JP3065235B2 - Propiophenone derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel propiophenone derivative having a hypoglycemic action and a method for producing the same.

[0002]

2. Description of the Related Art In the treatment of diabetes, a diet is essential, but when this alone does not provide sufficient control, insulin or an oral diabetes drug is used as necessary. Conventionally, biguanide compounds and sulfonylurea compounds have been used as diabetes drugs. However, biguanide compounds have the side effect of lactic acidosis, and sulfonylurea compounds have the side effect of severe hypoglycemia, and the development of new therapeutic agents for diabetes that does not have such disadvantages is desired.

[0003] In recent years, glucose toxicity theory, in which hyperglycemia itself is involved in the onset and progress of diabetes, has been proposed.
That is, chronic hyperglycemia reduces insulin secretion and insulin sensitivity, which causes a further rise in blood sugar and a vicious cycle of developing diabetes [Diabetrodia (Diabetrodia)
tologia) Volume 28, page 119 (1985), Diabetes Care, Volume 13, Volume 61
0 (1990)]. Therefore, it is said that by correcting hyperglycemia, the above-described vicious cycle can be broken and diabetes can be prevented or treated.

As one method for correcting hyperglycemia, it is conceivable that excess sugar is directly excreted in urine to normalize blood sugar levels. Phlorizin is a glycoside contained in the bark and root bark of Rosaceae plants such as apples and pears, and inhibits the Na ⁺ -glucose cotransporter present only in the intestinal tract and the chorion of the kidney, thereby causing phlorizin in the kidney. Inhibits sugar reabsorption, promotes excretion of sugar, and lowers blood sugar. Based on this effect, it has been confirmed that phlorizin is subcutaneously administered to diabetic animals daily to correct hyperglycemia and to maintain blood glucose levels normal for a long period of time, thereby improving and normalizing the condition of diabetic animals [ Journal of Clinical Investigation (J. Clin. Invest.) No. 79
Volume, p. 1510 (1987), Vol. 80, p. 103
7 (1987), Vol. 87, p. 561 (1991)
Year) etc.].

However, when phlorizin is administered orally, it is mostly hydrolyzed to the aglycones phloretin and glucose, and the rate of absorption as phlorizin is small, and the urinary glucose excretion effect is very weak. In addition, it is known that phloretin, which is an aglycone, strongly inhibits a facilitating diffusion type sugar transporter. For example, it has been reported that intravenous administration of phloretin to rats decreases brain glucose concentration. [Stroke, Vol. 14, p. 388 (1983)], and its use over a long period of time may adversely affect various tissues. Therefore, no attempt has been made so far to use phlorizin as a therapeutic drug for diabetes.

[0006]

DISCLOSURE OF THE INVENTION The present invention has an excellent urinary glucose increasing effect based on inhibition of re-absorption of glucose in the kidney, thereby exhibiting an excellent hypoglycemic effect, and its aglycone is effective in promoting glucose reduction. An object of the present invention is to provide a propiophenone derivative in which an inhibitory effect of a diffusion type sugar transporting carrier is extremely weak.

[0007]

The present invention provides a compound represented by the general formula [I]:

Embedded image (Wherein, R ¹ and R ² are the same or different, represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or an aryl group, or R ¹ and R ² is an oxo group together. However, R ¹ and When one of R ² is a phenyl group, the other is not a hydrogen atom) or a pharmacologically acceptable salt thereof.

As a specific example of the compound [I] of the present invention, in formula [I], one of R ¹ and R ² is a lower alkyl group, a lower alkoxy group or an aryl group, and the other is a hydrogen atom or a lower alkyl group. Group, lower alkoxy group or aryl group (however, when one is a phenyl group,
The other is not a hydrogen atom) or a compound in which R ¹ and R ² in the general formula [I] together form an oxo group.

The preferred compound of the present invention has the general formula
In [I], a compound in which ^one of R ¹ and R ² is a lower alkoxy group and the other is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, and R ¹ and R ² together It is a compound that is an oxo group.

[0010] Compounds having excellent medicinal properties include R ¹
And one of R ² is a C ₁ -C ₂ alkoxy group and the other is a hydrogen atom, a C ₁ -C ₂ alkyl group, a C ₁ -C ₂ alkoxy group or a phenyl group, or R ¹ and R ² together Is a compound that represents an oxo group.

The propiophenone derivative [I] of the present invention comprises
Both the free form and the pharmaceutically acceptable salt forms thereof can be used for the purposes of the present invention. Examples of pharmacologically acceptable salts include alkali metal salts. In the compound [I] of the present invention, when the substituents R ¹ and R ² are different groups, two types of diastereomers exist due to the asymmetry of the carbon to which they are bonded. Both of these two diastereomers and mixtures thereof are included in the range.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The compound [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and a medicament usually used for oral or parenteral administration An appropriate preparation can be prepared using a carrier.
Such pharmaceutical carriers include, for example, binders (syrups,
Gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine, etc.),
Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.) can be mentioned. In the case of oral administration, these pharmaceutical preparations may be solid preparations such as tablets, capsules, powders and granules, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, in the case of parenteral administration, for example, an injection or a drip can be prepared using distilled water for injection, physiological saline, an aqueous glucose solution or the like.

The dose varies depending on the age, weight, condition and degree of the disease of the patient, but usually the daily dose is 0.1 to 500 mg / kg, particularly 1 to 100 mg / kg for oral administration. kg, 0.0 for parenteral administration
It is preferably between 1 and 50 mg / kg, especially between 0.1 and 10 mg / kg.

According to the present invention, R ^{1 of the} object [I]
And R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or an aryl group (provided that
When one is a phenyl group, the other is not a hydrogen atom), that is, a compound represented by the following general formula [Ia]

Embedded image (In the formula, R ¹ ′ and R ² ′ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or an aryl group. However, when ^one of R ¹ ′ and R ² ′ is a phenyl group, Is not a hydrogen atom) or a pharmaceutically acceptable salt thereof is represented by the formula [II]

Embedded image (Wherein R ′ represents a hydrogen atom or a hydroxyl-protecting group) by a compound of the formula [III]

Embedded image (Wherein R ¹ ′ and R ² ′ are the same as described above, and R ″ represents a lower alkyl group), and if necessary, after a deprotecting group treatment according to a conventional method, To produce a pharmacologically acceptable salt.

The above condensation reaction can be carried out without a solvent or in an appropriate organic solvent in the presence of a condensing agent, under cooling to heating. As the organic solvent, any solvent can be used as long as it is inert to the reaction, and examples thereof include dichloromethane, chloroform, dichloroethane, and tetrahydrofuran. Examples of the condensing agent include pyridinium toluenesulfonic acid, arylsulfonic acid such as toluenesulfonic acid, alkanesulfonic acid such as methanesulfonic acid, hydrochloric acid, and sulfuric acid. This condensation reaction can be carried out in a stepwise manner. Compound [II] and compound [III] are reacted once in the presence of the same arylsulfonic acid and alkali metal halide as described above to give compound [II] ] Can be carried out by condensing only the hydroxyl group at the 6-position of glucopyranosyl with compound [III], followed by treatment with an organic base and trialkylsilyltrifluoroalkanesulfonate. Starting material [I
As the hydroxyl-protecting group in I], any known hydroxyl-protecting group, for example, an acetyl group may be used, and the protecting group may be removed by a conventional method, for example, treatment with an alkali such as sodium hydrogencarbonate or potassium carbonate. It is achieved by doing.

In the compound [I] of the present invention, R ¹ and R ² together represent an oxo group represented by the following formula [Ib]

Embedded image In the compound or a pharmaceutically acceptable salt thereof,
The compound of the formula [II] is reacted with an aryl halogenoformate such as p-nitrophenyl chloroformate, carbonyldiimidazole, or the like, and if necessary, treated with a deprotecting group. It is produced by converting it into a salt.

The above reaction comprises 2,4,6-collidine, 2,2
The reaction is carried out in a suitable organic solvent such as 6-lutidine, pyridine, tetrahydrofuran or the like, under cooling to room temperature.

The compound of the formula [II] used as a starting compound is represented by the formula [IV]

Embedded image (Wherein R ′ is the same as described above) represented by the formula [V]

Embedded image Is condensed with an aldehyde compound represented by the formula (VI) to remove the protecting group,

Embedded image The acrylophenone derivative represented by the formula is obtained, reduced, and, if necessary, after protecting the hydroxyl groups at the 4- and 6-positions of the glucopyranosyl moiety of the product with a benzylidene group, the hydroxyl groups at the 2- and 3-positions of the glucopyranosyl moiety and phenol It can be produced by protecting the hydroxyl group and removing the benzylidene group.

In the above method, the condensation reaction between the acetophenone derivative [IV] and the aldehyde compound [V] can be carried out by a conventional method, for example, in a solvent (such as an organic solvent such as methanol or ethanol, or an organic solvent such as methanol or ethanol). The reaction can be carried out under cooling to heating (particularly 10 ° C to 30 ° C) in the presence of a mixed solvent with water) and a base (such as an alkali metal hydroxide). As the protecting group for the hydroxyl group in the acetophenone derivative [IV], a conventional protecting group is used, and examples thereof include an alkanoyl group such as an acetyl group and an aralkyl group such as a benzyl group.

The reduction reaction of the acrylophenone derivative [VI] obtained by the above reaction can be carried out by a conventional method such as reduction with a metal hydride, catalytic hydrogen reduction and the like.
For example, the reduction with a metal hydride can be carried out by using a metal hydride in a solvent, and the catalytic hydrogen reduction can be carried out by catalytic reduction in a solvent under a normal pressure hydrogen stream using a catalyst. Specifically, in the catalytic hydrogen reduction, a common catalyst can be used as the catalyst, and for example, a catalyst such as palladium-carbon, platinum-carbon, and platinum oxide can be suitably used. In addition, the reduction with a metal hydride can be used as long as it is a metal hydride that can reduce a double bond, but those that do not reduce ketones are particularly preferable. And sodium tellurium hydride (NaTeH). Sodium telluride hydride synthesis
(Synthesis), p. 545 (1978).
It is preferred to use 1 to 3 molar equivalents, especially 1 to 1.5 molar equivalents.

As the solvent used in the above reduction reaction, any solvent can be used as long as it is inert to the reaction. For example, an organic solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, or an organic solvent such as these. A mixed solvent of a solvent and water can be used. The reduction reaction can be carried out under cooling to heating, and particularly preferably at 10 ° C to 30 ° C. Also,
The protection of the hydroxyl groups at the 4- and 6-positions of the glucopyranosyl moiety of the product can be carried out by reacting the product with a benzaldehyde dialkyl acetal in the presence of an arylsulfonic acid. Examples of the protecting group for the hydroxyl group at positions 2 and 3 of the glucopyranosyl moiety include an acetophenone derivative [I
V], and the introduction of such a protecting group is carried out, for example, by treating a compound in which the 4- or 6-position of the glucopyranosyl moiety is protected with a reactive derivative of an alkanoic acid in the presence of an organic base. Can be performed. Subsequent removal of the benzylidene group can be accomplished by treating the product with acetic acid, water and an aryl sulfonic acid.

The acetophenone derivative [IV] used in the production of the starting material compound [II] is described in (i) Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm. Chem.), 5 volumes,
According to the method described on page 1054 (1962), for example, 2 ′, 6′-dihydroxyacetophenone and 2,3,4,
6-tetra-O-acetyl-α-D-glucopyranosyl bromide is reacted in aqueous acetone in the presence of potassium hydroxide, or (ii) for example with 2 ′, 6′-dihydroxyacetophenone. 2,3,4,6-tetra-O
-Acetyl-α-D-glucopyranosyl bromide can be produced by heating and refluxing in toluene in the presence of cadmium carbonate.

In the present invention, the lower alkyl group may be a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. And a group having 1 to 4 carbon atoms is particularly preferable. Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a tert-butoxy group.
And straight-chain or branched-chain alkoxy groups having up to 6 carbon atoms, and particularly those having 1 to 4 carbon atoms are preferred.

As the aryl group, phenyl, tolyl,
Examples thereof include a substituted or unsubstituted aryl group having 6 to 10 carbon atoms such as quinolyl and naphthyl, and a phenyl group which may be unsubstituted or substituted with a lower alkyl group is particularly preferable.

[0026]

The compound [I] of the present invention or a pharmaceutically acceptable salt thereof exhibits excellent hypoglycemic action, for example,
When the compounds specifically exemplified in Examples described later were orally administered to rats, all of the compounds showed 25 times or more urine glucose as compared with phlorizin. Compound [I] also has low toxicity, and further has the advantage that the aglycone portion generated by hydrolysis in the body has a weak inhibitory effect on the facilitated-diffusion-type sugar transport carrier.
Therefore, the compound [I] of the present invention can correct hyperglycemia, break the vicious cycle of glucose toxicity,
It can be effectively used for the prevention and treatment of diabetes (eg, diabetes mellitus such as insulin-dependent diabetes mellitus (type I diabetes) and non-insulin-dependent diabetes mellitus (type II diabetes)).

[0027]

Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is not limited to these examples.

Example 1 889 mg of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone and pyridinium p-toluenesulfonic acid 5
0 mg was added to 10 ml of methyl orthoformate, stirred at room temperature for 3.5 hours, and concentrated under reduced pressure. Residue is methyl orthoformate 10
Then, 1 ml of methanol is added under ice cooling, and the mixture is stirred for 1 hour under ice cooling. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction solution,
The organic layer is separated, dried and the solvent is distilled off. The obtained residue is purified by column chromatography (solvent: chloroform / methanol), and 2 ′-(4,6-O-methoxymethylene-β-D-glucopyranosyloxy) -6′-hydroxy-3 is obtained. 425 mg of-(5-benzo [b] furanyl) propiophenone are obtained as a pale yellow foam.

ESI-MS (m / z): 509 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3420,1620 NMR (DMSO-d ₆ ) δ: 2.98 (2H, t, J = 7) .7
Hz), 3.2-3.8 (7H, m), 3.26 and 3.36 (3
H, s × 2), 3.80 and 4.07 (1H, m × 2), 5.15
And 5.13 (1H, d × 2, J = 7.7, 7.9Hz), 5.
37 and 5.50 (1 H, d × 2, J = 5.5, 5.3 Hz),
5.44 and 5.30 (1H, s × 2), 5.59 (1H, d, J
= 5.7 Hz), 6.56 (1 H, d, J = 8.1 Hz), 6.70 and 6.69 (1 H, d × 2, J = 8.1, 8.4 Hz), 6.88
(1H, dd, J = 0.9,2.2Hz), 7.20 (1H, dd, J =
1.7, 8.5 Hz), 7.23 (1 H, t, J = 8.3 Hz), 7.4
7 and 7.48 (1 H, d × 2, J = 8.4, 8.4 Hz), 7.
50 (1H, d, J = 1.7 Hz), 7.94 (1H, d, J = 2.2)
Hz), 10.83 and 10.82 (1H, s × 2)

Example 2 In the same manner as in Example 1 except that methyl phenylorthoformate was used instead of methyl orthoformate, 2 '-[4,6-O- ( α-methoxybenzylidene) -β-D-glucopyranosyloxy] -6 ′
-Hydroxy-3- (5-benzo [b] furanyl) propiophenone is obtained.

ESI-MS (m / z): 585 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3400,1620 NMR (DMSO-d ₆ ) δ: 3.01 (2H, t, J = 7) .0H
z), 3.01 (3H, s), 3.27 (2H, m), 3.39 (1H,
m), 3.55 (1H, m), 3.6-3.8 (2H, m), 3.89 (1
H, dd, J = 9.6,9.8 Hz), 3.97 (1H, dd, J = 5.
2,9.8 Hz), 5.19 (1H, d, J = 7.7 Hz), 5.45
(1H, d, J = 5.5Hz), 5.63 (1H, d, J = 5.7H
z), 6.57 (1 H, d, J = 7.7 Hz), 6.72 (1 H, d, J
= 8.1Hz), 6.89 (1H, dd, J = 1.0,2.2Hz),
7.22 (1H, dd, J = 1.8, 8.5 Hz), 7.24 (1H,
t, J = 8.3Hz), 7.40 (3H, m), 7.48 (1H, d, J
= 8.4 Hz), 7.53 (1 H, d, J = 1.6 Hz), 7.55
(2H, m), 7.94 (1H, d, J = 2.2Hz), 10.83 (1
H, s)

Example 3 A pale yellow foam 2 '-[4,6-O- () was prepared in the same manner as in Example 1 except that methyl methyl orthoformate was used instead of methyl orthoformate. 1-methoxy-
1,1-ethylene) -β-D-glucopyranosyloxy]
-6'-Hydroxy-3- (5-benzo [b] furanyl) propiophenone is obtained.

ESI-MS (m / z): 523 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3430,1620 NMR (DMSO-d ₆ ) δ: 1.39 (3H, s), 2. 98 (2
H, t, J = 7.7 Hz), 3.22 (3H, s), 3.2-3.8
(8H, m), 5.12 (1H, d, J = 7.7 Hz), 5.34 (1
H, d, J = 5.3 Hz), 5.57 (1 H, d, J = 5.7 Hz),
6.56 (1H, d, J = 8.5 Hz), 6.69 (1H, d, J =
7.8 Hz), 6.88 (1 H, dd, J = 0.9, 2.2 Hz), 7.
20 (1H, dd, J = 1.8,8.4Hz), 7.23 (1H, t, J
= 8.3 Hz), 7.47 (1 H, d, J = 8.5 Hz), 7.51
(1H, d, J = 1.5Hz), 7.93 (1H, d, J = 2.2H
z), 10.83 (1H, s)

Example 4 The procedure of Example 1 was repeated, except that ethyl ethoxyorthoformate was used in place of methyl orthoformate, to give 2 '-[4,6-O- ( Diethoxymethylene) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone is obtained.

ESI-MS (m / z): 567 [(M + N
a) ⁺ ] IR (nujol) cm ^-1 : 3400,1620 NMR (DMSO-d ₆ ) δ: 1.12 (3H, t, J = 7.1H)
z), 1.15 (3H, t, J = 7.1 Hz), 2.99 (2H, t, J
= 7.3 Hz), 3.2-3.8 (11 H, m), 3.94 (1 H, d
d, J = 3.7, 8.5 Hz), 5.15 (1 H, d, J = 7.7 H)
z), 5.44 (1 H, d, J = 5.3 Hz), 5.60 (1 H, d, J
= 5.7 Hz), 6.57 (1 H, d, J = 7.7 Hz), 6.70
(1H, d, J = 8.1 Hz), 6.88 (1H, dd, J = 1.0,
2.2Hz), 7.20 (1H, dd, J = 1.8,8.5Hz), 7.
23 (1H, t, J = 8.3 Hz), 7.46 (1H, d, J = 8.
5Hz), 7.51 (1H, d, J = 1.3Hz), 7.93 (1H,
d, J = 2.2 Hz), 10.81 (1 H, s)

Example 5 1333 mg of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone was added to 15 ml of 2,4,6-collidine. The mixture was cooled to -40 ° C with dry ice-acetone, and a solution of 786 mg of p-nitrophenyl chloroformate in 3 ml of methylene chloride was added dropwise with stirring. 1 hour 45 at -40 ° C
And then at room temperature for 1 hour and then at 50 ° C. for 6.5 hours. After cooling, pour the reaction into cold 10% hydrochloric acid and extract with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography (solvent: chloroform / acetone) to give 2′-
994 mg of (4,6-O-oxomethylene-β-D-glucopyranosyloxy) -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

Mp 70 ° C .- (gradual decomposition) FAB-MS (m / z): 493 [(M + Na) ⁺ ] IR (nujol) cm ⁻¹ : 3400, 1750, 1620 NMR (DMSO-d ₆ ) δ: 2 .98 (2H, t, J = 7.5H
z), 3.23 (2H, m), 3.33 (1H, m), 3.63 (1H,
m), 4.13 (1H, m), 4.17 (1H, dd, J = 8.9, 9.5
Hz), 4.25 (1 H, dd, J = 9.5,9.6 Hz), 4.47
(1H, dd, J = 5.5,9.2Hz), 5.21 (1H, d, J =
7.9 Hz), 5.77 (1 H, d, J = 5.9 Hz), 5.84 (1
H, d, J = 5.5 Hz), 6.58 (1 H, d, J = 8.1 Hz),
6.68 (1H, d, J = 8.1 Hz), 6.88 (1H, dd, J =
0.9, 2.2 Hz), 7.19 (1 H, dd, J = 1.8, 8.5 H
z), 7.24 (1H, t, J = 8.3 Hz), 7.48 (1H, d, J
= 8.5 Hz), 7.50 (1 H, d, J = 1.8 Hz), 7.93
(1H, d, J = 2.2Hz), 10.73 (1H, s)

Example 6 (1) 2 ′-(2,3-di-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-3- (5-benzo [b] furanyl) 2853 mg of propiophenone is dissolved in 30 ml of dimethoxymethane, 95 mg of p-toluenesulfonic acid and 87 mg of lithium bromide are added to the solution, and the mixture is stirred at room temperature for 4.5 hours and refluxed for 3 hours. After further stirring at room temperature overnight, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the reaction solution, and the organic layer was separated. After washing with water and drying, the solvent is distilled off to obtain 2500 mg of a crude product of a compound in which the hydroxyl group at position 6 of the glucose moiety is methoxymethylated. 1080 mg of the above crude product is dissolved in 20 ml of tetrahydrofuran, 283 mg of 2,6-lutidine and 0.51 ml of trimethylsilyltrifluoromethanesulfonate are added to the solution under ice cooling, and the mixture is stirred for 2 hours under ice cooling and then at room temperature for 2 hours. The reaction is poured into cold 5% hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried, and the solvent is distilled off. The residue obtained is purified by silica gel chromatography (solvent: chloroform / ethyl acetate) to give 2 ′-(2,3-di-O-acetyl-
4,6-O-methylene-β-D-glucopyranosyloxy) -6′-acetoxy-3- (5-benzo [b] furanyl)
634 mg of propiophenone are obtained as a colorless foam.

ESI-MS (m / z): 605 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 1750,1700 NMR (DMSO-d ₆ ) δ: 1.94 (3H, s), 2. 00 (3
H, s), 2.02 (3H, s), 2.8-3.1 (4H, m), 3.47
(1H, t, J = 10.1Hz), 3.61 (1H, t, J = 9.6H)
z), 3.86 (1H, m), 4.18 (1H, dd, J = 4.9, 10.
0 Hz), 4.57 (1 H, d, J = 6.3 Hz), 4.97 (1 H,
d, J = 6.0 Hz), 5.03 (1 H, dd, J = 7.9, 9.5 H)
z), 5.35 (1H, t, J = 9.6 Hz), 5.64 (1H, d, J
= 7.9Hz), 6.90 (1H, dd, J = 0.7,2.2Hz),
6.91 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J =
8.1 Hz), 7.17 (1 H, dd, J = 1.9, 8.4 Hz), 7.
45 (1H, t, J = 8.3 Hz), 7.49 (1H, d, J = 1.9)
Hz), 7.50 (1H, d, J = 8.5 Hz), 7.95 (1H, d,
J = 2.2Hz)

(2) 611 mg of the above product (1) is dissolved in a methanol-water mixture (20 ml-0.2 ml), 579 mg of potassium carbonate is added to the solution, and the mixture is stirred at room temperature for 2.5 hours.
The reaction solution is concentrated under reduced pressure, ethyl acetate and water are added to the obtained residue, and the mixture is neutralized with 10% hydrochloric acid under ice-cooling, and then the organic layer is separated. After washing with water and drying, the residue obtained by evaporating the solvent is subjected to silica gel column chromatography (solvent:
Purified with chloroform / methanol) to give 2 '-(4,6-
O-methylene-β-D-glucopyranosyloxy) -6 ′
444 mg of -hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

Mp 162.5-165.5 ° C. ESI-MS (m / z): 479 [(M + Na) ⁺ ] IR (nujol) cm ⁻¹ : 3600, 3330, 1625 NMR (DMSO-d ₆ ) δ: 2 .88 (2H, t, J = 7.6H
z), 3.13 (1H, dd, J = 9.2, 9.4Hz), 3.2-3.
4 (4H, m), 3.50 (2H, m), 4.05 (1H, dd, J = 4.
6,9.7 Hz), 4.55 (1 H, d, J = 6.2 Hz), 4.98
(1H, d, J = 6.1Hz), 5.12 (1H, d, J = 7.8Hz),
5.44 (1H, d, J = 5.3 Hz), 5.58 (1H, d, J =
5.7 Hz), 6.56 (1 H, d, J = 8.2 Hz), 6.69 (1
H, d, J = 8.1 Hz), 6.89 (1 H, dd, J = 0.9, 2.1)
Hz), 7.20 (1 H, dd, J = 1.7, 8.5 Hz), 7.23
(1H, t, J = 8.3Hz), 7.48 (1H, d, J = 8.5H
z), 7.51 (1H, d, J = 1.2 Hz), 7.93 (1H, d, J
= 2.2Hz), 10.84 (1H, s)

Reference Example 1 2 '-(2,3,4,6-tetra-O-acetyl-β-D-
To a mixture of 965 mg of glucopyranosyloxy) -6'-hydroxyacetophenone, 350 mg of benzo [b] furan-5-carbaldehyde and 10 ml of ethanol, 2 ml of a 50% aqueous solution of potassium hydroxide is added dropwise and stirred overnight at room temperature. The solvent is distilled off under reduced pressure, water and diisopropyl ether are added to the residue, and the mixture is stirred, and the aqueous layer is separated. 10% ice-cooled sewage layer
After neutralizing with hydrochloric acid, extract with ethyl acetate. After the obtained organic layer was washed with water and dried, the solvent was distilled off to obtain crude 2 ′-(β
-D-glucopyranosyloxy) -6'-hydroxy-3
This gives-(5-benzo [b] furanyl) acrylophenone.

This product is added to 15 ml of an ethanol solution of sodium tellurium hydride prepared in advance from 383 mg of tellurium and 270 mg of sodium borohydride, and then added at room temperature for 2 hours.
Incubate for 5 hours. The insoluble material is removed by filtration, water and ethyl acetate are added to the filtrate, and the organic layer is separated after stirring. After the organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography to give 2 ′-(β-D-glucopyranosyloxy) -6′-hydroxy-3- (5 -Benzo
[b] Furanyl) 480 mg of propiophenone are obtained.

FABMS (m / z): 467 [(M + Na) ⁺ ] NMR (DMSO-d ₆ ) δ: 3.00 (2H, t, J = 7.5H)
z), 3.1-3.4 (6H, m), 3.47 (1H, m), 3.71 (1
H, ddd, J = 1.7, 5.1, 11.4 Hz), 4.56 (1H, t,
J = 5.7 Hz), 4.93 (1 H, d, J = 7.4 Hz), 5.03
(1H, d, J = 5.2Hz), 5.10 (1H, d, J = 4.6H)
z), 5.25 (1 H, d, J = 5.3 Hz), 6.55 (1 H, d, J
= 8.2 Hz), 6.68 (1 H, d, J = 7.8 Hz), 6.87
(1H, dd, J = 1.0,3.2Hz), 7.21 (1H, dd, J =
1.8, 8.5 Hz), 7.24 (1 H, t, J = 8.3 Hz), 7.4
6 (1H, d, J = 8.5 Hz), 7.53 (1H, d, J = 1.3 H)
z), 7.92 (1H, d, J = 2.2 Hz), 10.98 (1H, s)

Reference Example 2 (1) A mixture of 4.44 g of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone and 80 ml of dichloromethane. 3.04 g of benzaldehyde dimethyl acetal and 0.19 g of p-toluenesulfonic acid are added to the mixture, and the mixture is stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue is dissolved in ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent: chloroform / methanol) to give 2 '-(4,6-O-
Benzylidene-β-D-glucopyranosyloxy) -6 ′
5.84 g of -hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained.

(2) 2 '-(4,6-O-benzylidene-β
-D-glucopyranosyloxy) -6'-hydroxy-3
-(5-benzo [b] furanyl) propiophenone 5.78 g
Was dissolved in 50 ml of pyridine, and 6.65 g of acetic anhydride was added.
Stir at room temperature for 4 hours. Ethyl acetate is added to the reaction solution, and the mixture is poured into ice-10% hydrochloric acid, stirred, and the organic layer is separated. After the obtained organic layer was washed with water and dried, the solvent was distilled off to obtain crude 2 ′-(2,3-di-O-acetyl-4,6-O-benzylidene-β-D-glucopyranosyl. 7.24 g of oxy) -6'-acetoxy-3- (5-benzo [b] furanyl) propiophenone are obtained. Dissolve 520mg of this product in 10ml of acetic acid,
1.5 ml of water and 45 mg of p-toluenesulfonic acid are added,
Stir at 50 ° C. for 5 hours. Water and ethyl acetate are added to the reaction solution, and after stirring, the organic layer is separated, washed with water and dried. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent: chloroform / methanol).
2 ′-(2,3-di-O-acetyl-β-D-glucopyranosyloxy) -6′-acetoxy-3- (5-benzo [b]
360 mg of (furanyl) propiophenone are obtained.

FABMS (m / z): 593 [(M + Na) ⁺ ] NMR (DMSO-d ₆ ) δ: 1.88 (3H, s), 2.00 (6
H, s), 2.9-3.1 (4H, m), 3.5-3.8 (4H, m),
4.75 (1H, t, J = 5.5Hz), 4.90 (1H, dd, J =
8.0, 9.8 Hz), 5.11 (1 H, t, J = 9.2 Hz), 5.5
0 (1H, d, J = 7.9 Hz), 5.59 (1H, d, J = 5.7 H)
z), 6.88 (1 H, d, J = 7.9 Hz), 6.90 (1 H, d, J
= 2.2Hz), 7.16 (1H, d, J = 8.1Hz), 7.17
(1H, dd, J = 1.7,8.5Hz), 7.44 (1H, t, J =
8.2 Hz), 7.48 (1 H, d, J = 1.8 Hz), 7.49 (1
H, d, J = 8.6 Hz), 7.94 (1 H, d, J = 2.2 Hz)

Continuation of the front page (72) Inventor Kozo Oka 3-4-1-16 Shikaglove, Urawa-shi, Saitama Shuttle Nakaura, 303 (56) References JP-A-6-298790 (JP, A) Patent 2847696 (JP, B2) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07H 15/26 CA (STN) CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, R ¹ and R ² are the same or different, represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or an aryl group, or R ¹ and R ² is an oxo group together. However, R ¹ and When one of R ² is a phenyl group, the other is not a hydrogen atom) or a pharmacologically acceptable salt thereof. 2. ^One of R ¹ and R ² is a lower alkyl group,
A lower alkoxy group or an aryl group, the other is a hydrogen atom, a lower alkyl group, a lower alkoxy group or an aryl group (provided that when one is a phenyl group, the other is not a hydrogen atom), or R ¹ and R ^2. The compound according to claim 1, wherein ² together are an oxo group. 3. ^One of R ¹ and R ² is a lower alkoxy group and the other is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, or R ¹ and R ² together form an oxo group. The compound according to claim 1, which is 4. ^One of R ¹ and R ² is a C ₁ -C ₂ alkoxy group, the other is a hydrogen atom, a C ₁ -C ₂ alkyl group,
₁ or an alkoxy group or a phenyl group -C _2, or R ¹ and R ² are an oxo group together claim 1
A compound as described. 5. A compound of the formula [II] (Wherein R ′ represents a hydrogen atom or a hydroxyl-protecting group) by a compound represented by the formula [III]: (Wherein R ¹ ′ and R ² ′ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or an aryl group, provided that ^one of R ¹ ′ and R ² ′ is a phenyl group. The other is not a hydrogen atom, R ″ represents a lower alkyl group), and if necessary, after a deprotecting group, optionally a pharmacologically acceptable salt. General formula [Ia] (Wherein R ¹ ′ and R ² ′ are the same as above) or a method of producing a propiophenone derivative or a pharmaceutically acceptable salt thereof. 6. A compound of the formula [II] (Wherein R ′ represents a hydrogen atom or a hydroxyl-protecting group) by reacting with a halogenoformate and, if necessary, a deprotecting group and, if desired, a pharmacologically acceptable salt. The formula [I-b] Or a pharmacologically acceptable salt thereof.