JP2002161100A - 4-alkoxy-2,3,6-trimethylphenylmannoside and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a mannoside of the formula (1) or its salt having an inhibiting activity on releasing histamine from a mast cell, the inhibiting activity being stronger than a mannoside compound expressed by the specification of Japanese unexamined patent publication 5-9295, and also having an inhibiting activity on the production of IgE antibody, and thereby useful as a preventing and treating agent for allergic diseases. SOLUTION: 4-Alkoxy-2,3,6-trimethylphenylmannosides expressed by the general formula (1) (wherein, the groups R1 are identical to or different from each other, and they are each H or an alkanoyl; and R2 is a 2-12C alkyl) or their salts. Further, a medicine containing the above mannoside or its salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to mannosides which have an inhibitory effect on the release of chemical mediators from mast cells and an inhibitory effect on IgE antibody production, and which are useful as preventive and therapeutic agents for allergic diseases, and pharmaceuticals containing the same.

[0002]

2. Description of the Related Art Type I (immediate type) allergy, such as hay fever and atopic dermatitis, is caused by IgE antibodies. The IgE antibody specifically binds to an Fc receptor present on the surface of mast cells or basophils in subcutaneous or mucosal tissues. When an antigen binds to IgE, basophils and mast cells are stimulated to release chemical mediators such as histamine, serotonin, and leukotriene. This causes an increase in vascular permeability, contraction of smooth muscle, and the like, causing allergic symptoms.

The present inventors have been studying to develop an antiallergic agent having a mechanism of inhibiting the release of chemical mediators from mast cells, and phenylglycosides have an inhibitory effect on histamine release. This was found and reported earlier (JP-A-5-9195).

[0004]

However, the histamine release inhibitory action of phenylglycosides described in Japanese Patent Application Laid-Open No. Hei 9-19595 is not yet sufficiently satisfactory, and a compound having a stronger action is required. I was

[0005]

Means for Solving the Problems The present inventors have synthesized compounds obtained by variously converting phenyl substituents and sugar residues in phenyl glycosides and have studied their pharmacological actions. 4-alkoxy-2,3,6-trimethylphenyl mannosides represented by the general formula (1) has a histamine release inhibitory action several times stronger than the corresponding glucosides, and furthermore IgE antibody The present inventors have also found that the phenylglycoside has an effect of inhibiting production, which is not expected from conventional phenylglycosides, and was found to be extremely useful as an agent for preventing and treating allergic diseases, thereby completing the present invention.

That is, the present invention provides the following general formula (1)

[0007]

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Wherein R ¹ is the same or different and represents a hydrogen atom or an alkanoyl group, and R ² represents an alkyl group having 2 to 12 carbon atoms.
It is intended to provide a 6-trimethylphenyl mannoside or a salt thereof, and a medicine containing the same as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), examples of the alkanoyl group represented by R ¹ include alkanoyl groups having 2 to 6 carbon atoms, such as acetyl and propionyl, with acetyl being more preferred. . R ¹ is more preferably a hydrogen atom or an acetyl group, and particularly preferably a hydrogen atom.

Examples of the alkyl group having 2 to 12 carbon atoms represented by R ² include a linear or branched alkyl group having 2 to 12 carbon atoms, and an alkyl group having 2 to 10 carbon atoms is more preferable. Particularly, an alkyl group having 4 to 8 carbon atoms is preferable. Specific examples of preferable R ¹ include an ethyl group, an n-butyl group, an n-hexyl group, an n-octyl group, and an n-decanyl group, and an n-butyl group and an n-hexyl group are more preferable. Hexyl groups are particularly preferred.

More preferred examples of the mannosides (1) include, in the general formula (1), R ¹ is a hydrogen atom and R ² is an alkyl group having 2 to 10 carbon atoms (particularly preferably an n-butyl group, n-butyl group). -Hexyl group).

Examples of the salt of the compound of the present invention include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate and amino acid salt. Note that solvates such as hydrates are also included in the present invention.

The mannosides (1) of the present invention can be produced, for example, according to the following reaction formula.

[0014]

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[0015] (wherein, R ³ represents an alkanoyl group, R ²
Is the same as above)

That is, pentaalkanoyl-α-D-
Compound (1a) is obtained by reacting mannose (2) with 4-alkoxy-2,3,6-trimethylphenol (3), and compound (1b) is obtained by hydrolyzing compound (1a). can get.

The pentaalkanoyl-α-D-mannose (2) can be obtained, for example, by reacting α-D-mannose with an alkanoylating agent such as acetic anhydride in the presence of a base such as pyridine. On the other hand, 4-alkoxy-
2,3,6-Trimethylphenol (3) can be obtained, for example, by reacting trimethylhydroquinone and an alcohol in the presence of phosphomolybdic acid.

The reaction of the compound (2) with the compound (3) is carried out in a non-aqueous solvent such as benzene, toluene and ether in the presence of a Lewis acid organic solvent complex such as BF ₃ · ether or BF ₃ · anisole. It is preferable to carry out. The reaction conditions are preferably from room temperature to reflux temperature for about 2 hours to 4 days.

The hydrolysis reaction of the compound (1a) is preferably carried out in the presence of a base typified by a metal alkoxide such as sodium methoxide and sodium ethoxide in a solvent such as an alcohol. The reaction condition is preferably from room temperature to reflux temperature for about 10 minutes to 1 day.

The obtained compound (1) of the present invention can be purified by a conventional method such as washing, recrystallization, chromatography and the like.

The compound (1) [mannoside] of the present invention is
Compound (3) has a histamine release inhibitory action several times stronger than that of a glucoside form in which glucose is bound to compound (3). In addition, since the compound (1) of the present invention also has an inhibitory action on IgE antibody production, it is apparently more effective than conventional glucosides for preventing allergic diseases such as hay fever, atopic dermatitis, allergic rhinitis and bronchial asthma. Useful as a therapeutic.

When the compound (1) of the present invention or a salt thereof is used as a medicine, it can be used in the form of various preparations depending on the purpose of administration. That is, in the case of oral administration, tablets,
Capsules, granules, powders or liquids can be administered, in the case of parenteral administration, injections, eye drops,
It can be administered in the form of nasal drops, suppositories, patches or external preparations.

These preparations are prepared by adding an effective amount of the compound (1) of the present invention or a salt thereof to a pharmaceutically acceptable carrier such as an excipient, a stabilizer, a preservative, a solubilizer, a wetting agent, an emulsifier, a lubricant. Formulations can be made by adding agents, sweetening agents, coloring agents, flavoring agents, tonicity adjusting agents, buffers, antioxidants and the like.

The dose of the preparation containing the compound of the present invention is appropriately selected according to the conditions such as the form of the preparation, usage, age, sex and symptoms of the patient.
The range is preferably 1 to 50 mg / kg / day.

[0025]

The present invention will be described below with reference to examples and reference examples, but the present invention is not limited to these examples.

Example 1 4-ethoxy-2,3,6-trimethylphenyl-O-
Tetraacetyl-α-D-mannopyranoside 4-ethoxy-2,3,6-trimethylphenol (1.23 g, 6.84 mmol) and α-D-mannose pentaacetate (2.67 g, 6.84 mmol) were converted to anhydrous benzene ( 20 mL), and BF _3. (C ₂ H ₅ ) ₂ O
(1.0 mL) and reacted at room temperature for 26 hours. The reaction solution was extracted with H ₂ O (30 mL) and 0.5 M NaOH (30 mL) using benzene (30 mL) and saturated brine (30 mL), and then dried over anhydrous MgSO ₄ . Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (benzene-ethyl acetate, 5: 1) to obtain the title compound (1.99 g, 3.90 mmol, 57%).

The colorless oil ^{IR (neat) cm -1: 2965} , 1474, 1128. 1 H-NMR (200MHz, CDCl 3) δ: 1.39 (3H, t, J = 7.0Hz), 2.05 (3
H, s), 2.10 (3H, s), 2.10 (3H, s), 2.11 (3H, s), 2.15 (3H,
s), 2.23 (3H, s), 2.31 (3H, s), 3.96 (2H, q, J = 7.0Hz), 4.
15-4.37 (2H, m), 4.47-4.55 (1H, m), 4.95 (1H, s), 5.40 (1
. H, t, J = 9.9Hz ), 5.61-5.67 (2H, m), 6.50 (1H, s) 13 C-NMR (50MHz, CDCl 3) δ: 12.0 (q), 13.8 (q), 15.0 ( q),
17.7 (q), 19.1 (q), 20.3 (q), 20.7 (q), 20.9 (q), 62.7
(t), 64.2 (d), 66.1 (d), 68.9 (t), 70.0 (d), 70.0 (d),
101.2 (d), 112.0 (d), 124.3 (s), 127.5 (s), 130.3 (s),
149.0 (s), 153.5 (s), 169.8 (s), 170.1 (s), 170.1 (s),
HR-EI-MS: 510.2098 (M ⁺ ) (Calcd for C ₂₅ H ₃₄ O ₁₁ : 510.21)
02). [Α] ²⁵ _D + 37 ° (c = 1.00, CHCl ₃ ).

Example 2 4-n-butoxy-2,3,6-trimethylphenyl-
O-tetraacetyl-α-D-mannopyranoside 4-n-butoxy-2,3,6-trimethylphenol (0.61 g, 2.92 mmol) and α-D-mannose pentaacetate (1.14 g, 2.92 mmol) Was dissolved in anhydrous benzene (20 mL), and BF _3. (C ₂ H ₅ ) ₂ O
(0.4 mL) and reacted at room temperature for 20 hours. The reaction solution was extracted with H ₂ O (30 mL) and 0.5 M NaOH (30 mL) using benzene (30 mL) and saturated brine (30 mL), and then dried over anhydrous MgSO ₄ . Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (benzene-ethyl acetate, 5: 1) to obtain the title compound (0.64 g, 1.19 mmol, 41%).

The colorless oil ^{IR (neat) cm -1: 2959} , 1474, 1129. 1 H-NMR (200MHz, CDCl 3) δ: 0.97 (3H, t, J = 7.0Hz), 1.39-
1.59 (2H, m), 1.69-1.83 (2H, m), 2.05 (3H, s), 2.10 (3H,
s), 2.11 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.23 (3H, s
s), 2.31 (3H, s), 3.96 (2H, t, J = 6.2Hz), 4.15-4.37 (2H,
m), 4.47-4.56 (1H, m), 4.95 (1H, s), 5.40 (1H, t, J = 9.9H
. z), 5.59-5.67 (2H, m), 6.50 (1H, s) 13 C-NMR (50MHz, CDCl 3) δ: 12.0 (q), 12.8 (q), 13.8 (q),
17.7 (q), 19.3 (q), 20.7 (q), 20.7 (q), 20.8 (q), 31.5
(t), 53.0 (t), 62.8 (t), 66.1 (d), 68.3 (t), 69.0 (d),
70.0 (d), 70.0 (d), 101.2 (d), 111.8 (d), 124.3 (s), 12
7.5 (s), 130.3 (s), 149.0 (s), 153.7 (s), 169.8 (s), 17
0.0 (s), 170.1 (s ), 170.6 (s) HR-EI-MS:. 538.2413 (M +) (Calcd for C 27 H 38 O 11: 538.24
14). [Α] ²⁵ _D + 37 ° (c = 1.00, CHCl ₃ ).

Example 3 4-n-hexyloxy-2,3,6-trimethylphenyl-O-tetraacetyl-α-D-mannopyranoside 4-n-hexyloxy-2,3,6-trimethylphenol (5. 00g, 21.19 mmol) and α-D-mannose pentaacetate (8.26 g, 21.19 mmol)
l) was dissolved in anhydrous benzene (100 mL), and BF _3.
2 H _{5) 2} O and (2.85 mL) was added, and reacted for 24 hours at room temperature. The reaction solution was H ₂ O using benzene (100 mL).
(100 mL) and 0.5M NaOH (100 mL) and saturated saline (100 mL), and then dried over anhydrous MgSO ₄ . Thereafter, the solvent was distilled off under reduced pressure, and silica gel column chromatography (benzene-ethyl acetate, 5: 1).
To give the title compound (6.31 g, 11.15 mmol, 5
3%).

The colorless oil ^{IR (neat) cm -1: 2933} , 1471, 1130. 1 H-NMR (200MHz, CDCl 3) δ: 0.91 (3H, t, J = 6.6Hz), 1.26-
1.50 (6H, m), 1.70-1.80 (2H, m), 2.05 (3H, s), 2.09 (3H, m
s), 2.10 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 2.23 (3H,
s), 2.31 (3H, s), 3.89 (2H, t, J = 6.4Hz), 4.15-4.37 (2H,
m), 4.47-4.55 (1H, m), 4.95 (1H, s), 5.39 (1H, t, J = 9.5H
. z), 5.59-5.67 (2H, m), 6.50 (1H, s) 13 C-NMR (50MHz, CDCl 3) δ: 12.0 (q), 13.8 (q), 14.0 (q),
17.7 (q), 20.7 (q), 20.7 (q), 20.7 (q), 20.8 (q), 22.6
(t), 25.8 (t), 29.4 (t), 31.5 (t), 62.7 (t), 66.1 (d),
68.6 (t), 69.0 (d), 70.0 (d), 70.0 (d), 101.2 (d), 111.
8 (d), 124.2 (s), 127.5 (s), 130.3 (s), 148.9 (s), 153.
6 (s), 169.8 (s ), 170.0 (s), 170.0 (s), 170.6 (s) HR-EI-MS:. 566.2726 (M +) (Calcd for C 29 H 42 O 11: 566.27
27). [Α] ²⁵ _D + 37 ° (c = 1.00, CHCl ₃ ).

Example 4 4-n-octyloxy-2,3,6-trimethylphenyl-O-tetraacetyl-α-D-mannopyranoside 4-n-octyloxy-2,3,6-trimethylphenol (1. 00g, 3.79 mmol) and α-D-mannose pentaacetate (1.48 g, 3.79 mmol) were dissolved in anhydrous benzene (20 mL), and BF _3. (C ₂ H ₅ ) ₂ was dissolved.
O (0.4 mL) was added, and the mixture was reacted at room temperature for 23 hours. The reaction solution was extracted with H ₂ O (30 mL) and 0.5 M NaOH (30 mL) using benzene (30 mL) and saturated brine (30 mL), and then dried over anhydrous MgSO ₄ . Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (benzene-ethyl acetate, 5: 1), and then recrystallized from ethanol-benzene to give the title compound (1.01 g,
(1.71 mmol, 45%).

The pale yellow powder mp:. 75-78 ℃ IR (neat ) cm -1: 2929, 1470, 1129. 1 H-NMR (200MHz, CDCl 3) δ: 0.88 (3H, t, J = 7.0Hz) , 1.30-
1.46 (10H, m), 1.73-1.80 (2H, m), 2.05 (3H, s), 2.09 (3H,
s), 2.10 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 2.23 (3H,
s), 2.31 (3H, s), 3.88 (2H, t, J = 6.6Hz), 4.16-4.37 (2H,
m), 4.45-4.58 (1H, m), 4.95 (1H, s), 5.39 (1H, t, J = 9.9H
. z), 5.59-5.67 (2H, m), 6.50 (1H, s) 13 C-NMR (50MHz, CDCl 3) δ: 12.0 (q), 13.8 (q), 14.1 (q),
17.7 (q), 19.3 (q), 20.6 (q), 20.7 (q), 20.7 (q), 22.6
(t), 26.2 (t), 29.2 (t), 29.3 (t), 29.4 (t), 31.8 (t),
62.8 (t), 66.1 (d), 68.6 (t), 69.0 (d), 70.0 (d), 70.1
(d), 101.3 (d), 111.8 (d), 124.3 (s), 127.5 (s), 130.3
(s), 149.0 (s), 153.7 (s), 169.8 (s), 170.1 (s), 170.7
(s), 170.7 (s) HR-EI-MS:. 594.3021 (M +) (Calcd for C 31 H 46 O 11: 594.30
40). [Α] ²⁵ _D + 36 ° (c = 1.00, CHCl ₃ ).

Example 5 4-n-Decanyloxy-2,3,6-trimethylphenyl-O-tetraacetyl-α-D-mannopyranoside 4-n-decanyloxy-2,3,6-trimethylphenol (2.00 g, 6.84 mmol) and α-D-mannose pentaacetate (2.67 g, 6.84 mmol) were dissolved in anhydrous benzene (40 mL), and BF _3. (C ₂ H ₅ ) ₂ was dissolved.
O (1.0 mL) was added, and the mixture was reacted at room temperature for 17 hours. The reaction solution was extracted with H ₂ O (30 mL) and 0.5 M NaOH (30 mL) using benzene (30 mL) and saturated brine (30 mL), and then dried over anhydrous MgSO ₄ . Thereafter, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (benzene-ethyl acetate, 5: 1), and then recrystallized from ethanol-benzene to give the title compound (1.71 g,
(3.76 mmol, 55%).

The pale yellow powder mp:. 75-76 ℃ IR (neat ) cm -1: 2927, 1470, 1130. 1 H-NMR (200MHz, CDCl 3) δ: 0.88 (3H, t, J = 7.0Hz) , 1.27-
1.45 (14H, m), 1.70-1.84 (2H, m), 2.04 (3H, s), 2.09 (3H, m
s), 2.10 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 2.23 (3H,
s), 2.31 (3H, s), 3.88 (2H, t, J = 6.6Hz), 4.15-4.36 (2H,
m), 4.48-4.55 (1H, m), 4.95 (1H, s), 5.39 (1H, t, J = 9.9H
. z), 5.59-5.67 (2H, m), 6.50 (1H, s) 13 C-NMR (50MHz, CDCl 3) δ: 12.0 (q), 13.8 (q), 14.1 (q),
17.7 (q), 20.7 (q), 20.7 (q), 20.7 (q), 20.8 (q), 22.6
(t), 26.2 (t), 29.3 (t), 29.4 (t), 29.4 (t), 29.5 (t),
29.6 (t), 31.9 (t), 62.8 (t), 66.1 (d), 68.6 (t), 69.0
(d), 70.0 (d), 77.7 (d), 101.3 (d), 111.8 (d), 124.3
(s), 127.5 (s), 130.3 (s), 149.0 (s), 153.7 (s), 169.8
(s), 170.0 (s) , 170.1 (s), 170.7 (s) HR-EI-MS:. 622.3364 (M +) (Calcd for C 33 H 50 O 11: 622.33
53). [Α] ²⁵ _D + 35 ° (c = 1.00, CHCl ₃ ).

Example 6 4-ethoxy-2,3,6-trimethoxyphenyl-α
-D-Mannoside The compound obtained in Example 1 (1.90 g, 3.73 mmol) was dissolved in anhydrous methanol (30 mL), and CH ₃ ONa (2
) And reacted at room temperature for 1 hour. After the reaction solution was neutralized with Amberlite IR-120 (H ⁺ ), activated carbon was added to decolorize the solution. After the reaction solution was filtered through celite with methanol, the solvent was distilled off under reduced pressure to give the title compound (1.49).
g, 4.36 mmol, 86%).

The white powder mp:. 186-188 ℃ IR (neat ) cm -1: 3348, 2932, 1476, 1123. 1 H-NMR (200MHz, pyridine-d 5) δ: 1.29 (3H, t, J = 7.0Hz),
2.12 (3H, s), 2.33 (3H, s), 2.45 (3H, s), 3.88 (2H, q, J = 7.
0Hz), 4.44-4.62 (2H, m), 4.82 (3H, s), 5.13 (1H, s), 5.5
. 8 (1H, d, J = 1.6Hz), 6.61 (1H, s) 13 C-NMR (50MHz, pyridine-d 5) δ: 12.0 (q), 14.0 (q), 1
4.9 (q), 17.9 (q), 63.0 (t), 64.0 (d), 68.5 (t), 72.2
(d), 72.7 (d), 77.0 (d), 106.3 (d, ¹ J _C1-H1 = 168.61Hz),
112.1 (d), 123.9 (s), 128.2 (s), 130.8 (s), 150.0 (s),
153.3 (s) HR-FAB- MS:. 365.1558 (M + + Na) (Calcd for C 17 H 26 O 7 Na: 3
[Α] ²² _D + 93 ° (c = 1.00, CH ₃ OH).

Example 7 4-n-butoxy-2,3,6-trimethylphenyl-
α-D-Mannoside Compound obtained in Example 2 (0.64
g, 1.19 mmol) was dissolved in anhydrous methanol (10 mL), CH ₃ ONa (2 drops) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction solution was neutralized with Amberlite IR-120 (H ⁺ ), activated carbon was added to decolorize the solution. After the reaction solution was filtered through celite with methanol, the solvent was distilled off under reduced pressure to obtain the title compound (0.39 g, 1.06 mmol, 89%).

The white powder mp:. 174-178 ℃ IR (neat ) cm -1: 3364, 2934, 1472, 1125. 1 H-NMR (200MHz, pyridine-d 5) δ: 0.89 (3H, t, J = 7.0Hz),
1.40-1.55 (2H, m), 1.63-1.76 (2H, m), 2.14 (3H, s), 2.35
(3H, s), 2.48 (3H, s), 3.86 (2H, t, J = 6.2Hz), 4.45-4.64
(2H, m), 4.83 (3H, s), 5.00 (1H, s), 5.61 (1H, d, J = 1.1H
z), 6.64 (1H, s). ¹³ C-NMR (50 MHz, pyridine-d ₅ ) δ: 12.1 (q), 13.9 (q), 1
4.2 (q), 18.1 (q), 19.6 (t), 31.7 (t), 63.3 (t), 68.2
(t), 68.8 (d), 72.4 (d), 72.9 (d), 77.1 (d), 106.4 (d, ¹
J _C1-H1 = 169.38Hz), 112.1 (d), 123.9 (s), 128.3 (s), 13
0.8 (s), 150.2 (s ), 153.5 (s) HR-FAB-MS:. 393.1914 (M + + Na) (Calcd for C 19 H 30 O 7 Na: 3
93.1890). [Α] ²² _D + 83 ° (c = 1.01, CH ₃ OH).

Example 8 4-n-hexyloxy-2,3,6-trimethylphenyl-α-D-mannoside The compound (1.00 g, 1.77 mmol) obtained in Example 3 was added to anhydrous methanol (40 mL). Dissolve and add CH ₃ ONa (3
) And reacted at room temperature for 1 hour. After the reaction solution was neutralized with Amberlite IR-120 (H ⁺ ), activated carbon was added to decolorize the solution. After the reaction solution was filtered through celite with methanol, the solvent was distilled off under reduced pressure to remove the title compound (0.68).
g, 1.71 mmol, 97%).

The white powder mp:. 165-169 ℃ UV (EtOH ):. Λ max (logε) 284 (3.08) nm IR (neat) cm -1: 3357, 2932, 1468, 1124. 1 H-NMR (200MHz , pyridine-d ₅ ) δ: 0.85 (3H, t, J = 6.2Hz),
1.21-1.31 (6H, m), 1.70-1.77 (2H, m), 2.16 (3H, s), 2.36
(3H, s), 2.49 (3H, s), 3.88 (2H, t, J = 6.6Hz), 4.50-4.59
(2H, m), 4.83 (3H, s), 4.99 (1H, s), 5.61 (1H, d, J = 1.5H
z), 6.67 (1H, s). ¹³ C-NMR (50 MHz, pyridine-d ₅ ) δ: 12.2 (q), 14.1 (q), 1
4.2 (q), 18.1 (q), 22.8 (t), 26.1 (t), 29.6 (t), 31.7
(t), 63.3 (t), 68.5 (t), 68.8 (d), 72.4 (d), 72.9 (d),
77.1 (d), 106.4 (d, ¹ J _C1-H1 = 166.64Hz), 112.1 (d), 123.
9 (s), 128.3 (s ), 130.9 (s), 150.2 (s), 153.5 (s) HR-FAB-MS:. 421.2221 (M + + Na) (Calcd for C 21 H 34 O 7 Na: 4
21.2202). [Α] ²² _D + 73 ° (c = 1.00, CH ₃ OH).

Example 9 4-n-octyloxy-2,3,6-trimethylphenyl-α-D-mannoside The compound obtained in Example 4 (1.30 g, 2.19 mmol) was added to anhydrous methanol (10 mL). Dissolve and add CH ₃ ONa (1
) And reacted at room temperature for 1 hour. After the reaction solution was neutralized with Amberlite IR-120 (H ⁺ ), activated carbon was added to decolorize the solution. After the reaction solution was filtered through celite with methanol, the solvent was distilled off under reduced pressure to give the title compound (1.02
g, 2.13 mmol, 97%).

The white powder mp:. 181-186 ℃ IR (neat ) cm -1: 3358, 2928, 1467, 1127. 1 H-NMR (200MHz, pyridine-d 5) δ: 0.85 (3H, t, J = 6.6Hz),
1.24 (8H, broad), 1.46-1.49 (2H, m), 1.69-1.80 (2H, m),
2.16 (3H, s), 2.34 (3H, s), 2.47 (3H, s), 3.90 (2H, t, J = 6.
6Hz), 4.44-4.62 (2H, m), 4.82 (3H, s), 5.01 (1H, s), 5.5
9 (1H, d, J = 1.5Hz), 6.68 (1H, s) 13 C-NMR (50MHz, pyridine-d 5) δ:. 12.1 (q), 14.1 (q), 1
8.0 (q), 22.7 (q), 26.3 (t), 29.3 (t), 29.4 (t), 29.6
(t), 31.8 (t), 63.1 (t), 68.5 (d), 68.6 (t), 72.3 (d),
72.8 (d), 77.0 (d), 106.3 (d, ¹ J _C1-H1 = 168.47Hz), 112.1
(d), 123.9 (s), 128.3 (s), 130.8 (s), 150.1 (s), 153.4
(s). HR-FAB-MS: 449.2578 (M ⁺ + Na) (Calcd for C ₂₃ H ₃₈ O ₇ Na: 4
49.2562). [Α] ²² _D + 65 ° (c = 1.00, CH ₃ OH).

Example 10 4-n-Decanyloxy-2,3,6-trimethylphenyl-α-D-mannoside The compound obtained in Example 5 (1.68 g, 2.70 mmol) was dissolved in anhydrous methanol (10 mL). And CH ₃ ONa (1
) And reacted at room temperature for 1 hour. After the reaction solution was neutralized with Amberlite IR-120 (H ⁺ ), activated carbon was added to decolorize the solution. After the reaction solution was filtered through celite with methanol, the solvent was distilled off under reduced pressure to remove the title compound (1.16).
g, 2.56 mmol, 95%).

The white powder mp:. 155-158 ℃ IR (neat ) cm -1: 3357, 2924, 1468, 1123. 1 H-NMR (200MHz, pyridine-d 5) δ: 0.85 (3H, t, J = 7.0Hz),
1.22 (12H, broad), 1.41-1.48 (2H, m), 1.74-1.81 (2H, m),
2.16 (3H, s), 2.34 (3H, s), 2.47 (3H, s), 3.91 (2H, t, J =
6.2Hz), 4.49-4.61 (2H, m), 4.81 (3H, s), 5.00 (1H, s),
5.58 (1H, d, J = 1.5Hz), 6.67 (1H, s) 13 C-NMR (50MHz, pyridine-d 5) δ:. 12.2 (q), 14.0 (q), 1
8.0 (q), 22.7 (q), 26.3 (t), 29.3 (t), 29.4 (t), 29.6
(t), 29.6 (t), 29.6 (t), 31.9 (t), 31.9 (t), 63.0 (t),
68.5 (d), 68.5 (t), 72.2 (d), 72.7 (d), 76.9 (d), 106.2
(d, ¹ J _C1-H1 = 167.55Hz), 112.0 (d), 123.9 (s), 128.2
(s), 130.7 (s) , 150.0 (s), 153.4 (s) HR-FAB-MS:. 477.2827 (M + + Na) (Calcd for C 25 H 42 O 7 Na: 4
[Α] ²² _D + 67 ° (c = 1.00, CH ₃ OH).

Test Example 1 The effect on histamine release from rat peritoneal mast cells was examined. (1) Preparation of rat peritoneal mast cell suspension A Wistar male rat was used. DNP- as antigen
When BSA was used, sensitized rats were used. When using concanavalin A as a releasing agent, normal rats were used. Rats are exsanguinated to death under anesthesia and 10 mM HEPE
15 mL of Tyrode's solution containing S, 0.05% gelatin was injected intraperitoneally. After massaging the abdomen for 1.5 minutes, the abdomen was opened, and the intraperitoneal exudate was collected. The peritoneal cavity was washed with 15 mL of the above solution, and the whole was centrifuged at 4 ° C. and 55 × g for 8 minutes. After the cells were washed three times with the above solution by the same operation, the above solution was prepared so that the final concentration of mast cells was 10 ⁵ cells / mL. Mast cells were identified by staining intracellular granules with 0.05% toluidine blue N.

(2) Histamine Release Method from Mast Cells Tyrode's solution (pH 7.4) containing 30 μg / mL L-α-phosphatidyl-L-serine and 10 mM HEPES, 0.05% gelatin to which a sample was added was added at 37 ° C. For 5 minutes. After adding the cell suspension and incubating at 37 ° C. for 15 minutes, 10 μg protein / mL DNP-BS
A was added and incubated at 37 ° C. for 20 minutes (final volume 2 mL). Incubation was performed at 37 ° C. for 15 minutes using concanavalin A (ConA) as a releasing agent. The reaction was stopped by ice-cooling for 10 minutes, 4 ° C., 300 × g, 1
Centrifuged for 0 minutes. Collect 1 mL of supernatant and add 0.2 mL
1 mL of NHCl was added. On the other hand, 0.1N HC
4 mL was added and heated in a boiling water bath for 10 minutes. After cooling on ice, the mixture was centrifuged at 780 xg for 10 minutes at 4 ° C.
mL was collected and used for quantification of histamine. (3) Quantification of histamine To 2 mL of a sample, 0.2 mL of 2N NaOH was added, and further 1%
0.1 mL of a MeOH solution of o-phthalaldehyde was added,
Rest for 4 minutes at room temperature. Next, 0.2 mL of 2M citric acid was added to stop the reaction. The fluorescence intensity of this sample was measured at an excitation wavelength of 3
Measurement was performed at 56 nm and a fluorescence wavelength of 440 nm, and the inhibition rate relative to the control was determined. Ketotifen fumarate was used as a positive control.

Table 1 shows the results when ConA was used as the releasing agent. As a result, all of the compounds of the present invention (1) have a stronger inhibitory effect on histamine release than 1 × 10 ⁻⁴ M of ketotifen fumarate used as a therapeutic agent for bronchial asthma at a concentration of 3 × 10 ⁻⁶ M. Had.

[0049]

[Table 1]

Further, as a releasing agent, an antigen (DNP-BS
When A) is used, the compound of Example 8 is 1 × 10 ⁻⁵ M
Had a histamine release inhibitory effect of about 50%.

Test Example 2 Inhibition of IgE Antibody Production Using Wistar rats, 1 mg of dinitrophenyl-ascaris (DNP-As) and 10 ¹⁰ cells of B. pertussis were suspended in physiological saline per rat, and The solution was dispensed into four footpads and used as an initial immunization. Five days later, DNP-AsO.
A 5 mg physiological saline solution was intramuscularly administered for booster immunization. On this day, day 0, blood was collected from the jugular vein on days 0, 5, 10, 15, 20, and 25, and plasma was obtained after centrifugation at 550 xg for 15 minutes. The amount of IgE was measured using a Morinaga rat IgE measurement kit. Plasma was stored at −20 ° C. and measured collectively. When examining the inhibitory effect of the drug on IgE antibody production, the rats were orally administered for 10 consecutive days from the boosting day, and each rat was fasted 3 hours before the administration. Sample is 0.2% CM
C, and the liquid volume was 0.5
Oral administration was performed using a sonde so that the volume became mL. Controls received 0.2% CMC. Suplatast tosylate was used as a positive control.

The plasma IgE concentration of the control group was 10
Day 1 was the end date of drug administration since it reached the highest on day 1.
Table 2 shows the results of comparing the plasma IgE concentrations on day 0. As a result, the compound of Example 8 was found to have a stronger inhibitory effect on IgE antibody production than suplatast tosilate, which is known as an IgE antibody production inhibitor.

[0053]

[Table 2]

[0054]

The compound of the present invention (1) which is a mannoside form
Or a salt thereof is disclosed in Japanese Patent Application Laid-Open No.
The compound has a stronger inhibitory effect on histamine release from mast cells than the compound described in Japanese Patent Application Laid-Open No. H10-209, and also has an inhibitory effect on IgE antibody production, so that it is useful as an agent for preventing and treating allergic diseases.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 37/08 A61P 37/08 (72) Inventor Takashi Hirano 2-2-2, Okihamahigashi, Tokushima City, Tokushima Prefecture Raster Twin 802 ( 72) Shoji Yoshioka 4-57-1, Shomachi, Tokushima-shi, Tokushima Pref. AA01 AA02 AA03 EA08 MA01 MA04 NA05 ZA59 ZA89 ZB13

Claims (4)

[Claims] 1. The following general formula (1): (Wherein, R ¹ is the same or different and represents a hydrogen atom or an alkanoyl group, and R ² represents an alkyl group having 2 to 12 carbon atoms) 4-alkoxy-2,3,6-trimethylphenylman Nosides or salts thereof. 2. R ¹ is a hydrogen atom, and R ² has ² to ² carbon atoms.
The 4-alkoxy-2,3,6-trimethylphenyl mannoside or a salt thereof according to claim 1, which is an alkyl group of 10. 3. The 4-alkoxy- according to claim 1 or 2.
A medicament comprising 2,3,6-trimethylphenyl mannoside or a salt thereof as an active ingredient. 4. The medicament according to claim 3, which is a drug for preventing or treating allergic diseases.