JP4092402B2 - Pseudocyclic amide compounds and lipid nanotubes - Google Patents

Description

  The present invention includes various industrial treatment agents, various household cleaning agents and various detergents, drug delivery systems and other pharmaceuticals, cosmetics, food additives, gas storage materials, molecular separation media, conductive nanotubes, etc. The present invention relates to a novel quasi-cyclic amide compound and a hollow fiber-like lipid nanotube obtained by self-assembly of a quasi-cyclic amide compound.

Conventionally, lipids ester-bonded with 1 molecule and 2 molecules of saturated or unsaturated fatty acid have surface activity, and various industrial treatment agents used for mining, metal processing, surface finishing, and washing, Widely used as emulsifiers, demulsifiers, detergents, dispersants, hydrotropes, etc., such as various household detergents and detergents, pharmaceuticals, cosmetics and food additives (Non-Patent Document 1) ).
However, a cyclic amide having four amide bonds in one molecule instead of an ester bond has never been synthesized.
Certain lipids self-assemble to form stable molecular aggregates and are used as functional materials in the fine chemical and medical fields. Spherical molecular assemblies composed of such lipids, such as naturally-derived phospholipids, so-called liposomes, are prepared by ultrasonic irradiation, stationary hydration, cholic acid, reverse phase evaporation, etc. All of these methods are complicated, and it is difficult to put them to practical use because skilled techniques must be used. In addition, all the molecular assemblies obtained by these methods have a spherical shape, and a hollow fiber-like molecular assembly cannot be obtained.
On the other hand, it is known that fibrous or rod-like molecular aggregates can be obtained by dispersing certain lipids in water (Non-patent Document 2).
However, although the molecular assembly obtained by this method is in the form of a ribbon or string, the nanotube structure has a one-dimensional isolated vacancy and a large surface area that are effective for gas occlusion and separation of useful biomolecules. It was impossible to form a body, and it could hardly be used as a fibrous molecular assembly.

"Science and chemistry dictionary" published by Iwanami Shoten Journal of American Chemical Society), 107, 509-510 (1985).

  The present invention is expected as various industrial treatment agents, household cleaning agents and detergents, pharmaceuticals, cosmetics and food additives, gas storage materials, molecular separation media, conductive nanotubes and the like. It is an object of the present invention to provide a quasicyclic amide compound and a hollow fibrous lipid nanotube obtained by self-organizing a quasicyclic amide compound and applicable as a gas occlusion body, a molecular separation medium, a conductive nanotube, etc. .

（式中、Ｒ ^１ とＲ ^２ は同一でも異なっていてもよいアルキレン基を、Ｒ ^３ とＲ ^４ は同一でも異なっていてもよいアルキル基を、Ｒ ^５ とＲ ^６ は水素原子を表す。）
〈２〉下記一般式（２）乃至一般式（５）で表される群から選ばれる少なくとも一種の擬環状アミド化合物。

（式中、Ｒ ^１ とＲ ^２ は、同一でも異なっていてもよいアルキレン基を、Ｒ ^３ とＲ ^４ は同一でも異なっていてもよいアルキル基を、Ｒ ^５ とＲ ^６ は水素原子を表す。）
〈３〉上記一般式（１）乃至一般式（５）で表される擬環状アミド化合物から選ばれた少なくとも１種の化合物が自己組織化することにより得られる中空繊維状脂質ナノチューブ。 The inventors of the present invention have made extensive studies on the above problems, and reacting a diamino group-containing hydroxy compound such as 2,3-diaminopropane-1-ol with a diyne-based carboxylic acid yields two 2,3-diaminopropanes. It is found that a novel pseudo-cyclic amide compound in which -1-ol and the like are bonded by four amide bonds can be obtained, and this pseudo-cyclic amide compound unexpectedly self-assembles to form a hollow fiber lipid nanotube. As a result, the present invention has been completed.
That is, according to this application, the following invention is provided.
<1> A pseudo-cyclic amide compound represented by the following general formula (1).

(In the formula, R ¹ and R ² represent an alkylene group which may be the same or different, R ³ and R ⁴ represent an alkyl group which may be the same or different, and R ⁵ and R ⁶ represent a hydrogen atom.)
<2> At least one pseudo-cyclic amide compound selected from the group represented by the following general formulas (2) to (5).

(In the formula, R ¹ and R ² represent an alkylene group which may be the same or different, R ³ and R ⁴ represent an alkyl group which may be the same or different, and R ⁵ and R ⁶ represent a hydrogen atom. )
<3> A hollow fibrous lipid nanotube obtained by self-organizing at least one compound selected from the pseudocyclic amide compounds represented by the general formulas (1) to (5).

  The pseudo-cyclic amide compound according to the present invention is a novel compound not yet described in the literature, and is used as various industrial processing agents, various household cleaning agents and various detergents, pharmaceuticals, cosmetics, food additives, and the like. Can do. In particular, since it has a lactam structure, it can be used as a constituent intermediate such as penicillin and cephalosporin. Further, since it is a chiral compound, it can be applied to products that require the characteristics of optical isomers. Moreover, the hollow fibrous lipid nanotubes obtained by self-organizing this quasi-cyclic amide compound can be applied as gas storage materials, molecular separation media, conductive nanotubes and the like.

（式中、Ｒ^１〜Ｒ^４は、同一でも異なっていてもよい２価の炭化水素を表し、Ｒ^５とＲ^６は、水素原子、金属原子、リン酸残基、炭化水素を表し、同一でも異なっていてもよい。） The novel pseudo-cyclic amide compound of the present invention is represented by the following general formula (1).
Here, the pseudo-cyclic amide compound means a compound containing four amide groups in one molecule, two of which are connected by an alkyl group containing a diacetylene group, and the remaining two are not bonded to each other.

(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 metal atom, a phosphate residue, and a hydrocarbon, and are the same. But it may be different.)

（式中、Ｒ^１〜Ｒ^６は前記一般式（１）と同じ。）
また、前記一般式（１）から（５）で表される化合物の立体配置は、たとえば、２，３−ジアミノプロパン−１−オールの２位のアミノ基の組み合わせに応じて、２分子の２，３−ジアミノプロパン−１−オールの２位のアミノ基が（Ｒ、Ｒ）、（Ｒ、Ｓ）、（Ｓ、Ｒ）、（Ｓ、Ｓ）の４種類が存在する。 In the pseudo-cyclic amide compound represented by the general formula (1), there are isomers represented by the following four general formulas (2) to (5).

(Wherein R ^{1 to} R ⁶ are the same as those in the general formula (1).)
The steric configuration of the compounds represented by the general formulas (1) to (5) is, for example, 2 molecules of 2 depending on the combination of the 2-position amino group of 2,3-diaminopropan-1-ol. , 3-Diaminopropan-1-ol has four types of amino groups (R, R), (R, S), (S, R), and (S, S).

R represented by the general formulas (1) to (5) ¹ ~ R ⁶ Will be described.
R ¹ And R ² Are alkylene groups which may be the same or different. The alkylene group is a group selected from linear or branched alkylene groups. The number of carbon atoms is usually 100 or less, preferably 72 or less, more preferably 32 or less, and is in the range of 3 or more as a whole. Such an alkylene group is usually represented as a group obtained by removing one hydrogen from a corresponding alkyl group.
R ³ And R ⁴ Are alkyl groups which may be the same or different. Specific examples of the alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, n-hexyl group, isohexyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, heptyl group, octyl group, isooctyl group, 2-ethylhexyl group, Nonyl group, decyl group, undecyl group, dodecyl group, tetradecyl group, hexadecyl group, octadecyl group, eicosyl group and the like can be mentioned.

R ⁵ And R ⁶ Is a hydrogen atom.

  The pseudo-cyclic amide compound represented by the general formula (1) of the present invention can be synthesized according to the following reaction formula, for example, by reacting a diamino group-containing hydroxy compound with a diyne or tetrayne carboxylic acid.

As the diamino group-containing hydroxy compound as a raw material, alcohols having at least two amino groups in the molecule can be used. Examples of such alcohols include 2,3-diaminopropan-1-ol and derivatives thereof (R ⁵ and R ⁶ are those described above, those having metal atoms, phosphoric acid and hydrocarbon groups).

In this case, when a chiral compound, for example, a compound represented by HOCH ₂ CH (NH ₂ ) CH ₂ NH ₂ is used as a raw material, an alkylene group or a cyclic alkylene group which is a divalent hydrocarbon group bonded by an amide bond A novel quasi-cyclic amide compound consisting of a chiral isomer connected by a group of four amide bonds, into which a group selected from the group of an arylene group and an aralkylene group is introduced can be selectively obtained. .

  Chiral compounds, such as 2,3-diaminopropan-1-ol, are D-serine, L-serine, D-serine methyl ester monohydrochloride, L-serine methyl ester monohydrochloride, D-serine ethyl ester monohydrochloride, L -Starting with L-serine or D-serine such as serine ethyl ester monohydrochloride, or their methyl ester, or their hydrochlorides, the carboxyl group is reduced, azidated, then reduced to convert the carboxyl group to an amine Can be obtained.

  Examples of the diynes that are the other raw materials include commercially available products such as 4-pentynoic acid and 10-undecic acid, 16-heptadesic acid (J. Org. Chem., 1964, 2968), 4-penta-4. -Synthesis reagents such as inyloxybenzoic acid (J. Med. Chem., 1967, 130) and the synthesis reagents described in Table 1 can be used.

Further, propargyl alcohol, 3-butyn-1-ol, 1-ethynyl-1-cyclohexanol, 10-decyn-1-ol, 4-ethynylphenol, and diyne or tetrayne alcohols such as those listed in Table 2 Permanganic acid, sulfuric acid chromate (Jones oxidation), pyridinium chlorochromate (PCC oxidation), pyridinium dichromate (PDC oxidation), oxalyl chloride-dimethyl sulfoxide (Swern oxidation), manganese dioxide (MnO ₂ oxidation), SO ₃ - pyridine, it can also be used those obtained by converting the carboxylic acid by oxidation in the presence of such NaClO ₂ acid.

  This synthesis reaction is usually performed at a reaction temperature of −78 to 200 ° C., a reaction pressure of normal pressure to 2 atm (about balloon pressure), and preferably acetone, methanol, ethanol, N, N-dimethylformamide, N-methylpyrrolidinone, , 3-dimethyl-2-imidazolidinone, diethyl ether, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, pyridine, dimethyl sulfoxide, acetonitrile, 2-propanol and the like. .

  The pseudo-cyclic amide compound obtained by the present invention can be used as various industrial processing agents, various household cleaning agents and various detergents, pharmaceuticals, cosmetics, food additives, and the like. In particular, since it has a lactam structure, it can be used as a constituent intermediate such as penicillin and cephalosporin. Further, since it is a chiral compound, it can be applied to products that require the characteristics of optical isomers.

  In addition, this pseudo-cyclic amide compound has a so-called pseudo-cyclic amide structure (containing four amide groups in one molecule, two of which are linked by an alkyl group containing a diacetylene group, and the other two are bonded to each other. A hollow fiber-like lipid nanotube is obtained by self-assembly.

  In order to produce such hollow fiber-like lipid nanotubes, first, an organic solvent is added to the raw pseudo-cyclic amide compound and heated to prepare a saturated solution. 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 quasi-cyclic amide compound saturated solution prepared in this manner is gradually cooled and allowed to stand at room temperature or ice-cooling to spontaneously produce hollow fiber lipid nanotubes. 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 can be used as long as it can dissolve the pseudo-cyclic amide compound. Examples of such a solvent include chloroform, dichloromethane, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, and the like.

By collecting the fibrous substance that immediately precipitates from the solution by the operation as described above, and air-drying or vacuum-drying, it is stable in the air, having an outer diameter of 10 to 100 nm and a length of several nm to several hundred μm. Hollow fibrous lipid nanotubes having a size are obtained. The structure of the obtained nanotube can be easily observed using an optical microscope. The tube structure can be confirmed in more detail by using a laser microscope, an atomic force microscope, an electron microscope, or the like.
The hollow fibrous lipid nanotubes obtained by the present invention can be applied as, for example, a gas occlusion body, a molecular separation medium, or a conductive nanotube by utilizing the structural characteristics.

EXAMPLES Hereinafter, although an Example is given and demonstrated about this invention, unless it exceeds the summary, it is not limited to the following. The reaction temperature represents degrees Celsius.
Example 1

Compound 3 listed in Table 3 was synthesized as follows.
[Synthesis of Compound 1]
Compound 1 was synthesized according to the method described in Synlett No. 3, pages 349-352 (2003).

[Synthesis of Compound 2]
Under ice cooling, trifluoroacetic acid (0.9 mL) was added dropwise to Compound 1 ( (300 mg, 0.253 mmol) dissolved in dichloromethane (0.9 mL). After stirring for 30 minutes under ice cooling, the temperature of the reaction solution was adjusted. The temperature was gradually raised to room temperature over 1 hour, and then the solvent was removed from the reaction solution under reduced pressure, and trifluoroacetic acid remaining in the resulting oily substance was removed by azeotroping with dry benzene. This oily substance was combined with undecanoic acid (142 mg, 0.76 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (146 mg, 0.76 mmol) and 1-hydroxybenzotriazole (103 mg, .0. 76 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.5 mL, 3.0 mL) was cooled with ice. After stirring at room temperature for 3 hours, the reaction was stopped by adding saturated brine to the reaction solution, followed by extraction with chloroform (30 mL × 3 times). The residue was obtained by drying with sodium, followed by concentration under reduced pressure, and the target compound 2 (300 mg) was obtained by flash column chromatography (silica gel, developing solvent methanol: chloroform 0 = 1: 200).

[Synthesis of Compound 3]
Compound 2 (50 mg, 0.038 mmol) was dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (1N solution (tetrahydrofuran), 80 μL, 0.076 mmol) was added under ice cooling, followed by 2 hours at room temperature. Stir. The solution was concentrated under reduced pressure, and the obtained residue was purified by gel permeation chromatography to obtain the target compound 3 (28 mg).

Compound 3 was identified by ¹ H-NMR spectrum, ¹³ C-NMR spectrum, and mass spectrometry.

The results are as follows.
¹ H NMR (500 MHz, CDCl ₃ ) δ 6.74 (t, J = 6.1 Hz, 2H), 6.48 (d, J = 7.9 Hz, 2H), 4.35-4.29 (m, 2H), 3.92-3.85 (m, 2H), 4.35-4.29 (m, 2H), 3.67 (d, J = 11.9 Hz, 2H), 3.55-3.47 (m, 4H), 3.28-3.20 (m, 2H), 2.25 (t, J = 6.7 Hz , 4H), 2.23 (t, J = 7.8 Hz, 4H), 2.18 (t, J = 7.6 Hz, 4H), 1.54-1.47 (m, 4H), 1.43-1.36 (m, 4H), 1.34-1.22 ( m, 48H), 0.88 (t , J = 7.0 Hz, 6H) ppm. 13 C NMR δ 175.66, 173.93, 77.45, 65.45, 61.50, 51.40, 39.60, 36.74, 36.40, 31.88, 29.57, 29.50, 29.35, 29.30, 29.25, 29.11, 29.07, 28.84, 28.55, 28.10, 25.74, 22.67, 19.12, 14.11 ppm.LRMS (FAB): m / z 866 (M + Na) ⁺ , 844 (M + H) ⁺ .
Example 2

  Compound 3 (2.0 mg) was placed in a test tube, followed by addition of chloroform (0.2 mL), followed by heating at 50-60 degrees to obtain a clear solution. The resulting solution was cooled with an ice bath. A white suspension was obtained after 30 minutes. The resulting suspension was placed on a carbon-coated grid for an electron microscope, and chloroform was removed by air drying. Observation (low magnification and high magnification) was performed with a transmission electron microscope. The results are shown in FIGS. Hollow fiber-like lipid nanotubes having a diameter of approximately 50 nm and a length of several micrometers were confirmed.

Transmission electron micrograph of the hollow fibrous lipid nanotubes obtained in Example 2 (low magnification; bar is 0.2 μm) Transmission electron micrograph of the hollow fibrous lipid nanotube obtained in Example 2 (high magnification; bar is 50 nm)

Claims (3)

A pseudo-cyclic amide compound represented by the following general formula (1).

(In the formula, R ¹ and R ² represent an alkylene group which may be the same or different, R ³ and R ⁴ represent an alkyl group which may be the same or different, and R ⁵ and R ⁶ represent a hydrogen atom.) At least one pseudocyclic amide compound selected from the group represented by the following general formula (2) to general formula (5).

(Wherein R ¹ And R ² Are the same or different alkylene groups, R ³ And R ⁴ Are the same or different alkyl groups, R ⁵ And R ⁶ Represents a hydrogen atom. ) A hollow fibrous lipid nanotube obtained by self-organizing at least one compound selected from the pseudocyclic amide compounds represented by the general formulas (1) to (5).

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