JPH09124685A - 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 inhibition 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 is formula II (X is 0, a single bond; ring A is a benzene ring, a pyridine ring; R<a> is H, a lower alkyl, a lower alkoxy, a halogen; where in the case that the ring A is a benzene ring, R<a> is not H)] and shows excellent urinary sugar increase and thus excellent hypoglycemic action based on its 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 acylating a compound of formula III with a carboxylic acid of formula IV and, if desired, conversion of the product to its 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 [diabetodia (Diabetodia).
logia) 28, 119 (1985), Diabetes Care, 13th, 610th.
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 (Where R is the formula:

Embedded image A group represented by, X is -O- or a single bond, ring A is a benzene ring or a pyridine ring, ^Ra is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, provided that when ring A is a benzene ring R ^a is not ^a hydrogen atom)
And a pharmacologically acceptable salt thereof.

As specific examples of the compound [I] of the present invention, in the general formula [I], R is a lower alkyl group, a lower alkoxy group or a benzoyl group or a phenoxycarbonyl group which may be substituted with a halogen atom, or A compound that is a pyridylcarbonyl group.

Preferred compounds of the present invention include those of the general formula
In [I], R is a lower alkyl group, a lower alkoxy group, or a benzoyl group substituted with a halogen atom; a phenoxycarbonyl group substituted with a lower alkyl group or a lower alkoxy group; or a pyridylcarbonyl group.

Compounds having excellent drug efficacy include R ₁ is a C ₁ -C ₂ alkoxy group or a benzoyl group substituted with a fluorine atom; C ₁ -C ₂ alkyl group or C ₁ -C ₂ alkoxy group. A compound which is a substituted phenoxycarbonyl group or a pyridylcarbonyl 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.

[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 50 mg / kg in the case of oral administration. kg, 0.01 for parenteral administration
It is preferably -50 mg / kg, especially 0.1-10 mg / kg.

According to the present invention, the above-mentioned general formula, which is the object, is obtained.
The compound represented by [I] or a pharmaceutically acceptable salt thereof has the formula [II]

Embedded image A compound represented by the formula [III]

Embedded image (In the formula, X represents -O- or a single bond, ring A represents a benzene ring or a pyridine ring, Ra represents ^a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom.
When R is a benzene ring, R ^a is not ^a hydrogen atom), and is acylated with a carboxylic acid compound, a salt thereof, or a reactive derivative thereof to obtain a pharmacologically acceptable salt, if desired.

The above acylation reaction is carried out by using a carboxylic acid compound.
[III], its salt or its reactive derivative and raw material compound
It can be carried out by reacting [II]. The reaction between the carboxylic acid compound [III] or a salt thereof and the starting compound [II] is carried out in a suitable solvent in the presence or absence of a condensing agent, and the reactive derivative of the carboxylic acid compound and the starting compound [II]. The reaction can be carried out in a suitable solvent or without solvent in the presence or absence of a deoxidizing agent.

As the salt of the carboxylic acid compound [III],
Examples thereof include alkali metal salts such as sodium salt, potassium salt and calcium salt, and alkaline earth metal salts. When using salts of these carboxylic acid compounds in the condensation reaction,
It is preferable to use a free acid in the reaction. Further, as the reactive derivative, the carboxylic acid compound [II
I] acid halides, acid anhydrides, active esters and the like. Further, when Ring A is a pyridine ring, the reactive derivative also includes a mineral acid salt such as a hydrochloride thereof.

As the condensing agent, a conventional condensing agent can be used, for example, dicyclohexylcarbodiimide,
Diethyl cyanophosphate, carbonyldiimidazole, N, N-bis (2-oxo-3-oxazolidinyl)
Examples thereof include phosphinic acid chloride.

As the deoxidizing agent, a conventional deoxidizing agent can be used. For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; sodium hydride and potassium hydride. Examples thereof include inorganic bases such as alkali metal hydrides or tri-lower alkylamines such as triethylamine and diisopropylethylamine; pyridine; dimethylaminopyridine; aniline; dimethylaniline and other organic bases. Any solvent can be used as long as it does not adversely influence the reaction, and examples thereof include dichloromethane, dimethylformamide, tetrahydrofuran, acetonitrile, pyridine,
Mention may be made of conventional solvents such as 2,4,6-collidine. This reaction can be carried out under cooling to heating, preferably at -40 ° C to room temperature.

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

Embedded image (In the formula, R ′ represents a hydrogen atom or a hydroxyl-protecting group), an acetophenone compound represented by the formula [V]

Embedded image The compound of formula [VI] is condensed with an aldehyde compound represented by

Embedded image The acrylophenone derivative represented by is obtained, and it can be produced by reducing this.

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 (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.

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. Also,
Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group,
Examples thereof include linear or branched alkoxy groups having 1 to 6 carbon atoms such as an isobutoxy group and a tert-butoxy group, and those having 1 to 4 carbon atoms are particularly preferable.

The halogen atom includes a fluorine atom, a bromine atom, a chlorine atom and an iodine atom.

[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 the Examples described below were orally administered to rats, all the compounds exhibited a urinary sugar amount 35 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 1333 mg of 2 '-(β-D-glucopyranosyloxy) -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone was added to 12 ml of 2,4,6-collidine. The mixture was dissolved in water, cooled to -40 ° C with dry ice-acetone, and a solution of 614 mg of o-methoxybenzoyl chloride in 2 ml of methylene chloride was added dropwise with stirring. Stir at -40 ° C for 2 hours and then at room temperature overnight. 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 is dissolved in a tetrahydrofuran-methanol mixed solution (5 ml-5 ml), 656 mg of sodium bicarbonate is added, and the mixture is stirred at 40 ° C. for 6 hours. Ethyl acetate and water are added to the reaction solution, the organic layer is separated, dried and the solvent is evaporated. The residue was purified by silica gel chromatography (solvent: chloroform / methanol) and 2 ′-[6-O- (o
1227 mg of -methoxybenzoyl) -β-D-glucopyranosyloxy] -6'-hydroxy-3- (5-benzo [b] furanyl) propiophenone are obtained as a colorless foam.

ESI-MS (m / z): 601 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3400,1700,1625 NMR (DMSO-d ₆ ) δ: 2.97 (2H, t, J = 7.4H
z), 3.25-3.74 (6H, m), 3.76 (3H, s), 4.2
3 (1H, dd, J = 7.0,12Hz), 4.51 (1H, dd, J =
1.8, 12Hz), 5.01 (1H, d, J = 7.4Hz), 5.2
6 (1H, d, J = 4.6Hz), 5.37 (2H, d, J = 4.3H)
z), 6.53 (1H, d, J = 7.7Hz), 6.67 (1H, d, J
= 8.1 Hz), 6.85 (1 Hz, dd, J = 0.9, 2.2 Hz),
6.98 (1H, dt, J = 0.9, 7.5Hz), 7.07 (1H,
t, J = 8.3 Hz), 7.12 (1 H, d, J = 7.9 Hz), 7.1
7 (1H, dd, J = 1.8,8.5Hz), 7.43 (1H, d, J =
8.5Hz), 7.48 (1H, d, J = 1.3Hz), 7.54 (1
H, dt, J = 1.8,7.4 Hz), 7.62 (1H, dd, J = 0.
9,7.5Hz), 7.92 (1H, d, J = 2.2Hz), 10.9
(1H, s)

Example 2 The same procedure as in Example 1 was repeated except that p-methoxybenzoyl chloride was used instead of o-methoxybenzoyl chloride as the acylating agent in Example 1, and 2′-
[6-O- (p-methoxybenzoyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo
[b] Furanyl) propiophenone is obtained.

Mp107-111 ° C. ESI-MS (m / z): 601 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3375,1720,1600 NMR (DMSO-d ₆ ) δ: 2.97 (2H) , t, J = 7.4H
z), 3.25-3.81 (6H, m), 3.84 (3H, s), 4.2
2 (1H, dd, J = 7.3,12Hz), 4.57 (1H, dd, J =
1.8, 12Hz), 5.02 (1H, d, J = 7.1Hz), 5.2
7 (1H, d, J = 4.6Hz), 5.40 (2H, d, J = 5.2H
z), 6.54 (1H, d, J = 8.4Hz), 6.69 (1H, d, J
= 8.4 Hz), 6.86 (1 Hz, dd, J = 0.8, 2.2 Hz),
7.03 (2H, dt, J = 2.1, 9.0Hz), 7.11 (1H,
t, J = 8.3Hz), 7.18 (1H, dd, J = 1.7,8.5H
z), 7.44 (1H, d, J = 8.5Hz), 7.49 (1H, d, J
= 1.4 Hz), 7.89 (2 Hz, dt, J = 2.0,8.9 Hz),
7.92 (1H, d, J = 2.2Hz), 10.9 (1H, s)

Example 3 2 ′-[6-O— was prepared in the same manner as in Example 1 except that p-methylphenoxycarbonyl chloride was used as the acylating agent in place of o-methoxybenzoyl chloride. (p-methylphenoxycarbonyl)
-Β-D-Glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone is obtained as a pale yellow foam.

ESI-MS (m / z): 601 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 3380,1760,1625 NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 2.99 (2
H, t, J = 7.5 Hz), 3.2-3.4 (5H, m), 3.73
(1H, m), 4.29 (1H, dd, J = 6.4,11.6Hz), 4.
46 (1H, dd, J = 1.9, 11.5Hz), 5.05 (1H, d,
J = 7.5 Hz), 5.24 (1 H, d, J = 5.0 Hz), 5.38
(1H, d, J = 5.3Hz), 5.41 (1H, d, J = 5.3H
z), 6.57 (1H, d, J = 8.3Hz), 6.70 (1H, d, J
= 8.1Hz), 6.86 (2H, dd, J = 0.9,2.2Hz),
6.98 (2H, ddd, J = 2.1, 2.7, 8.5Hz), 7.17
(1H, d, J = 8.8Hz), 7.20 (1H, dd, J = 1.8,
8.5Hz), 7.23 (1H, t, J = 8.3Hz), 7.45 (1
H, d, J = 8.5Hz), 7.51 (1H, d, J = 1.2Hz),
7.92 (1H, d, J = 2.2Hz), 10.88 (1H, s)

Example 4 In the same manner as in Example 1 except that p-methoxyphenoxycarbonyl chloride was used in place of o-methoxybenzoyl chloride as the acylating agent in Example 1, 2 '-[6-O- (p-Methoxyphenoxycarbonyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] furanyl) propiophenone is obtained.

Mp 57 ° C .- (gradual melting) ESI-MS (m / z): 617 [(M + Na) ⁺ ] IR (nujol) cm ⁻¹ : 3425, 1760, 1630 NMR (DMSO-d ₆ ) δ: 2 .99 (2H, t, J = 7.5H
z), 3.1-3.4 (5H, m), 3.72 (1H, m), 3.73 (3
H, s), 4.28 (1H, dd, J = 6.4,11.6Hz), 4.4
5 (1H, dd, J = 1.9,11.5Hz), 5.05 (1H, d, J
= 7.4 Hz), 5.25 (1 H, d, J = 4.9 Hz), 5.39
(1H, d, J = 5.3Hz), 5.42 (1H, d, J = 5.3H)
z), 6.57 (1H, d, J = 7.7Hz), 6.69 (1H, d, J
= 8.1 Hz), 6.86 (1 Hz, dd, J = 1.0, 2.2 Hz),
6.90 (2H, d, J = 9.2Hz), 7.03 (2H, d, J =
9.2 Hz), 7.20 (1 Hz, dd, J = 1.8, 8.5 Hz), 7.
23 (1H, t, J = 8.3Hz), 7.45 (1H, d, J = 8.5)
Hz), 7.51 (1H, d, J = 1.4Hz), 7.92 (1H, d,
J = 2.2Hz), 10.88 (1H, s)

Example 5 2 ′-[6— was carried out in the same manner as in Example 1 except that nicotinoyl chloride hydrochloride was used as the acylating agent instead of o-methoxybenzoyl chloride.
O- (nicotinoyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo [b] furanyl)
Get Propiophenone.

Mp 98-101 ° C. ESI-MS (m / z): 572 [(M + Na) ⁺ ], 550
[(M + H) ⁺ ] IR (nujol) cm ^-1 : 1730 NMR (DMSO-d ₆ ) δ: 2.97 (2H, t, J = 7.3H
z), 3.20-3.40 (5H, m), 3.82 (1H, t, J = 8.
3Hz), 4.33 (1H, dd, J = 7.4, 11.7Hz), 4.6
4 (1H, dd, J = 2.1,11.7Hz), 5.03 (1H, d, J
= 7.3 Hz), 5.27 (1 H, d, J = 4.7 Hz), 5.40
(1H, d, J = 5.2Hz), 5.43 (1H, d, J = 5.2H
z), 6.52 (1H, d, J = 8.1Hz), 6.68 (1H, d, J
= 8.1Hz), 6.86 (1H, dd, J = 0.9,2.2Hz),
7.04 (1H, t, J = 8.3Hz), 7.17 (1H, dd, J =
1.8, 8.5 Hz), 7.43 (1 H, d, J = 8.4 Hz), 7.4
8 (1H, d, J = 1.3Hz), 7.56 (1H, dd, J = 4.8,
7.5Hz), 7.92 (1H, d, J = 2.2Hz), 8.24 (1
H, ddd, J = 1.9,2.0,8.0Hz), 8.83 (1H, d, J
= 1.7, 4.8Hz), 9.09 (1H, d, J = 1.5Hz), 1
0.82 (1H, s)

Example 6 The procedure of Example 1 was repeated except that p-fluorobenzoyl chloride was used instead of o-methoxybenzoyl chloride as the acylating agent in Example 1, and 2'-
[6-O- (p-fluorobenzoyl) -β-D-glucopyranosyloxy] -6′-hydroxy-3- (5-benzo
[b] Furanyl) propiophenone is obtained.

Mp 68-71 ° C. ESI-MS (m / z): 589 [(M + Na) ⁺ ] IR (nujol) cm ^-1 : 1720 NMR (DMSO-d ₆ ) δ: 2.97 (2H, t, J = 7.3H
z), 3.20-3.40 (5H, m), 3.75-3.85 (1H,
m), 4.26 (1H, dd, J = 7.5, 11.9Hz), 4.59
(1H, dd, J = 1.8,11.7Hz), 5.02 (1H, d, J =
7.3 Hz), 5.26 (1 H, d, J = 4.5 Hz), 5.39 (1
H, d, J = 5.1Hz), 5.40 (1H, d, J = 5.2Hz),
6.53 (1H, d, J = 8.1Hz), 6.67 (1H, d, J =
8.1Hz), 6.86 (1H, d, J = 2.2Hz), 7.09 (1H,
t, J = 8.3Hz), 7.17 (1H, dd, J = 1.8,8.5H
z), 7.35 (2H, dd, J = 8.9,8.9Hz), 7.44 (1
H, d, J = 8.7Hz), 7.48 (1H, d, J = 1.4Hz),
7.92 (1H, d, J = 2.2Hz), 7.99 (2H, dd, J =
5.5,8.9Hz), 10.82 (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 from 383 mg of tellurium and 270 mg of sodium borohydride in advance, and 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)

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

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R is a formula: , X is -O- or a single bond, Ring A is a benzene ring or pyridine ring, ^Ra is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom. However, when Ring A is a benzene ring, R ^a is not ^a hydrogen atom)
The propiophenone derivative represented by or a pharmacologically acceptable salt thereof. 2. The formula [II]: A compound represented by the formula [III] (In the formula, X represents —O— or a single bond, ring A represents a benzene ring or pyridine ring, R ^a represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, or a halogen atom.
When ring A is a benzene ring, R ^a is not ^a hydrogen atom), a general formula characterized by acylating with a carboxylic acid compound, a salt thereof or a reactive derivative thereof to form a pharmacologically acceptable salt [I] (In the formula, R is the formula: The group represented by and the ring A, X and R ^a are the same as the above), or a method for producing a pharmaceutically acceptable salt thereof.