JPH059195A - New phenylglycoside - Google Patents

Abstract

PURPOSE:To provide a new phenylglycoside having excellent activity to suppress the isolation of histamine from mast cell and, accordingly, useful as a new antiallergic agent effective for suppressing the isolation of histamine itself from mast cell. CONSTITUTION:The phenylglycoside of formula I [X is sugar residue obtained by removing all hydroxyl groups from a sugar having (n+1) hydroxyl groups; (n) is 3 or 4; R<1> is 9-18C alkyl], e.g. 4-decyloxyphenyl-beta-D-glycopyranoside. The compound can be produced by the deacetylation of the compound of formula II The compound of formula II is obtained e.g. by reacting a monoalkylhydroquinone of formula III with a peracetylated sugar of formula IV in a non-aqueous solvent (e.g. benzene) in the presence of an organic solvent complex of a Lewis acid as a catalyst. The organic acid complex of Lewis acid is e.g. BF3.ether.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a substance having an inhibitory action on histamine release and an antiallergic agent utilizing this action, and particularly to a phenylglycoside having an inhibitory action on histamine release and an antiallergic agent using this phenylglycoside. Regarding

[0002]

BACKGROUND ART Allergic diseases such as bronchial asthma, allergic rhinitis, eczema, and urticaria develop due to the production of antibodies by the invasion of allergens into the body. There are chemical transmitters of. Such chemical mediators include histamine, quinines, serotonin, acetylcholine,
SRS-A and the like are known. And histamine is released from mast cells and platelets by the antigen-antibody reaction,
It has been thought to cause allergic symptoms.

Based on such knowledge, various substances (diphenhydramine hydrochloride, clemastine fumarate, cyproheptadine hydrochloride, promethazine hydrochloride, etc.) that antagonize histamine have been developed up to now, and antiallergic agents using these substances have been developed. Agents (so-called antihistamines) are used to treat allergic diseases. In recent years,
Various tocopheryl glycosides have been developed as substances that suppress histamine release itself from mast cells, and antiallergic agents using these substances have also been developed (JP-A-59-151895). Further, substances such as azelastine hydrochloride that antagonize histamine and suppress the release of histamine from mast cells have been developed, and antiallergic agents containing such substances have also been developed.

[0004]

OBJECT OF THE INVENTION The first object of the present invention is to provide a novel phenylglycoside as a new substance excellent in the action of inhibiting histamine release from mast cells.
A second object of the present invention is to provide a method for producing the phenyl glycoside. Furthermore, the third aspect of the present invention
The purpose of is to provide a novel anti-allergic agent that suppresses the release of histamine from mast cells.

[0005]

The novel phenylglycoside of the present invention which achieves the above first object has the general formula (I)

[0006]

[Chemical 5]

[0007] In addition, the general formula (I
I)

[0008]

[Chemical 6]

The novel phenylglycoside of the present invention represented by: also achieves the first object.

The method for producing the phenylglycoside represented by the general formula (I), which achieves the second object, is described by the general formula (III)

[0011]

[Chemical 7]

It is characterized by deacetylating the compound represented by the formula (hereinafter, this production method is referred to as production method A). In addition, a method for producing the phenylglycoside represented by the general formula (II), which achieves the second object, is
General formula (IV)

[0013]

[Chemical 8]

It is characterized by deacetylating the compound represented by the formula (hereinafter, this production method is referred to as production method B).

The antiallergic agent of the present invention that achieves the third object comprises the phenylglycoside represented by the general formula (I) and / or the phenylglycoside represented by the general formula (II) as an active ingredient. To do.

The present invention will be described in detail below. First, the phenyl glycoside represented by the general formula (I), which is one of the novel phenyl glycosides of the present invention, will be described. This novel phenylglycoside has the formula as shown in the general formula (I).

[0017]

[Chemical 9]

A unit (a) represented by

[0019]

[Chemical 10]

And a unit (b) represented by. Unit (a) forming part of the general formula (I)
In, X is a sugar residue obtained by removing all hydroxyl groups from a sugar having (n + 1) hydroxyl groups, and n is an integer of 3 or 4. That is, X means a sugar residue obtained by removing all hydroxyl groups from a sugar having 4 or 5 hydroxyl groups. Here, examples of the sugar having five hydroxyl groups as the base of X include hexose (glucose, galactose, mannose, etc.). As sugars having four hydroxyl groups, pentose (xylose, arabinose, ribose, etc.), methylpentose (fucose, rhamnose, etc.), amino sugars (glucosamine, galactosamine, etc.), N-acetylamino sugars (N-acetylglucosamine, etc.). , N-acetylgalactosamine, etc.) and the like.
On the other hand, in the unit (b), R ¹ has 9 to 18 carbon atoms.
Is an alkyl group. The carbon number of the alkyl group of R ¹ is 9 to
The reason for limiting the number to 18 is that phenylglycoside in which R ¹ is an alkyl group having 8 or less carbon atoms or an alkyl group having more than 18 carbon atoms has a low action of suppressing histamine release from mast cells.

The novel phenylglycoside represented by the general formula (II) can be produced according to the production method A of the present invention in which the compound represented by the general formula (III) is deacetylated. Deacetylation of the compound represented by the general formula (III) can be carried out by a conventional method using CH ₃ ONa, C ₂ H ₅ ONa and the like. The general formula (III)
The compound represented by the general formula (V)

[0022]

[Chemical 11]

A monoalkylhydroquinone represented by the general formula (VI)

[0024]

[Chemical 12]

In a non-aqueous solvent such as benzene, toluene or ether, a compound represented by (sugar peracetylated product) is added to an organic solvent complex of Lewis acid (BF ₃ · ether, B).
The F ₃ · anisole) can be obtained by reacting as a catalyst. Here, specific examples of the compound represented by the general formula (VI) include penta-O-acetyl-glucose, penta-O-acetyl-galactose and penta-.
O-acetyl-mannose, tetra-O-acetyl-xylose, tetra-O-acetyl-arabinose, tetra-O-acetyl-ribose, tetra-O-acetyl-
Fucose, tetra-O-acetyl-rhamnose, N-benzyl-tetra-O-acetyl-glucosamine, N-benzyl-tetra-O-acetyl-galactosamine, tetra-O-acetyl-N-acetylglucosamine, tetra-O-acetyl. -N-acetylgalactosamine etc. are mentioned.

Next, the phenylglycid represented by the general formula (II), which is another one of the novel phenylglycosides of the present invention, will be explained. As is clear from the above general formula (II), this novel phenylglycoside has the above-mentioned unit (a) and formula

[0027]

[Chemical 13]

And a unit (c) represented by. R ² to R ⁴ in the unit (c) are each a hydrogen atom or a lower alkyl group, these R ²
~ R ⁴ may be the same as or different from each other. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group. R ⁵ in the unit (c) is an alkyl group having 4 to 18 carbon atoms. The reason for limiting the number of carbon atoms in the alkyl group of R ⁵ to 4 to 18, in the phenyl glycoside R ⁵ is an alkyl group of more than an alkyl group or a C 18 3 carbon atoms, histamine release from mast cells This is because the suppressing effect is low.

The novel phenylglycoside represented by the general formula (II) can be produced according to the production method B of the present invention in which the compound represented by the above general formula (IV) is deacetylated. The deacetylation of the compound represented by the general formula (IV) can be performed in the same manner as the deacetylation of the general formula (III) described above. The compound represented by the general formula (IV) has the general formula (VII)

[0030]

[Chemical 14]

In a non-aqueous solvent such as benzene, toluene or ether, a monoalkylhydroquinone derivative represented by and the compound of the general formula (VI) (sugar peracetylated product) are mixed with an organic solvent complex of Lewis acid ( BF ₃ · ether, BF ₃ · anisole, etc.) can be used as a catalyst for the reaction.

The novel phenylglycoside of the general formula (I) and the novel phenylglycoside of the general formula (II) obtained as described above are both excellent in the action of inhibiting histamine release from mast cells. Therefore, these novel phenyl glycosides are useful as an active ingredient of the antiallergic agent of the present invention described later.

Next, the antiallergic agent of the present invention will be described. The antiallergic agent of the present invention comprises the novel phenylglycoside of the general formula (I) and / or the novel phenylglycoside of the general formula (II) as an active ingredient. The dosage form of the antiallergic agent of the present invention is not particularly limited, and powders, fine granules, granules, tablets, coated tablets, oral solid preparations such as capsules and oral liquid preparations such as syrups, It may be a transdermal agent, an injection, a suppository, an oral agent, an ophthalmic agent and the like. And when formulating,
It can be produced by a conventional method using only the novel phenylglycoside of the present invention or in combination with an ordinary pharmaceutical carrier.

The dose of the antiallergic agent of the present invention cannot be specified because it varies depending on the type and degree of disease, dosage form, age and health condition of the patient, etc., but the lower limit of a single dose is , The total amount of the novel phenylglycoside of the general formula (I) and / or the novel phenylglycoside of the general formula (II) is about 1 mg / dose / person, and the upper limit is about 3000 mg / dose / person for oral administration. . By administering the antiallergic agent of the present invention within such a range,
The desired effect can be obtained.

[0035]

EXAMPLES Examples of the present invention will be described below. Example 1 [Production of novel phenylglycoside of general formula (I)] Production of 1-decylhydroquinone 2.3 g (21.0 mmol) of hydroquinone was dissolved in 30 ml of n-decyl alcohol to prepare a solution of P ₂ O ₅ · 24.
After adding 0.7 g of MoO ₃ · xH ₂ O and stirring, 120
Heated at ° C for 6 hours. Water and EtOH are added to the solution after heating.
100 ml of each was added and shaken. After shaking, the organic layer was separated, dried over anhydrous MgSO ₄ and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography and eluted with a mixed solution of hexane and EtOAc, A crude product of 1-decylhydroquinone was obtained. After that, the crude product obtained was recrystallized from n-hexane,
2.57 g (yield 49%) of the desired title compound was obtained.

Melting point: 68.5-69 ° C. H-NMR; [CDCl ₃ ] δ: 0.88 (3H, t, J = 5.7 Hz), 1.02-1.
75 (16H, m), 3.89 (2H, t, J = 6.2)
Hz), 6.76 (4H, s).

4-decyloxyphenyl-2,3
4,6-Tetra-O-acetyl-β-D-glycopyranoside [n = 4 in the general formula (III), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ¹ = -C ₁₀ H ₂₁ compound ]
2.5 g of 1-decylhydroquinone obtained above
(10 mmol) and penta-O-acetyl-β-D-glucose (1.95 g, 5 mmol) in 50 ml of dry benzene
BF ₃ · (C ₂ H ₅ ) ₂ O 1.0 in the solution dissolved in
ml (7.25 mmol) was added, and the mixture was stirred at room temperature for 8 hours.
100 ml of benzene was added to the reaction solution after stirring, 100 ml of water and 100 ml of EtOAc were further added, and the mixture was shaken. After shaking, the organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and EtOAc. 4-decyloxyphenyl-2,
A crude product of 3,4,6-tetra-O-acetyl-β-D-glycopyranoside was obtained. Then, the crude product obtained was recrystallized from EtOH to give the desired title compound (1.45).
g (yield 50%) was obtained.

Melting point: 95-97 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
1.1 °.

4-decyloxyphenyl-β-D-glycopyranoside [n = 4 in the general formula (I), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ¹ = -C ₁₀ H ₂₁
The compound of 4-decyloxyphenyl-2,3 obtained above
4,6-Tetra-O-acetyl-β-D-glycopyranoside (1.40 g, 2.41 mmol) in MeOH (100 ml)
0.1M CH ₃ ONa (1.9 ml)
Was added and the mixture was stirred at room temperature for 1.5 hours. Next, polystyrene sulfonate type ion exchange resin (trade name: Amberlite IR
-120 (H ⁺ , manufactured by Organo) was added for desalting, followed by decolorization with activated carbon and filtration. After filtration, the solvent was evaporated, and the residue was recrystallized from EtOH to obtain 0.97 g (yield 98%) of the desired title compound.

Melting point: 102-106 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH):-3
6.9 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.86 (2H, d, J =
6.8 Hz), 6.99 (2H, d, J = 6.8 Hz). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.4, 71.3, 72.9, 74.7,
78.2, 103.2.

Example 2 [Production of novel phenylglycoside of general formula (I)] Production of 1-dodecylhydroquinone Instead of n-decyl alcohol in Example 1, n-
In the same manner as in Example 1 except that dodecyl alcohol was used, 3.22 g (yield 55%) of the desired title compound was obtained. Melting point: 77 to 78 ° C. H-NMR; [CDCl ₃ ] δ: 0.88 (3H, t,
J = 6.2 Hz), 1.26 to 1.75 (20H, m),
3.89 (2H, t, J = 6.4Hz), 6.76 (4
H, s).

4-dodecyloxyphenyl-2,3
4,6-Tetra-O-acetyl-β-D-glycopyranoside [n = 4 in the general formula (III), X = a sugar residue obtained by removing all hydroxyl groups from glucose, R ¹ = -C ₁₂ H ₂₅ ]
In the same manner as in Example 1 except that 1-dodecylhydroquinone obtained above was used instead of 1-decylhydroquinone in Production Example 1, 2.18 g (yield 62%) of the desired title compound was obtained. It was Melting point: 98-99 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
0.8 °.

4-dodecyloxyphenyl-β-D-
Glycopyranoside [n = 4 in the general formula (I), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ¹ = -C ₁₂ H
₂₅ compounds] 4-decyloxyphenyl-2 in Example 1
Instead of 3,4,6-tetra-O-acetyl-β-D-glycopyranoside, 4-dodecyloxyphenyl-2,3,4,6-tetra-O-acetyl-obtained above was obtained.
In the same manner as in Example 1 except that β-D-glycopyranoside was used, 1.42 g of the desired title compound (yield 90
%) Was obtained. Melting point: 201 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH): -3
1.0 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.85 (2H, d, J =
6.8 Hz), 6.99 (2H, d, J = 6.8 Hz). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.5, 71.4, 74.9, 78.4
78.6, 103.2.

Example 3 [Production of novel phenylglycoside of general formula (II)] Production of 1-butyl-2,3,5-trimethylhydroquinone Trimethylhydroquinone was used in place of hydroquinone in Example 1, and Example 1 The title compound of interest 3. was obtained in the same manner as in Example 1 except that n-butyl alcohol was used instead of n-decyl alcohol.
19 g (yield 73%) was obtained. Melting point: 65.5-66.5 ° C. H-NMR; [CDCl ₃ ] δ: 0.97 (3H, t,
J = 6.6Hz), 1.30 to 1.90 (4H, m),
1.57 (4H, m), 2.14 (3H, s), 2.1
7 (3H, s), 2.21 (3H, s), 3.87 (2
H, t, J = 6.2 Hz), 6.58 (H, s).

4'-butyloxy-2 ', 3', 6 '
-Trimethylphenyl-2,3,4,6-tetra-O-
Acetyl-β-D-glycopyranoside [n = 4 in the general formula (IV), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R ⁴ = -C
H ₃ , R ⁵ = -C ₄ H ₉ compound] was carried out except that 1-butyl-2,3,5-trimethylhydroquinone obtained above was used instead of 1-decylhydroquinone in Example 1. In the same manner as in Example 1, 2.68 g (yield 65%) of the desired title compound was obtained. Melting point: 120 to 128 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
6.7 °.

4'-butyloxy-2 ', 3', 6 '
-Trimethylphenyl-β-D-glycopyranoside [n = 4 in the general formula (II), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R
_{^{4 = -CH 3, R 5 =}} -C 4 Compound Production Example 4 decyloxyphenyl 2 in 1 of H _9,
Instead of 3,4,6-tetra-O-acetyl-β-D-glycopyranoside, 4′-butyloxy-2 ′, 3 ′, 6′-trimethylphenyl-2,3, obtained above, was obtained.
1.75 g (yield 95%) of the desired title compound was obtained in the same manner as in Example 1 except that 4,6-tetra-O-acetyl-β-D-glycopyranoside was used. Melting point: 188-191 ° C ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH): -5.
5 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.54 (H, s). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.8, 71.8, 75.6, 77.8,
78.2, 106.2.

Example 4 [Production of novel phenylglycoside of general formula (II)] Production of 1-hexyl-2,3,5-trimethylhydroquinone n-butyl alcohol in place of n-butyl alcohol in Example 3 was used.
In the same manner as in Example 3 except that hexyl alcohol was used, 3.17 g (yield 64%) of the desired title compound was obtained. Melting point: 72.5 to 73 ° C. H-NMR; [CDCl ₃ ] δ: 0.97 (3H, t,
J = 6.5 Hz), 2.14 (3H, s), 2.17 (3
H, s), 2.21 (3H, s), 3.87 (2H,
t, J = 5.9 Hz), 6.51 (H, s).

4'-hexyloxy-2 ', 3',
6'-trimethylphenyl-2,3,4,6-tetra-
O-acetyl-β-D-glycopyranoside [general formula (I
V) n = 4, X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R ⁴ =-
CH ₃ , R ⁵ = -C ₆ H ₁₃ compound] In place of 1-butyl-2,3,5-trimethylhydroquinone in Example 3, 1-hexyl-2,3,5-obtained above was obtained. In the same manner as in Example 3 except that trimethylhydroquinone was used, the desired title compound 1.6
0 g (yield 42%) was obtained. Melting point: 128.5 to 130 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
6.4 °.

4'-hexyloxy-2 ', 3',
6′-trimethylphenyl-β-D-glycopyranoside [n = 4 in the general formula (II), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R _{^{4 = -CH 3, R 5 =}} -C 6 4'- butyloxy in preparation example 3 compound of H ₁₃ -2 ', 3',
6'-trimethylphenyl-2,3,4,6-tetra-
Instead of O-acetyl-β-D-glycopyranoside, 4′-hexyloxy-2 ′, 3 ′, obtained above,
6'-trimethylphenyl-2,3,4,6-tetra-
The target title compound 1.07 was obtained in the same manner as in Example 3 except that O-acetyl-β-D-glycopyranoside was used.
g (yield 95%) was obtained. Melting point: 184-186 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH):-4.
7 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.53 (H, s). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.9, 71.9, 75.7, 78.0,
78.4, 106.4.

Example 5 [Production of novel phenylglycoside of general formula (II)] Production of 1-octyl-2,3,5-trimethylhydroquinone In place of n-hexyl alcohol in Example 4, n
In the same manner as in Example 4 except that octyl alcohol was used, 2.99 g (yield 54%) of the desired title compound was obtained. Melting point: 70-71 ° C. H-NMR; [CDCl ₃ ] δ: 0.89 (3H, t,
J = 6.2 Hz), 1.10 to 1.76 (12H, m),
2.14 (3H, s), 2.17 (3H, s), 2.2
1 (3H, s), 3.86 (2H, t, J = 6.2H
z), 6.52 (H, s).

4'-octyloxy-2 ', 3',
6'-trimethylphenyl-2,3,4,6-tetra-
O-acetyl-β-D-glycopyranoside [general formula (I
V) n = 4, X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R ⁴ =-
CH ₃ , R ⁵ = -C ₈ H ₁₇ compound] In place of 1-hexyl-2,3,5-trimethylhydroquinone in Example 4, 1-octyl-2,3,5-obtained above was obtained. The desired title compound was obtained in the same manner as in Example 4 except that trimethylhydroquinone was used.
36 g (yield 70%) was obtained. Melting point: 95-97.5 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
5.2 °.

4'-octyloxy-2 ', 3',
6′-trimethylphenyl-β-D-glycopyranoside [n = 4 in the general formula (II), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R _{^{4 = -CH 3, R 5 =}} -C 8 4'- hexyloxy in preparation example 4 compound of H ₁₇ -2 ',
Instead of 3 ′, 6′-trimethylphenyl-2,3,4,6-tetra-O-acetyl-β-D-glycopyranoside, 4′-octyloxy-2 ′, obtained above,
In the same manner as in Example 4 except that 3 ′, 6′-trimethylphenyl-2,3,4,6-tetra-O-acetyl-β-D-glycopyranoside was used, 1.66 g of the desired title compound (yield: Rate of 98%). Melting point: 176 to 179 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH): −4.
4 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.53 (H, s). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.8, 71.8, 75.5, 77.6.
78.2, 106.1.

Example 6 [Production of novel phenylglycoside of general formula (II)] Production of 1-decyl-2,3,5-trimethylhydroquinone Instead of n-octyl alcohol in Example 5, n
In the same manner as in Example 5 except that decyl alcohol was used, 2.57 g (yield 42%) of the desired title compound was obtained. Melting point: 76-77 ° C. H-NMR; [CDCl ₃ ] δ: 0.88 (3 H, t,
J = 5.1 Hz), 1.05 to 1.94 (16 H, m),
1.35 (16H, m), 2.14 (3H, s), 2.
17 (3H, s), 2.21 (3H, s), 3.86
(2H, t, J = 6.4 Hz), 6.51 (H, s).

4'-decyloxy-2 ', 3', 6 '
-Trimethylphenyl-2,3,4,6-tetra-O-
Acetyl-β-D-glycopyranoside [n = 4 in the general formula (IV), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R ⁴ = -C
H ₃ and R ⁵ = —C ₁₀ H ₂₁ compound] In place of 1-octyl-2,3,5-trimethylhydroquinone in Example 5, 1-decyl-2,3,5-obtained above was obtained. In the same manner as in Example 5 except that trimethylhydroquinone was used, the desired title compound 0.8
5 g (yield 32%) was obtained. Melting point: 94-95 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
4.6 °.

4'-decyloxy-2 ', 3', 6 '
-Trimethylphenyl-β-D-glycopyranoside [n = 4 in the general formula (II), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R
_{^{4 = -CH 3, R 5 =}} -C 10 4'- octyloxy in Preparation Example 5 of the compound on the H ₂₁ -2 ',
Instead of 3 ′, 6′-trimethylphenyl-2,3,4,6-tetra-O-acetyl-β-D-glycopyranoside, 4′-decyloxy-2 ′, obtained above,
In the same manner as in Example 5 except that 3 ′, 6′-trimethylphenyl-2,3,4,6-tetra-O-acetyl-β-D-glycopyranoside was used, 0.61 g of the desired title compound (yield: Rate of 98%). Melting point: 189-192 ° C ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH):-3.
5 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.53 (H, s). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.8, 71.8, 75.5, 77.7,
78.2, 106.2.

Example 7 [Production of novel phenyl glycoside of general formula (II)] Production of 1-dodecyl-2,3,5-trimethylhydroquinone n-decyl alcohol in place of n-decyl alcohol in Example 6
In the same manner as in Example 6 except that dodecyl alcohol was used, 3.62 g (yield 55%) of the desired title compound was obtained. Melting point: 81 to 83 ° C. H-NMR; [CDCl ₃ ] δ: 0.88 (3H, t,
J = 6.4 Hz), 1.26 to 1.97 (20H, m),
2.14 (3H, s), 2.17 (3H, s), 2.2
1 (3H, s), 3.86 (2H, t, J = 6.2H
z), 6.51 (H, s).

4'-dodecyloxy-2 ', 3',
6'-trimethylphenyl-2,3,4,6-tetra-
O-acetyl-β-D-glycopyranoside [general formula (I
V) n = 4, X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R ⁴ =-
CH _3, R ⁵ = -C ₁₂ compounds of H _25] instead of 1-decyl-2,3,5-trimethyl hydroquinone in Preparation Example 6, the 1-dodecyl -2,3,5 obtained above In the same manner as in Example 6 except that trimethylhydroquinone was used, the desired title compound 1.
97 g (yield 53%) was obtained. Melting point: 67 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CHCl ₃ ):-1
3.8 °.

4'-dodecyloxy-2 ', 3',
6′-trimethylphenyl-β-D-glycopyranoside [n = 4 in the general formula (II), X = sugar residue obtained by removing all hydroxyl groups from glucose, R ² = -CH ₃ , R ³ = hydrogen atom, R _{^{4 = -CH 3, R 5 =}} -C 12 4'- decyloxy 2 in preparation example 6 of H compound _25] ', 3',
6'-trimethylphenyl-2,3,4,6-tetra-
Instead of O-acetyl-β-D-glycopyranoside, 4′-dodecyloxy-2 ′, 3 ′, obtained above,
6'-trimethylphenyl-2,3,4,6-tetra-
The target title compound 1.47 was obtained in the same manner as in Example 6 except that O-acetyl-β-D-glycopyranoside was used.
g (yield 99%) was obtained. Melting point: 179-181 ° C. ₂₀ [α] _D (c = 10.0 mg / ml, CH ₃ OH): −3.
3 ° H-NMR (aromatic proton signal of aglycone part); [CD ₃ OD] δ: 6.54 (H, s). ¹³ C-NMR (carbon signal of sugar moiety); [Py-
d ₅ ] δ: 62.8, 71.8, 75.5, 77.7,
78.2, 106.2.

Example 8 (Pharmacological test) Each of the novel phenylglycosides of the general formula (I) obtained in Examples 1 to 2 and each of the general formula (II) obtained in Examples 3 to 7 Each of the novel phenyl glycosides was tested for histamine release inhibitory activity as follows. At the same time, the conventional antiallergic agents (tocopheryl glucoside and azelastine hydrochloride) were also tested for histamine release inhibitory activity in the same manner.

1. Preparation of Rat Peritoneal Mast Cell Suspension Liquid First, male SD rats (body weight 250 to 280 g) were exsanguinated and killed, and then Hanks liquid [trade name: Nissui, manufactured by Nissui Pharmaceutical Co., Ltd., the same applies hereinafter. ] To which 0.1% of bovine serum albumin was added (hereinafter referred to as solution A) 1
0 ml was intraperitoneally injected, the abdomen was massaged for about 90 seconds, and the abdominal cavity was opened to collect peritoneal fluid (hereinafter referred to as peritoneal fluid A). Then, the abdominal cavity was washed with 5 ml of solution A, and this solution was collected and mixed with peritoneal fluid A (this mixed solution is referred to as peritoneal fluid B). The peritoneal fluid B was centrifuged at 500 rpm and 4 ° C. for 5 minutes, ice-cold Hanks' solution was added to the resulting precipitate, and the pellet was washed twice, and the number of mast cells was about 1 × 10 ⁵ cells /
Hank's solution was added so that the amount became ml, to prepare a rat peritoneal mast cell suspension.

2. Con. Mast cells induced by A
Inhibitory effect test on the release of histamine from rat: 0.3 ml of rat peritoneal mast cell suspension and 1.0 ml of Hank's solution solution of the test drug prepared at the concentrations shown in Table 1 were used.
L-α-phosphatidyl-prepared to a concentration of 0 μg / ml
0.2 ml of Hank's solution solution of L-serine (extracted from bovine brain; manufactured by Sigma) and 0.3 ml of Hank's solution were added, and the mixture was allowed to stand at 37 ° C. for 5 minutes. After this, 400 μg / ml
Of Con. 0.2 ml of physiological saline solution A
Was added and reacted at 37 ° C. for 10 minutes. After stopping the reaction by cooling with ice, centrifugation was performed under the conditions of 2500 rpm and 4 ° C., and the amount of histamine in the supernatant (the amount of free histamine: Pr)
And the amount of histamine in the sediment (residual histamine amount: Ps) were determined according to the method of Shore et al. That is, 0.1 ml of water and 0.2 ml of 100% trichloroacetic acid were added to the supernatant, 1.5 ml of Hank's solution and 0.2 ml of 100% trichloroacetic acid were added to the sediment, and the mixture was allowed to stand at room temperature for 30 minutes. After that, each was centrifuged at 3000 rpm for 15 minutes.
Collect 0.35 ml of supernatant after centrifugation and 0.35 ml of supernatant after centrifugation, and add 1.65 ml of water to each.
And 0.4 ml of 1N NaOH were added sequentially, then 0.5
0.1 ml of a MeOH solution of% orthophthalaldehyde was added to each and the mixture was reacted at room temperature for 4 minutes. After the reaction was stopped by adding 0.2 ml of 2M citric acid to each, the fluorescence intensity of each was measured by a fluorometer to determine the amount of histamine in the supernatant and the amount of histamine in the sediment. In the control test, 1.0 ml of Hank's solution was used instead of 1.0 ml of Hank's solution of the test drug, and Con. The procedure was performed using 0.2 ml of physiological saline instead of 0.2 ml of the physiological saline solution of A.

Based on these results, S: Histamine release rate (A value) when a test drug was used C: A value of control test B: A value of blank The histamine release inhibition rate was calculated by. The results are shown in Table 1.

[0063]

[Table 1]

As is clear from Table 1, each of the novel phenylglycosides obtained in Examples 1 to 7 has a histamine release inhibitory effect superior to that of azelastine even at a concentration of 1/10 that of azelastine. Show. Further, even at a concentration of 3/100 of tocopheryl glucoside, it shows a 21/100 to 140 / 100-fold histamine release inhibitory effect of tocopheryl glucoside.

Toxicity test No death occurred in any of the novel phenylglycosides of Examples 1 to 7 when orally administered to ICR mice (body weight 25 to 35 g) at a rate of 30 mg / kg body weight. Moreover, no special changes were observed in the observation of general symptoms.

[0066]

INDUSTRIAL APPLICABILITY As described above, the novel phenylglycoside of the present invention is a novel substance excellent in the action of suppressing the release of histamine from mast cells, and the antiallergic agent of the present invention contains the histamine from mast cells. It is a new anti-allergic agent that suppresses release itself.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): Is a phenyl glycoside. 2. A compound represented by the general formula (II): Is a phenyl glycoside. 3. A compound represented by the general formula (III): The method for producing a phenylglycoside of the general formula (I) according to claim 1, wherein the compound represented by the formula (3) is deacetylated. 4. A compound represented by the general formula (IV): The method for producing a phenylglycoside of the general formula (II) according to claim 2, wherein the compound represented by the formula (9) is deacetylated. 5. A phenylglycoside of general formula (I) according to claim 1 and / or a general formula (II) according to claim 2.
An anti-allergic agent containing phenylglycoside as an active ingredient.