JPH0155278B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel tocopherol derivatives, and more particularly to tocopheryl glycosides.

Tocopherols have traditionally been known as anti-infertility vitamins (vitamin E) and as antioxidants, but in recent years they have also been frequently used as various pharmaceuticals because they have various pharmacological effects such as peripheral vasodilation. It is becoming more and more common. However, tocopherols are very unstable compounds, and because they are fat-soluble substances, they have the problem of poor absorption from the intestinal tract and skin. It is proposed to do so.

The present invention provides novel tocopheryl glycosides useful as such tocopherol derivatives, and the tocopheryl glycosides of the present invention have the following formula: [In the formula, R ₁ is a glucose residue, a galactose residue, a cellobiose residue, or an acetylated derivative residue of glucose, galactose or cellobiose, and R ₂ and R ₃ are the same or different,
Each represents hydrogen or methyl] It has a structure in which a sugar residue or an acetylated sugar residue is introduced into the 6-position hydroxy group of tocopherol.

In formula [I], -C ₁₆ H ₃₃ at the 2-position of the 3,4-dihydrobenzopyran ring represents a 4,8,12-trimethyltridecyl group at the 2-position side chain of tocopherol.
In addition, isomers exist in tocopherol and the sugar introduced into the 6-position hydroxyl group, but in this specification, all of these are represented by formula [I], including isomer mixtures and isolated isomers. shall be expressed.

Preferably R ₂ and R ₃ are both methyl or both hydrogen, ie α- or δ-tocopheryl glycoside.

Representative compounds of formula [I] include dl-α-tocopheryl glucoside, dl-α-tocopheryl galactoxiside, dl-α-tocopheryl cellobioside, d-δ-tocopheryl galactoside, 6- O-(β-2,3,4,6-tetraacetylglucopyranosyl)-dl-α-tocopherol, 6-O-(β-2,3,4,6-tetraacetylgalactopyranosyl)- dl-α-tocopherol, 6-O-(4-O-β-d-2′,3′,4′,6′-tetraacetylglucopyranosyl-2,3,6-triacetylglucopyranosyl )-dl-α-tocopherol, 6-O-(β-2,3,4,6-tetraacetylgalactopyranosyl)-d-δ-tocopherol.

In the compound of formula [I], R ₁ is a glucose residue,
Those with galactose or cellobiose residues are useful as derivatives with improved stability and absorption of tocopherol, and those with R ₁ as an acetylated sugar residue are useful as intermediates for their production.

The compound of formula [I] can be produced according to the Helferich method, which is a known method for synthesizing aryl glycosides.

That is, tocopherols and the desired peracetylated sugar are heated in a suitable solvent at a high temperature, e.g., 80-100°C.
For example, by carrying out a heating reaction for 3 to 7 hours, a compound of formula [I] in which R ₁ is an acetylated sugar residue can be obtained. It has been found that this reaction proceeds suitably when ethylene glycol diacetate or nitrobenzene is used as a solvent and p-toluenesulfonic acid is added as a catalyst.

The tocopherols used as starting materials are α-,
It may be β-, γ- or δ-tocopherol, and peracetylated sugars are known or can be produced by acetylating a desired sugar by a known acetylation method.

The obtained compound of formula [I] in which R ₁ is an acetylated sugar residue is heated to reflux in a conventional manner, for example, in the presence of anhydrous methanol or sodium methoxide, and then heated to reflux with Amberlite IR-120 (H ⁺ type). Deacetylation by treatment with an ion exchange resin such as ) yields compounds of formula [I] in which R ₁ is a glucose, galactose or cellobiose residue. This compound is obtained as stable crystals that are soluble in organic solvents such as alcohol, chloroform, and benzene, and poorly soluble in water, and can be further purified by conventional methods such as recrystallization.

The tocopheryl glycoside thus obtained is
Since a sugar component, which is a water-soluble molecule, is introduced, it is expected that the fat solubility of tocopherols will be improved, and by extension, the absorption will be improved.
It is metabolically hydrolyzed in vivo to produce free tocopherol, and its activity can be expressed.

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

Example 1 6-O-(β-2,3,4,6-tetraacetylglucopyranosyl)-dl-α-tocopherol 2.3 g (5.30 mmol) of dl-α-tocopherol and 186 mg of p-toluenesulfonic acid ( 1.08 mmol) is warmed and dissolved in 6 ml of ethylene glycol diacetate. 2.0 g (5.12 mmol) of β-D-glucopyrano-pentaacetate is added to this solution, and the mixture is reacted for 4 hours in a boiling water bath under reduced pressure of 60 mmHg while distilling off the acetic acid produced. Next, add 300ml of water to the reaction mixture and add 50ml of benzene.
Extract 3 times at a time. The benzene extracts were combined, dehydrated, and the solvent was distilled off under reduced pressure to form a black-purple oil.
Get 3.45g.

3.45 g of the obtained oil was subjected to column chromatography on a 180 g silica gel medium pressure column (320 mm x 500 mm) at a pressure of 5 Kg/ ^cm2 , eluted with a benzene-ethyl acetate gradient, and the solvent was removed. to obtain 0.59 g of the title compound as a yellow oil.

In silica gel thin layer chromatography (Merck Art.7749, developing solvent: chloroform)
R _f =0.37 (single spot).

UV: λ ^MeOH _nax nm (logε) = 223 (2.69), 282 (2.15
).

[α] ²⁴ _D = +1.0° (c = 1.0, MeOH).

IR: 1776 (C=0) cm ^-1 .

MS: m/e760 (M ⁺ ), 761 (M ⁺ +1), 430 (M ⁺
−330, tocopherol), 331 (M ⁺ −429, sugar).

Example 2 dl-α-tocopheryl glucoside 6-O-(β-2,3,4,
6-tetraacetylglucopyranosyl)-dl-α
- Dissolve 0.59 g (0.77 mmol) of tocopherol in 8 ml of dry methanol, add 2 ml of 0.1N sodium methoxide and heat to reflux in a boiling water bath. 5
After minutes, cool the reaction mixture and incubate the Amberlite IR.
Neutralize with 5 ml of −120 (H ⁺ form). The resulting methanol solution is evaporated under reduced pressure to obtain 0.40 g (87.0% yield) of the crude title compound as white crystals.

Melting point: 133-137℃.

The obtained crude crystals are recrystallized from water-ethanol (1:1) at 50°C to obtain 0.28 g (yield 71%) of the purified title compound.

Melting point: 140-141℃.

UV: λ ^MeOH _nax nm (logε) = 293 (2.68), 210 (3.28
).

[α] ²⁴ _D = −4.5° (c = 1.0, MeOH).

IR: 3390 (OH), 2915 (C-H), 1250 (δ-
CH) cm ^-1 .

MS: m/e 592 (M ⁺ ), ₄₃₀ (M ⁺ _{-C6H10O5 )} .

Elemental analysis, as C ₃₅ H ₆₀ O ₇ Calculated value (%): C, 70.91; H, 10.20 Actual value (%): C, 70.28; H, 10.48 Example 3 6-O-(β-2,3 ,4,6-tetraacetylglucopyranosyl)-dl-α-tocopherol dl-α-tocopherol 2.82 g (6.55 mmol)
and 188.5 mg (1.10 mmol) of p-toluenesulfonic acid are heated and dissolved in 4 ml of ethylene glycol diacetate. 3.17 g (8.12 mmol) of β-D-galactopyranose pentaacetate was added to this solution, and the mixture was heated at 100°C under reduced pressure of 70 mmHg in an oil bath.
The reaction is allowed to proceed for 4 hours while distilling off the acetic acid produced.
Then, 150 ml of water was added to the reaction mixture, and the mixture was mixed three times with 50 ml of ethyl acetate each time. The ethyl acetate extracts were combined, dried, and the solvent was evaporated under reduced pressure to obtain 6.33 g of a black-purple oil.

6.33 g of the obtained oil was subjected to column chromatography on a 180 g silica gel medium pressure column (320 mm x 500 mm) at a pressure of 5 Kg/cm ² and eluted with a benzene-ethyl acetate gradient. Removal of the solvent from the eluate yields 0.84 g of the title compound as an orange oil.

R _f =0.8 (single spot) in silica gel thin layer chromatography (Merck Art. 7749, developing solvent: benzene-methanol (6:1)).

UV: λ ^MeOH _nax nm (logε) = 223 (2.69), 282 (2.19
).

[α] ²⁴ _D = +1.6° (c = 1.0, MeOH).

IR: 1766 (C=0) cm ^-1 .

MS: m/e760 (M ⁺ ), 430 (M ⁺ -330, tocopherol), 331 (M ⁺ -429, sugar).

Example 4 dl-α-tocopheryl galactoside 6-O-(β-2,3,4,
6-tetraacetylgalactopyranosyl)-dl-
0.83 g (1.1 mmol) of α-tocopherol is dissolved in 8 ml of dry methanol, 2 ml of 0.2N sodium methoxide is added, and the mixture is heated to reflux in a boiling water bath.
After 5 minutes, cool the reaction mixture and add Amberlite.
Neutralize with 5 ml of IR-120 (H ⁺ type). The resulting methanol solution is evaporated under reduced pressure to obtain 0.54 g (83% yield) of the crude title compound as white crystals.

The obtained crude crystals were recrystallized from water-ethanol (3:7) at 50°C to obtain 0.38 g (yield 70%) of the purified title compound.

Melting point: 176-177℃.

UV: λ ^MeOH _nax nm (logε) = 210 (3.30), 293 (2.70
).

[α] ²⁴ _D = +10.1° (c = 1.0, MeOH).

MS: m/e 592 (M ⁺ ), ₄₃₀ (M ⁺ _{-C6H10O5 )} .

Elemental analysis, as C ₃₅ H ₆₀ O ₇ Calculated value (%): C, 70.91; H, 10.20 Actual value (%): C, 70.93; H, 10.26 Example 5 6-O-(4-O-β -d-2',3',4',6'-tetraacetylglucopyranosyl-2,3,6-
Triacetylglucopyranosyl)-dl-α-tocopherol Following the method of Example 1, dl-α-tocopherol and octaacetylcellobiose are reacted to give the title compound as an oil.

UV: λ ^MeOH _nax nm (logε) = 207 (3.50), 292 (2.72
).

[α] ²⁴ _D = +2.3° (c = 1.0, MeOH).

Example 6 dl-α-Tocopheryl Cellobioside The product of Example 5 is deacetylated according to the method of Example 2 to give crystals of the title compound.

Melting point: >300℃.

UV: λ ^MeOH _nax nm (logε) = 206 (3.30), 290 (2.48
).

[α] ²⁴ _D = +3.1° (c = 1.0, MeOH).

Example 7 6-O-(β-2,3,4,6-tetraacetylgalactopyranosyl)-d-δ-tocopherol 5.2 g (12.9 mmol) d-δ-tocopherol
and 76 mg (0.44 mmol) of p-toluenesulfonic acid are heated and dissolved in 5 ml of nitrobenzene. Then, 3.3 g (8.50 mmol) of β-galactopyranose pentaacetate was added, and the mixture was heated in an oil bath for 20 min.
4 while distilling off the acetic acid produced under reduced pressure of mmHg.
Allow time to react. Next, add 300ml of water to the reaction mixture.
and extract three times with 50 ml of chloroform each time.
The chloroform extracts were combined, dried, and the solvent was evaporated under reduced pressure to obtain 10 g of a black-purple oil.

5 g of the obtained oil was subjected to column chromatography on a 360 g silica gel medium pressure column (320 mm x 1500 mm) at a pressure of 5 Kg/cm ² and eluted with a benzene-ethyl acetate gradient. Removal of the solvent from the eluate yields 4.0 g of the title compound as a yellow oil.

R _f =0.6 (single spot) in silica gel thin layer chromatography (Merck Art. 7749, developing solvent: benzene-ethyl acetate (9:1)).

MS: m/e402 (M ⁺ -330, δ-tocopherol), 331 (M ⁺ -399, sugar).

Example 8 d-δ-Tocopheryl Galactoside 3.8 g (5.2 mmol) of the product of Example 7 are dissolved in 10 ml of dry methanol, 2 ml of 0.1N sodium methoxide are added and heated to reflux in a boiling water bath. 5
After minutes, cool the reaction mixture and incubate the Amberlite IR.
Neutralize with 5 ml of -120 (H ⁺ form) and evaporate the resulting methanol solution under reduced pressure to obtain 2.50 g (87.5% yield) of the crude title compound as white crystals.

The obtained crude crystals were recrystallized from water-ethanol (2:3) at 60°C to obtain 1.8 g of the purified title compound.

Melting point: 140℃.

UV: λ ^CH3OH _nax nm (logε) = 206 (1.99), 282
(1.498).

[α] ²⁰ _D = −11.0° (c = 1.0, MeOH).

MS: m/e 564 (M ⁺ ), 402 (M ⁺ −162).

dl-α-tocopheryl galactoside and d-δ-tocopheryl galactoside obtained in the above example were treated with β-galactosidase at 37°C in a 30% t-butanol-water system to observe the progress of hydrolysis. Investigation revealed that dl-α-tocopheryl galactoside is responsible for the initiation of β-galactosidase action.
About 40% of the d-δ-tocopheryl galactoside is hydrolyzed after about 15 minutes, and about 50% of the d-δ-tocopheryl galactoside is hydrolyzed after about 15 minutes.
%, and about 70% is hydrolyzed after about 30 minutes,
Each yielded the corresponding free α- or δ-tocopherol.

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ is a glucose residue, a galactose residue, a cellobiose residue, or an acetylated derivative residue of glucose, galactose or cellobiose, and R ₂ and R ₃ are the same or different,
Each means hydrogen or methyl. ] A compound represented by 2. The compound of item 1 above which is dl-α-tocopheryl glucoside. 3. The compound of item 1 above which is dl-α-tocopheryl galactoside. 4. The compound of item 1 above which is dl-α-tocopheryl cellobioside. 5. The compound of item 1 above which is d-δ-tocopheryl galactoside. 6. The compound of item 1 above which is 6-O-(β-2,3,4,6-tetraacetylglucopyranosyl)-dl-α-tocopherol. 7. The compound of item 1 above which is 6-O-(β-2,3,4,6-tetraacetylgalactopyranosyl)-dl-α-tocopherol. 8 6-O-(4-O-β-d-2', 3', 4', 6'-
Tetraacetylglucopyranosyl-2,3,6-
The compound according to item 1 above, which is triacetylglucopyranosyl)-dl-α-tocopherol. 9 6-O-(β-2,3,4,6-tetraacetylgalactopyranosyl)-d-δ-tocopherol, the compound of item 1 above.