JP2008162953A - Cyclic ether amide compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new cyclic ether amide lipid constructing molecular aggregates by self-organization, and a lipid membrane forming a moderate intramolecular hydrogen bond. <P>SOLUTION: This new cyclic ether amide lipid of 2 glycerol derivatives and 2 long chain alkyl compounds, having a diether bond backbone and an amide bond backbone simultaneously is obtained by synthesizing a diether lipid of a glycerol derivative building-in asymmetric groups and the long chain alkyl compound and then passing through a new intermediate material obtained by introducing an azide group having high reactivity. The obtained cyclic ether amide lipid is provided by forming the molecular aggregates by the self-organization, having a property close to that of a cyclic amide lipid and forming a lipid membrane having a somewhat weakened intramolecular hydrogen bond. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a novel cyclic ether / amide compound, a process for producing the same, and an intermediate compound.
The present invention also relates to a lipid membrane mainly composed of a novel cyclic ether / amide compound and a method for producing the same.

The present inventors modeled cyclic lipids found in archaeal biofilms that survive in extreme environments as models, and as artificial cyclic lipids to construct various forms of lipid nanostructures, glycerol 2 molecules have four ether bonds. A cyclic ether lipid (Patent Document 1) bound by two groups, a cyclic ester lipid in which two glycerol molecules are bound by four ester bonds (Patent Document 2), and a cyclic amide lipid in which two glycerol molecules are bound by four amide bonds ( Patent document 3) has been created.
These cyclic lipids, that is, cyclic ether lipids, cyclic ester lipids, and cyclic amide lipids are all amphiphilic compounds, and include a hydrophobic part composed of a long-chain alkyl group, a hydrophilic part composed of a phosphocholine group or a hydroxyl group, and a hydrophobic part. It consists of four linkers that connect the hydrophilic parts. And since all have the effect | action as a stable surface active substance, they can be utilized as various industrial processing agents, various household cleaning agents and various detergents, pharmaceuticals, cosmetics, food additives, and the like.
In addition, these artificial cyclic lipids can usually form a molecular assembly in an aqueous solvent, and attempts have been made to produce nano-sized lipid tubes and two-dimensional sheet membranes. Originally, these artificial cyclic lipids are modeled on membrane lipids of archaea inhabiting extreme environments, have excellent environmental properties, and have hydrocarbon chains (R ^{1 to} R ⁴ groups). As a lipid nanostructure having both “flexibility” because an unbranched alkylene group is selected as the terminal, when the terminal R ⁵ and / or R ⁶ group is a choline group, it has even better biocompatibility It is.
Therefore, the molecular assembly formed by these artificial cyclic lipids is highly expected as a lipid nanostructure that is controlled at the nano level and is extremely stable and has a high affinity for biomolecules.

However, the mechanical strength of a cyclic ester lipid (cyclic PC type lipid) or a molecular assembly formed by a cyclic ether lipid, such as a two-dimensional sheet membrane (lipid membrane), is low. This is because a strong and directional intermolecular bond such as a hydrogen bond is not formed between the ester bond or the ether bond of these lipids, and the intermolecular bond formed in the molecular assembly is mechanically This is thought to be due to brittleness. On the other hand, the amide bond of cyclic amide lipid is expected to build a mechanically strong molecular assembly based on the strong intermolecular hydrogen bond, but the intermolecular hydrogen bond network is so strong that different molecules are inserted into the molecular assembly. The gap to be accommodated cannot be constructed and cannot be used as a lipid membrane imitating a biological membrane.
As described above, the conventional molecular assemblies formed by self-organizing cyclic lipids have their merits and demerits, and their respective applications must be limited. Therefore, it has been desired to provide a novel cyclic lipid capable of forming a molecular assembly having properties different from those of the conventional one.
Japanese Patent Laid-Open No. 2003-286281 Japanese Patent Laid-Open No. 2004-75586 Japanese Patent Laid-Open No. 2004-196703

An object of the present invention is to provide a novel cyclic lipid that can be self-assembled to construct a molecular assembly. Specifically, the cyclic ether amide is an asymmetric lipid having an amide bond and an ether bond in the molecule. Is to provide lipids.
It is also an object of the present invention to provide a lipid membrane that forms an appropriate intermolecular hydrogen bond using the cyclic ether / amide lipid.

The present inventors pay attention to the degree of intermolecular hydrogen bond formation in the molecular structure of each cyclic lipid, and an asymmetric structure having an amide bond that forms a strong intermolecular hydrogen bond and an ether bond that hardly forms an intermolecular hydrogen bond. We thought that there is a possibility that lipid membranes that form moderate intermolecular hydrogen bonds can be constructed by synthesizing cyclic ether / amide lipids.
However, since such asymmetric cyclic lipids have not been synthesized in the past, the conventional synthesis method of cyclic lipids cannot be applied as it is, so that the difficulty of synthesis can be predicted as well as synthesis. Even so, it was unclear whether or not it would form a molecular assembly similar to conventional cyclic lipids.
As a result of intensive studies on a route for efficiently synthesizing a cyclic lipid having both a diether bond skeleton and an amide bond skeleton, the present inventors have once conducted an asymmetrical study. A cyclic ether / amide lipid can be efficiently obtained by synthesizing a diether lipid of a glycerol derivative incorporating a group and a long-chain alkyl compound, and then via a novel intermediate having a highly reactive azide group. And the present invention was completed.
The obtained cyclic ether / amide lipid is self-assembled to form a molecular assembly in the same manner as the conventional cyclic lipid, and is close to the cyclic amide lipid, but has an appropriate lipid membrane with slightly weak intermolecular hydrogen bonds. It was confirmed that it could be formed.
In the examples, since chiral glycerol was used as the starting material glycerol, the obtained cyclic ether amide lipid was a chiral compound.

According to the present invention, the following inventions are provided.
(1) A cyclic ether / amide compound represented by the following [Chemical Formula 1].
(In the formula, R ^{1 to} R ⁴ represent divalent hydrocarbons which may be the same or different, and R ⁵ and R ⁶ represent a hydrogen atom, a phospholipid group and a hydrocarbon group, and are the same or different. May be.)
(2) The cyclic ether / amide compound according to the above (1) represented by the following general formula [Chemical Formula 2].
(3) The cyclic ether / amide compound according to the above (1) represented by the following general formula [Chemical Formula 3].
(In the formula, m and n represent the same or different natural numbers of 2 to 100.)
(4) The cyclic ether / amide compound according to the above (3) represented by the following general formula [Chemical Formula 4].
(5) A compound represented by the following general formula [Formula 5].
(In the formula, R ^{1 to} R ⁴ represent divalent hydrocarbons which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.)
(6) A compound represented by the following general formula [Formula 6].
(In the formula, R ¹ and R ² represent a divalent hydrocarbon which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.)
(7) After using a compound represented by the following general formula [Chemical Formula 7] as a raw material or an intermediate and treating with methyl chloride sulfate (MeSO ₃ Cl), triethylamine (Et ₃ N) and methylene chloride (CH ₂ Cl ₂ ) A process for producing a compound of the general formula [Chem. 6], characterized by treatment with sodium azide (NaN ₃ ) / DMSO.
(In the formula, R ¹ and R ² represent a divalent hydrocarbon which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.)
(8) A compound represented by the general formula [Chemical Formula 6] is used as a raw material or intermediate, and is treated in the presence of triphenylphosphine (PPh ₃ ), water and THF, and then the general formula [Chemical Formula 8] and / or [ A process for producing a compound of the general formula [Chemical Formula 5], wherein the compound represented by Chemical Formula 9] is treated with EDCHCl and HOBt, Et ₃ N, CH ₂ Cl ₂ .
(Ryoshikichu, R ¹ to R ⁴ represents a divalent hydrocarbon may be the same or different, wherein the R ⁵ is R ⁶ represents a hydrogen atom or a protecting group.)
(9) Using the compound represented by the above general formula [Chemical Formula 5] as a raw material or intermediate, the reaction is carried out by refluxing in the presence of copper (II) acetate and pyridine, and then the resulting compound is p-toluenesulfone. A method for producing a compound of the above general formula [Chemical Formula 1], wherein the compound is treated with an acid (p-TsOH) in an organic solvent.
(10) The cyclic ether / amide compound according to any one of the above (1) to (4) is dissolved in an organic solvent alone or together with other components to be incorporated into the lipid membrane to obtain a saturated solution, and the substrate surface A method for producing a lipid membrane comprising a cyclic ether / amide compound as a main component, which is dried on a thin film and formed on a thin film.
(11) A lipid membrane mainly comprising the cyclic ether / amide compound according to any one of (1) to (4), which is obtained by the production method according to (10).

The cyclic ether amide lipid obtained in the present invention is not only a lipid nanostructure having the same excellent characteristics as the conventional cyclic ether lipid, cyclic amide lipid and the like as described above, Unlike asymmetric lipids, membrane fluidity based on hydrophobic interactions and intermolecular hydrogen bonds formed between two amide groups in lipids can exert moderate intermolecular interactions.
As a result, the lipid membrane as a molecular assembly constructed by this molecule has membrane fluidity and high mechanical strength, and a gap that allows foreign molecules to enter the peripheral site of the ether bond is formed. Can be used as a matrix for composition. In addition, if a chiral compound is used as the starting glycerol derivative, a chiral cyclic ether / amide lipid can be obtained, and a choline group is introduced into the terminal R ⁵ and / or R ⁶ group to provide excellent biocompatibility. It is possible to reproduce a state that more closely approximates a biological membrane.

The cyclic ether / amide compound of the present invention is represented by the following [Chemical Formula 1].
R ^{1 to} R ⁴ in the formula represent a divalent hydrocarbon, which may be the same or different, and preferably a chiral compound represented by the following [Chemical Formula 2]. Preferably, it represents a divalent unbranched alkylene group, the carbon number of which is 3 or more and 100 or less, and the carbon number of R ³ and R ^{4 is} the carbon number of R ¹ and R ² (m and n ) Is one less than each (m−1 and n−1), and is represented by the following [Chemical Formula 3]. More preferably, both m and n are 10 or less, and most preferably, R ¹ and R ² are 8 carbon atoms, R ³ and R ⁴ are 7 carbon atoms, and are represented by the following [Chemical Formula 4]: The
R ⁵ and R ⁶ represent a hydrogen atom, a phospholipid group, or a hydrocarbon group, and may be the same or different. Preferably, R ⁵ and R ⁶ are a hydrogen atom or a choline group.

  In addition, to obtain the chiral cyclic ether / amide compound of [Chemical Formula 2], chiral glycerol is used as a raw material glycerol. Chiral glycerol is in the 1-position or 2-position or 1-position and 2-position of glycerol. What protected the hydroxyl group can be obtained by optical resolution or resolution using an enzyme.

The steps of the method for producing the cyclic ether / amide compound of the present invention will be described in the order of steps a to l according to FIG. 1 in the case of the typical cyclic ether / amide compound ([Chemical Formula 1]) described in the Examples.
Step a: 3-Decin-1-ol is reacted with NaH and 1,3-diaminopropane (DAP) at 10 ° C. to 100 ° C./40 minutes to obtain 9-decin-1-ol.
Step b: 9-decin-1-ol is reacted with MeSO ₃ Cl and Et ₃ N in the presence of CH ₂ Cl ₂ at 0 ° C./30 minutes to obtain compound (2).
Step c: Compound (3) is obtained by reacting 9-decin-1-ol in the presence of chromic acid (CrO ₃ ), sulfuric acid and water at −5 ° C./2 hours 30 minutes.
Step d: D-1,2-O-isopropylidene-sn-glycerol is reacted at room temperature in the presence of 4-methoxybenzoyl chloride (PMBCl) and potassium hydroxide and dimethyl sulfoxide (DMSO) for 24 hours, Subsequently, it is made to react at room temperature for 36 hours in presence of para-toluenesulfonic acid (p-TsOH), and a compound (4) is obtained.
Step e: Compound (4) was treated in the presence of 4-dimethylaminopyridine (DMAP), trityl chloride (TrCl) and pyridine at room temperature to 80 ° C. for 7 hours 30 minutes, and then treated at room temperature for 9 hours to give compound ( 5) get.
Step f: Add NaH, tetrabutylammonium iodide (TBAI), N, N-dimethylformamide (DMF) to the compound (2) obtained in step b and the compound (5) obtained in step e. The compound (6) is obtained by treating at 0 ° C. to room temperature / 19 hours.
Step g: Compound (7) is obtained by adding CuCl, tetramethylethylenediamine (TMEDA) and acetone to compound (6) and treating in the presence of O ₂ at room temperature to 60 ° C./15 hours.
Step h: To compound (7), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and CH ₂ Cl ₂ are added, and in the presence of a phosphate buffer (pH 7.2). To give a compound (8).
Step i: Compound (8) the MeSO ₃ Cl, was added Et ₃ N and CH ₂ Cl _2, treated -20 ° C. / 1 hr, then NaN ₃ and 60 ° C. / 8 hours to give compound with DMSO ( 9) get.
Step j: Compound (9) is treated in the presence of PPh ₃ , water and THF, and further Compound (3) is added, and EDCHCl, HOBt, Et ₃ N, CH ₂ Cl ₂ is added at 0 ° C. to room temperature / 19 hours. Treatment gives compound (10).
Step k: Compound (11) is obtained by refluxing Compound (10) in the presence of copper acetate and pyridine at 115 to 120 ° C./3 hours.
Step 1: Compound (11) is treated with p-toluenesulfonic acid (p-TsOH) in the presence of methanol and chloroform (chloroform-methanol 4: 1 solution) at room temperature for 3 hours to obtain compound (1).

  The cyclic ether / amide compound obtained as described above is an asymmetric cyclic lipid having an ether bond and an amide bond, and forms a self-assembled molecular assembly. For example, a monolayer lipid membrane similar to a biological membrane can be produced as follows.

  In order to produce a monolayer lipid membrane, a saturated solution is prepared by dissolving a raw material cyclic ether / amide compound in an organic solvent by heating. The heating temperature at this time is preferably raised to the boiling temperature in order to increase the amount of the pseudo-cyclic amide compound dissolved as much as possible, but of course, a temperature lower than this can also be used.

  Next, the saturated solution of the cyclic ether / amide compound thus prepared is gradually cooled and allowed to stand at room temperature or under ice cooling to spontaneously produce a lipid membrane. As the solvent for preparing this saturated solution, a single organic solvent is usually used, but if desired, a plurality of organic solvents or a mixed solvent composed of water and an organic solvent can be used. Any organic solvent may be used as long as it can dissolve the cyclic ether / amide compound. Examples of such a solvent include chloroform, dichloromethane, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, and the like. A chloroform-methanol solution (4: 1) is preferably used.

A lipid monolayer film is immediately formed from the solution by the operation as described above. A multilayer film can also be formed by adjusting the amount of the solution, and a lipid film that is stable even in air can be obtained by appropriately performing a drying treatment. The structure of the obtained lipid membrane can be easily observed using an optical microscope. By using a transmission electron microscope or the like, the film structure can be confirmed in more detail.
Along with the cyclic ether / amide compound of the present invention, proteins, lipids and the like on biological membranes can be incorporated into the lipid membrane formed by the cyclic ether / amide compound by dissolving or dispersing them in the organic solvent in advance. Therefore, it is possible to observe properties, behaviors, and the like on the biological membrane such as proteins and lipids on the biological membrane under conditions simulating the biological membrane.

Hereinafter, in the following [Chemical Formula 4], which is a typical compound among the cyclic ether / amide lipids of the present invention, when R ₅ and R ₆ are both hydrogen atoms and are chiral compounds: Compound (1) ([Chemical 13]) will be described as Examples 1 and 2. The present invention is not limited to the following unless it exceeds the gist.
[Example 1]
Compound (1) was synthesized by the following steps a to l. Hereinafter, the synthesis process of the compound (1) will be described with reference to FIG.
Each step is referred to as “step a” or the like, and the compound obtained in each step is referred to as “compound (2)” or the like.

Step a: Synthesis of 9-decyn-1-ol from 3-decyn-1-ol:
3-Decin-1-ol (commercially available) was reacted with NaH and 1,3-diaminopropane (DAP) for 40 minutes under conditions of 10 ° C. to 100 ° C. to obtain 9-decin-1-ol. The yield was 81%.

Step b: Synthesis of compound (2) from 9-decyn-1-ol:
9-Decin-1-ol was reacted with MeSO ₃ Cl and Et ₃ N in the presence of CH ₂ Cl ₂ at 0 ° C. for 30 minutes to obtain Compound (2) in a yield of 93%.

Step c: Synthesis of compound (3) from 9-decyn-1-ol:
9 decyne-1-O - Le chromic acid (CrO ₃₎ and 2 hours 30 minutes reacted with compounds at -5 ° C. in the presence of sulfuric acid and water (3) was obtained in 61% yield.

Step d: Synthesis of compound (4) from D-1,2-O-isopropylidene-sn-glycerol:
First, D-1,2-O-isopropylidene-sn-glycerol was reacted for 24 hours at room temperature in the presence of 4-methoxybenzoyl chloride (PMBCl) and potassium hydroxide and dimethyl sulfoxide (DMSO), then The reaction was carried out in the presence of p-toluenesulfonic acid (p-TsOH) for 36 hours to obtain compound (4) in a yield of 80%.

Step e: Step of producing compound (5) from compound (4):
Compound (4) was treated with 4-dimethylaminopyridine (DMAP) in the presence of trityl chloride (TrCl) and pyridine at room temperature to 80 ° C. for 7 hours 30 minutes and then at room temperature for 9 hours, yield 92 % Gave compound (5).

Step f: Step of producing compound (6) from compound (2) and compound (5):
To the compound (2) obtained in step b and the compound (5) obtained in step e, NaH, tetrabutylammonium iodide (TBAI), N, N-dimethylformamide (DMF) are added, and 0 When the mixture was treated at 0 ° C. to room temperature for 19 hours, compound (6) was obtained in a yield of 99%.

Step g: Step of reacting compound (6) to obtain compound (7):
To the compound (6), CuCl, tetramethylethylenediamine (TMEDA) and acetone were added and treated at room temperature to 60 ° C. for 15 hours in the presence of O ₂ to obtain the compound (7) with a yield of 93%. .

Step h: Step of obtaining compound (8) from compound (7):
To the compound (7), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and CH ₂ Cl ₂ are added, and 0 ° C. in the presence of a phosphate buffer (pH 7.2). The compound (8) was obtained in 89% yield.

Step i: Step of obtaining compound (9) from compound (8):
Compound (8) was treated with MeSO ₃ Cl, Et ₃ N and CH ₂ Cl ₂ , treated at −20 ° C. for 1 hour, and then with NaN ₃ and DMSO at 60 ° C. for 8 hours. ) Could be obtained in a yield of 63%. Compound (9) is a novel compound having the structural formula of [Chemical Formula 10] below.

Step j: Step of obtaining compound (10) from compound (9) and compound (3):
Compound (9) was treated in the presence of PPh ₃ , water and THF, and further compound (3) was added and EDCHCl, HOBt, Et ₃ N, and CH ₂ Cl ₂ were treated at 0 ° C. to room temperature for 19 hours. Compound (10) was obtained in a yield of 42%. Compound (10) is a novel compound having the following structural formula [Chemical Formula 11].

Step k: Step of obtaining Compound (11) from Compound (10) When Compound (10) is refluxed at 115 to 120 ° C. for 3 hours in the presence of copper (II) acetate and pyridine, Compound (11) is obtained. 28% could be obtained. Compound (11) is a novel compound having the following structural formula [Chemical Formula 12].

Step l: Step of obtaining compound (1) from compound (11):
Compound (11) is treated with p-toluenesulfonic acid (p-TsOH) in the presence of methanol and chloroform (chloroform-methanol 4: 1 solution) at room temperature for 3 hours to give the object compound (1) of the present invention. ) Was obtained in a yield of 77%.
Compound (1) was identified as [Chemical 13] by ¹ H-NMR spectrum, ¹³ C-NMR spectrum and the like.

The measurement results are as follows.
<Thin layer chromatography>
R _f = 0.32 [CHCl ₃ / MeOH (20: 1, v / v)];
^<1 H-NMR spectrum>
¹ H NMR (CDCl ₃ ) ・ 5.90 (brs, 2H), 3.69-3.32 (m, 14H), 3.21 (brs, 1H), 2.34-2.17 (m, 12H), 1.68-1.48 (m, 16H), 1.44 -1.24 (m, 28H);
< ^13C -NMR spectrum>
¹³ C NMR (CDCl ₃ / CD ₃ OD = 20: 1) 78.03, 77.37, 69.89, 65.30, 60.81, 50.17, 49.30, 39.58, 36.48, 29.86, 29.12, 28.91, 28.87, 28.63, 28.52, 28.47, 28.09, 28.04, 25.93, 25.59, 19.03;
<Mass spectrum>
TOF-MS calcd.for C ₆₄ H ₇₄ O ₆ Na (M) ⁺ m / z 750.55414. Found: 750.54743.

[Example 2]
0.5 mg of the compound (1) obtained in Example 1 was dissolved by heating in about 1 ml of a 4: 1 chloroform-methanol solution to prepare a saturated solution.
Next, the obtained solution (1.5 μl) was dropped onto an observation grid of a transmission electron microscope and dried to obtain a lipid membrane. The lipid membrane is stable in air, and TEM measurement was performed with a transmission electron microscope after staining, and a lipid monolayer membrane with a slightly higher membrane fluidity was obtained, which was similar to that of cyclic amide lipids. It was. The result is shown in FIG.

Synthesis scheme of cyclic ether / amide compound obtained in Example 1 (Note that compounds 9, 10, 11 and 1 are novel compounds) Transmission electron micrograph of the lipid membrane obtained in Example 2

Claims (11)

The cyclic ether amide compound represented by the following general formula [Chemical Formula 1]
(Wherein, R ¹ to R ⁴ represents a hydrocarbon divalent may be the same or different, R ⁵ and R ⁶ is a hydrogen atom, the phospholipid group, a hydrocarbon group, are identical or different May be.) The cyclic ether / amide compound according to claim 1 represented by the following general formula [Chemical Formula 2].
The cyclic ether / amide compound according to claim 1 represented by the following general formula [Chemical Formula 3].
(In the formula, m and n represent the same or different natural numbers of 2 to 100.) The cyclic ether-amide compound according to claim 3, which is represented by the following general formula [Chemical Formula 4].
A compound represented by the following general formula [Formula 5].
(In the formula, R ^{1 to} R ⁴ represent divalent hydrocarbons which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.) A compound represented by the following general formula [Chem. 6].
(In the formula, R ¹ and R ² represent a divalent hydrocarbon which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.) A compound represented by the following general formula [Chemical Formula 7] is used as a raw material or an intermediate, treated with methyl chloride sulfate (MeSO ₃ Cl), triethylamine (Et ₃ N) and methylene chloride (CH ₂ Cl ₂ ), and then sodium azide A process for producing a compound of the general formula [Chemical Formula 6], characterized by treatment with (NaN ₃ ) / DMSO.
(In the formula, R ¹ and R ² represents a divalent hydrocarbon may be the same or different, wherein the R ⁵ is R ⁶ represents a hydrogen atom or a protecting group.) A compound represented by the general formula [Chemical Formula 6] is used as a raw material or an intermediate, and is treated in the presence of triphenylphosphine (PPh ₃ ), water and THF, and then the general formula [Chemical Formula 8] and / or [Chemical Formula 9]. A process for producing a compound of the general formula [Chemical Formula 5], wherein the compound represented by the formula is treated with EDCHCl and HOBt, Et ₃ N, CH ₂ Cl ₂ .
(In both formulas, R ^{1 to} R ⁴ represent divalent hydrocarbons which may be the same or different, and here, R ⁵ and R ⁶ represent a hydrogen atom or a protecting group.)   The compound represented by the above general formula [Chemical Formula 5] is used as a raw material or an intermediate, and reacted by refluxing in the presence of copper acetate (II) and pyridine, and then the resulting compound is converted into p-toluenesulfonic acid (p A process for producing a compound of the above general formula [Chemical Formula 1], wherein the compound is treated in an organic solvent together with -TsOH).   The cyclic ether / amide compound according to any one of claims 1 to 4 is dissolved in an organic solvent alone or together with other components to be incorporated into a lipid membrane to obtain a saturated solution, which is dried on the substrate surface. A method for producing a lipid membrane comprising a cyclic ether / amide compound as a main component, which is formed on a thin film.   A lipid membrane comprising the cyclic ether / amide compound according to any one of claims 1 to 4 as a main component, which is obtained by the production method according to claim 10.