.

  Oligomeric or polymeric carboxylic chain derivatives of ethylene glycol are likewise obtained, for example, by ether formation with alcohols having terminally protected carboxy groups.

  A benzoic acid derivative having the same hydrocarbon group bonded to the 3, 4, 5 position via an oxygen atom is obtained by etherifying 3,4,5-trihydroxybenzoic acid ester and then hydrolyzing the ester. .

  A benzoic acid derivative in which the 5-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 4-position via an oxygen atom, and 3- and 4-positions are simultaneously etherified using 3,4-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, a benzoic acid derivative in which different hydrocarbon groups are bonded to the 3-position and 4-position via an oxygen atom, for example, selectively etherifies the 4-position by utilizing the difference in reactivity between the 3-position and 4-position. Subsequently, it is obtained by hydrolyzing the ester after etherification of the 3-position with a hydrocarbon group different from the 4-position.

A benzoic acid derivative having a hydrocarbon group different from the 3rd and 4th positions through an oxygen atom at the 5th position is, for example, the 3rd and 4th positions of the 3,4,5-trihydroxybenzoic acid ester of the boronic acid derivative. Protection with selective crosslinking, etherification at the 5-position followed by deprotection of the boronic acid derivative, etherification at the 3- and 4-positions followed by hydrolysis of the ester in the same manner as above Obtained by.
A benzoic acid derivative in which the 4-position is hydrogen and the same hydrocarbon group is bonded to the 3-position and 5-position via an oxygen atom, and 3- and 5-positions are simultaneously etherified using 3,5-dihydroxybenzoate as a raw material. And then obtained by hydrolyzing the ester. In addition, a benzoic acid derivative having different hydrocarbon groups at the 3-position and 5-position via an oxygen atom, for example, can be obtained by reducing the equivalent of a hydrocarbonating agent during etherification and by simply converting one etherified. And the remaining hydroxyl group is etherified with a different hydrocarbonating agent and then the ester is hydrolyzed.

  A benzoic acid derivative having a hydrocarbon group different from the 3rd and 5th positions through an oxygen atom at the 4th position utilizes, for example, the difference in reactivity at the 4th position of 3,4,5-trihydroxybenzoic acid ester. First, after etherification at the 4-position, it is obtained by etherification at the 3-position and 5-position and subsequent hydrolysis of the ester in the same manner as described above.

  The benzamide derivative represented by the formula (2) can be used as a hydrogelator as a mixture with the benzamide derivative represented by the formula (1) as a substance that does not hinder its hydrogelation. In the case of a mixture, the benzamide derivative represented by the formula (2) can be synthesized through the same synthetic route as the benzamide derivative represented by the formula (1), but both are synthesized independently and mixed together. Alternatively, if both are obtained as a mixture in the former or the latter synthesis process, they may be used as a mixture.

  The hydrogel is obtained by suspending an appropriate amount of a hydrogelator containing a benzamide derivative represented by the formula (1) or a mixture of benzamide derivatives represented by the formula (1) and the formula (2) as an active ingredient in water, and Heat to the temperature at which the hydrogel is used, or heat to a temperature at which the hydrogelator dissolves and then cool to room temperature, reheat after the cooling, or cool to a lower temperature after the cooling Manufactured by.

  The present invention will be described in more detail below, but the present invention is not limited to the following description. Here, the analysis results by typical mass spectrometry are shown, but the benzamide derivative represented by the formula (2) synthesized via the same synthesis route includes the both-end benzamide derivative represented by the formula (1). Conceivable.

  In the following, EDC.HCl is an abbreviation for water-soluble carbodiimide hydrochloride, HOBt is an abbreviation for 1-hydroxybenzotriazole hydrate, and PEG is an abbreviation for polyethylene glycol.

<Synthesis Example 1>
(Synthesis of PEG having a molecular weight of 2000, in which a hydroxyl group is converted to an amino group)
PEG (4.00 g, 2.00 mmol) having a molecular weight of 2000 was dissolved in pyridine (10 ml), p-toluenesulfonyl chloride (0.76 g, 4.00 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, chloroform (100 ml) was added, neutralized with 1M HCl (100 ml), the solution was washed with 4% NaHCO ₃ and saturated NaCl in this order, and the organic phase was 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 = 10: 1) to obtain PEG (4.140 g, 1.92 mmol, 96%) having a molecular weight of 2000 having a hydroxyl group tosylated.
¹ H-NMR (CDCl ₃ ) δ = 7.79 (2H, d, J = 8.0 Hz, 2,6-H of TsO), 7.34 (2H, d, J = 8.0 Hz, 3,5-H of Ts), 4.16 (2H, t, J = 5.2 Hz, CH ₂ OTs), 3.83 ~ 3.45 (~ 178H, m, OCH ₂ × 89), 2.45 (3H, s, 4-CH ₃ of Ts).

PEG (4.140 g, 1.92 mmol) having a molecular weight of 2,000 tosylated hydroxyl group was dissolved in acetonitrile (20 ml), sodium azide (0.195 g, 3.00 mmol) was added, and the mixture was heated to reflux for 32 hours. After completion of the reaction, the temperature was returned to room temperature, and water (20 ml) was added. Dichloromethane was added to extract the organic phase, and the organic phase was dehydrated with anhydrous sodium sulfate. The desiccant was filtered off and the solvent was distilled off to obtain PEG (3.280 g, 1.62 mmol, 84%) having a molecular weight of 2000 and having a hydroxyl group azidated.
¹ H-NMR (CDCl ₃ ) δ = 3.83 to 3.45 (~ 178H, m, OCH ₂ × 89), 3.39 (2H, t, J = 5.2 Hz, CH ₂ N ₃ ).

PEG (1.537 g, 0.759 mmol) having a molecular weight of azidated with a hydroxyl group of 2000 was dissolved in pyridine (5 ml), triphenylphosphine (0.394 g, 1.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 28% NH ₄ OH (10 ml) was added and allowed to stand for 2 hours. The product containing PEG having a molecular weight of 2000, in which the solvent was distilled off and the hydroxyl group was converted to an amino group, was obtained.
¹ H-NMR (CDCl ₃ ) δ = 3.83 to 3.45 (~ 178H, m, OCH ₂ × 89), 2.86 (2H, t, J = 5.2 Hz, CH ₂ N).

<Example 1>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 1, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Synthesis of a composition comprising ₃ compounds)

Glycine (0.375 g, 5.00 mmol) was dissolved in methanol (5 ml), and thionyl chloride (1.07 ml, 15.0 mmol) was added dropwise while cooling the solution to 0 ° C. After dropping, the mixture was heated to 60 ° C. and heated to reflux overnight. After completion of the reaction, the solvent was distilled off to obtain glycine methyl ester hydrochloride (0.370 g, 0.175 mmol, 58%).
¹ H-NMR (CDCl ₃ ) δ = 3.80 (3H, s, COOCH ₃ ), 3.73 (2H, s, NCH ₂ ).

3,5-bis (tetradecyloxy) -4-methoxybenzoic acid (Bioorganic. Med. Chem. 2002, 10 vol., P. 4013-4022) (0.577 g, 1.00 mmol) Was dissolved in THF (5 ml), HOBt (0.170 g, 1.20 mmol) and EDC.HCl (0.230 g, 1.20 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Then, glycine methyl ester hydrochloride (0.151 g, 1.20 mmol) was dissolved in THF (5 ml), and a mixed solution in which triethylamine (0.222 ml, 1.60 mmol) was added was added to the reaction solution and stirred overnight at room temperature. . After completion of the reaction, the solution was diluted with chloroform, washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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), and methyl N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminoacetate (0.499 g, 0.770 mmol). , 77%).

White powder; ¹ H-NMR (CDCl ₃ ) δ = 7.00 (2H, s, 2,6-H), 6.52 (1H, br-t, NH), 4.23 (2H, d, J = 6 Hz, NCH ₂ ), 4.03 (4H, t, J = 7 Hz, 3,5-OCH ₂ ), 3.87 (3H, s, 4-OCH ₃ ), 3.81 (3H, s, COOCH ₃ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ) , 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

  Methyl N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminoacetate (0.100 g, 0.154 mmol) is dissolved in ethanol (9 ml) and water (3 ml) and hydroxylated. Potassium (0.1 g) was added, and the mixture was heated to reflux at 78 ° C. overnight. The reaction solution was returned to room temperature, 2% HCl (20 ml) and dichloromethane (12 ml) were added, and the mixture was further stirred for 50 hours. After completion of the reaction, the solvent was distilled off and recrystallized from methanol to give N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminoacetic acid (0.955 g, 0.151 mmol, 98% )

White powder; ¹ H-NMR (CDCl ₃ ) δ = 7.00 (2H, s, 2,6-H), 6.56 (1H, br-t, NH), 4.28 (2H, d, J = 5 Hz, NCH ₂ ), 4.03 (4H, t, J = 7 Hz, 3,5-OCH ₂ ), 3.87 (3H, s, 4-OCH ₃ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.25 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminoacetic acid (0.0317 g, 0.0500 mmol) was dissolved in dichloromethane (5 ml) and HOBt (0.0085 g, 0.060 mmol) was dissolved. EDC · HCl (0.0115 g, 0.060 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The PEG derivative of 2000 molecular weight synthesized in Synthesis Example 1 (excess amount of unpurified product) was dissolved in dichloromethane (5 ml), and the mixture was further stirred for 2 hours while dropping into the reaction solution using a dropping funnel. After completion of the reaction, the solution was washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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 = 9: 1) to obtain a product (0.0809 g, 0.0310 mmol, 62%) (calculated as a compound represented by formula (2)).
¹ H-NMR (CDCl ₃ ) δ = 7.08 (2H, s, 2,6-H), 4.11 (2H, d, J = 5 Hz, NCH ₂ ), 4.03 (4H, t, J = 7 Hz, 3 , 5-OCH ₂ ), 3.86 (3H, s, 4-OCH ₃ ), 3.86-3.49 (~ 180H, m, OCH ₂ CH ₂ × 45), 1.82 (4H, quintet, J = 7 Hz, 3,5 -OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

<Analysis example 1>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 1, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Mass spectrometry of compound ₃ )
Using Shimadzu AXIMA CFR plus, nitrogen laser (337 nm), reflectron mode, positive ion detection, accumulation of 500 times, ionization aid as sodium iodide acetone solution (1 mg / ml), matrix as dithranol chloroform solution ( The product of Example 1 was subjected to MALDI-TOF / MS measurement under the conditions of 10 mg / ml), sample concentration 1 mg / ml (chloroform solution), and scan range m / z 1-5000.

It has a molecular weight distribution similar to that of PEG having a molecular weight of 2000, and in formula (2), X = OH, k = 0, m = 42 to 45, n = 2, Z = NHCO, p = 1, R ₁ = In addition to the peak having a molecular weight distribution corresponding to the compound of R ₃ ═OC ₁₄ H ₂₉ , R ₂ ═OCH ₃ , the molecular weight is 614 large. In formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 1, R ₁ = R ₃ = OC ₁₄ H ₂₉ , a peak having a molecular weight distribution corresponding to the compound of R ₂ = OCH ₃ was detected, and both ends of the benzamide derivative Confirmed generation.

For the lots analyzed, the peak height ratio was about 10: 1.
<Example 2>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 2, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Synthesis of a composition comprising ₃ compounds)
While methanol (5 ml) was cooled to 0 ° C., thionyl chloride (1.07 ml, 15.0 mmol) was added dropwise and stirred for 30 minutes. β-Alanine (0.445 g, 5.00 mmol) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off to obtain β-alanine methyl ester hydrochloride (0.546 g, 3.91 mmol, 78%).
¹ H-NMR (CDCl ₃ ) δ = 3.80 (3H, s, COOCH ₃ ), 3.18 (2H, t, J = 6 Hz, NCH ₂ ), 2.79 (2H, t, J = 6 Hz, NCCH ₂ ).

3,5-bis (tetradecyloxy) -4-methoxybenzoic acid (0.289 g, 0.500 mmol) was dissolved in dichloromethane (5 ml), and HOBt (0.085 g, 0.600 mmol) and EDC · HCl (0.115 g, 0.600) were dissolved. mmol) was added and stirred at room temperature for 30 minutes. Then, β-alanine methyl ester hydrochloride (0.105 g, 0.750 mmol) was suspended in dichloromethane (5 ml), and the mixed solution with triethylamine added gradually was added to the previous reaction solution until the sample was completely dissolved. In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, the solution was diluted with chloroform, washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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), and methyl N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminopropionate (0.239 g, 0.361). mmol, 72%).

White powder; ¹ H-NMR (CDCl ₃ ) δ = 7.00 (2H, s, 2,6-H), 6.53 (1H, br-t, NH), 4.03 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.86 (3H, s, 4-OCH ₃ ), 3.71 (3H, s, COOCH ₃ ), 3.70 (2H, t, J = 6 Hz, NCH ₂ ), 2.70 (2H, t, J = 6 Hz, NCCH ₂ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 ( 40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

  Methyl N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminopropionate (0.239 g, 0.361 mmol) is dissolved in ethanol (20 ml) and water (9 ml). Potassium oxide (0.5 g) was added, and the mixture was heated to reflux at 78 ° C. overnight. The reaction solution was returned to room temperature, 2% HCl (50 ml) and dichloromethane (30 ml) were added, and the mixture was further stirred for 50 hours. After completion of the reaction, the solvent was distilled off and recrystallized from methanol to give N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminopropionic acid (0.215 g, 0.332 mmol, 92% )

White powder; ¹ H-NMR (CDCl ₃ ) δ = 6.95 (2H, s, 2,6-H), 6.65 (1H, br-t, NH), 4.02 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.86 (3H, s, 4-OCH ₃ ), 3.72 (2H, quartet, J = 6 Hz, NCH ₂ ), 2.73 (2H, t, J = 6 Hz, NCCH ₂ ), 1.82 ( 4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminopropionic acid (0.0648 g, 0.100 mmol) was dissolved in dichloromethane (10 ml) and HOBt (0.0170 g, 0.120 mmol) And EDC · HCl (0.0230 g, 0.120 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The PEG derivative of 2000 molecular weight synthesized in Synthesis Example 1 (excess amount of unpurified product) was dissolved in dichloromethane (5 ml), and the mixture was further stirred for 2 hours while dropping into the reaction solution using a dropping funnel. After completion of the reaction, the solution was washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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 = 9: 1) to obtain a product (0.149 g, 0.0568 mmol, 57%) (calculated as a compound represented by formula (2)).

White powder; ¹ H-NMR (CDCl ₃ ) δ = 7.00 (2H, s, 2,6-H), 6.75 (1H, br-t, NH), 4.03 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.85 (3H, s, 4-OCH ₃ ), 3.86-3.44 (~ 180H, m, OCH ₂ CH ₂ × 45), 2.52 (2H, t, J = 6 Hz, NCCH ₂ ), 1.81 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.25 (40H, m, 3,5- OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

<Analysis example 2>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 2, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Mass spectrometry of compound ₃ )
Under the same conditions as in Analysis Example 1, the product of Example 2 was subjected to MALDI-TOF / MS measurement.
It has a molecular weight distribution similar to that of PEG having a molecular weight of 2000, and in formula (2), X = OH, k = 0, m = 42 to 45, n = 2, Z = NHCO, p = 2, R ₁ = In addition to the peak having a molecular weight distribution corresponding to the compound of R ₃ ═OC ₁₄ H ₂₉ , R ₂ ═OCH ₃ , the molecular weight is 628 large. In formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 2, R ₁ = R ₃ = OC ₁₄ H ₂₉ , a peak having a molecular weight distribution corresponding to the compound of R ₂ = OCH ₃ was detected, and both ends of the benzamide derivative Confirmed generation.
For the lots analyzed, the peak height ratio was about 10: 1.

<Example 3>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 3, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Synthesis of a composition comprising ₃ compounds)
While methanol (5 ml) was cooled to 0 ° C., thionyl chloride (1.07 ml, 15.0 mmol) was added dropwise and stirred for 30 minutes. 4-Aminobutyric acid (0.445 g, 5.00 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off to obtain 4-aminobutyric acid methyl ester hydrochloride (0.550 g, 3.58 mmol, 72%).
¹ H-NMR (CDCl ₃ ) δ = 3.27 (3H, s, COOCH ₃ ), 2.89 (2H, t, J = 6 Hz, NCH ₂ ), 2.37 (2H, t, J = 6 Hz, NC ₂ CH ₂ ), 1.87 (2H, quintet, J = 6 Hz, NCCH ₂ ).

3,5-bis (tetradecyloxy) -4-methoxybenzoic acid (0.289 g, 0.500 mmol) was dissolved in dichloromethane (5 ml), and HOBt (0.085 g, 0.600 mmol) and EDC · HCl (0.115 g, 0.600) were dissolved. mmol) was added and stirred at room temperature for 30 minutes. Then, 4-aminobutyric acid methyl ester hydrochloride (0.115 g, 0.750 mmol) was suspended in dichloromethane (5 ml), and the mixed solution was gradually added with triethylamine until the sample was completely dissolved. And stirred at room temperature overnight. After completion of the reaction, the solution was diluted with chloroform, washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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) and methyl N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminobutyrate (0.220 g, 0.325 mmol). , 65%).

White powder; ¹ H-NMR (CDCl ₃ ) δ = 7.00 (2H, s, 2,6-H), 6.53 (1H, br-t, NH), 4.04 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.86 (3H, s, 4-OCH ₃ ), 3.67 (3H, s, COOCH ₃ ), 3.49 (2H, quartet, J = 6 Hz, NCH ₂ ), 2.47 (2H, t, J = 6 Hz, NC ₂ CH ₂ ), 1.97 (2H, quintet, J = 6 Hz, NCCH ₂ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH _3).
N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminobutyric acid (0.220 g, 0.325 mmol) dissolved in ethanol (20 ml) and water (7 ml) (0.5 g) was added, and the mixture was heated to reflux at 78 ° C. overnight. The reaction solution was returned to room temperature, 2% HCl (50 ml) and dichloromethane (30 ml) were added, and the mixture was further stirred for 50 hours. After completion of the reaction, the solvent was distilled off and recrystallized from methanol to give N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminobutyric acid (0.203 g, 0.307 mmol, 95%) Got.

White powder; ¹ H-NMR (CDCl ₃ ) δ = 6.97 (2H, s, 2,6-H), 6.43 (1H, br-t, NH), 4.03 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.89 (3H, s, 4-OCH ₃ ), 3.53 (2H, quartet, J = 6 Hz, NCH ₂ ), 2.48 (2H, t, J = 6 Hz, NC ₂ CH ₂ ), 1.97 (2H, quintet, J = 6 Hz, NCCH ₂ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5-OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

N- (3,5-bis (tetradecyloxy) -4-methoxy) benzoyl-2-aminobutyric acid (0.0662 g, 0.100 mmol) was dissolved in dichloromethane (10 ml) and HOBt (0.0170 g, 0.120 mmol) was dissolved. EDC · HCl (0.0230 g, 0.120 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The PEG derivative of 2000 molecular weight synthesized in Synthesis Example 1 (excess amount of unpurified product) was dissolved in dichloromethane (5 ml), and the mixture was further stirred for 2 hours while dropping into the reaction solution using a dropping funnel. After completion of the reaction, the solution was washed with 4% NaHCO ₃ aqueous solution and saturated NaCl aqueous solution in this order, and the organic phase 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 = 9: 1) to obtain a product (0.146 g, 0.0552 mmol, 55%) (calculated as a compound represented by formula (2)).

White powder; ¹ H-NMR (CDCl ₃ ) δ = 6.97 (2H, s, 2,6-H), 6.43 (1H, br-t, NH), 4.03 (4H, t, J = 7 Hz, 3, 5-OCH ₂ ), 3.89 (3H, s, 4-OCH ₃ ), 3.76-3.47 (~ 180H, m, OCH ₂ CH ₂ × 45), 2.48 (2H, t, J = 6 Hz, NC ₂ CH ₂ ), 1.97 (2H, quintet, J = 6 Hz, NCCH ₂ ), 1.82 (4H, quintet, J = 7 Hz, 3,5-OCCH ₂ ), 1.46 (4H, quintet, J = 7 Hz, 3,5 -OC ₂ CH ₂ ), 1.26 (40H, m, 3,5-OC ₃ C ₁₀ H ₂₀ ), 0.88 (6H, t, J = 7 Hz, 3,5-OC ₁₃ CH ₃ ).

<Analysis example 3>
(In the formula (1), k = 0, m = 42 to 45, n = 2, Z ₁ = CONH, Z ₂ = NHCO, p = 3, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH Mass spectrometry of compound ₃ )
Under the same conditions as in Analysis Example 1, the product of Example 3 was subjected to MALDI-TOF / MS measurement.

It has a molecular weight distribution similar to that of PEG having a molecular weight of 2000, and in formula (2), X = OH, k = 0, m = 42 to 45, n = 2, Z = NHCO, p = 3, R ₁ = In addition to the peak having a molecular weight distribution corresponding to the compound of R ₃ ═OC ₁₄ H ₂₉ , R ₂ ═OCH ₃ , the molecular weight is 642 large. In formula (1), k = 0, m = 42 to 45, n = 2, a peak having a molecular weight distribution corresponding to a compound of Z ₁ = CONH, Z ₂ = NHCO, p = 3, R ₁ = R ₃ = OC ₁₄ H ₂₉ , R ₂ = OCH ₃ was detected. Confirmed generation.
For the lots analyzed, the peak height ratio was about 10: 1.

<Example 4>
(Hydrogel formation)
Each benzamide derivative composition synthesized in Examples 1, 2, and 3 was prepared as a 60 mM aqueous solution, and formation of a hydrogel due to an increase in temperature was observed. In any case, it was confirmed by the inversion method that a hydrogel was formed within one hour by allowing to stand at 37 degrees.

  The hydrogel provided by the present invention has an ethylene glycol oligomer or polymer structure known to be biocompatible, and can be used for three-dimensional cell culture, separation and purification of cells and proteins, sustained release of protein drugs, and the like. .

Claims (10)

A benzamide derivative represented by the formula (1).

(Wherein Z ₁ and Z ₂ are NHCO or CONH amide bonds, k is an integer from 0 to 4, m is an integer from 1 to 100, n is an integer from 1 to 6, p Represents an integer of 1 to 6. R ₁ represents a hydrocarbon group having 8 to 22 carbon atoms bonded through oxygen, and R ₂ represents H or 1 to C 1 bonded through oxygen. (In the hydrocarbon group up to 22, R ₃ represents H or a hydrocarbon group having 1 to 22 carbon atoms bonded through oxygen, and R ₂ and R ₃ are not H at the same time.)   A hydrogelator comprising the compound according to claim 1 as an active ingredient.   A hydrogel comprising the hydrogelator according to claim 2 and water. A hydrogelator comprising the compound according to claim 1 and a benzamide derivative represented by the formula (2) as active ingredients.

Wherein X is OH or NH ₂ , Z is an amide bond of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 1 to 100, and n is from 1 to 6. P is an integer from 1 to 6. R ₁ is a hydrocarbon group having 8 to 22 carbon atoms bonded through oxygen, and R ₂ is bonded through H or oxygen. (The hydrocarbon group having 1 to 22 carbon atoms, R ₃ represents H or a hydrocarbon group having 1 to 22 carbon atoms bonded through oxygen, and R ₂ and R ₃ are not H at the same time.)   A hydrogel comprising the hydrogelator according to claim 4 and water. A benzamide derivative represented by the formula (3).

(Wherein Z ₁ and Z ₂ are NHCO or CONH amide bonds, k is an integer from 0 to 4, m is an integer from 7 to 100, n is an integer from 2 to 6, p Represents an integer from 1 to 6. In addition, R ₁ and R ₃ are a hydrocarbon group having 12 to 18 carbon atoms bonded through an oxygen atom, and R ₂ is bonded through H or an oxygen atom. Represents a hydrocarbon group having 1 to 18 carbon atoms.)   A hydrogelator comprising the compound according to claim 6 as an active ingredient.   A hydrogel comprising the hydrogelator according to claim 7 and water. A hydrogelator comprising the compound according to claim 6 and a benzamide derivative represented by the formula (4) as active ingredients.

Wherein X is OH or NH ₂ , Z is an amide bond of NHCO or CONH, k is an integer from 0 to 4, m is an integer from 7 to 100, and n is from 2 to 6. P represents an integer of 1 to 6. R ₁ and R ₃ represent a hydrocarbon group having 12 to 18 carbon atoms bonded via an oxygen atom, and R ₂ represents H or an oxygen atom. Represents a hydrocarbon group having 1 to 18 carbon atoms bonded via   A hydrogel comprising the hydrogelator according to claim 9 and water.