JP2001288178A - C-glycoside, method for producing the same and medicine containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new C-glycoside, a method for producing the same and to obtain a therapeutic remedy and a prophylactic for diabetes, and a hypoglycemic remedy containing the same. SOLUTION: This compound is represented by general formula (I) [R1 is H, OH, a lower alkyl, an O-lower alkyl group or a group of formula (II); R2 us H, a COO-lower alkyl group, a group of formula (III) or a group of formula (IV); R5 is CH2OH, CH2OCOO-lower alkyl group, a group of formula (V), a group of formula (VI), CH2OSO3H, COOH or COONa; A1 is a group of formula (VII), a group of formula (VIII), a group of formula-(IX), a group of formula (X), a group of formula (XI) or a group of formula (XII); X is an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom, R3 is a lower alkyl group, OH or O lower alkyl group; line is a double bond or a saturated single bond; m is an integer of 0 or 1; n is an integer of 0, 1, 2 or 3] or its pharmacologically effective salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel C-glycoside useful as a therapeutic / prophylactic agent for diabetes and a hypoglycemic agent, a method for producing the same, and a therapeutic agent containing the same.

[0002]

2. Description of the Related Art As an antidiabetic agent for rapidly normalizing hyperglycemia and simultaneously improving the energy balance in the body, it inhibits Na ⁺ -glucose cotransporter (SGLT) that reabsorbs glucose in the intestinal tract and kidney. Drugs are needed. Phlorizin, an O-glycoside, inhibits the Na ⁺ -glucose cotransporter present in the intestinal tract and kidney, thereby excreting excess sugar as urine sugar and lowering blood sugar (for example, Welch CAet al.) ., J.Natr., 1989,119 (11) 169
8). In addition, it has been reported that a recently reported synthetic O-glycoside also inhibits the Na ⁺ -glucose cotransporter, excretes excess sugar as urine sugar outside the body, and lowers blood sugar. (For example, Hongu, M. et al., Chem. Pharm.
l. 1998, 46 (1) 22; JP-A-11-021243).
However, these O-glycosides have an O-glucosidic bond between the sugar and the aglycone moiety, and upon oral absorption, the following chemical reaction formula (hydrolysis of O-glycosides by intestinal glucosidase):

[0003]

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[0004] As shown in (1), it is hydrolyzed by glucosidase or the like present in the small intestine, and its action is diminished. Also,
In the case of phlorizin, it has been reported that the aglycone moiety, phloretin, strongly inhibits the accelerated diffusion type sugar transporter. For example, it has been reported that administration of phloretin to a rat vein has a negative effect of reducing brain glucose concentration (eg, Stroke, 1983, 14, 388).

[0005] As an attempt to remedy the drawbacks of these O-glycosides, in recent years, as a sugar derivative stable to decomposition by β-glucosidase, acid or base, a C-glycoside obtained by converting oxygen of a glucoside bond into carbon has been converted. Has been reported (for example,
RJ Linhardt. Et al., Tetrahedron, 1998, 54, 9913; DE
Levy, The Chemistry of C-Glycosides.Pergamon; Oxfor
d, 1995.; MHDPostema, C-Glycoside Synthesis.CRC P
ress; Boca Raton. 1995), to date, there is no report of a Na ⁺ -glucose cotransporter inhibitor of a C-glycoside that is stable to degradation by β-glucosidase and hydrolysis by acid or base.

[0006]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and has a high Na ⁺ -glucose cotransporter inhibitory effect, and has the ability to be decomposed by β-glucosidase.
C-glycoside which is stable to acid or base, and a method for producing the same,
And to provide a therapeutic / prophylactic agent for diabetes and a hypoglycemic agent containing the C-glycoside, ie, to treat and prevent diabetes.
An object of the present invention is to provide a C-glycoside useful as a prophylactic agent and a hypoglycemic agent, and a method for producing the same.

[0007]

Means for Solving the Problems The present inventors have proposed Na ⁺ −
Novel C- having a glucose cotransporter inhibitory action and being stable to degradation by β-glucosidase, acid or base
As a result of research on glycosides for the purpose of creating a therapeutic / preventive agent for diabetes and a hypoglycemic agent, it was found that the novel C-glycoside represented by the general formula (I) has an excellent antihyperglycemic effect. They have found and completed the present invention. That is, the present invention provides the following general formula (I):

[0008]

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Or a pharmaceutically acceptable salt thereof. The present invention is also a method for producing a compound represented by the general formula (I) or a pharmaceutically acceptable salt. The present invention is also a therapeutic or prophylactic agent for diabetes and a hypoglycemic agent comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention are illustrated below, but the present invention is not limited thereto.

[0011]

[Table 1]

[0012]

[Table 2]

[0013]

[Table 3]

[0014]

[Table 4]

[0015]

[Table 5]

[0016]

[Table 6]

[0017]

[Table 7]

Hereinafter, examples of the method for producing the compound of the general formula (I) of the present invention will be described, but the present invention is not limited thereto. (1) A method for producing a compound of the general formula (I) wherein all of R ₂ are hydrogen atoms: wherein R ₁ , R ₄ , A ₁ , m, and n are the same as above, and R ₂ is a hydrogen atom ), The compound represented by the general formula (II) and the aldehyde represented by the general formula (IV) are subjected to an aldol reaction, and if necessary, the double bond is subjected to catalytic reduction to obtain a compound represented by the general formula ( The compound shown by I) was obtained.

[0019]

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(2) R _{1 in the} general formula (I) is —OH and R ₂
There manufacturing method the following chemical formula of -H or -COOCH _3, compound (wherein, A _1, m, n are as defined above) as shown in, the phenolic hydroxyl group of the compound represented by the general formula (I) After protection with an allyl group, it was reacted with methyl chloroformate in the presence of a base to give a compound of the general formula (V).
Deprotecting the allyl group of compound (V) using a Pd catalyst,
Optionally followed by catalytic reduction of the double bond, a compound of general formula (VI) is obtained.

[0021]

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(3) R _{1 in the} general formula (I) is -OH, R ₂
There -H or -CO- (CH ₂₎ in ₂ -COOH, R ₅ is -C
Method for producing compound of H ₂ O—CO— (CH ₂ ) ₂ —COOH As shown in the following chemical formula (where A 1 and m are the same as above), a compound represented by the general formula (I) is By reacting with succinic anhydride in pyridine, the compound represented by the general formula (XVI)
Compounds I) and (XVIII) were obtained.

[0023]

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(4) In the general formula (I), R ₂ is all hydrogen atoms, and R ₅ is the following formula:

[0025]

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As shown in the following chemical formula (where A ₁ and m are the same as those described above), the phenolic hydroxyl group of the compound represented by the general formula (I) and 4-bromomethyl-5- The compound of the general formula (XIX) was obtained by reacting methyl-1,3-dioxolene in the presence of a base.

[0027]

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Next, a method for producing the compound represented by the general formula (II) will be described. (A) In the case of a compound of general formula (II) where m = 0, the following chemical formula [wherein R ₁ and n are the same as above. X
Represents a leaving group such as halogen (Br, F, etc.) or CF ₃ .CO.O—, and Bn represents a benzyl group.] And a compound represented by the general formula (VII) and a benzene derivative (VII).
I) and a Lewis acid (eg, BF ₃ .Et ₂ O, SnC
A compound of the general formula (IX) is synthesized by a coupling reaction in the presence of l ₄ , AlCl ₃ , AgOSO ₂ CF _{3 and the} like (for example, Jaramillo, C. et al., Synthesis, 1994, 1).

[0029]

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In addition, the following chemical formula (where R ₁ , X, n
Is the same as described above), the compound of the general formula (IX) can be obtained by reacting the compound of the general formula (VII) with the Grignard reagent (XI) (for example, Yokoya
ma, M. et al., Synthesis, 1998, 409).

[0031]

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(B) Compound of general formula (II) where m = 1 The compound of general formula (XII) which is a starting material is synthesized by reacting the corresponding lactone (XI) with a Tebbe reagent. Tebbe, FNet al., J. Am. Chem. Soc., 1978, 100, 361
1). As shown in the following chemical formula (wherein R ₁ and n are the same as described above), the compound of the general formula (XII) is hydroborated with 9-borabicyclo [3,3,1] nonane (9-BBN). After the reaction, a compound represented by the general formula (XIII) is subjected to a Suzuki coupling reaction in the presence of a palladium catalyst to obtain a compound represented by the general formula (XIV) (for example, Johnson, CR et al., Synlett., 1997). , 1406).

[0033]

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Further, the following chemical formula (where R ₁ , X, n
Is the same as described above), 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranose (XX) is reacted with an arylmethyl halide (XXI) to obtain a sulfide. (XXII) followed by oxone (OX
ONE; a sulfone (XX)
III) with Ramberg-Beckland
nd) Rearrangement to obtain an olefin compound (XXIV). By hydrogenating this in the presence of a palladium catalyst, it is possible to synthesize a large amount of the compound represented by the general formula (XIV).

[0035]

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(C) Preparation of the compound represented by the general formula (II) As shown by the following chemical formula (wherein R ₁ and n are the same as those described above), the compound is obtained in the above-mentioned step (a) or (b). The general formula (X
The compound (V) (m = 0 or 1) is catalytically reduced to a debenzyl form, and then acetylated with Ac ₂ O and pyridine (Py) to give a compound of the general formula (XVI). The compound of the general formula (XVI) is subjected to a Friedel-Crafts reaction to obtain a compound of the general formula (II) wherein R ₄ is an acetyl group. Subsequently, a compound in which R ₄ of the general formula (II) is a hydrogen atom can be obtained by a deacetylation reaction with NaOMe.

[0037]

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In general formula (II), when m = 1,
As shown in the following chemical formula (wherein R ₁ , X and n are the same as described above), the compound (XXV) having an acetyl group previously introduced at the time of the above step (b) is subjected to Suzuki coupling to form a compound ( After obtaining XXVI), it can also be obtained by debenzylation or subsequent acetylation.

[0039]

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The pharmacologically acceptable salts of the compounds represented by the general formula (I) of the present invention include sodium salts and potassium salts as salts of inorganic bases. When A ₁ contains a pyridine base, salts of inorganic acids and salts of organic acids can be mentioned. Salts of inorganic acids include salts with hydrochloric acid or sulfuric acid, and salts of organic acids include acetic acid, succinic acid, and fumaric acid.

Further, the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is used as it is.
Alternatively, it can be orally administered after being formulated into a powder, granule, tablet or capsule by a known formulation technique. In addition, parenteral administration in the form of direct intestinal administration, injection, etc. is possible. The dose varies depending on the patient's symptoms, age, weight, etc., but is, for example, 10 to 1000 m per adult per day.
The effect is expected by administering g in one to several divided doses.

Test Examples The following are pharmacological test examples of the action of increasing urinary sugar in rats. Urinary glucose increasing action in rats Test drug (20 mg) was treated with 20% dimethyl sulfoxide (D
(MSO) -physiological saline (10 mL) to prepare a test solution. The test solution was intraperitoneally administered to male SD rats (6 weeks old, 3 rats per group) twice at 8-hour intervals (dose: 10 mg
/ Kg / time). In addition, 20% DMSO was used as a control group.
Only saline was administered intraperitoneally. Twenty-four hours after the first administration, the rats were placed in a metabolic gauge and urine was collected. After measuring the amount of urine, remove the contaminants by centrifugation
Urine sugar concentration was measured using II Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.). From the urine volume (mL) and urine sugar concentration (mg / dl),
The amount of urinary sugar excreted at the time (mg / 24 hours) was calculated. Table 5 shows the results.

[0043]

[Table 8]

[0044]

EXAMPLES The present invention will be described in more detail with reference to the following Examples and Reference Examples, but the present invention is not limited to these Examples. In addition, the compound 1-the compound 31 and the compound 42-the compound 58 in the following correspond to the compound of the compound numbers 1-31 and 42-58 in Tables 1-7.

Example 1 3- (benzo [b] furan-5-yl) -1- (2'-
β-D-glucopyranosylmethyl-6′-hydroxy-
Production example of 4'-methoxy) acrylophenone (compound 1)

[0046]

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(A) 1- (3,5-dimethoxyphenylmethyl) -1-deoxy-2,3,4,6-tetra-O
-Benzyl-β-D-glucopyranose (Compound 33)
Manufacturing of

[0048]

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(Example 1) 2,6- obtained by reacting Tebbe reagent with tetrabenzylglucunolactone (XI)
Anhydro-3,4,5,7-tetra-O-benzyl-
1-Deoxy-D-glucohepto-1-enitol (2.0 g) (XII) was added to 9-BBN (0.5 M TH).
F solution, 18 mL) at room temperature and heat to reflux for 7 hours. The reaction solution was cooled to room temperature, and K ₂ PO ₄ (3M aqueous solution,
3.3 mL) and stir for 15 minutes. There, 1,3-
Dimethoxy-5-iodobenzene 1.2 g, PdCl
₂ (dppf) (160 mg, 32 mL of DMF solution) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was treated with Et ₂ O (30
mL), and the organic layer was washed with saturated saline and dried over sodium sulfate. After evaporating the organic solvent, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain compound 33 in a 92% yield. Mass (m / e): 675 (M + +1), 583,475,369,91 (BP) IR (cm -1): 3022,2908,1455,1413,1389 1 H-NMR (CDCl 3): 2.75 (dd, 1H, J = 14.0, 9.0Hz), 3.17 (d, 1H,
J = 9.0Hz), 3.37 (m, 2H), 3.52 (m, 1H), 3.60-3.74 (m, 4H), 3.
70 (S, 6H), 4.52 to 4.70 (m, 4H), 4.82 to 4.96 (m, 4H), 6.35 (S,
1H), 6.42 (S, 2H), 7.20-7.38 (m, 25H)

Example 2 (i) 1-[(3,5-Dimethoxyphenyl) methylthio] -1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose

[0051]

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2,3,4,6-tetra-O-benzyl-
1-thio-β-D-glucopyranose (XX) 5.43
g was dissolved in 40 mL of acetone, 1.82 g of 3,5-dimethoxybenzyl chloride was added, then 1.35 g of potassium carbonate and 10 mL of water were added, and the mixture was refluxed for 2 hours. The reaction solution was concentrated, water was added, and ethyl acetate (2 × 30 mL)
Extract with. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8) to give 90.5% of the desired compound (XX).
II) is obtained. IR (cm ^-1 ): 3022, 2854, 1734, 1596, 1494, 1455, 1431, 1398, ^{1
_{350,1320,1293,1203,1149,1062,909,831,735,696 1 H-NMR (CDCl 3}} ) δ: 3.71 (s, 6H), 3.39-3.98 (m, 8H), 4.30
(d, 1H, J = 9.8Hz), 4.53-4.89 (m, 8H), 6.33 (t, 1H, J = 2.0Hz),
6.51 (d, 2H, J = 2.5 Hz), 7.15-7.37 (m, 20H) (ii) 1-[(3,5-dimethoxyphenyl) methyl]
Sulfonyl-1-deoxy-2,3,4,6-tetra-
O-benzyl-β-D-glucopyranose

[0053]

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The compound obtained in the above (i) (5.25)
g) was dissolved in 45 mL of acetone, 15 mL of water and 13.7 g of oxone (OXONE; registered trademark) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture is concentrated, water is added and extracted with ethyl acetate (2 × 50 mL). The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain 79.5.
% To give compound (XXIII). IR (cm ^-1 ): 3058, 3022, 2914, 1731, 1599, 1494, 1455, 1431, ¹
401, 1329, 1269, 1242, 1206, 1152, 1092, 1026, 996, 933, 88
_{^{2,837,738,696,540 1 H-NMR (CDCl 3}} ) δ: 3.51-4.09 (m, 6H), 3.71 (s, 6H), 4.22
(d, 1H, J = 9.3Hz), 4.51-4.98 (m, 8H), 4.57 (s, 2H), 6.42 (m, 1
H), 6.63 (d, 2H, J = 2.4 Hz), 7.15-7.34 (m, 20H) (iii) 1-[(3,5-dimethoxyphenyl) methylene] -1-deoxy-2,3,4, 6-tetra-O-benzyl-β-D-glucopyranose

[0055]

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The compound (1.42) obtained in the above (ii)
g) was dissolved in 15 mL of carbon tetrachloride and 15 mL of 2-methyl-2-propanol, 1.5 mL of water and 7 g of potassium hydroxide were added, and the mixture was refluxed for 1 hour. The reaction solution is returned to room temperature, poured into ice water, and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with water (1 × 10 mL) and saturated saline (1 ×
10 mL), and then dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain the compound (XXIV) at 63.7%. Mass (m / e): 672 (M ⁺ ), 247, 181, 135, 91 (BP), 51 IR (cm- ¹ ): 3058, 3022, 2920, 2860, 1656, 1593, 1494, 1452, ^{1
_{425,1359,1329,1299,1257,1203,1149,1065,912,846,735 1 H-NMR (CDCl 3}} ) δ: 3.64 (s, 3H), 3.73 (s, 3H), 3.61-4.79
(m, 14H), 5.60-6.90 (m, 4H), 7.05-7.37 (m, 20H) (iv) 1- (3,5-dimethoxyphenylmethyl) -1
-Deoxy-2,3,4,6-tetra-o-benzyl-
β-D-glucopyranose (XIV)

[0057]

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The compound obtained in the above (iii) (0.76
g) was dissolved in MeOH (10 mL), and 5% palladium-carbon (0.2 g) was added.
Stir for a minute. The reaction solution was filtered and concentrated, and then subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
Purification in 8) gives compound (XIV) in a yield of 56.8%. Mass (m / e): 675 (M ⁺ +1), 583, 475, 369, 91 (BP) IR (cm ^-1 ): 3022, 2908, 1455, 1413, 1389 ¹ H-NMR (CDCl ₃ ) δ : 2.65-3.11 (dABq, 2H, J = 14.2Hz), 3.32-
3.74 (m, 7H), 3.69 (s, 6H), 4.49-4.95 (m, 8H), 6.30 (t, 1H, J =
2.0 Hz), 6.46 (d, 2H, J = 2.4 Hz), 7.18-7.37 (n, 20H) (b) 1- (3,5-dimethoxyphenylmethyl) -1
-Deoxy-β-D-glucopyranose (Compound 34)
Manufacturing of

[0059]

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The compound obtained in the above (a) (3.0 g)
Was dissolved in methanol, and 5% palladium-carbon (1.0%
g), and the mixture is stirred at room temperature under a hydrogen stream for 15 minutes. The reaction solution was filtered through celite and concentrated to obtain Compound 34 quantitatively (1.4 g). ¹ H-NMR (DMSO: CDCl ₃ = 2: 1): 2.57-3.28 (m, 7H), 3.46-3.69
(dABq, 2H), 3.72 (s, 6H), 6.26 (t, 1H), 6.47 (d, 2H) (c) 1- (3,5-dimethoxyphenylmethyl) -1
Production of -Deoxy- (2,3,4,6-tetra-O-acetyl) -β-D-glucopyranose (Compound 35)

[0061]

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Compound (1.0 g) obtained in the above (b)
Pyridine (Py) (10 mL), acetic anhydride (5 mL)
At 0 ° C. and stir for 12 hours. The reaction solution was poured into ethyl acetate (30 mL), and the organic layer was washed with saturated saline and dried over sodium sulfate. After evaporating the organic solvent, the residue is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain Compound 35 in a yield of 81% (1.24 g). mp = 103-105 ° C Mass (m / e): 482 (M ⁺ ), 303, 247, 217, 189, 152 (BP), 109, 81,
^{51 IR (cm -1): 1737,1596,1368,1242} 1 H-NMR (CDCl 3): 1.99,2.00,2.02,2.03 (12H), 2.74~2.76
(m, 2H), 3.78 (S, 6H), 3.58-5.19 (m, 7H), 6.33-6.36 (m, 3
H) (d) 2-hydroxy-4-methoxy-6- (2,3,
Production of 4,6-tetra-O-acetyl-β-D-glucopyranosylmethyl-acetophenone (Compound 36)

[0063]

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Compound (1.2 g) obtained in the above (c)
Was dissolved in diethyl ether (20 mL), and
After dropping the solution in Et ₂ O (20 mL) of lCl ₃ (3.5g), was added dropwise Ac ₂ O (0.7mL), stirred for 12 hours at room temperature. Pour the reaction solution into dilute hydrochloric acid water (260 mL),
The organic layer is extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. After evaporating the organic solvent, silica gel column chromatography (ethyl acetate = 1: 4)
Compound 36 is obtained in a yield of 58% (742 mg). mp = 159-160 ° C Mass (m / e): 510 (M ⁺ ), 474, 417, 373, 331, 275, 233, 205, 16
9, 139, 109 (BP), 81, 47 IR (cm ^-1 ): 3400, 2914, 1752, 1686, 16
_{^{05,1371,1218,1173 1 H-NMR (CDCl 3}} ): 2.00~2.03 (m, 12H), 2.65 (S, 3H), 3.61~
3.68 (m, 2H), 3.90 (S, 3H), 4.06-5.21 (m, 7H), 6.23 (S, 1H),
6.44 (S, 1H), 13.27 (S, 1H) (e) 3- (benzo [b] furan-5-yl) -1-
Production of (2′-β-D-glucopyranosylmethyl-6′-hydroxy-4′-methoxy) acrylophenone (Compound 1)

[0065]

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The compound obtained in the above (d) (203 m
g) and 5-benzofuranaldehyde (70 mg) in Et.
Dissolve in OH (2 mL). At 0 ° C., 50% KOH
(0.4 mL) and stirred at room temperature for 12 hours. 10% HCl is added to the reaction solution to adjust the pH to about 4, and the organic layer is extracted with ethyl acetate. The organic layer is saturated aqueous sodium bicarbonate,
Wash with saturated saline and dry with sodium sulfate. After evaporating the organic solvent, the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain Compound 1 (55: 1).
% (102 mg) in yield. mp = 135-13
_{^{6 ℃, [α] 23 D}} = -1.59 Mass (m / e) (C = 1, Py.): 470 (M +), 434,403,350,319,290,261,219,19
¹ , 164, 131 (BP), 91, 60 IR (cm ^-1 ): 3370, 2914, 1605, 1440, ^{1
_{263,1197,1155,1086,1026 1 H-NMR (CDCl 3}} ): 2.63~2.65,2.95~3.00 (m, 3H), 3.07~
3.78 (m, 6H), 3.81 (S, 3H), 6.40, 6.48 (ABq, 2H, J = 2.4Hz), 6.
79 (S, 1H), 7.13-7.73 (ABq, 2H, J = 15.6Hz), 7.49-7.57 (AB
q, 2H, J = 8.3Hz), 7.65 (S, 1H), 7.81 (S, 1H), 10.02 (brs, 1H)

Example 2 3- (benzo [b] furan-5-yl) -2'-β-D
-Glucopyranosylmethyl-6'-hydroxy-4'-
Production Example of Methoxypropiophenone (Compound 21)

[0068]

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Compound 1 obtained in (e) of Example 1
(0.13 g) in a THF-MeOH solution (1: 1, 10
Then, 5% Pd-carbon (0.1 g) was added, and the mixture was stirred at room temperature for 30 minutes under a hydrogen stream. After the reaction solution is filtered through celite, it is concentrated. Purification by silica gel column chromatography (chloroform: methanol = 10: 1) gives compound 21 in a yield of 61% (80 mg). mp = 103-105 ° C. [α] ²³ _D = −2.39
(C = 0.5, Py.) Mass (m / e): 472 (M ⁺ ), 434, 374, 319, 291, 243, 205, 177, 131
(BP), 91,57 IR (cm -1): 3400,2914,1605,1443,1266,1197,1104 1 H-NMR (CDCl 3: DMSO = 1: 2): 3.04~3.13 (m, 2H) , 3.83 (S, 3
H), 3.34-5.60 (m, 11H), 6.42-7.83 (m, 7H)

Reference Example 1 Production Example of 2- (β-D-glucopyranosylmethyl) -6-hydroxy-4-methoxyacetophenone (Compound 32)

[0071]

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Compound 3 obtained in (d) of Example 1
6 (336 mg) was dissolved in methanol (5 mL).
Then, 28 mg of sodium methoxide is added, and the mixture is stirred at room temperature for 1 hour. About 1 g of an ion exchange resin is added, and the mixture is stirred for 10 minutes, filtered and concentrated. The residue was subjected to silica gel column chromatography (methanol: chloroform = 1: 1).
Purification in 0) gave 99% (225 mg) of compound 32. This compound 32 is used as a raw material when synthesizing compound 1 and compound 21. mp = 98-99
° C, [α] ²³ _D = -2.80 (C = 1.0, Py.) Mass (m / e): 342 (M ⁺ ), 324, 306, 221, 191 (BP), 165, 137, 11
5, 91, 69, 51 IR (cm ^-1 ): 3388, 1608, 1356, 1263, 1200, 1155, 1080 ¹ H-NMR (CDCl ₃ : DMSO = 1: 2): 2.46 (S, 3H), 2.55 ~ 2.61 (m, 1
H), 2.91 (t, 1H, J = 9.3,8.8Hz), 2.98-3.19 (m, 5H), 3.42--
3.65 (dABq, 2H, J = 11Hz), 3.72 (S, 3H), 4.14 (brs, 1H), 4.79,
4.83 (brs, 2H), 4.95 (brs, 1H), 6.27 (d, 1H, J = 2.0Hz), 6.41
(d, 1H, J = 2.4Hz), 9.86 (S, 1H)

Reference Example 2 2,4-Dimethoxy-5- (2,3,4,6-tetra-
Production example of O-acetyl-β-D-glucopyranosyl acetophenone (Compound 37)

[0074]

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[0075]

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Known methods (R. Tschesche et al., Liebigs)
Ann. Chem. 902-907 (1982))
4,6-Tetra-O-acetyl-1- (2,4-dimethoxyphenyl) -1-deoxy-β-D-glucopyranose (17.8 g) was reacted with aluminum chloride and acetic anhydride to obtain Friedel-Crafts. By performing the reaction, 10.78 g (57.1%) of a known compound 38 (Formula 22) was obtained, and as a by-product, Compound 37 (Formula 21) was obtained in an amount of 1.9.
5 g (10.1%) are obtained. This compound 37 is used as a raw material when synthesizing compound 23. Compound 38 is used as a starting material for synthesizing compound 3.
The measured values of the compound 37 are as follows. Mass (m / e): 510 (M ⁺ ), 317, 275 (BP), 209, 179, 139, 97, 69 IR (cm ^-1 ): 3460, 2939, 1746, 1653, 1605, 1578, 1500, 1443,
1368 ¹ H-NMR (CDCl ₃ ): 1.77 (S, 3H), 2.01 (S, 3H), 2.05 (S, 3H), 2.
08 (S, 3H), 2.56 (S, 3H), 3.78 to 3.81 (m, 1H), 3.92 (S, 3H), 3.
93 (S, 3H), 4.12-4.26 (dABq, 2H, J = 12.2Hz), 4.71 (d, 1H, J =
10.3Hz), 5.21 (t, 1H, J = 9.6Hz), 5.32 (t, 1H, J = 9.6Hz), 5.44
(t, 1H, J = 10.3Hz), 6.39 (S, 1H), 7.88 (S, 1H)

Example 3 3- (benzo [b] furan-5-yl) -3'-β-D
Production Example of -Glucopyranosyl-6'-hydroxy-4'-methoxy-acrylophenone (Compound 3)

[0078]

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Known methods (R. Tschesche et al., Liebigs)
Ann. Chem. 902-907 (1982))
(2.0 g) and 5-benzofuranaldehyde (0.71
g) in ethanol (25 mL), and
Add 0% potassium hydroxide solution and stir at room temperature for 12 hours. After adding water to the reaction solution and washing with chloroform, 10% hydrochloric acid is added to the aqueous layer to adjust the pH to 3, followed by extraction with chloroform. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (methanol: chloroform = 1: 10).
To give Compound 3 in 63% (1.15 g) yield. mp = 250 ° C. or higher, [α] ²³ _D = −24.80
(C = 0.5, Py.) Mass (m / e): 456 (M ⁺ ), 259, 195, 145, 177, 66 (BP) IR (cm ⁻¹ ): 3376, 2908, 1632, 1566, 1497, 1446, 1368, 1281,
1260 ¹ H-NMR (CDCl ₃ : DMSO = 1: 2): 3.22 to 3.57 (m, 4H), 3.73 (d, 2
H), 3.88 (s, 3H), 4.48 (d, 1H), 6.51 (s, 1H), 6.98 (d, 1H), 7.6
4 (d, 1H), 7.87 to 8.09 (m, 3H), 8.15 (s, 1H), 8.16 (d, 1H), 13.
61 (s, 1H)

Example 4 3- (benzo [b] furan-5-yl) -3'-β-D
Production Example of -Glucopyranosyl-4'-methoxy-6 '-(2-propen-1-yl) oxy-acrylophenone (Compound 39)

[0081]

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Compound 3 (1.15 g) was added to acetone (20
(mL). Potassium carbonate (0.97 g) and aryl bromide (0.3 mL) are added, and the mixture is refluxed for 12 hours. The reaction solution was poured into ice water, the organic layer was extracted with chloroform, washed with saturated saline, and dried over sodium sulfate. After evaporating the organic solvent, the residue is purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain compound 39 in a yield of 83% (1.04 g). mp
= 139-140 ° C, [α] ²³ _D = -14.60 (C =
1, Py. ) Mass (m / e): 497 (M ⁺ +1), 435, 358, 311, 283, 253, 207, 177 (B
P), 147, 119, 92, 65 IR (cm ^-1 ): 3400, 2896, 1608, 1575, 1443, 1314, 1260, 1200, ¹
122, 1083 ¹ H-NMR (CDCl ₃ : CD3OD = 9: 1): 3.45 to 3.47 (m, 1H), 3.54 to 3.
65 (m, 3H), 3.73 to 3.89 (dABq, 2H, J = 12.2Hz), 3.93 (S, 3H),
4.68 to 4.72 (m, 3H), 5.31 (dd, 1H, J = 10.3, 10.7Hz), 5.48 (d
d, 1H, J = 17.1, 17.6Hz), 6.06-6.13 (m, 1H), 6.54 (S, 1H), 6.
82 (S, 1H), 7.52 (d, 1H, J = 8.4Hz), 7.59 (d, 1H, J = 8.0Hz), 7.6
4 (S, 1H), 7.69 (S, 1H), 7.80-7.84 (S + m, 3H)

Example 5 3- (benzo [b] furan-5-yl) -3 ′-(6-
O-methoxycarbonyl-β-D-glucopyranosyl)
-4'-methoxy-6 '-(2-propen-1-yl)
Production Example of Oxy-acrylophenone (Compound 40)

[0084]

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Compound 39 (0.97 g) was treated with methylene chloride.
(5 mL). 2,4,6-collidine (2.
6 mL), and methyl chlorocarbonate (0.
18 mL) of methylene chloride solution was added dropwise,
While stirring. The reaction solution was poured into dilute hydrochloric acid, and the organic layer was extracted with acetic acid.
Extract with chill ester. Organic layer was saturated with aqueous sodium bicarbonate, saturated
Wash with saline and dry with sodium sulfate. After evaporating the organic solvent,
Ricagel column chromatography (chloroform:
Compound 40 was purified by purification with 20: 1
% (0.77 g). mp = 137-13
8 ° C, [α]^{twenty three} _D= -4.79 (C = 1, Py.) Mass (m / e): 554 (M⁺), 505, 478, 446, 404, 361, 310, 282, 24
3, 213 (BP), 183, 156, 124 IR (cm^-1): 3400, 2908, 1743, 1608, 1575, 1503, 1443, 1263,
1197, 1125¹ H-NMR (CDCl_Three): 3.07 (d, 1H, J = 3.6Hz), 3.46,3.50 (brs, 2
H), 3.63--3.85 (m, 4H), 3.76 (S, 3H), 3.90 (S, 3H), 4.43--4.
47 (ABq, 2H), 4.65-4.66 (m, 2H), 4.71 (d, 1H, J = 9.8Hz), 5.2
8 (dd, 1H, J = 10.7, 10.2Hz), 5.45 (dd, 1H, J = 17.1Hz), 6.02--
6.09 (m, 1H), 6.48 (S, 1H), 6.75, 7.65 (d, 2H, J = 2.4Hz), 7.48
~ 7.58 (ABq, 2H, J = 8.4Hz), 7.57 (S, 1H), 7.76,7.81 (d, 2H, J
= 1.2Hz), 7.85 (S, 1H)

Example 6 3- (benzo [b] furan-5-yl) -3 '-(6-
O-methoxycarbonyl-β-D-glucopyranosyl)
Production example of -6'-hydroxy-4'-methoxy-acrylophenone (compound 4)

[0087]

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Compound 40 (0.35 g) is dissolved in acetonitrile (3 mL). PdCl2 (Ph ₃ P) 2
(14 mg) and ammonium formate (0.24 g) were added, and the mixture was stirred under reflux for 12 hours. After the reaction solution is filtered and concentrated, it is purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain compound 4 at 39.3% (0.13 g). mp = 195-1
96 ° C, [α] ²³ _D = -40.19 (C = 1, Py.) Mass (m / e): 514 (M ⁺ ), 438, 378, 336, 307, 257, 219, 163 (B
^{P), 131,74 IR (cm -1} ): 3400,2902,1746,1629,1560,1440,1371,1260 1 H-NMR (DMSO: CDCl 3 = 2: 1): 3.37~3.39 (m, 1H ), 3.47-3.5
1 (m, 1H), 3.65 (S, 3H), 3.75 to 3.79 (ABq, 1H), 3.88 (S, 3H),
4.12 to 4.17 (m, 1H), 4.40 to 4.47 (m, 2H), 4.83 (d, 1H, J = 5.4H
z), 5.07 (d, 2H, J = 3.4 Hz), 5.19 (d, 2H, J = 4.4 Hz), 6.53 (S, 1
H), 6.99 (S, 2H), 8.07 (S, 2H), 7.65 (d, 2H, J = 8.3Hz), 7.90
(d, 2H, J = 8.8Hz), 7.97 (S, 1H), 8.18 (S, 1H), 13.61 (S, 1H)

Example 7 3- (benzo [b] furan-5-yl) -3 '-(6-
O-methoxycarbonyl-β-D-glucopyranosyl)
Production example of -6'-hydroxy-4'-methoxy-propiophenone (compound 5)

[0090]

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Compound 4 (114 mg) was dissolved in MeOH-TH
Dissolve in F mixed solution (1: 1, 2 mL). 5% Pd-
Carbon (50 mg) was added, and the mixture was stirred under a hydrogen stream at room temperature for 15 minutes. The reaction is filtered and concentrated. Silica gel column chromatography (chloroform: methanol = 4
0: 1), compound 5 was obtained in a yield of 77% (88%).
mg). mp = 120-121 ° C., [α] ²³ _D =
-35.80 (C = 1, Py.) Mass (m / e): 516 (M ⁺ ), 403, 348, 307, 277, 227, 193, 163, 12
0, 91, 62 (BP) IR (cm ^-1 ): 3394, 2908, 1743, 1629, 1494, 1443, 1337, 175, ¹
206 ¹ H-NMR (CDCl ₃ ): 2.12 (d, 1 H, J = 3.9 Hz), 2.88 (d, ¹ H, J = 2.0 H)
z), 2.96 to 3.00 (m, 2H), 3.15 to 3.24 (m, 3H), 3.48 to 3.68 (m,
4H), 3.75 (S, 3H), 3.87 (S, 3H), 4.40-4.51 (dABq, 2H), 4.53
~ 4.62 (m, 2H), 4.63 (d, 1H), 6.44 (S, 1H), 6.72 (d, 1H, J = 7.8
Hz), 6.99 (d, 1H, J = 6.8 Hz), 7.09 (S, 1H), 7.68 (S, 1H), 12.86
(S, 1H)

Reference Example 3 1- (4-methoxy-2-methylphenyl) -1-deoxy- (2,3,4,6-tetra-O-benzyl-β-
Production Example of D-Glucopyranose (Compound 41)

[0093]

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2,3,4,6-tetra-O-benzyl-
D-glucopyranosyl fluoride (13.6 g) was added to TH
F (50 mL) at 0 ° C.
A THF solution of -methylphenylmagnesium bromide (prepared from 6 g of magnesium and 50 g of 2-bromo-5-methoxytoluene) is added dropwise, and the mixture is stirred at room temperature for 12 hours. The reaction solution is poured into ice water, neutralized with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over sodium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 8) to obtain 81% (13.1 g) of compound 41. Compound 41 can be used as a starting material for synthesizing compound 9 and compound 27. Mass (m / e): 644 (M ⁺ ), 553, 433, 341, 283, 241, 181 (BP) 135,
92, 50 IR (cm ^-1 ) (Neat): 3052, 3016, 2890, 2854, 1608, 1578, 149
_{^{7,1452,1393 1 H-NMR (CDCl 3}} ): 2.37 (s, 3H), 3.52~3.85 (m, 6H), 3.81 (s,
3H), 4.36 (d, 1H), 4.46-4.96 (m, 8H), 6.71 (s, 1H), 6.78 (d,
1H), 6.92-7.33 (m, 20H), 7.39 (d, 1H)

Examples 8 to 23 Compounds 2 and 6 to 20 can be synthesized according to Example 3 using an acetophenone compound as a starting material via an aldol reaction. Examples 24 to 34 Compounds 21 to 31 can be synthesized by catalytically reducing the double bond of each enone compound according to Example 2.

Example 35 3-[({6- [5- (3-benzo [b] furan-5-
Ilpropanoyl) -4-hydroxy-2-methoxyphenyl] -1-deoxy-β-D-glucopyranose-
1-yl @ carbonyl] propionic acid (compound 47)

[0097]

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330 mg of the compound (22) was added to 5 m of pyridine.
L, add 144 mg of succinic anhydride, and stir at room temperature for 12 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 20) to obtain 0.14 g (34.8).
%). mp = 113-114 ℃, [α] D = -18.39 (C = 0.5, MeOH) Mass (m / e, ESI): 557 (MH) - 1 H-NMR (CDCl 3) δ: 2.67 (m, 4H ), 2.96 (t, 2H, J = 7.8Hz), 3.1
0-5.07 (m, 12H), 3.83 (s, 3H), 6.42 (s, 1H), 6.72 (s, 1H), 6.9
6-7.73 (m, 5H), 12.87 (s, 1H) Example 36 3- (Benzo [b] furan-5-yl) -3 '-(6-
Sulfonate-β-D-glucopyranosyl) -4′-methoxy-6′-hydroxyacrylophenone (compound 4
4)

[0099]

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60 mg of the compound (3) is dissolved in 2 mL of DMF, 403 mg of DMF / SO ₃ complex is added at room temperature, and the mixture is stirred for 2 hours. EtOH / AcOEt
(4: 1) was added and stirred, and the precipitated crystals were collected by filtration and 38 mg
(54%) of red crystals are obtained. mp = 177-179 ° C Mass (m / e, ESI): 537 (M + H) ⁺ IR (cm ^-1 ) 3382,1637,1563,1467,1368,1257,1107,1086,9
93 ¹ H-NMR (DMSO + CD ₃ OD) δ: 3.36 (m, 1H), 3.46 (m, 2H), 3.65 (d
d, 1H, J = 5.7Hz), 3.67-3.83 (m, 2H), 3.95 (s, 3H), 6.63 (s, 1
H), 7.07 (d, 1H, J = 2.0 Hz), 7.73 (d, 1H, J = 8.8 Hz), 7.97 (dd, 1
H, J = 8.8Hz, 2.0Hz), 8.01-8.10 (m, 3H), 8.23 (d, 2H, J = 10.7H
z) Example 37 3- (benzo [b] furan-5-yl) -3 '-(6-
Sodium carboxylate-β-D-glucopyranosyl)
-4'-methoxy-6'-hydroxyacrylophenone (compound 43)

[0101]

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Compound (3) (100 mg) was dissolved in acetonitrile (3 mL), and TEMPO (4 mg, KBr) was added at room temperature.
4 mg, then ₃ mL of saturated NaHCO ₃ solution, NaO
Add 3 mL of Cl and stir for 30 minutes. AcOEt 50
After diluting with mL and neutralizing by adding 10% HCl, the organic layer is dried over anhydrous Na ₂ SO ₄ and the solvent is distilled off. The residue was subjected to column chromatography (MeOH: CHCl ₃ )
To give 63 mg (61%) of carboxylic acid.
1 mL of acetone and 5 mg (1 eq) of NaOH are added thereto, and the mixture is stirred for 30 minutes. The acetone is distilled off, and the precipitated crystals are filtered to obtain 43 mg of the desired product. mp = 115-117 ℃ Mass (m / e, ESI): 492 (M + H) + IR (cm -1) 3364,1608,1548,1446,1257,1152,108,735,594 1 H-NMR ( D ₂ O) δ: 3.30 (m, 1H), 3.54 (m, 3H), 3.83 (s, 3H), 4.
55 (m, 1H), 6.27 (s, 1H), 6.95 (s, 1H) 7.60-8.10 (m, 7H) Example 38 4-({2- (3-benzo [b] furan-5-ylpropa Noyl) -5-methoxy-4- (β-D-glucopyranosyl) phenoxydimethyl) -5-methyl-1,3-
Dioxolen-2-one (Compound 49)

[0103]

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Compound (22) (0.25 g) was added to DMF (3 mL).
Was dissolved in potassium carbonate 75 mg, 4-bromomethyl-5-methyl-1,3-dioxolen-2-one 0.1
Add 3 g and stir at room temperature for 3 hours. The reaction solution is poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent,
Purification by silica gel column chromatography (methanol: chloroform = 1: 20) gives 42 mg of the desired product. mp = 128-128.5 ℃, [α] D = + 2.80 (C = 1.0, MeOH) Mass (m / e, ESI): 539 (M + Na) + 1 H-NMR (CDCl 3) δ: 2.05 (s , 3H), 2.90 (t, 2H, J = 7.8Hz), 3.0
7-3.89 (m, 9H), 3.91 (s, 3H), 4.54-4.69 (ABq, 2H), 6.47 (s, 1
H), 6.73 (s, 1H), 6.80-7.10 (ABq, 2H), 7.39 (s, 1H), 7.59 (s,
1H), 7.85 (s, 1H)

Example 39 Compound 46 was prepared using the compound 3 as a starting material.
When succinic anhydride is used in an amount of 4 mol equivalent in the method of 5, a compound in which all the hydroxyl groups of the sugar moiety are esterified can be obtained. Example 40 Compound 42 can be synthesized according to Example 35 using Compound 3 as a starting material. Examples 41 to 43 Compounds 45, 48 and 50 can be synthesized from the corresponding carboxylic acid according to the method of converting into the sodium salt of Example 37. Example 44 3- (benzo [b] furan-5-yl) -1- [6-hydroxy-4-methyl-2-{(β-D-glucopyranose-1-yl) methyl}] propiophenone ( Production Example of Compound 52)

[0106]

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(A) 1- [6-hydroxy-4-methyl-2-４− (2,3,4,6-tetra-O-benzyl-β
-D-Glucopyranosyl) methyl}] acetophenone (Compound 59)

[0108]

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Tetrabenzyl glucnolactone (XI)
To a 2,6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glucohepto-1-enitol (4.5)
g) 9-BBN (0.5 M THF solution,
42 mL) at room temperature and heat to reflux for 7 hours. The reaction solution was cooled to room temperature, and K ₃ PO ₄ (7.2 mL of a 3M aqueous solution)
And stir for 15 minutes. There, 2-bromo-6-hydroxy-4-methylacetophenone (2.1 g), P
dCl ₂ (dppf) (610 mg, DMF solution 66 m
L) and stirred at 50 ° C. for 2 hours. The reaction solution was Et ₂ O
(60 mL), and the organic layer is washed with saturated saline and dried over sodium sulfate. After evaporating the organic solvent, the residue is purified by silica gel column chromatography (benzene: ethyl acetate = 60: 1) to obtain compound 59 in a yield of 53%. Mass (m / e, ESI): 709 (M + Na) ⁺ , 687 (M + H) ⁺ IR (cm ^-1 ): 2914, 1359, 1083, 750, 696 ¹ H-NMR (CDCl ₃ ) δ: 2.21 (s, 3H), 2.59 (s, 3H), 2.97-3.01
(m, 1H), 3.22-3.67 (m, 8H), 4.42-5.00 (m, 8H), 6.68 (s, 1H),
6.67 (s, 1H), 7.18-7.38 (m, 20H), 11.7 (s, 1H) (b) 3- (benzo [b] furan-5-yl) -1-
[6-Hydroxy-4-methyl-2-｛(2,3,4,
6-Tetra-O-benzyl) -β-D-glucopyranosylmethyl {] acrylophenone (Compound 60)

[0110]

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The compound (9.89 g) obtained in (a) of the above example and 5-benzofuranaldehyde (2.3)
1 g) is dissolved in EtOH (140 mL). 5 at 0 ° C
Add 0% KOH (17 mL) and stir at room temperature for 40 hours. H ₂ O (200 mL) is added to the reaction solution, and the organic layer is extracted with ethyl acetate. The organic layer is washed with a saturated saline solution and dried with sodium sulfate. After evaporating the organic solvent, the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to give compound 60 at 61%.
(7.2 g) obtained in yield. Mass (m / e, ESI): 837 (M + Na) ⁺ , 815 (M + H) ⁺ , 849 (M + Cl) ⁻ , 813
^{(MH) - IR (cm -1} ): 1732,1628,1578,1240,1100,760 1 H-NMR (CDCl 3) δ: 2.27 (s, 3H), 3.07-3.80 (m, 9H), 4.40-
4.94 (m, 8H), 6.70 (s, 1H), 6.73 (s, 1H), 6.76 (dd, 1H, J = 1.0H
(z, 2.0 Hz), 7.14-7.81 (m, 26H), 10.8 (s, 1H) (c) 3- (benzo [b] furan-5-yl) -1-
Production of [6-hydroxy-4-methyl-2-{(β-D-glucopyranose-1-yl) methyl}] acrylophenone (Compound 51)

[0112]

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The compound (7.2) obtained in the above (b)
The g) was dissolved in CH ₂ Cl ₂ (86mL), was added dropwise BBr ₃ a (1.0 M CH ₂ Cl ₂ solution 53 mL) at -78 ° C., stirred for 2 hours at -78 ° C. ~ room temperature. The reaction solution was poured into ice water (200 mL), and the organic layer was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate, and saturated saline, and dried over sodium sulfate. After evaporating the organic layer, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain Compound 51 in a yield of 76% (3.0 g). Mass (m / e, ESI) : 455 (M + H) +, 453 (MH) - IR (cm -1): 3394,3004,2908,1575,1443,1263,1215,1089 1 H-NMR (CDCl ₃ ) δ: 2.27 (s, 3H), 2.89-3.75 (m, 13H), 6.68
(d, 2H, J = 12.7Hz), 6.77 (d, 1H, J = 1.5Hz), 7.08 (d, 1H, J = 16.
1Hz), 7.47-7.53 (m, 2H), 7.63-7.66 (m, 2H), 7.77 (s, 1H), 8.
68 (bs, 1H) (d) 3- (benzo [b] furan-5-yl) -1-
[6-Hydroxy-4-methyl-2-{(β-D-glucopyranose-1-yl) methyl}] propiophenone (Compound 52)

[0114]

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The compound 51 obtained in the above (c) (3.
0 g) in methanol (100 mL)
P (0.81 g) 5% Pt-carbon (0.30 g) was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen stream. After the reaction solution is filtered through celite, it is concentrated. Residue in ethyl acetate (200 mL)
And washed with 10% HCl, saturated aqueous layer solution, and saturated saline solution, and dried with sodium sulfate. After evaporating the organic solvent, the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 83% of compound 52 (2.
Obtained in a yield of 5 g). Mass (m / e, ESI): 456 (M ⁺ ), 438, 305, 261, 175, 131 (BP), 91 IR (cm ^-1 ): 3394, 2908, 1614, 1083, 1032 ¹ H-NMR ( CDCl ₃ ) δ: 2.24 (s, 3H), 2.47-3.73 (m, 15H), 6.62
(d, 1H, J = 2.2Hz), 6.68 (s, 1H), 7.08 (d, 1H, J = 8.8Hz), 7.37-
7.57 (m, 2H), 7.57 (s, 1H), 8.83 (bs, 1H) Example 45 3-benzo [b] furan-5-yl-1- (6-hydroxy-4-methyl-2-{[ 6-methoxycarbonyl-
β-D-Glucopyranose-1-yl] methyl {) Production of propiophenone (compound 53).

[0116]

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Compound 53 was prepared according to Examples 4, 5 and 6
It can be obtained by protecting the phenolic hydroxyl group of compound 52 synthesized in the above Example 44, alkylating only the primary hydroxyl group of the sugar moiety to obtain a methoxycarbonate, and finally deprotecting the phenolic hydroxyl group. . Example 46 1- [2,4-dihydroxy-6-{(β-D-glucopyranosyl) methyl} phenyl] -3- (4-hydroxyphenyl) propan-1-one (compound 54)

[0118]

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According to Example 1, compound 54 (1.2 g) obtained by the aldol reaction using 4-benzyloxybenzaldehyde is dissolved in methanol (20 mL). 5% Pd-C (1.2 g) was added, and the mixture was made to flow with hydrogen and stirred at room temperature for 6 hours. The reaction solution is filtered and then concentrated. The residue is purified by silica gel cal chromatography (chloroform: methanol = 4: 1) to obtain Compound 54 in a yield of 88% (0.52 g). mp = 227-228 ° C., [α] D = -10.80 (C = 1.0, MeOH) Mass (m / e, ESI): 457 (M + Na) ⁺ , 469 (M + Cl) ⁻ , 433 (MH) ^{- IR (cm -1): 3358,2914,1605,1510,1460,1365,1260,1160} ,
1100, 840 ¹ H-NMR (DMSO: CDCl ₃ = 2: 1) δ: 2.43 (dABq, 1H, J = 15.1 Hz),
2.75 (t, 2H, J = 7.6Hz), 2.87-3.64 (m, 10H), 4.56 (t, 1H, J = 5.
9Hz), 4.77 (d, 1H, J = 4.9Hz), 4.81 (d, 1H, J = 4.4Hz), 4.91 (d,
1H, J = 5.4Hz), 6.61 (d, 1H, J = 2.0Hz), 6.20 (d, 1H, J = 2.0Hz),
6.64 (d, 1H, J = 8.8Hz), 7.00 (d, 2H, J = 8.3Hz), 8.99 (s, 1H),
9.32 (s, 1H), 9.59 (s, 1H) Reference Example 4 1- [2,4-dihydroxy-6-{(β-D-glucopyranosyl) methyl}] acetophenone (Compound 61)
Manufacturing of

[0120]

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According to Example 1, compound 61 (1.5 g) obtained by Suzuki coupling using the corresponding aryl halide is dissolved in dichloromethane (20 mL). At −78 ° C., BBr 3 (1M CH ₂ Cl ₂ solution, 1
2 mL), and the mixture is stirred at −78 ° C. to room temperature for 2.5 hours. The reaction solution was poured into ice water (50 mL) and n-BuOH (5
The organic layer is extracted with 0 mL × 3). The organic layer is washed with a saturated saline solution and dried with sodium sulfate. After evaporating the organic solvent, the residue was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to give compound 61 as 57%.
(0.41 g). The compound 61
Can also be used as a raw material when synthesizing compound 54. mp = 227-228 ° C., [α] D = −12.00 (C = 1.0, MeOH) Mass (m / e, ESI): 351 (M + Na) ⁺ , 329 (M + H) ⁺ IR (cm ⁻¹ ) ): 3394, 1599, 1455, 1353, 1269, 1161, 1083, 1008,
843, 573 ¹ H-NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 2.59 (dABq, 1H, J = 14.7H
z), 2.91-3.50 (m, 7H), 3.65 (dABq, 1H, J = 11.7Hz), 4.25 (bs,
5H), 6.18 (d, 1H, J = 2.0 Hz), 6.27 (d, 1H, J = 2.4 Hz), 9.88 (bs,
1H)

Example 47 According to Example 44, compound 55 can be synthesized through an aldol reaction using an acetophenone compound as a starting material. Example 48 Compound 56 can be synthesized by catalytic reduction of the double bond part of an enone compound according to Example 44. Example 49 Compound 57 can be synthesized according to Example 44 by subjecting a compound obtained by Suzuki coupling using a corresponding aryl halide to an aldol reaction and finally debenzylation. Example 50 According to Example 45, compound 58 can be obtained by protecting the phenolic hydroxyl group, using only the primary hydroxyl group of the sugar moiety as a carbonate, and finally deprotecting the phenolic hydroxyl group.

[0123]

Industrial Applicability The novel C-glycoside of the present invention has an inhibitory effect on Na ⁺ -glucose cotransporter, is stable to degradation by β-glucosidase, is stable to acids or bases, and is an agent for treating or preventing diabetes. And it is useful as a hypoglycemic agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4725 A61K 31/4725 A61P 3/10 A61P 3/10 C07D 401/08 C07D 401/08 403/08 403/08 407/08 407/08 409/08 409/08 (72) Inventor Tsuyoshi Toyama 1113 F, Sakajo, Sakajo-cho, Hanishina-gun, Nagano F-term (reference) 4C062 AA08 4C063 AA01 BB05 CC78 DD76 EE01 4C086 AA01 AA03 AA04 BA05 BA07 BB02 BB03 BC13 BC17 BC28 GA06 MA01 MA04 MA52 NA14 ZC35

Claims (4)

[Claims] 1. A compound represented by the following general formula (I): Or a pharmaceutically acceptable salt thereof. 2. A compound represented by the following general formula (II): (Wherein, R ₁ , m and n are the same as above; R ₄ represents a hydrogen atom, an acetyl group or a benzyl group) by converting the compound represented by the general formula (IV): OHC-A ₁ (provided that Where A ₁
Is the same as above. A process for producing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which comprises subjecting the compound represented by the formula (1) to an aldol reaction, and optionally followed by catalytic reduction of a double bond. 3. An agent for treating or preventing diabetes, comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt. 4. A hypoglycemic agent containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt.