JPH01121253A - Inclusion compound of ethanolamine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A cyclodextrin inclusion compound of ethanolamine derivative shown by the formula (R<1> is H or acyl derived from nicotinic acid, triene higher fatty acid or pentaene higher fatty acid). USE:Useful as a raw material for preparation of ethanolamine derivative having strongly inhibitory action on blood platelet aggregation. Having excellent stability to light and oxygen, readily soluble in water, suppressing odor and improving pharmaceutical manufacturing. PREPARATION:An aqueous solution of cyclodextrin is blended with a solution of an ethanolamine derivative shown by the formula in an atmosphere substantially containing no oxygen, heated and gradually cooled to room temperature to give the titled compound.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a novel compound and a method for producing the same.

That is, the present invention relates to an ethanolamine derivative cyclodextrin clathrate compound characterized by reacting an ethanolamine derivative with a cyclodextrin, and a method for producing the same.

[Conventional technology]

Conventionally, -R' NHCH2CH2OR2 (R in the formula
1 represents a hydrogen atom or R1 is nicotinic acid.

It represents an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid, and R2 represents a hydrogen atom, or R2 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. It was known that the ethanolamine derivative represented by ) has a strong platelet aggregation inhibitory effect and is useful as a preventive agent for diseases caused by platelet aggregation, such as thrombosis and cancer metastasis.

Ethanolamine derivatives are obtained by condensing nicotinic acid, triene higher fatty acids, pentaene higher fatty acids, or reactive derivatives thereof with ethanolamine. As the condensing agent, for example, ethyl chlorocarbonate is preferably used.

Examples of the reactive derivatives include thiazolidine thionamide derivatives of carboxylic acids. Further, the ethanolamine derivative can be obtained by subjecting the alcoholic hydroxyl group to a condensation reaction with a triene higher fatty acid or a pentaene higher fatty acid following the above condensation reaction.

[Problem that the invention seeks to solve]

Since the ethanolamine derivative of the present invention has an acyl group derived from a triene higher fatty acid such as α-linolenic acid or γ-linolenic acid or an acyl group derived from a pentaene higher fatty acid such as eicosapentaenoic acid in the molecule, It was easily affected by light and oxygen, lacked stability, and lacked water solubility. Furthermore, the acyl group derived from eicosapentaenoic acid had an odor characteristic of blue fish such as sardines and mackerel.

Furthermore, it has a low melting point and is liquid at room temperature, making it difficult to prepare it as a solid preparation.

An object of the present invention is to provide an ethanolamine derivative clathrate compound that has excellent stability against light and oxygen, is easily soluble in water, suppresses odor, and has excellent formulation properties.

[Means for solving problems]

In order to achieve the above object, the present invention has the following configuration. That is, the present invention provides (1) - R'NH'CHzCHz OR2 (
In the formula, 171 represents a hydrogen atom, or R1 represents an acyl group derived from nicotinic acid, a triene higher fatty acid, or a pentaene higher fatty acid, and R2 represents a hydrogen atom, or Rt represents a nicotinic acid, a triene higher fatty acid. and a cyclodextrin clathrate compound of an ethanolamine derivative (indicating an acyl group derived from either a pentaene or higher fatty acid).

(2) The acyl group derived from triene higher fatty acid is α
- The cyclodextrin clathrate compound according to item 1, which is an acyl group derived from linolenic acid or T-linolenic acid.

(3) The cyclodextrin clathrate compound according to item 1, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid.

(4) The cyclodextrin clathrate compound according to any one of items 1 to 3, wherein the cyclodextrin is β-cyclodextrin.

(5) The cyclodextrin clathrate compound according to any one of items 1 to 3, wherein the cyclodextrin is a branched cyclodextrin.

(6) Cyclodextrin aqueous solution and general formula % formula % (in the formula, nl represents a hydrogen atom or R1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid or pentaene higher fatty acid, and R2 represents hydrogen or R2 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid) in an organic solvent solution containing substantially no oxygen. A method for producing a cyclodextrin clathrate compound of an ethanolamine derivative, which comprises mixing in an atmosphere, heating to form a substantially homogeneous solution, and then gradually cooling to room temperature.

(7) A production method in which 1 to 10 moles of cyclodextrin are reacted with 1 mole of the ethanolamine derivative.

(8) Organic solvent is acetone, methanol, ethanol,
A manufacturing method selected from the group consisting of isopropanol and tetrahydrofuran.

(9) Cyclodextrin, 0.5 to 10 parts by weight of water based on the cyclodextrin, and substantially equal moles or less of the general formula % formula % (wherein R1 represents a hydrogen atom). or R1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid; Rt represents a hydrogen atom; or R2 represents nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. A method for producing a cyclodextrin clathrate compound of an ethanolamine derivative, which comprises kneading an ethanolamine derivative represented by (indicating an acyl group to be derived) in an atmosphere substantially free of oxygen.

(10) A production method in which 1 to 10 moles of cyclodextrin are reacted with 1 mole of the ethanolamine derivative.

It consists of:

The ethanolamine derivative that is the host (guest) for the clathrate compound of the present invention has a molecular weight of 450. A yellow to orange-yellow oily substance,
It has a slight odor characteristic of raw blue fish such as sardines and mackerel. It is easily soluble in organic solvents and almost insoluble in water. It is also easily decomposed by light and oxygen, giving off a reddish color and a unique odor. Other examples include the following compounds:

Cyclodextrin (CD) in the present invention refers to starch,
α-CD and β-CD produced from amylose etc. by cyclodextrin luctutransferase etc.
, CD such as γ-CD, or maltosil CD (manufactured by Isoelite 0 Shisui Minato Seito), which uses CD and maltose as raw materials and binds maltose to CD using pullulanase.

The present invention relates to a compound in which the above-mentioned ethanolamine derivative is included in this cyclodextrin. The method for producing clathrate compounds is the solution method.

A kneading method can be used as appropriate.

In the solution method, an aqueous solution of cyclodextrin is prepared, and this is gradually added to a gently heated solution of an ethanolamine derivative in an organic solvent, and the mixture is stirred for 2 to 6 hours to obtain the clathrate compound as a precipitate.

On the other hand, in the kneading method, cyclodextrin contains about 0.5 to 10
Parts by weight of water are added to form a paste, and then an ethanolamine derivative in a substantially equimolar amount or less relative to the cyclodextrin is added and thoroughly kneaded.

The kneading time is 1 to 12 hours, preferably 2 to 6 hours, and the temperature at that time is preferably room temperature (10 to 35°C).
).

Both the solution method and the kneading method are preferably carried out in an atmosphere substantially free of oxygen. An atmosphere substantially free of oxygen is an inert gas, nitrogen.

This shows the state in which the air is replaced with air, etc. from which oxygen has been removed.

Further, the organic solvent used in the present invention may be any solvent as long as it is soluble in water and does not form a strong clathrate with cyclodextrin, such as acetone, methanol, ethanol, isopropanol, and tetrahydrofuran.

A small amount of organic solvent may also be added in the kneading method.

After the clathration is completed, the mixture is washed with hydrous alcohol and dried under reduced pressure to obtain a powdery clathrate compound.

It was also found that the obtained powder did not develop a reddish color even when left in the air, had almost no odor, and was not susceptible to rancidity.

The obtained powder may be used as it is or mixed with a pharmaceutical carrier or excipient in a conventional manner to form a tablet.

It is formulated into powders, capsules, and granules. Examples of carriers or excipients include starch, lactose, crystalline cellulose, talc, magnesium stearate, and the like. In addition to the above-mentioned solid preparations, the compound of the present invention can also be made into liquid preparations and emulsifiers.

Next, the present invention will be explained in detail with reference to Examples.

Example 1 Preparation of ethanolamine derivative-cyclodextrin clathrate.

0.3 ml of compound A 27■ (0.06 mmol)
Separately, 210 mg (0.3 mmol) of β-cyclodextrin was dissolved in 4.7 mf of water.
Add the solution prepared by heating and dissolving the solution in 100°C, heat and dissolve at 50°C, and then gradually cool to room temperature to form a precipitate.

This was left overnight at room temperature, filtered, washed with a 50% aqueous ethanol solution, and dried under reduced pressure to obtain an ethanolamine derivative cyclodextrin clathrate compound.

It was a white powdery crystal with a melting point of 300°C or higher.

Eight types were also prepared using maltosyl-cyclodextrin instead of β-cyclodextrin.

Furthermore, compounds B, C, and D were operated in the same manner to obtain clathrate compounds.

The content of ethanolamine derivative in this clathrate is
It was measured by the following method. Weigh out about 50 μm of the clathrate, add water IM to dissolve it, and add 10 μm of ethyl acetate.
Extract twice with m and dry the extract under reduced pressure. It was determined by dissolving the residue in ethanol and measuring the absorbance at 263 nm. The results are shown in Table 1.

Furthermore, the infrared absorption spectrum of the β-CD clathrate of Compound A was measured. The results are shown in Figure 1.

Table 1 As is clear from the results in Table 1, the clathrate compound was produced regardless of the type of CD, and the amount of ethanolamine derivative contained in the clathrate compound was about 50%. Furthermore, when these clathrate compounds were dissolved in water to a concentration of 0.5 W/V%, it was found that all of them were easily dissolved.

Example 2 Preparation of ethanolamine derivative-cyclodextrin clathrate.

111 d of water and 27 g of compound A were added to 105 g of β-cyclodextrin, the mixture was tightly stoppered, and the mixture was kneaded at room temperature for 5 hours.

Thereafter, the mixture was suction filtered using filter paper, washed with water and ethanol, and then dried to obtain a clathrate compound. Furthermore, a product using maltosyl-cyclodextrin instead of β-cyclodextrin was also prepared.

Furthermore, compounds B, C, and D were operated in the same manner to obtain clathrate compounds.

The content of ethanolamine derivatives in these clathrates is shown in Table 2.

An example of the analysis of the β-cyclodextrin clathrate compound of Compound A using IATROSCAN is shown in FIG.

(Left below) As is clear from the results in Table 2, clathrates were formed regardless of the type of CD, and the amount of ethanolamine derivatives contained in the clathrates was approximately 50%. When these clathrate compounds were dissolved in water to a concentration of 0.5 W/V%, it was found that all of them were easily dissolved.

The clathrate compound of Compound A prepared in Stability Test Examples 1 and 2 was
It was stored at 0°C and the residual rate of Compound A was measured. The results are shown in Table 3.

The measurement was carried out in the same manner as when measuring the content in clathrate compounds, after extraction and drying, cholesterol acetate was added as an internal standard substance and dissolved in chloroform. The test was carried out under the following conditions.

Development conditions (deployed in 3 steps) ■ Chloroform:methanol (9:1, V/V
) 3cm development ■ n-hexane: diethyl ether: formic acid (70:3
0:1) 6 c+a expansion■ n-hexane:diethyl ether (70:3)1
0cm deployment rod Chromatorod S ■ Iatoroscan H! Flow rate: 0.8 kg/c++t (blank below) Table 3 As is clear from the results in Table 3, the clathrate compound showed excellent stability over time, regardless of the type of CD or the method of preparation. Furthermore, in the comparative example, the odor became more intense as the number of days of storage increased, but the clathrate compound of the present invention only had a faint odor.

Although not shown in the table, other clathrate compounds also showed almost similar stability over time.

〔Effect of the invention〕

According to the present invention, a novel ethanolamine derivative clathrate compound and a method for producing the same are provided.

The ethanolamine derivative clathrate compound of the present invention has the inherent instability to light and oxygen due to the acyl group derived from triene or pentaene higher fatty acids in its structure. Significant improvement. Furthermore, it was possible to improve the thermal instability and difficulty in formulation caused by the low melting point of the ethanolamine derivative itself.

Furthermore, the clathrate compound of the present invention suppresses the characteristic odor of the ethanolamine derivative itself and also has water solubility, so it can be used as an excellent pharmaceutical raw material for platelet aggregation inhibitors. It is suggestive.

[Brief explanation of the drawing]

FIG. 1 shows an infrared absorption spectrum of the β-cyclodextrin clathrate of Compound A, and FIG. 2 is an example of analysis of the β-cyclodextrin clathrate of Compound A by IATROScan. In FIG. 2, 1 is a peak derived from cholesterol acetate, which is an internal standard substance, and 2 is a peak derived from compound A.

Claims (10)

[Claims] (1) General formula R^1-NH-CH_2CH_2-O-R
^2 (In the formula, R^1 represents a hydrogen atom or R^1 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid, R^1
2 represents a hydrogen atom, or R^2 represents an acyl group derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid). A cyclodextrin clathrate compound of an ethanolamine derivative. (2) The acyl group derived from triene higher fatty acid is α
The cyclodextrin clathrate compound according to claim 1, which is an acyl group derived from -linolenic acid or γ-linolenic acid. (3) The cyclodextrin clathrate compound according to claim 1, wherein the acyl group derived from pentaene higher fatty acid is an acyl group derived from eicosapentaenoic acid. (4) The cyclodextrin clathrate compound according to any one of claims 1 to 3, wherein the cyclodextrin is β-cyclodextrin. (5) The cyclodextrin clathrate compound according to any one of claims 1 to 3, wherein the cyclodextrin is a branched cyclodextrin. (6) Cyclodextrin aqueous solution and the general formula R^1-NH-CH_2CH_2CH_2-O-R^2 (in the formula R
^1 represents a hydrogen atom or R^1 is nicotinic acid,
Indicates an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid, and R^2 represents a hydrogen atom, or R^2 is derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. An organic solvent solution of an ethanolamine derivative (representing an acyl group) is mixed in an atmosphere substantially free of oxygen, heated to form a substantially homogeneous solution, and then gradually cooled to room temperature. A method for producing a cyclodextrin clathrate compound of an ethanolamine derivative, characterized by: (7) The production method according to claim 6, wherein 1 to 10 moles of cyclodextrin are reacted with 1 mole of the ethanolamine derivative. (8) Organic solvent is acetone, methanol, ethanol,
7. The method according to claim 6, wherein the isopropanol and tetrahydrofuran are selected from the group consisting of isopropanol and tetrahydrofuran. (9) Cyclodextrin, 0.5 to 10 parts by weight of water based on the cyclodextrin, and substantially equimolar or less of the general formula R^1-NH-CH_2CH_2-O-R^ with respect to the cyclodextrin. 2 (in the formula R
^1 represents a hydrogen atom or R^1 is nicotinic acid,
Indicates an acyl group derived from either triene higher fatty acid or pentaene higher fatty acid, and R^2 represents a hydrogen atom, or R^2 is derived from either nicotinic acid, triene higher fatty acid, or pentaene higher fatty acid. A method for producing a cyclodextrin clathrate compound of an ethanolamine derivative, which comprises kneading an ethanolamine derivative represented by (representing an acyl group) in an atmosphere substantially free of oxygen. (10) The production method according to claim 9, wherein 1 to 10 moles of cyclodextrin are reacted with 1 mole of the ethanolamine derivative.