JPH09124684A - Propiophenone derivative and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new propiophenone derivative which is a specific propiophenone derivative bearing a benzofuran ring, has excellent hypoglycemic action based on its inhibitory action of glucose reabsorption in kidney and is useful as a therapeutic and preventive agent for diabetes. SOLUTION: This novel propiophenone derivative or its salt is represented by formula I (R<1> and R<2> are each H, a lower alkyl, a lower alkoxy, an aryl or they may incorporate with each other to form oxo where in the case tat either R<1> or R<2> is phenyl the other is not H) and shows excellent hypoglycemic action based on the inhibition of glucose reabsorption in kidney. In the meanwhile, its aglycon has very weak inhibitory action on the saccharide carrier of a facilitated diffusion type, thus this derivative is useful as a therapeutic and preventive agent for diabetes. This compound is prepared by allowing a compound of formula II (R' is H, a hydroxyl group-protecting group) to react with an acetal of formula III (R<1> ' and R<2> ' are each H, a lower alkyl, a lower alkoxy, an aryl; R" is a lower alkyl), when necessary, effecting deprotection and, if desired, conversion to its pharmacologically permissible salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel propiophenone derivative having a hypoglycemic effect and a method for producing the same.

[0002]

2. Description of the Related Art Diet therapy is essential for the treatment of diabetes, but if this alone does not provide sufficient control, insulin or an oral diabetes drug is used as needed. As a diabetes drug, a biguanide compound and a sulfonylurea compound have been conventionally used. 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.

Recently, a glucose toxicity theory has been proposed in which hyperglycemia itself is involved in the onset and progress of diabetes.
That is, chronic hyperglycemia lowers insulin secretion as well as insulin sensitivity, which causes a further rise in blood glucose, leading to a vicious cycle in which diabetes progresses [Diabetrosia (Diabetrosia
tologia) 28, 119 (1985), Diabetes Care, 13th, 61st.
0 page (1990) etc.]. Therefore, it is said that by correcting hyperglycemia, it is possible to prevent the above-mentioned vicious circle and prevent / treat diabetes.

As one method for correcting hyperglycemia, it is considered that excess sugar is directly excreted in urine to normalize the blood sugar level. Floridin is a glycoside contained in the bark and root bark of Rosaceae plants such as apples and pears. It inhibits Na ⁺ -glucose cotransporter existing only in the intestinal tract and chorion of the kidney, and It can inhibit the reabsorption of sugar and promote the excretion of sugar to lower blood sugar. Based on this action, it has been confirmed that phlorizin is subcutaneously administered to diabetic animals every day to correct hyperglycemia and to maintain normal blood glucose levels for a long period of time, thereby improving and normalizing the disease state of diabetic animals [ Journal of Clinical Investigation (J. Clin. Invest.) 79th
Volume 1510 (1987), Volume 80, 103.
7 (1987), 87, 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. It is known that phloretin, which is an aglycone, strongly inhibits the facilitative diffusion type sugar transporter. For example, it has been reported that intravenous administration of phloretin to rats reduces brain glucose concentration. [Stroke, Vol. 14, p. 388 (1983)], it is thought that use of this for a long period of time may adversely affect various tissues. Therefore, no attempts have 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 action based on inhibition of glucose reabsorption in the kidney, thereby exhibiting an excellent hypoglycemic action, and its aglycone promotes The present invention provides a propiophenone derivative which has a markedly weak inhibitory effect on a diffusion-type sugar transport carrier.

[0007]

The present invention has 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 propiophenone derivative or a pharmaceutically acceptable salt thereof.

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

Preferred compounds of the present invention include those of 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 are taken together. It is a compound that is an oxo group.

Compounds having excellent medicinal effects include R ¹
And one of R ² is a C ₁ -C ₂ alkoxy group, 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 are the same. Is a compound that represents an oxo group.

The propiophenone derivative [I] of the present invention is
Both the free form and the pharmaceutically acceptable salt forms thereof can be used for the purposes of the present invention. Examples of the pharmacologically acceptable salt include alkali metal salts and the like. In the compound [I] of the present invention, when the substituents R ¹ and R ² are different groups, there are two diastereomers due to the asymmetry of the carbon to which they are bonded. All 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 drug usually used for oral or parenteral administration. An appropriate formulation can be prepared using the carrier.
As such a pharmaceutical carrier, for example, a binder (syrup,
Gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.),
Lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.), wetting agents (sodium lauryl sulfate, etc.) and the like can be mentioned. When administered orally, 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, distilled water for injection, physiological saline, aqueous glucose solution or the like can be used to prepare an injection or drip.

Although the dose varies depending on the age, weight, condition of the patient or the degree of disease, the daily dose is usually 0.1 to 500 mg / kg, especially 1 to 100 mg / kg in the case of oral administration. kg, 0.0 for parenteral administration
It is preferably from 1 to 50 mg / kg, especially from 0.1 to 10 mg / kg.

According to the present invention, among the objects [I], 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
When one is a phenyl group, the other is not a hydrogen atom), that is, the following general formula [Ia]

Embedded image (In the formula, R ¹ 'and R ² ' are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, or an aryl group, provided that when ^one of R ¹ 'and R ² ' is a phenyl group. And the other is not a hydrogen atom) or a pharmaceutically acceptable salt thereof has the formula [II]

Embedded image (In the formula, R ′ represents a hydrogen atom or a hydroxyl-protecting group), a compound represented by 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 after reacting with a deprotecting group according to a conventional method, if desired, Can be produced by preparing a pharmacologically acceptable salt thereof.

The above condensation reaction can be carried out in the absence of solvent or in a suitable 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, toluenesulfonic acid and other arylsulfonic acids, methanesulfonic acid and other alkanesulfonic acids, hydrochloric acid, sulfuric acid and the like. Further, this condensation reaction can be carried out stepwise, and the compound [II] and the compound [III] are once reacted in the presence of the same arylsulfonic acid and alkali metal halide as described above to give the compound [II]. ] The glucopyranosyl 6-position hydroxyl group of [] is condensed with the compound [III], and then further treated with an organic base and trialkylsilyltrifluoroalkanesulfonate. Starting material [I
As the hydroxyl group-protecting group in [I], any known hydroxyl group-protecting group such as acetyl group can be used, and elimination of the protecting group can be carried out by an ordinary method, for example, by treating with an alkali such as sodium hydrogen carbonate or potassium carbonate. It is achieved by

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

Embedded image The compound represented by or a pharmacologically acceptable salt thereof,
The compound of the formula [II] is reacted with an arylhalogenoformate such as p-nitrophenyl chloroformate, or carbonyldiimidazole, and optionally treated with a deprotecting group, and then optionally pharmacologically acceptable. It is manufactured by making it a salt.

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

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

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

Embedded image Is condensed with an aldehyde compound represented by

Embedded image The acrylophenone derivative represented by is obtained and reduced, and if necessary, the 4th and 6th position hydroxyl groups of the glucopyranosyl moiety of the product are protected with a benzylidene group, and then the 2nd and 3rd position hydroxyl groups of the glucopyranosyl moiety and phenol. It can be produced by protecting the volatile hydroxyl group and removing the benzylidene group.

In the above method, the condensation reaction of the acetophenone derivative [IV] and the aldehyde compound [V] can be carried out by a conventional method, for example, in a solvent (organic solvent such as methanol, ethanol or the like or these organic solvents). It can be carried out under cooling to heating (especially 10 ° C to 30 ° C) in the presence of a mixed solvent with water) and a base (alkali metal hydroxide, etc.). As the hydroxyl-protecting group in the acetophenone derivative [IV], a commonly used 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 or catalytic hydrogen reduction.
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 commonly used catalyst can be used as the catalyst, and for example, a catalyst such as palladium-carbon, platinum-carbon or platinum oxide can be preferably used. Further, for the reduction with a metal hydride, any metal hydride capable of reducing a double bond can be used, but one that does not reduce a ketone is particularly preferable, and as such a substance, for example, , Sodium tellurium hydride (NaTeH) may be mentioned. Sodium tellurium hydride synthesis
(Synthesis), page 545 (1978), the compound [VI] can be prepared.
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 thereof. 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 aryl sulfonic acid. As the protective group for the hydroxyl groups at the 2- and 3-positions of the glucopyranosyl moiety, an acetophenone derivative [I
V], and the introduction of such a protecting group is carried out, for example, by treating a compound protected at the 4- and 6-positions of the glucopyranosyl moiety with a reactive derivative of an alkanoic acid in the presence of an organic base. Can be done by. Subsequent removal of the benzylidene group can be accomplished by treating the product with acetic acid, water and arylsulfonic acid.

The acetophenone derivative [IV] used for producing the starting compound [II] is (i) Journal of Medicinal and Pharmaceutical Chemistry (J. Med. Pharm. Chem.), No. Volume 5,
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 water-containing 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 is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group and tert-butyl group. Examples thereof include groups, and those having 1 to 4 carbon atoms are particularly preferable. The lower alkoxy group has, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, and the like, and has 1 carbon atom.
Examples of the straight-chain or branched-chain alkoxy group having 6 to 6 carbon atoms are preferable, and those having 1 to 4 carbon atoms are particularly preferable.

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 substituted with an unsubstituted or lower alkyl group is particularly preferable.

[0026]

INDUSTRIAL APPLICABILITY The compound [I] of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent hypoglycemic action.
When the compounds specifically exemplified in Examples below were orally administered to rats, all the compounds exhibited a urinary sugar amount 25 times or more that of phlorizin. In addition, the compound [I] has low toxicity, and further has a feature that it has a weak inhibitory effect on the facilitated diffusion type sugar transport carrier of the aglycone portion generated by hydrolysis in the body.
Therefore, the compound [I] of the present invention can correct hyperglycemia and break the vicious cycle of glucose toxicity,
It can be effectively used for the prevention and treatment of diabetes mellitus (for example, diabetes mellitus such as insulin-dependent diabetes mellitus (type I diabetes) and non-insulin-dependent diabetes mellitus (type II diabetes)).

[0027]

EXAMPLES 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.

Example 1 889 mg of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone and 5 of pyridinium p-toluenesulfonic acid
0 mg was added to 10 ml of methyl orthoformate, stirred at room temperature for 3.5 hours, and concentrated under reduced pressure. The residue is methyl orthoformate 10
Dissolve in 1 ml, add 1 ml of methanol under ice cooling, and stir for 1 hour under ice cooling. Saturated aqueous sodium hydrogen carbonate 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) to give 2 '-(4,6-O-methoxymethylene-β-D-glucopyranosyloxy) -6'-hydroxy-3. 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 (1 H, d × 2, J = 7.7, 7.9 Hz), 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 =
1.7,8.5Hz), 7.23 (1H, t, J = 8.3Hz), 7.4
7 and 7.48 (1 H, d × 2, J = 8.4, 8.4 Hz), 7.
50 (1H, d, J = 1.7Hz), 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 in Example 1, 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) 0.0H
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 = 9.6,9.8Hz), 3.97 (1H, dd, J = 5.
2,9.8 Hz), 5.19 (1 H, d, J = 7.7 Hz), 5.45
(1H, d, J = 5.5Hz), 5.63 (1H, d, J = 5.7H
z), 6.57 (1H, d, J = 7.7Hz), 6.72 (1H, d, J
= 8.1 Hz), 6.89 (1 Hz, dd, J = 1.0, 2.2 Hz),
7.22 (1H, dd, J = 1.8, 8.5Hz), 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 The procedure of Example 1 was repeated except that methyl orthoformate was used in place of methyl orthoformate, and 2 ′-[4,6-O- ( 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 = 7.7Hz), 5.34 (1
H, d, J = 5.3Hz), 5.57 (1H, d, J = 5.7Hz),
6.56 (1H, d, J = 8.5Hz), 6.69 (1H, d, J =
7.8 Hz), 6.88 (1 Hz, 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 In the same manner as in Example 1 except that ethyl ethoxyorthoformate was used instead of methyl orthoformate in Example 1, 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 = 7.1Hz), 2.99 (2H, t, J
= 7.3 Hz), 3.2-3.8 (11 H, m), 3.94 (1 H, d)
d, J = 3.7,8.5Hz), 5.15 (1H, d, J = 7.7H
z), 5.44 (1H, d, J = 5.3Hz), 5.60 (1H, d, J
= 5.7 Hz), 6.57 (1 H, d, J = 7.7 Hz), 6.70
(1H, d, J = 8.1Hz), 6.88 (1H, dd, J = 1.0,
2.2 Hz), 7.20 (1 H, dd, J = 1.8, 8.5 Hz), 7.
23 (1H, t, J = 8.3Hz), 7.46 (1H, d, J = 8.
5Hz), 7.51 (1H, d, J = 1.3Hz), 7.93 (1H,
d, J = 2.2Hz), 10.81 (1H, 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 dissolved in water, 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. 45 hours at -40 ° C
Stir for minutes, then room temperature for 1 hour, then 50 ° C. for 6.5 hours. After cooling, the reaction solution is poured into cold 10% hydrochloric acid and extracted 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 (1H, dd, J = 9.5, 9.6Hz), 4.47
(1H, dd, J = 5.5,9.2Hz), 5.21 (1H, d, J =
7.9Hz), 5.77 (1H, d, J = 5.9Hz), 5.84 (1
H, d, J = 5.5Hz), 6.58 (1H, d, J = 8.1Hz),
6.68 (1H, d, J = 8.1Hz), 6.88 (1H, dd, J =
0.9, 2.2Hz), 7.19 (1H, dd, J = 1.8, 8.5H
z), 7.24 (1H, t, J = 8.3Hz), 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 then heated under reflux for 3 hours. After stirring overnight at room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate are added to the reaction solution, and the organic layer is 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 6-position hydroxyl group of the glucose moiety is methoxymethylated. 1080 mg of the 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 under ice cooling for 2 hours and then at room temperature for 2 hours. The reaction solution is poured into cold 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. The resulting residue was 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.
0Hz), 4.57 (1H, d, J = 6.3Hz), 4.97 (1H,
d, J = 6.0Hz), 5.03 (1H, dd, J = 7.9,9.5H
z), 5.35 (1H, t, J = 9.6Hz), 5.64 (1H, d, J
= 7.9 Hz), 6.90 (1 Hz, dd, J = 0.7, 2.2 Hz),
6.91 (1H, d, J = 8.1Hz), 7.15 (1H, d, J =
8.1 Hz), 7.17 (1 Hz, dd, J = 1.9, 8.4 Hz), 7.
45 (1H, t, J = 8.3Hz), 7.49 (1H, d, J = 1.9)
Hz), 7.50 (1H, d, J = 8.5Hz), 7.95 (1H, d,
J = 2.2Hz)

(2) 611 mg of the product of (1) above is dissolved in a methanol-water mixture (20 ml-0.2 ml), potassium carbonate (579 mg) 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 resulting residue, and 10% hydrochloric acid is added under neutralization with ice to neutralize, and then the organic layer is separated. After washing with water and drying, the solvent is distilled off and the resulting residue is subjected to silica gel column chromatography (solvent:
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 0.88 (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 = 5.3Hz), 5.58 (1H, d, J =
5.7 Hz), 6.56 (1 H, d, J = 8.2 Hz), 6.69 (1
H, d, J = 8.1Hz), 6.89 (1H, dd, J = 0.9,2.1)
Hz), 7.20 (1H, dd, J = 1.7,8.5Hz), 7.23
(1H, t, J = 8.3Hz), 7.48 (1H, d, J = 8.5H
z), 7.51 (1H, d, J = 1.2Hz), 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 glucopyranosyloxy) -6'-hydroxyacetophenone (965 mg), benzo [b] furan-5-carbaldehyde (350 mg) and ethanol (10 ml) was added dropwise 50% aqueous potassium hydroxide solution (2 ml), and the mixture was stirred at room temperature overnight. The solvent is distilled off under reduced pressure, water and diisopropyl ether are added to the residue, the mixture is stirred, and the aqueous layer is separated. 10% ice-cooled sewage layer
After neutralizing with hydrochloric acid, extract with ethyl acetate. The obtained organic layer was washed with water and dried, and then the solvent was distilled off to give a crude 2 ′-(β
-D-glucopyranosyloxy) -6'-hydroxy-3
-(5-benzo [b] furanyl) acrylophenone is obtained.

This product was 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 the mixture was added at room temperature to 2.
Allow to react for 5 hours. The insoluble material is filtered off, water and ethyl acetate are added to the filtrate, and the organic layer is separated after stirring. After washing the organic layer with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5 -Benzo
480 mg of [b] furanyl) 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 = 1.7,5.1,11.4Hz), 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 (1H, d, J = 5.3Hz), 6.55 (1H, 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 = 8.5Hz), 7.53 (1H, d, J = 1.3H
z), 7.92 (1H, d, J = 2.2Hz), 10.98 (1H, s)

Reference Example 2 (1) 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone 4.44 g and dichloromethane 80 ml To the mixture are added benzaldehyde dimethyl acetal (3.04 g) and p-toluenesulfonic acid (0.19 g), 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 washing the organic layer with water and drying, 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
5.78 g of-(5-benzo [b] furanyl) propiophenone
Was dissolved in 50 ml of pyridine, 6.65 g of acetic anhydride was added,
Stir at room temperature for 4 hours. Ethyl acetate is added to the reaction solution, which is poured into ice-10% hydrochloric acid and stirred to separate the organic layer. The obtained organic layer was washed with water and dried, and then 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 520 mg of this product in 10 ml of acetic acid,
1.5 ml of water and 45 mg of p-toluenesulfonic acid were 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, 9.8Hz), 5.11 (1H, t, J = 9.2Hz), 5.5
0 (1H, d, J = 7.9Hz), 5.59 (1H, d, J = 5.7H)
z), 6.88 (1H, d, J = 7.9Hz), 6.90 (1H, d, J
= 2.2 Hz), 7.16 (1 H, d, J = 8.1 Hz), 7.17
(1H, dd, J = 1.7,8.5Hz), 7.44 (1H, t, J =
8.2Hz), 7.48 (1H, d, J = 1.8Hz), 7.49 (1
H, d, J = 8.6Hz), 7.94 (1H, d, J = 2.2Hz)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kozo Oka 3-4-16 Shikaguro, Urawa-shi, Saitama Chateau Nakaurawa 303

Claims (3)

[Claims] 1. A compound represented by 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.) A propiophenone derivative or a pharmaceutically acceptable salt thereof. 2. The formula [II]: (In the formula, R ′ represents a hydrogen atom or a hydroxyl-protecting group), a compound represented by the formula [III] (In the formula, R ¹ ′ and R ² ′ are the same or different and 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. When the other is not a hydrogen atom, R "represents a lower alkyl group), the compound is reacted with an acetal compound, optionally after deprotection, and then optionally converted into a pharmacologically acceptable salt. General formula [Ia] (Wherein R ¹ ′ and R ² ′ are the same as above), or a method of producing a pharmaceutically acceptable salt thereof. 3. The formula [II]: (Wherein R ′ represents a hydrogen atom or a hydroxyl-protecting group) is reacted with a halogenoformate, optionally after deprotecting, and then optionally converted to a pharmacologically acceptable salt. With the formula [Ib] A method for producing a propiophenone derivative represented by or a pharmacologically acceptable salt thereof.