JP4651934B2 - Benzylphenol derivative, pharmaceutical composition containing it, and pharmaceutical use thereof - Google Patents

Description

  The present invention relates to a benzylphenol derivative useful as a pharmaceutical or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.

  More specifically, the present invention is caused by a disease caused by hyperglycemia such as diabetes, impaired glucose tolerance, abnormal fasting blood glucose, diabetic complications or obesity, or increased blood galactose levels such as galactosemia. The present invention relates to a benzylphenol derivative having a human SGLT1 activity inhibitory activity or a pharmacologically acceptable salt thereof, or a prodrug thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof, useful as a preventive or therapeutic agent for diseases Is.

  Diabetes is one of the lifestyle-related diseases due to changes in diet and lack of exercise. Therefore, dietary therapy and exercise therapy are performed for diabetic patients, but drug therapy is used in combination when sufficient control and continuous therapy are difficult. In addition, large-scale clinical trials have confirmed that long-term strict blood glucose control is necessary to prevent the onset and progression of chronic complications by treating diabetes (for example, Non-Patent Document 1 and 2). In addition, many epidemiological studies on glucose intolerance and macrovascular disorders have shown that in addition to diabetes, borderline glucose tolerance is also a risk factor for macrovascular disorders, and the need for correction of postprandial hyperglycemia Has attracted attention (for example, see Non-Patent Document 3).

  Currently, various drugs have been developed as antidiabetic drugs against the background of the rapid increase in the number of diabetic patients. In particular, α-glucosidase inhibition that delays digestion and absorption of carbohydrates in the small intestine to improve postprandial hyperglycemia Medicine is used. In addition, acarbose, which is one of them, has been reported to have an effect of preventing or delaying the onset of diabetes by adapting to those with impaired glucose tolerance (see, for example, Non-Patent Document 4). However, since an α-glucosidase inhibitor does not act on an increase in blood sugar due to ingestion of glucose, which is a monosaccharide (see, for example, Non-Patent Document 5), a wider range of sugars has been accompanied by recent changes in carbohydrate composition in the diet. The development of a drug that exhibits a substance absorption inhibitory action is highly desired.

  On the other hand, it is known that SGLT1 (sodium-dependent glucose transporter 1) is present in the small intestine that controls carbohydrate absorption. In addition, it has been reported that glucose and galactose absorption is poor in patients with dysfunction due to congenital abnormalities of human SGLT1 (see, for example, Non-Patent Documents 6 to 8), and SGLT1 is involved in glucose and galactose absorption. (See, for example, Non-Patent Documents 9 and 10).

  Further, it has been confirmed that SGLT1 mRNA and protein are increased in OLETF rats and streptozotocin-induced diabetic rats, and absorption of glucose and the like is enhanced (for example, see Non-Patent Documents 11 and 12). In addition, diabetic patients generally have enhanced digestion and absorption of carbohydrates. For example, it has been confirmed that SGLT1 mRNA and protein are highly expressed in the human small intestine (for example, non-patent literature). 13).

  Therefore, by inhibiting human SGLT1, it is possible to inhibit the absorption of carbohydrates such as glucose in the small intestine and suppress the increase in blood glucose level, and in particular, delay the absorption of carbohydrates based on the above action mechanism. It is considered possible to correct postprandial hyperglycemia. In addition, since the increase in carbohydrate absorption in diabetic patients is expected to result from an increase in SGLT1 in the small intestine, early development of a drug having a strong human SGLT1 activity inhibitory action is highly anticipated for the prevention and treatment of diabetes. Is done.

As benzylphenol derivatives, compounds having a hypocholesterolemic action and a hypolipidemic action (see Patent Document 1) and compounds having a urinary glucose excretion promoting action based on SGLT2 inhibitory activity (see Patent Document 2) are known. However, the benzylphenol derivative according to the present invention has SGLT1 inhibitory activity, and it has never been reported that it is useful as a drug that inhibits the absorption of glucose or galactose in the small intestine.
JP-A-60-41691 International Publication No. WO01 / 74834 Pamphlet The Diabetes Control and Complications Trial Research Group, “N. Engl. J. Med.”, September 1993, 329, 14, p. 977-986 UK Prospective Diabetes Study Group, “Lancet”, September 1998, Vol. 352, No. 9131, p. 837-853 Makoto Tominaga, “Endocrinology / Diabetics”, November 2001, Vol. 13, No. 5, p. 534-542 Jean-Louis Chiasson, 5 others, “Lancet”, June 2002, 359, 9323, p. 2072-2077 Hiroyuki Kodaka, three others, “Journal of Japanese Society of Nutrition and Food”, 1992, Vol. 27 Baba Tadao, 1 other, "Separate volume of Japanese clinical syndrome series", 1998, No. 19, p. 552-554 Michihiro Kasahara, 2 others, “Latest Medicine”, January 1996, Vol. 51, No. 1, p. 84-90 Tomoya Tsuchiya, 1 outside, “Nippon Rinkan”, August 1997, Vol. 55, No. 8, p. 2131-2139 Yoshikatsu Kanai, “Kidney and Dialysis”, December 1998, Volume 45, Special Issue, p. 232-237 E. Turk, 4 others, “Nature”, March 1991, vol. 350, p. 354-356 Y. Fujita, 5 others, “Diabetologia”, 1998, Vol. 41, p. 1459-1466 J. Dyer, et al., “Biochem. Soc. Trans.”, 1997, Vol. 25, p. 479S J. Dyer, 4 others, “Am. J. Physiol.”, February 2002, Vol. 282, No. 2, p. G241-G248

  The present invention provides a novel compound that exhibits an action of inhibiting human SGLT1 activity and exhibits an excellent inhibitory action on an increase in blood glucose level by inhibiting the absorption of carbohydrates such as glucose in the small intestine.

  As a result of intensive investigations to find a compound that expresses human SGLT1 activity inhibitory activity, the present inventors have found that certain benzylphenol derivatives represented by the following general formula (I) have human SGLT1 inhibitory activity in the small intestine as described below. And obtained the knowledge that it exerts an excellent inhibitory effect on the increase in blood glucose level, and has reached the present invention.

That is, the present invention
(1) A human SGLT1 activity inhibitor containing, as an active ingredient, a benzylphenol derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein R ¹ represents a hydroxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkylthio group, a hydroxy (C _1-6 alkyl) group, a hydroxy (C _1-6 alkoxy) group, A hydroxy (C _1-6 alkylthio) group, or —W—X—Y—N (R ⁸ ) —Z (except for —W—X—Y—N (R ⁸ ) —Z, Is a group represented by the following formula (B));
W is an oxygen atom, a sulfur atom or a single bond;
X is a C _1-6 alkylene group optionally having a hydroxyl group, a C _2-6 alkenylene group or a single bond (provided that W is a single bond in the case of a single bond);
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ⁸ , R ^B , R ^D , R ^E and R ^F may be the same or different and each have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α. An aryl group, a heteroaryl group optionally having an arbitrary group selected from the following substituent group β, or 1 to 5 arbitrary groups selected from the following substituent group γ or also C _1-6 alkyl group; or Z and together with the nitrogen atom to which R ⁸ is adjacent bonded, may have any group selected from the following substituent group [delta] C _2-6 Forming a cyclic amino group;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ];

(2) A human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula (Ia) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(With W in the formula, X, Y, Z, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and G are as defined above);
(3) Human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula (Ib) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(Wherein X ¹ is a C _2-6 alkenylene group; W, Y, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and G have the same meaning as described above. Have);
(4) A human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula (Ic) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(Y ¹ in the formula is —C (═NH) —; W, X, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and G have the same meaning as described above. );
(5) A human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula (Id) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(Z ¹ in the formula is —CON (R ^D ) R ^E or —C (═NR ^G ) N (R ^H ) R ^I ; W, X, Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^D , R ^E , R ^G , R ^H , R ^I and G have the same meaning as above);
(6) A human SGLT1 activity inhibitor containing, as an active ingredient, a benzylphenol derivative represented by the following general formula (Ie) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(G ¹ in the formula is the formula

A group represented by:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the same meaning as above);

(7) R ² is a hydrogen atom, a C _1-6 alkyl group, a phenoxy group or a halogen atom, R ³ , R ⁴ and R ⁵ are hydrogen atoms, R ⁶ is a methyl group, and R ⁷ is a hydroxyl group , A benzylphenol derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (6) above, which is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group, or An inhibitor of human SGLT1 activity containing a prodrug of
(8) The human SGLT1 activity inhibitor according to any one of (1) to (7), which is a postprandial hyperglycemia inhibitor;
(9) The human SGLT1 activity inhibitor according to any one of (1) to (7) above, which is a preventive or therapeutic agent for a disease caused by hyperglycemia;
(10) The diseases caused by hyperglycemia are diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, The human SGLT1 activity inhibitor according to (9), which is a disease selected from the group consisting of atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout;
(11) The human SGLT1 activity inhibitor according to any one of the above (1) to (7), which is an agent for inhibiting transition of a person with impaired glucose tolerance to diabetes;
(12) The human SGLT1 activation inhibitor according to any one of (1) to (7), which is a preventive or therapeutic agent for a disease caused by an increase in blood galactose level;
(13) The human SGLT1 activation inhibitor according to (12), wherein the disease caused by an increase in blood galactose level is galactosemia;
(14) The human SGLT1 activity inhibitor according to any one of (1) to (13), wherein the dosage form is a sustained-release preparation;

(15) Insulin sensitivity enhancer, sugar absorption inhibitor, biguanide, insulin secretagogue, SGLT2 activity inhibitor, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor Dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D- Kaileusitol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1-analogue, glucagon-like peptide-1 agonist, amylin, amylin analogue, a Phosphorus agonist, aldose reductase inhibitor, terminal glycation product production inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N -Acetylated-alpha-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy -1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antipruritic, laxative, hydroxymethylglutaryl coenzyme A reductase inhibitor, fibrate compound, β ₃ -adrenergic receptor agonist, acylcoenzyme A : Cholesterol Syltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low density lipo Protein receptor enhancer, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - add A combination of at least one drug selected from the group consisting of a narin receptor agonist, an antiplatelet drug, a uric acid production inhibitor, a uric acid excretion promoter, and a urinary alkalinizing drug. It relates to the human SGLT1 activity inhibitor described in any one of the above.

The present invention also provides:
(16) A benzylphenol derivative represented by the following general formula (Ib) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(W, X ¹ , Y, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and G in the formula have the same meaning as above);
(17) A benzylphenol derivative represented by the following general formula (Ic) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(W, X, Y ¹ , Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and G in the formula have the same meaning as above);
(18) A benzylphenol derivative represented by the following general formula (Id) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(W, X, Y, Z ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and G in the formula have the same meaning as above);
(19) A benzylphenol derivative represented by the following general formula (Ie) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and G ¹ have the same meaning as above);

(20) R ² is a hydrogen atom, a C _1-6 alkyl group, a phenoxy group or a halogen atom, R ³ , R ⁴ and R ⁵ are hydrogen atoms, R ⁶ is a methyl group, and R ⁷ is a hydroxyl group , A benzylphenol derivative or a pharmaceutically acceptable salt thereof according to any one of (16) to (19), which is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group, or Prodrugs of
(21) A pharmaceutical composition comprising the benzylphenol derivative or the pharmaceutically acceptable salt thereof according to any one of (16) to (20), or a prodrug thereof as an active ingredient;
(22) The pharmaceutical composition according to the above (21), wherein the dosage form is a sustained-release preparation;

(23) (A) The benzylphenol derivative according to any one of (16) to (20) or a pharmacologically acceptable salt thereof, or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar Absorption inhibitor, biguanide drug, insulin secretagogue, SGLT2 activity inhibitor, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulator, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein Tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-kaileunositol, glycogen synthase Nase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1-analogue, glucagon-like peptide-1 agonist, amylin, amylin analogue, amylin agonist, aldose reductase inhibitor, terminal glycation endogenesis inhibitor, protein Kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like Growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128 , Antidiarrheal, laxative, hydroxy Methylglutaryl coenzyme A reductase inhibitors, fibrate compounds, beta ₃ - adrenergic receptor agonists, acyl-coenzyme A: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors , Microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low density lipoprotein receptor potentiator, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor Cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, en Serine converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, antiplatelet agents, uric acid production inhibitor , A pharmaceutical comprising a combination of at least one drug selected from the group consisting of a uric acid excretion promoting drug and a urine alkalizing drug.

In the present invention, the C _1-6 alkyl group is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, A linear or branched alkyl group having 1 to 6 carbon atoms such as a tert-pentyl group and a hexyl group. The C _1-6 alkylene group is a linear or branched alkylene group having 1 to 6 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, or a 1,1-dimethylethylene group. Say. The hydroxy (C _1-6 alkyl) group means the above C _1-6 alkyl group substituted with a hydroxyl group. An amino (C _1-6 alkyl) group means the above C _1-6 alkyl group substituted with an amino group, such as an aminomethyl group or a 2-aminoethyl group. The carbamoyl (C _1-6 alkyl) group refers to the above C _1-6 alkyl group substituted with a carbamoyl group. C _1-6 alkoxy group means methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy A straight-chain or branched alkoxy group having 1 to 6 carbon atoms such as a group, a tert-pentyloxy group, and a hexyloxy group. The hydroxy (C _1-6 alkoxy) group refers to the above C _1-6 alkoxy group substituted with a hydroxyl group. The C _2-6 alkenylene group refers to a linear or branched alkenylene group having 2 to 6 carbon atoms such as vinylene group or propenylene group. C _1-6 alkylthio group means methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group A straight-chain or branched alkylthio group having 1 to 6 carbon atoms such as a group, a tert-pentylthio group, and a hexylthio group. The term “hydroxy (C _1-6 alkylthio) group” means the above C _1-6 alkylthio group substituted with a hydroxyl group. The mono- or di (C _1-6 alkyl) amino group refers to an amino group mono-substituted with the C _1-6 alkyl group or an amino group di-substituted with a different or the same C _1-6 alkyl group. . The mono- or di [hydroxy (C _1-6 alkyl)] amino group is an amino group mono-substituted by the hydroxy (C _1-6 alkyl) group or a different or similar hydroxy (C _1-6 alkyl) group. An amino group disubstituted with The mono- or di (C _1-6 alkyl) ureido group, refers to a disubstituted ureido group in the above C _1-6 alkyl group ureido group or heterologous or homologous which is mono-substituted by the above C _1-6 alkyl group . The mono- or di (C _1-6 alkyl) sulfamide group refers to a sulfamide group mono-substituted with the C _1-6 alkyl group or a sulfamide group di-substituted with a different or similar C _1-6 alkyl group. . The C _2-7 acyl group means a linear or branched acyl group having 2 to 7 carbon atoms such as acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, hexanoyl group and the like. The C _2-7 acylamino group refers to an amino group substituted with the above C _2-7 acyl group. An amino (C _2-7 acylamino) group refers to the above C _2-7 acylamino group substituted with an amino group, such as a 2-aminoacetylamino group, a 3-aminopropionylamino group or the like. The C _1-6 alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms such as a methanesulfonyl group or an ethanesulfonyl group. The C _1-6 alkylsulfonylamino group refers to an amino group substituted with the above C _1-6 alkylsulfonyl group. The carbamoyl (C _1-6 alkylsulfonylamino) group refers to the above C _1-6 alkylsulfonylamino group substituted with a carbamoyl group, such as a carbamoylmethanesulfonylamino group. The C _1-6 alkylsulfonylamino (C _1-6 alkyl) group, refers to a C _1-6 alkyl group substituted by the above C _1-6 alkylsulfonylamino group. The C _3-7 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. C _2-6 heterocycloalkyl group means oxygen atom, sulfur atom and nitrogen derived from morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine, imidazolidine, oxazoline, piperidine, piperazine, pyrazolidine and the like. The above C _3-7 cycloalkyl group containing 1 or 2 hetero atoms selected from atoms in the ring other than the bonding site. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. C _2-7 alkoxycarbonyl group means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutyloxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxy A linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms such as a carbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group and the like. The aryl group refers to 1 to 3 cyclic aromatic hydrocarbon groups such as a phenyl group and a naphthyl group. The aryl (C _1-6 alkoxy) group refers to the C _1-6 alkoxy group substituted with the aryl group. The aryl (C _1-6 alkylthio) group refers to the C _1-6 alkylthio group substituted with the aryl group. An arylsulfonylamino group refers to an amino group substituted with an arylsulfonyl group such as a benzenesulfonyl group. An aryl (C _2-7 alkoxycarbonyl) group refers to the C _2-7 alkoxycarbonyl group substituted with the aryl group. A heteroaryl group is an oxygen atom derived from thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene, imidazole, pyrazole, oxadiazole, thiodiazole, tetrazole, furazane, etc. A 5- or 6-membered heteroaryl group containing 1 to 4 hetero atoms of the same or different types selected from a sulfur atom and a nitrogen atom in a ring other than the bonding site. C _2-6 cyclic amino group means morpholino group, thiomorpholino group, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group, 1-imidazolidinyl group, 1-piperazinyl group, pyrazolidinyl group, etc. A 5- or 6-membered monocyclic ring having 2 to 6 carbon atoms, which may have one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to the nitrogen atom at the bonding site Sex amino group. C _1-4 aromatic cyclic amino group refers to 1 to 3 nitrogen atoms in addition to the nitrogen atom of the bonding site, such as 1-imidazolyl group, 1-pyrrolyl group, pyrazolyl group, 1-tetrazolyl group The C1-C4 5-membered aromatic monocyclic amino group which may have. The C _1-6 alkyl (C _1-4 aromatic cyclic amino) group refers to the C _1-4 aromatic cyclic amino group substituted with the C _1-6 alkyl. Hydroxyl protecting groups are generally used in organic synthesis reactions such as methyl, benzyl, methoxymethyl, acetyl, pivaloyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, allyl, etc. This refers to a protecting group for a hydroxyl group. The amino-protecting group refers to amino-protecting groups generally used in organic synthesis reactions such as benzyloxycarbonyl group, tert-butoxycarbonyl group, benzyl group, acetyl group, trifluoroacetyl group and the like. The carboxy-protecting group refers to a carboxy-protecting group generally used in organic synthesis reactions, such as benzyl group, tert-butyldimethylsilyl group, and allyl group.

As the compound of the present invention, for example,
5-hydroxy-3-methyl-2- {4- [3- (3-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-ureidobenzyl) phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- {4- [3- (2-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (4-hydroxy-3-methoxybenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- (4- {3-[(S) -1-carbamoyl-2- (4-hydroxyphenyl) ethyl] ureido} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- {4-[(E) -2- (2-pyridylmethylcarbamoyl) vinyl] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-{(E) -2- [3- (morpholin-4-yl) propylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-{(E) -2- [2- (sulfamoylamino) ethylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside;
2- [4- (3-aminopropoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- (4- {3- [2-cyano-3- (2-hydroxyethyl) guanidino] propoxy} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3-benzylureido) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (3,4-dimethoxybenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (4-methanesulfonylbenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- {4- [3- (3-aminomethylbenzyl) ureido] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [3- (imidazol-1-yl) propyl] ureido} benzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [2- (4-hydroxyphenyl) ethyl] ureido} benzyl) -3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (2-aminoethylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (3-aminopropylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (4-aminobutylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- {4-[(E) -2- (2-methanesulfonylaminoethylcarbamoyl) vinyl] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- (4-{(E) -2- [2- (2-aminoacetylamino) ethylcarbamoyl] vinyl} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (4-aminobutoxy) benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4- [3- (2-cyano-3-methylguanidino) propoxy] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3-guanidinopropoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (4-guanidinobutoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- (4-ethylbenzyl) -5-hydroxy-3-methylphenyl β-D-galactopyranoside;
2- (4-aminobenzyl) -5-methoxycarbonyloxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside;
2- [4- (3-aminopropoxy) benzyl] -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside;
2- (4- {3- [2- (carbamoyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- (4- {3- [1-carbamoyl-1- (methyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3- {2-[(S) -1-carbamoyl-2-hydroxyethylcarbamoyl] ethylamino} propoxy) -2-phenoxybenzyl] -5-hydroxy-3-methylphenyl β-D- Glucopyranoside;
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O- Acetyl-β-D-glucopyranoside;
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O- Acetyl-β-D-glucopyranoside;
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxyphenyl 2,3,4,6-tetra-O-acetyl-β- D-glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) Phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- [2-phenoxy-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside;
5-hydroxy-3-methyl-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside;
5-hydroxy-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D-glucopyranoside; etc. Can be illustrated.

  The compound represented by the general formula (I) of the present invention can be produced, for example, according to the following method.

(In the formula, G ² is the above-mentioned G in which any hydroxyl group is protected; M is a hydrogen atom or a hydroxyl-protecting group; L ¹ and L ² are either MgBr, MgCl, MgI or lithium atoms. And the other is a formyl group; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and G have the same meaning as described above, provided that a hydroxyl group and an amino group are included in each compound. When a carboxy group is present, one having a protective group may be used as appropriate.)

Step 1-1
The benzaldehyde derivative represented by the general formula (II) and the Grignard reagent or lithium reagent represented by the general formula (III), or the Grignard reagent or lithium reagent represented by the general formula (II) and the general formula (II) The compound represented by the general formula (IV) can be produced by condensing the benzaldehyde derivative represented by III) in an inert solvent. Examples of the solvent used include tetrahydrofuran, diethyl ether, a mixed solvent thereof, and the like. The reaction temperature is usually −78 ° C. to reflux temperature, and the reaction time is the starting material and solvent used, the reaction temperature, and the like. Usually, it is 10 minutes to 1 day, depending on the situation.

Step 1-2
The compound represented by the general formula (V) can be produced by oxidizing the compound represented by the general formula (IV) using a Dess-Martin reagent in an inert solvent. Examples of the solvent used include methylene chloride, chloroform, acetonitrile, a mixed solvent thereof, and the like. The reaction temperature is usually 0 ° C. to reflux temperature, and the reaction time is the starting material and solvent used, the reaction temperature. Usually, it is 1 hour to 1 day, although it varies depending on the above.

Step 1-3
After removing the protecting group according to a conventional method as necessary, the compound represented by the general formula (V) is (1) a base such as triethylamine, diisopropylethylamine, N, N-dimethylaminopyridine in an inert solvent. In the presence, it is condensed with methyl chloroformate, and (2) the resulting carbonate derivative is reduced using a reducing agent such as sodium borohydride to produce the compound represented by the general formula (VI). be able to. Examples of the solvent used in the reaction (1) include tetrahydrofuran, methylene chloride, acetonitrile, ethyl acetate, diethyl ether, a mixed solvent thereof, and the like. The reaction temperature is usually 0 ° C. to reflux temperature. The time is usually 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like. Examples of the solvent used in the reaction (2) include a mixed solvent of tetrahydrofuran and water. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is the starting material, solvent, and reaction used. Although it varies depending on the temperature and the like, it is usually 1 hour to 1 day.

Step 1-4
The compound represented by the general formula (IV) is catalytically reduced using an palladium-based catalyst such as palladium carbon powder in an inert solvent in the presence or absence of an acid such as hydrochloric acid, and then as necessary. The compound represented by the general formula (VI) can be produced by removing the protecting group according to a conventional method. Examples of the solvent used in the catalytic reduction include methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, 2-propanol, a mixed solvent thereof, and the like. The reaction temperature is usually room temperature to reflux temperature, and the reaction time Depending on the raw material used, solvent, reaction temperature, etc., it is usually 30 minutes to 1 day.

Step 1-5
The benzylphenol derivative represented by the general formula (VI) or a salt thereof is converted into 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose, 2,3 , 4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-β-D-glucopyranose, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose, 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl fluoride, 1 , 2,3,4,6-penta-O-acetyl-β-D-galactopyranose and the like, in an inert solvent, boron trifluoride / diethyl ether complex, silver trifluoromethanesulfonate, Stannic chloride, It is possible to produce a glycoside represented by the general formula (VII) by glycosylation in the presence of an activating agent such as trifluoromethanesulfonic acid trimethylsilyl. Examples of the solvent used include methylene chloride, toluene, acetonitrile, nitromethane, ethyl acetate, diethyl ether, chloroform, a mixed solvent thereof, and the like, and the reaction temperature is usually −30 ° C. to reflux temperature. The time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 10 minutes to 1 day.

Step 1-6
The compound represented by the general formula (I) of the present invention can be produced by alkaline hydrolysis of the glycoside represented by the general formula (VII) to remove the protecting group. Examples of the solvent used include water, methanol, ethanol, tetrahydrofuran, and mixed solvents thereof, and examples of the basic substance include sodium hydroxide, sodium methoxide, sodium ethoxide, and the like. be able to. The treatment temperature is usually from 0 ° C. to the reflux temperature, and the treatment time is usually from 30 minutes to 6 hours, although it varies depending on the raw material used, the solvent, the treatment temperature and the like.

Among the compounds represented by the general formula (I) of the present invention, R ¹ is —W—X ² —NH ₂ (wherein X ² is a C _1-6 alkylene group or a C _2-6 alkenylene group). And W has the same meaning as described above, for example, can also be produced according to the following method.

(In the formula, L ³ is a leaving group such as a mesyloxy group and a tosyloxy group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , G, G ² , W and X ² are (However, when a hydroxyl group, an amino group and / or a carboxy group are present in each compound, those having a protecting group may be used as appropriate.)

Step 2-1
In the presence of a base such as triethylamine or N, N-diisopropylethylamine, a leaving group is introduced into the compound represented by the general formula (VIII) using an acid chloride such as mesyl chloride or tosyl chloride in an inert solvent. Thus, the compound represented by the general formula (IX) can be produced. Examples of the solvent used for the introduction reaction include methylene chloride, ethyl acetate, tetrahydrofuran, pyridine, and a mixed solvent thereof. The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 2-2
The compound represented by the general formula (X) can be produced by azidating the compound represented by the general formula (IX) in an inert solvent using an azide reagent such as sodium azide. it can. Examples of the solvent used in the azidation reaction include methylene chloride, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylimidazolidinone, and mixed solvents thereof. Can do. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.

Step 2-3
The compound represented by the general formula (XI) can be produced by catalytic reduction of the compound represented by the general formula (X) in an inert solvent using a palladium catalyst such as palladium carbon powder. . Examples of the solvent used in the catalytic reduction reaction include tetrahydrofuran, methanol, ethanol, ethyl acetate, a mixed solvent thereof and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature, and the like.

Step 2-4
The benzylphenol derivative represented by the general formula (If) of the present invention can be produced by alkaline hydrolysis of the compound represented by the general formula (XI) to remove the protecting group. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Among the compounds represented by the general formula (I) of the present invention, the compound in which R ¹ is an amino group can also be produced, for example, according to the following method.

(In the formula, M, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , G and G ² have the same meaning as described above, provided that each compound has a hydroxyl group, an amino group and / or a carboxy group. If a group is present, one having a protective group may be used as appropriate.)

Step 3-1
Friedel-Crafts reaction between the compound represented by the general formula (XII) and the p-nitrobenzoyl chloride derivative represented by the general formula (XIII) in an inert solvent in the presence of a Lewis acid such as aluminum chloride. The compound represented by the general formula (XIV) can be produced by performing Examples of the solvent used include methylene chloride, carbon disulfide, 1,2-dichloroethane, chlorobenzene, a mixed solvent thereof, and the like. The reaction temperature is usually −78 ° C. to reflux temperature, and the reaction time is Although it varies depending on the raw material used, the solvent, the reaction temperature, etc., it is usually 1 hour to 2 days.

Step 3-2
After removing the protecting group according to a conventional method as necessary, the compound represented by the general formula (XIV) is converted to a base such as triethylamine, diisopropylethylamine, N, N-dimethylaminopyridine in an inert solvent (1). In the presence, it is condensed with methyl chloroformate, and (2) the resulting carbonate derivative is reduced using a reducing agent such as sodium borohydride to produce the compound represented by the general formula (XV). be able to. Examples of the solvent used in the reaction (1) include tetrahydrofuran, methylene chloride, acetonitrile, ethyl acetate, diethyl ether, a mixed solvent thereof, and the like. The reaction temperature is usually 0 ° C. to reflux temperature. The time is usually 30 minutes to 1 day, although it varies depending on the raw material used, the solvent, the reaction temperature, and the like. Examples of the solvent used in the reaction (2) include a mixed solvent of tetrahydrofuran and water. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is the starting material, solvent, and reaction used. Although it varies depending on the temperature and the like, it is usually 1 hour to 1 day.

Step 3-3
The benzylphenol derivative represented by the general formula (XV) or a salt thereof is converted into 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose, 2,3 , 4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-β-D-glucopyranose, 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose, 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl fluoride, 1 , 2,3,4,6-penta-O-acetyl-β-D-galactopyranose and the like, in an inert solvent, boron trifluoride / diethyl ether complex, silver trifluoromethanesulfonate, Stannic chloride, It is possible to produce a glycoside represented by the general formula (XVI) by glycosylation in the presence of an activating agent such as trifluoromethanesulfonic acid trimethylsilyl. Examples of the solvent used include methylene chloride, toluene, acetonitrile, nitromethane, ethyl acetate, diethyl ether, chloroform, a mixed solvent thereof, and the like, and the reaction temperature is usually −30 ° C. to reflux temperature. The time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 10 minutes to 1 day.

Step 3-4
The compound represented by the general formula (XVII) is produced by catalytic reduction of the nitro group of the compound represented by the general formula (XVI) using a palladium catalyst such as palladium carbon powder in an inert solvent. can do. Examples of the solvent used in the catalytic reduction reaction include methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, and mixed solvents thereof. The reaction temperature is usually room temperature to reflux temperature, and the reaction time is used. Although it varies depending on the starting material, solvent, reaction temperature, etc., it is usually 1 hour to 2 days.

Step 3-5
The benzylphenol derivative represented by the general formula (Ig) of the present invention can be produced by alkaline hydrolysis of the compound represented by the general formula (XVII) to remove the protecting group. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Among the compounds represented by the general formula (I) of the present invention, R ¹ is —W—X—NH (Z ² ) (wherein Z ² is a C _2-7 alkoxycarbonyl group, —COR ^C , —SO ₂ R ^C , —CON (R ^D ) R ^E or —C (═NR ^G ) NH (R ^H ); R ^C , R ^D , R ^E , R ^G , R ^H , W and X are The compound having the same meaning as can also be produced, for example, according to the following method.

(In the formula, L ⁴ is a leaving group such as a pyrazolyl group, a methylthio group, a benzotriazolyl group; R ^1C is the same as R ^C or a C _1-6 alkoxy group; R ^1G and R ^1H are the same. But may be different, each represents a hydrogen atom, a benzyloxycarbonyl group or a tert- butoxycarbonyl ^{group; R 2, R 3, R} 4, R 5, R 6, R 7, R C, R D, R ^E , G, G ² , W, X and Z ² have the same meaning as described above, provided that each compound has a protective group as appropriate when a hydroxyl group, amino group and / or carboxy group is present. May be used.)

Step 4-1
After the treatment according to the following methods 1 to 4, the protective group is removed according to a conventional method as necessary, whereby the compound represented by the general formula (XXIII) is converted from the compound represented by the general formula (XI). Can be manufactured.

<Method 1>
The compound represented by the general formula (XI) is converted into triethylamine, N, N-diisopropylethylamine, pyridine, 1,8 in an inert solvent such as methylene chloride, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile, and a mixed solvent thereof. -In the presence of a base such as diazabicyclo [5.4.0] unde-7-cene, the acid chloride represented by the general formula (XVIII) or (XIX) and usually from 0 ° C to reflux temperature, usually from 30 minutes to 1 Perform the reaction for 1 day.

<Method 2>
The compound represented by the general formula (XI) is converted into triethylamine, N, N-diisopropylethylamine, pyridine, 1 in an inert solvent such as methylene chloride, ethyl acetate, tetrahydrofuran, pyridine, acetonitrile, toluene, and a mixed solvent thereof. , 8-diazabicyclo [5.4.0] unde-7-cene in the presence or absence of an isocyanate compound represented by the above general formula (XX) and usually at 0 ° C. to reflux temperature for usually 30 minutes. Perform reaction for ~ 1 day.

<Method 3>
The compound represented by the general formula (XI) is converted into 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in an inert solvent such as N, N-dimethylformamide, methylene chloride or a mixed solvent thereof. In the presence of a condensing agent such as dicyclohexylcarbodiimide and in the presence or absence of a base such as triethylamine or N, N-diisopropylethylamine, 1-hydroxybenzotriazole is appropriately added as necessary, and the above general formula ( The reaction is carried out with the carboxylic acid compound represented by XXI) usually at 0 ° C. to reflux temperature for usually 1 hour to 2 days.

<Method 4>
The compound represented by the general formula (XI) is mixed with an N- (benzyloxycarbonyl) -1H-pyrazole-1-carboxamidine or the like in an inert solvent such as tetrahydrofuran, methanol, ethanol, toluene, or a mixed solvent thereof. The reaction is carried out with the guanidinating reagent represented by the general formula (XXII) usually at room temperature to reflux temperature for usually 1 hour to 5 days.

Step 4-2
The benzylphenol derivative represented by the general formula (Ih) of the present invention is obtained by alkaline hydrolysis of the compound represented by the general formula (XXIII) and then removing the protective group according to a conventional method as necessary. Can be manufactured. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Step 5-1
Presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] unde-7-cene in an inert solvent and the compound represented by the general formula (XI) The active ester compound represented by the general formula (XXV) can be produced by condensing with the active esterification reagent represented by the formula (XXIV). Examples of the solvent used in the condensation reaction include methylene chloride, tetrahydrofuran, ethyl acetate, acetonitrile, pyridine, and mixed solvents thereof. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Step 5-2
The compound represented by the general formula (XXV) in an inert solvent is triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] unde-7-cene, sodium hydride, In the presence or absence of a base such as potassium tert-butoxide, potassium carbonate, cesium carbonate or the like, after condensation with an amine compound represented by the above general formula (XXVI) or a salt thereof, a protective group is obtained according to a conventional method as necessary. The benzylphenol derivative represented by the general formula (XXVII) can be produced by removing. Examples of the solvent used for the condensation reaction include methylene chloride, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, a mixed solvent thereof and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 2 days, although it varies depending on the raw material used, the solvent, the reaction temperature and the like.

Step 5-3
The benzylphenol derivative represented by the general formula (Ii) of the present invention can be produced by alkaline hydrolysis of the compound represented by the general formula (XXVII) to remove the protecting group. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Among the compounds represented by the general formula (I) of the present invention, R ¹ is —W—X ² —N (R ⁸ ) R ^B (wherein R ⁸ , R ^B , W and X ² are The compound having the same meaning can also be produced, for example, according to the following method.

(In the formula, L ³ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^B , G, G ² , W and X ² have the same meaning as described above, provided that When a hydroxyl group, an amino group and / or a carboxy group are present in each compound, those having a protective group may be used as appropriate.)

Step 6
The compound represented by the general formula (IX) in an inert solvent is triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] unde-7-cene, sodium hydride, In the presence or absence of a base such as potassium tert-butoxide, potassium carbonate, cesium carbonate or the like, sodium iodide is added as necessary to condense with the amine compound represented by the above general formula (XXVIII) or a salt thereof. Then, the benzylphenol derivative represented by the general formula (Ij) of the present invention can be produced by alkaline hydrolysis to remove the protecting group. Examples of the solvent used in the condensation reaction include acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, and mixed solvents thereof. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Among the compounds represented by the general formula (I) of the present invention, R ¹ is —W—X—NH—C (═NCN) N (R ⁹ ) R ¹⁰ (wherein R ⁹ has the same meaning as R ^8). And R ¹⁰ is synonymous with R ^B ; W and X have the same meaning as described above, for example, can also be produced according to the following method.

(In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^B , G, G ² , W and X have the same meaning as described above. However, when a hydroxyl group, an amino group and / or a carboxy group are present in each compound, those having a protecting group may be used as appropriate.)

Step 7-1
A compound represented by the general formula (XXX) is produced by condensing the compound represented by the general formula (XI) with an isothioureaation reagent represented by the formula (XXIX) in an inert solvent. be able to. Examples of the solvent used for the condensation reaction include methanol, ethanol, 2-propanol, tetrahydrofuran, toluene, a mixed solvent thereof and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 7-2
The compound represented by the general formula (XXX) in an inert solvent is triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] unde-7-cene, sodium hydride, In the presence or absence of a base such as potassium tert-butoxide, potassium carbonate, cesium carbonate or the like, it is condensed with the amine compound represented by the above general formula (XXVIII) or a salt thereof, and is subjected to alkali hydrolysis to remove the protective group. Thus, the compound represented by the general formula (Ik) of the present invention can be produced. Examples of the solvent used in the condensation reaction include methanol, ethanol, acetonitrile, 2-propanol, N, N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, although it varies depending on the raw material used, solvent, reaction temperature and the like. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and methyl. Examples include amines and dimethylamine. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Of the compounds represented by the above general formula (I) of the invention, R ¹ is _{^{-CH 2 CH 2 -X 3 -Y 2}} -N (R 8) R B or -CH = CH-X ³ -Y ² —N (R ⁸ ) R ^B (wherein X ³ is a single bond or a C _1-4 alkylene group; Y ² is a carbonyl group or a sulfonyl group; R ⁸ and R ^B have the same meaning as described above) ) Can also be produced, for example, according to the following method.

(In the formula, L ⁵ is a leaving group such as chlorine atom, bromine atom, iodine atom, trifluoromethanesulfonyloxy group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^B , G, G ² , X ³ and Y ² have the same meaning as described above, provided that each compound has a protective group as appropriate when a hydroxyl group, amino group and / or carboxy group is present. May be used.)

Step 8-1
The benzylphenol derivative represented by the general formula (XXXI) and the olefin derivative represented by the general formula (XXXII) in an inert solvent, palladium carbon powder, palladium acetate, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium In the presence or absence of a phosphine ligand such as tris (2-methylphenyl) phosphine and triphenylphosphine, and using a palladium-based catalyst such as bistriphenylphosphine palladium dichloride, and triethylamine, sodium tert-butoxide, potassium By performing the Heck reaction in the presence of a base such as tert-butoxide or cesium fluoride, an olefin derivative represented by the general formula (XXXIII) can be produced. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 8-2
Presence of a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and dicyclohexylcarbodiimide and a base such as triethylamine and diisopropylethylamine in an inert solvent for the compound represented by the general formula (XXXIII) A compound represented by the above general formula (XXXIV) by adding 1-hydroxybenzotriazole as necessary under the absence or absence and condensing with an amine derivative represented by the above general formula (XXXVIII) Can be manufactured. Examples of the solvent used for the condensation reaction include N, N-dimethylformamide, tetrahydrofuran, methylene chloride, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 8-3
The benzylphenol derivative represented by the general formula (XXXI) and the olefin derivative represented by the general formula (XXXV) in an inert solvent, palladium carbon powder, palladium acetate, tetrakistriphenylphosphine palladium, dibenzylideneacetone palladium In the presence or absence of phosphine ligands such as tris (2-methylphenyl) phosphine and triphenylphosphine, and using a palladium-based catalyst such as bistriphenylphosphine palladium dichloride, and triethylamine, sodium tert-butoxide, potassium A compound represented by the general formula (XXXIV) can be produced by performing a Heck reaction in the presence of a base such as tert-butoxide or cesium fluoride. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 8-4
The pyrazole derivative represented by the general formula (Il) of the present invention can be produced by alkaline hydrolysis of the compound represented by the general formula (XXXIV) to remove the protective group. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and the like. Can be mentioned. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

Step 8-5
The compound represented by the general formula (XXXVI) can be produced by catalytic reduction of the compound represented by the general formula (XXXIV) using a palladium-based catalyst such as palladium carbon powder in an inert solvent. it can. Examples of the solvent used in the catalytic reduction reaction include methanol, ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 8-6
The compound represented by the general formula (Im) of the present invention is produced by catalytic reduction of the compound represented by the general formula (Il) in an inert solvent using a palladium catalyst such as palladium carbon powder. can do. Examples of the solvent used in the catalytic reduction reaction include methanol, ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 1 hour to 2 days, although it varies depending on the raw material used, solvent, reaction temperature and the like.

Step 8-7
The compound represented by the general formula (Im) of the present invention can be produced by alkaline hydrolysis of the compound represented by the general formula (XXXVI) to remove the protecting group. Examples of the solvent used in the hydrolysis reaction include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like. Examples of the base include sodium hydroxide, sodium methoxide, sodium ethoxide, and the like. Can be mentioned. The reaction temperature is usually from 0 ° C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, although it varies depending on the raw materials and solvents used, the reaction temperature and the like.

  In the said manufacturing method, in the compound which has a hydroxyl group, an amino group, and / or a carboxy group, it can use for reaction, after introducing a protective group arbitrarily according to a conventional method suitably as needed. Further, the protecting group can be appropriately removed in a subsequent step according to a conventional method.

  The compound represented by the general formula (I) of the present invention obtained in the production method is a fractional recrystallization method, a purification method using chromatography, a solvent extraction method, a solid phase extraction method, etc., which are conventional separation means. Can be isolated and purified.

  The benzylphenol derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method. Such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, sodium Salts with inorganic bases such as salts and potassium salts, organic bases such as N-methyl-D-glucamine, N, N′-dibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) aminomethane, arginine and lysine Can be mentioned.

  The compound represented by the general formula (I) of the present invention includes a solvate with a pharmaceutically acceptable solvent such as water and ethanol.

  Among the benzylphenol derivatives represented by the above general formula (I) of the present invention and prodrugs thereof, the compound having an unsaturated bond includes two geometric isomers, a cis (Z) isomer compound and a trans ( E) Although there are compounds in the form, any of these compounds may be used in the present invention.

  Of the benzylphenol derivatives represented by the general formula (I) of the present invention and prodrugs thereof, there are two types of compounds having an asymmetric carbon atom except for the glucopyranosyloxy moiety or the galactopyranosyloxy moiety. In the present invention, any of these optical isomers may be used, or a mixture of these optical isomers may be used. Absent.

The prodrug of the compound represented by the general formula (I) of the present invention is a hydroxyl group in the compound represented by the general formula (I) by a conventional method using a prodrug-forming reagent such as a corresponding halide. In addition, after appropriately introducing a group constituting a prodrug according to a conventional method into one or more arbitrary groups selected from amino groups, it can be produced by isolation and purification according to a conventional method as appropriate. Examples of the group constituting a prodrug used for a hydroxyl group or an amino group include a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl (C _{2- 7} acyl) group, C _2-7 alkoxycarbonyl group, C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group and the like. The C _1-6 alkoxy (C _2-7 acyl) group refers to the C _2-7 acyl group substituted with the C _1-6 alkoxy group, and is a C _2-7 alkoxycarbonyl (C _2-7 acyl) group. The group refers to the C _2-7 acyl group substituted with the C _2-7 alkoxycarbonyl group, and the C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group refers to the C _1-6 alkoxy group. The C _2-7 alkoxycarbonyl group substituted with In addition, examples of the group constituting the prodrug include a glucopyranosyl group or a galactopyranosyl group. For example, the prodrug is introduced into the hydroxyl group at the 4-position or 6-position of the glucopyranosyloxy group or galactopyranosyloxy group. It is more preferable that it is introduced into the hydroxyl group at the 4-position or 6-position of the glucopyranosyloxy group.

  The benzylphenol derivative represented by the general formula (I) of the present invention exhibits a strong human SGLT1 activity inhibitory action in, for example, the following human SGLT1 activity inhibitory action confirmation test, and also suppresses the increase in blood glucose level using rats. In the confirmation test, it exhibited an excellent inhibitory effect on the increase in blood glucose level. Thus, the benzylphenol derivative represented by the general formula (I) of the present invention exhibits an excellent SGLT1 activity inhibitory action in the small intestine, and increases or decreases the blood glucose level by inhibiting or delaying the absorption of glucose and galactose. Can be significantly suppressed and / or the blood galactose level can be reduced. Therefore, the benzylphenol derivative represented by the general formula (I) of the present invention, a pharmacologically acceptable salt thereof, and a prodrug thereof are a postprandial hyperglycemia inhibitor, a glucose intolerant (IGT) person, Inhibitors of fasting glycemic abnormalities (IFG) in transition to diabetes and SGLT1 activity in the small intestine, such as diabetes, impaired glucose tolerance, fasting glycemic abnormalities, diabetic complications (eg retinopathy, neuropathy) , Nephropathy, ulcer, macroangiopathy), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, congestive heart failure, A preventive or therapeutic agent for diseases caused by hyperglycemia such as edema, hyperuricemia, gout and the like, and a prophylactic or therapeutic agent for diseases caused by elevated blood galactose levels such as galactoseemia Is extremely useful Te.

Moreover, the compound of this invention can also be used in combination with at least 1 sort (s) of drugs other than SGLT1 activity inhibitor suitably. Examples of drugs that can be used in combination with the compound of the present invention include insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin Receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate Dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-chiroinositol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon Peptide-1 analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin agonist, aldose reductase inhibitor, advanced glycation end product generation inhibitor, protein kinase C inhibitor, γ-aminobutyric acid Receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase (N-acetylated-α-linked-acid-dipeptidase) inhibition Drugs, insulin-like growth factor-I, platelet derived growth factor (PDGF), platelet derived growth factor (PDGF) analogs (eg, PDGF-AA, PDGF-BB, PDGF-AB), epithelial growth factors (EGF), nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antipruritic, laxative, hydroxymethylglutaryl Coenzyme A reductase inhibitor, fibrate compound, β ₃ -adrenergic receptor agonist, acylcoenzyme A: cholesterol acyltransferase inhibitor, probucol, thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride Transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low density lipoprotein receptor potentiator, nicoti Acid derivatives, bile acid adsorbents, sodium-conjugated bile acid transporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin Converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calcium antagonist, vasodilatory antihypertensive, switching nerve blocker, central antihypertensive, α ₂ -adrenergic receptor agonist, antiplatelet agent, uric acid production inhibitor, Examples thereof include uric acid excretion promoters and urine alkalizing agents.

  When a compound of the present invention and one or more of the above agents are used in combination, the present invention includes simultaneous administration as a single formulation, simultaneous administration by the same or different routes of administration as separate formulations, and separate A pharmaceutical comprising a combination of the compound of the present invention and the above-mentioned drug, including any dosage form in which the same or different administration routes are used as a preparation, and a combination of the above-mentioned drugs is a dosage form as described above And dosage forms that combine separate formulations.

  When the compound of the present invention is used in appropriate combination with one or more kinds of the above drugs, an advantageous effect more than an additive effect in preventing or treating the above diseases can be obtained. Or similarly, compared with the case where it uses independently, the usage-amount can be decreased, or the side effect of drugs other than the SGLT1 activity inhibitor used together can be avoided or reduced.

  Specific compounds of the drugs used in combination and suitable diseases to be treated are exemplified as follows, but the contents of the present invention are not limited to these, and the specific compounds are free forms thereof. And other or pharmacologically acceptable salts thereof.

  Insulin sensitivity enhancers include troglitazone, pioglitazone hydrochloride, rosiglitazone maleate, dalglitazone sodium, GI-262570, isaglitazone, LG-1000064, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium, peroxisome proliferator activated receptor γ agonist such as NIP-221, peroxisome proliferator activated receptor α agonist such as GW-9578, BM-170744, GW- 409544, KRP-297, NN-622, CLX-0940, LR-90, SB-2199994, DRF-4158, DRF-MDX8 and other peroxisome proliferator-activated receptors α / γ Gonists, ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-10074, retinoid X receptor agonists such as bexarotene, and regrixan, ONO-5816, MBX-102, CRE-1625, FK -614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242 And other insulin sensitivity enhancers such as LY-510929, AR-H049020, GW-501516. Insulin sensitivity-enhancing drugs, especially diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis It is preferable for the treatment of diabetes mellitus, and it improves blood glucose uptake by reducing blood glucose uptake by improving abnormalities in the mechanism of insulin stimulation in peripheral eradication. Diabetes, impaired glucose tolerance, hyperinsulinemia More preferred for the treatment of

  Examples of sugar absorption inhibitors include acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25, 637, camiglibose, MDL-73, 945 and other α-glucosidase inhibitors, and AZM-127 and other α-amylase inhibitors And compounds other than SGLT1 activity inhibitors. A sugar absorption inhibitor is particularly preferable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity, and hyperinsulinemia, and also inhibits the enzymatic digestion of carbohydrates contained in foods into the body. Is more preferable for the treatment of impaired glucose tolerance.

  Examples of biguanides include phenformin, buformin hydrochloride, metformin hydrochloride and the like. The biguanide is particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, and hyperinsulinemia, and also inhibits gluconeogenesis in the liver, promotes anaerobic glycolysis in tissues, or improves insulin resistance in peripheral elimination. Since the blood glucose level is lowered by the action or the like, it is more preferable for the treatment of diabetes, impaired glucose tolerance, and hyperinsulinemia.

  Insulin secretagogues include tolbutamide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glyburide (glibenclamide), gliclazide, 1-butyl-3-methanilylurea, carbutamide, glibornuride, glipizide, glyxone, glyoxepide, glyb Examples include thiazole, glybazole, glychexamide, glymidin sodium, glipinamide, fenbutamide, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repaglinide and the like, and glucokinase activators such as RO-28-1675 are also included. Insulin secretagogues are particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, and lower blood glucose levels by acting on pancreatic β-cells to increase insulin secretion, resulting in diabetes, impaired glucose tolerance More preferred for the treatment of

  Examples of SGLT2 activity inhibitors include T-1095, JP-A-10-237089, JP-A-2001-288178, WO01 / 16147, WO01 / 27128, WO01 / 68660, WO01 / 74834, WO01. / 74835 gazette, WO02 / 28872 gazette, WO02 / 36602 gazette, WO02 / 44192 gazette, WO02 / 53573 gazette, etc. are mentioned. SGLT2 activity inhibitor is particularly suitable for the treatment of diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, and lowers blood glucose levels by suppressing glucose reabsorption in renal tubules Therefore, it is more preferable for the treatment of diabetes, impaired glucose tolerance, obesity, and hyperinsulinemia.

  Examples of insulin or insulin analogs include human insulin, animal-derived insulin, human or animal-derived insulin analogs. These drugs are particularly preferable for the treatment of diabetes, impaired glucose tolerance and diabetic complications, and are more preferable for the treatment of diabetes and impaired glucose tolerance.

  Examples of glucagon receptor antagonists include BAY-27-9955, NNC-92-1687, and examples of insulin receptor kinase stimulants include TER-17411, L-78321, KRX-613, and tripeptidyl. Examples of peptidase II inhibitors include UCL-1397, and examples of dipeptidyl peptidase IV inhibitors include NVP-DPP728A, TSL-225, and P-32 / 98, and protein tyrosine phosphatase-1B inhibitors. PTP-112, OC-86839, PNU-177496 and the like, glycogen phosphorylase inhibitors include NN-4201, CP-368296 and the like, and fructose-bisphosphatase inhibitors include R-13291. Examples of the pyruvate dehydrogenase inhibitor include AZD-7545, examples of the hepatic gluconeogenesis inhibitor include FR-225659, and examples of the glucagon-like peptide-1 analog include exendin-4. (Exendin-4), CJC-1131 and the like, glucagon-like peptide-1 agonists include AZM-134, LY-315902, and amylin, amylin analogs or amylin agonists include pramlintide acetate and the like. It is done. These drugs, glucose-6-phosphatase inhibitor, D-kaileunositol, glycogen synthase kinase-3 inhibitor and glucagon-like peptide-1 are particularly diabetic, impaired glucose tolerance, diabetic complications, hyperinsulinemia It is preferable for the treatment of diabetes mellitus and more preferable for the treatment of diabetes and impaired glucose tolerance.

  As aldose reductase inhibitors, ascorbyl gamolate, tolrestat, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat, sol vinyl, ponalrestat (ponalrestat) ), Risarestat, zenarestat, minarerestat, metsol vinyl, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ- 314, SG-210, JTT-811, Lindolerestat. Aldose reductase inhibitors reduce intracellular sorbitol, which is excessively accumulated by the enhancement of the polyol metabolic pathway in the persistent hyperglycemic state observed in diabetic complication tissues, by inhibiting aldose reductase. Is preferred for the treatment of diabetic complications.

  Examples of the terminal glycation product production inhibitor include pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedin hydrochloride and the like. A terminal glycation product production inhibitor is particularly preferable for the treatment of diabetic complications because it reduces cell damage by inhibiting the production of terminal glycation products that are enhanced by continuous hyperglycemia in diabetic conditions.

  Examples of protein kinase C inhibitors include LY-333531, midostaurin and the like. Protein kinase C inhibitors are particularly preferred for the treatment of diabetic complications because they suppress the increase in protein kinase C activity observed with persistent hyperglycemia in diabetic conditions.

Examples of γ-aminobutyric acid receptor antagonists include topiramate, sodium channel antagonists include mexiletine hydrochloride, oxcarbazepine and the like, and transcription factor NF-κB inhibitors include dexlipotam and the like. Examples of lipid peroxidase inhibitors include tirilazad mesylate and the like, N-acetylated-α-linked-acid-dipeptidase inhibitors include GPI-5893, and carnitine derivatives. , Carnitine, lebasecarnin hydrochloride, levocarnitine chloride, levocarnitine, ST-261 and the like. These agents, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide and Y-128 is particularly preferred for the treatment of diabetic complications.
Examples of antidiarrheal agents or laxatives include polycarbophil calcium, albumin tannate, bismuth subnitrate and the like. These drugs are particularly preferable for the treatment of diarrhea and constipation associated with diabetes.

  Hydroxymethylglutaryl coenzyme A reductase inhibitors include cerivastatin sodium, pravastatin sodium, lovastatin, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101, BB- 476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987, pitavastatin calcium, rosuvastatin calcium, cholestrone, dalvastatin, acymate, Mevastatin, Crilvastatin, BMS-180431, BMY-21950, Glenva Statins, carvastatin, BMY-22089, bervastatin (bervastatin), and the like. Hydroxymethylglutaryl coenzyme A reductase inhibitors are particularly preferred for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and hydroxymethylglutaryl coenzyme A Since blood cholesterol is lowered by inhibiting reductase, it is more preferable for the treatment of hyperlipidemia, hypercholesterolemia, and atherosclerosis.

  Examples of fibrate compounds include bezafibrate, beclobrate, vinylibrate, ciprofibrate, clinofibrate, clofibrate, clofibrate aluminum, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonfibrate, simfibrate, Theofibrate, AHL-157, etc. are mentioned. Fibrate compounds are particularly suitable for the treatment of hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, and activation of lipoprotein lipase in the liver In addition, blood triglycerides are reduced by increasing fatty acid oxidation, and therefore, it is more preferable for the treatment of hyperlipidemia, hypertriglyceridemia, and atherosclerosis.

β ₃ - as the adrenergic receptor agonist, BRL-28410, SR-58611A , ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW- 427353, N-5984, GW-2696, YM178 and the like. β ₃ -adrenergic receptor agonists are particularly preferred for the treatment of obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, and β ₃ -adrenergic reception in fat Since it stimulates the body and consumes energy by increasing fatty acid oxidation, it is more preferable for the treatment of obesity and hyperinsulinemia.

  Acylcoenzyme A: Cholesterol acyltransferase inhibitors include NTE-122, MCC-147, PD-13301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139, CP- 113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-C8- 434, avasimibe, CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E, lecimide, 447C88, YM-750E 24, KW-3033, HL-004, and the like eflucimibe (eflucimibe) or the like. Acylcoenzyme A: Cholesterol acyltransferase inhibitor is particularly preferable for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and dyslipidemia, and also inhibits acylcoenzyme A: cholesterol acyltransferase Therefore, it is more preferable for the treatment of hyperlipidemia and hypercholesterolemia.

  Thyroid hormone receptor agonists include liothyronine sodium, levothyroxine sodium, KB-2611, etc., cholesterol absorption inhibitors include ezetimibe, SCH-48461, etc., and lipase inhibitors include orlistat, ATL-962, AZM-131, RED-103004, and the like, carnitine palmitoyltransferase inhibitors include etomoxyl and the like, and squalene synthase inhibitors include TAK-475, SDZ-268-198, BMS- 188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856, etc., and nicotinic acid derivatives include nicotinic acid, nicotinic acid amide, nicomol, niceritrol And bile acid adsorbents include cholestyramine, colestillan, colesevelam hydrochloride, GT-102-279, etc., and sodium-conjugated bile acid transporter inhibitors include 264W94 and S-8922. SD-5613 and the like, and cholesterol ester transfer protein inhibitors include PNU-107368E, SC-795, JTT-705, CP-529414 and the like. These drugs, probucol, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor and low density lipoprotein receptor potentiator are especially useful for the treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and lipid metabolism disorders. preferable.

Appetite suppressants include monoamine reabsorption inhibitors, serotonin reabsorption inhibitors, serotonin release stimulants, serotonin agonists (especially 5HT _2C -agonists), noradrenaline reabsorption inhibitors, noradrenaline release stimulators, α ₁ -adrenergic receptors. Agonist, β ₂ -adrenergic receptor agonist, dopamine agonist, cannabinoid receptor antagonist, γ-aminobutyric acid receptor antagonist, H ₃ -histamine antagonist, L-histidine, leptin, leptin analog, leptin receptor agonist, melanocortin receptor Agonist (especially MC3-R agonist, MC4-R agonist), α-melanocyte stimulating hormone, cocaine-and amphetamine-regulated transcript, mahogany protein, entero Tatin agonist, calcitonin, calcitonin gene related peptide, bombesin, cholecystokinin agonist (especially CCK-A agonist), corticotropin releasing hormone, corticotropin releasing hormone analogue, corticotropin releasing hormone agonist, urocortin, somatostatin, somatostatin analogue, somatostatin receptor Agonist, Pituitary Adenylate Cyclase Activating Peptide, Brain-derived Nerve Growth Factor, Serially Neutropic Factor, Thyrotropin Releasing Hormone, Neurotensin, Sorbazine, Neuropeptide Y Antagonist, Opioid Peptide Antagonist, Galanin Antagonist, Melanin-Concentrating Hormone receptor antagonist, agouti-related protein inhibitor, Shin receptor antagonist, and the like. Specifically, examples of monoamine reabsorption inhibitors include mazindol, and serotonin reabsorption inhibitors include dexfenfluramine hydrochloride, fenfluramine hydrochloride, sibutramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride, and the like. Examples of serotonin agonists include inotriptan and (+) norfenfluramine, examples of noradrenaline reabsorption inhibitors include bupropion and GW-320659, and examples of noradrenaline release stimulants include rolipram, YM- 992 and the like, beta ₂ - adrenoreceptor agonist, amphetamine, dextroamphetamine, phentermine, benzphetamine, methamphetamine, phendimetrazine, phenmetrazine, diethylpropion, off Nylpropanolamine, clobenzorex, etc., dopamine agonists include ER-230, doprexin, bromocriptine mesylate, cannabinoid receptor antagonists include rimonabant, etc., and γ-aminobutyric acid receptor antagonists Examples include topiramate and the like. Examples of H ₃ -histamine antagonists include GT-2394. Examples of leptin, leptin analogs and leptin receptor agonists include LY-355101. Cholecystokinin agonists ( Particularly, as CCK-A agonist), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771 GW-7854, A-71378, and the like. Examples of the neuropeptide Y antagonist include SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO. -3304, CP-671906-01, J-115814 and the like. Appetite suppressants, especially diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, atherosclerosis, hypertension, congestive It is preferable for the treatment of heart failure, edema, hyperuricemia, and gout. It also suppresses appetite and reduces energy intake by promoting or inhibiting the action of brain monoamines and bioactive peptides in the central appetite regulating system. More preferred for the treatment of obesity.

  Angiotensin converting enzyme inhibitors include captopril, enalapril maleate, alacepril, delapril hydrochloride, ramipril, lisinopril, imidapril hydrochloride, benazepril hydrochloride, celonapril monohydrate, cilazapril, fosinopril sodium, perindopril erbumine, mobile primipril calcium Quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calcium, moexipril hydrochloride, wrench april, and the like. An angiotensin converting enzyme inhibitor is particularly preferable for the treatment of diabetic complications and hypertension.

  Neutral endopeptidase inhibitors include omapatrilate, MDL-100240, fasidotril, sampatrilate, GW-660511X, mixampril, SA-7060, E-4030, SLV-306, ecadoril and the like. Can be mentioned. Neutral endopeptidase inhibitors are particularly preferred for the treatment of diabetic complications and hypertension.

  Angiotensin II receptor antagonists include candesartan cilexetil, candesartan cilexetil / hydrochlorothiazide, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, tasosartan , KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. An angiotensin II receptor antagonist is particularly preferable for the treatment of diabetic complications and hypertension.

  Examples of endothelin converting enzyme inhibitors include CGS-31447, CGS-35066, SM-19712 and the like, and examples of endothelin receptor antagonists include L-740805, TBC-3214, BMS-182874, BQ-610, TA-0201. SB-215355, PD-180988, sitaxsentan sodium (Sitaxsentan), BMS-193384, darusentan, TBC-3711, bosentan, tezosentan sodium, J-104132, YM-598, S-0139 SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 and the like. These drugs are particularly preferred for the treatment of diabetic complications and hypertension, and more preferred for the treatment of hypertension.

  Examples of diuretics include chlorthalidone, metolazone, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflutide, methycrothiazide, indapamide, tripamide, mefluside, azosemide, ethacrynic acid, torasemide, piretanide, piretanide, , Methiclan, potassium canrenoate, spironolactone, triamterene, aminophylline, cicletanine hydrochloride, LLU-α, PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin, acetozolamide, metazolamide, FR-179544, OPC-31260, Examples include lixivaptan and conivaptan hydrochloride. Diuretics are particularly suitable for the treatment of diabetic complications, hypertension, congestive heart failure, edema, and lower blood pressure by increasing urinary excretion or improve edema, so that hypertension, congestive heart failure, More preferred for the treatment of edema.

Calcium antagonists include alanidipine, efonidipine hydrochloride, nicardipine hydrochloride, varnidipine hydrochloride, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besylate, pranidipine, lercanidipine hydrochloride, isradipinel Examples include rasidipine, batanidipine hydrochloride, remildipine, diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridil hydrochloride, galopamil hydrochloride, etc., and vasodilatory antihypertensive drugs include indapamide, todralazine hydrochloride, hydralazine hydrochloride , Cadralazine, budralazine, etc., and examples of exchange blocking agents include amosulalol hydrochloride, terazol hydrochloride , Bunazosin hydrochloride, prazosin hydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol, metoprolol tartrate, carvedilol, nipradilol, seriprolol hydrochloride, nebivolol, betaxolol hydrochloride, pindolol, tartatrol hydrochloride, bevantolol hydrochloride, timolol maleate hydrochloride, carteolol hydrochloride , bisoprolol fumarate, bopindolol malonate, nipradilol, sulfuric penbutolol, acebutolol hydrochloride, hydrochloric tilisolol, nadolol, urapidil, indoramin and the like, as the central antihypertensives, reserpine and the like, alpha ₂ - adrenergic receptor Agonists include clonidine hydrochloride, methyldopa, CHF-1035, guanabenz acetate, guanfacine hydrochloride, moxonidine (moxo) nisine), lofexidine, and talipexol hydrochloride. These agents are particularly preferred for the treatment of hypertension.

  Antiplatelet drugs include ticlopidine hydrochloride, dipyridamole, cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dirazep hydrochloride, trapidil, beraprost sodium, aspirin and the like. Antiplatelet drugs are particularly preferred for the treatment of atherosclerosis and congestive heart failure.

  Examples of uric acid production inhibitors include allopurinol and oxypurinol, examples of uric acid excretion promoters include benzbromarone and probenecid, and examples of urinary alkalinizing agents include sodium bicarbonate, potassium citrate, citric acid, and the like. Examples include sodium acid. These drugs are particularly preferable for the treatment of hyperuricemia and gout.

For example, when used in combination with a drug other than an SGLT1 activity inhibitor, in the treatment of diabetes, an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide drug, an insulin secretagogue, an SGLT2 activity inhibitor, insulin or an insulin analog Body, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose -Bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-kaileusitol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like pep It is preferably combined with at least one drug selected from the group consisting of a do-1 analog, a glucagon-like peptide-1 agonist, amylin, an amylin analog, an amylin agonist and an appetite suppressant, and an insulin sensitivity enhancer, biguanide Drugs, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors Drugs, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-kaileunositol, Lycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analogue, glucagon-like peptide-1 agonist, amylin, amylin analogue and amylin agonist In combination with an insulin sensitivity enhancer, biguanide, insulin secretagogue, SGLT2 activity inhibitor, and at least one drug selected from the group consisting of insulin or insulin analogs. . Similarly, in the treatment of diabetic complications, insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinases Stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor , Hepatic gluconeogenesis inhibitor, D-kaileusitol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonis Amylin, amylin analog, amylin agonist, aldose reductase inhibitor, terminal glycation product inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid Peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine Derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor , Endseri Preferably combined with at least one drug selected from the group consisting of receptor antagonists and diuretics, aldose reductase inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors and angiotensin II receptor antagonists More preferably, it is combined with at least one drug selected from the group consisting of: In the treatment of obesity, insulin sensitivity enhancer, sugar absorption inhibitor, biguanide drug, insulin secretagogue, SGLT2 activity inhibitor, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, Tripeptidyl peptidase II inhibitor, dipeptidyl peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, liver sugar Angiogenesis inhibitor, D-kaileusitol, glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide-1 analog, glucagon-like peptide-1 agonist, amiri , Amylin analogues, amylin agonists, beta ₃ - is preferably combined with at least one agent selected from the group consisting of adrenergic receptor agonist and an appetite suppressant agent, SGLT2 activity inhibitors, beta ₃ - adrenergic receptor agonists and More preferably, it is combined with at least one drug selected from the group consisting of appetite suppressants.

  When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, etc. It is administered orally. In addition, the pharmaceutical composition of the present invention includes sustained-release preparations including gastrointestinal mucosa-adhesive preparations and the like (for example, International Publication No. WO99 / 10010 Pamphlet, International Publication No. WO99 / 26606 Pamphlet, JP-A No. 2001-2567). Issue gazette).

  These pharmaceutical compositions are prepared according to the method used in pharmacology depending on the dosage form, and include appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, It can be produced by mixing or diluting / dissolving appropriately with pharmaceutical additives such as wetting agents, emulsifying agents, dispersing agents, stabilizing agents, solubilizing agents, etc., and dispensing according to conventional methods. Moreover, when using in combination with chemical | medical agents other than SGLT1 activity inhibitor, it can manufacture by formulating each active ingredient simultaneously or separately like the above.

  When the pharmaceutical composition of the present invention is used for actual treatment, the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, or a prodrug thereof, which is an active ingredient thereof, is The dose is appropriately determined depending on the patient's age, sex, weight, disease and degree of treatment, etc., but in the case of oral administration, it is generally in the range of 0.1 to 1000 mg per day for adults, and is generally 0 per day for parenteral administration. In the range of 0.01 to 300 mg, it can be appropriately administered in one or several divided doses. Further, when used in combination with a drug other than an SGLT1 activity inhibitor, the dose of the compound of the present invention can be reduced according to the dose of a drug other than the SGLT1 activity inhibitor.

  The benzylphenol derivative represented by the above general formula (I) of the present invention, a pharmacologically acceptable salt thereof, and a prodrug thereof express a human SGLT1 activity inhibitory action and are a carbohydrate such as glucose in the small intestine. Inhibition of absorption can suppress an increase in blood glucose level, and in particular, by suppressing the absorption of glucose and galactose based on this mechanism of action, the increase in blood glucose level is remarkably suppressed and / or blood galactose level For example, postprandial hyperglycemia can be corrected. Therefore, according to the present invention, excellent diabetes, impaired glucose tolerance, abnormal fasting blood glucose, diabetic complications, diseases caused by hyperglycemia such as obesity, and increased blood galactose levels such as galactosemia Can be provided.

  The contents of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited to the contents.

Reference example 1
3,5-dimethoxy-2- (4-nitrobenzoyl) toluene To a solution of 3,5-dimethoxytoluene (8 g) and 4-nitrobenzoyl chloride (10.7 g) in methylene chloride (150 mL) was added aluminum chloride (7 .36 g) was added and stirred at room temperature for 14 hours. After ice water was added to the reaction mixture, the mixture was poured into 1 mol / L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with 1 mol / L hydrochloric acid, 1 mol / L sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (8.72 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.19 (3H, s), 3.6 (3H, s), 3.86 (3H, s), 6.36 (1H, d, J = 1.9Hz), 6.43 (1H, d, J = 1.9Hz), 7.92 (2H, d , J = 9.2Hz), 8.26 (2H, d, J = 9.2Hz)

Reference example 2
5-Hydroxy-3-methyl-2- (4-nitrobenzoyl) phenol Boron halide (6.79 mL) was added, the temperature was raised to 40 ° C., and the mixture was stirred for 15 hours. Ice water was added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7 / 1-3 / 1) to give the title compound (6.3 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.85 (3H, s), 5.83 (1H, s), 6.2-6.3 (1H, m), 6.36 (1H, d, J = 2.6Hz), 7.7-7.8 (2H, m), 8.25-8.4 (2H, m), 10.98 (1H, s)

Reference example 3
5-methoxycarbonyloxy-3-methyl-2- (4-nitrobenzyl) phenol 5-hydroxy-3-methyl-2- (4-nitrobenzoyl) phenol (1.65 g) and triethylamine (2.1 mL) in tetrahydrofuran To the (20 mL) solution, methyl chloroformate (1.03 mL) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 3,5-dimethoxycarbonyloxy-2- (4-nitrobenzoyl) toluene (2.37 g). It was. This was suspended in tetrahydrofuran (20 mL) -water (20 mL), sodium borohydride (921 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1) to obtain the title compound (1.62 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.23 (3H, s), 3.91 (3H, s), 4.1 (2H, s), 5.1-5.25 (1H, brs), 6.5-6.6 (1H, m), 6.6-6.7 (1H, m), 7.3 ( 2H, d, J = 9.1Hz), 8.1 (2H, d, J = 9.1Hz)

Reference example 4
5-methoxycarbonyloxy-3-methyl-2- (4-nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-methoxycarbonyloxy-3-methyl-2- (4-Nitrobenzyl) phenol (1 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose (2.02 g) in methylene chloride (30 mL) ) Boron trifluoride / diethyl ether complex (0.2 mL) was added to the solution under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 3/2) to obtain the title compound (1.93 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.75 (3H, s), 2.0 (3H, s), 2.04 (3H, s), 2.08 (3H, s), 2.19 (3H, s), 3.8-4.05 (5H, m), 4.05-4.2 (2H, m), 4.24 (1H, dd, J = 12.5Hz, 6.1Hz), 5.05-5.2 (2H, m), 5.2-5.35 (2H, m), 6.75-6.9 (2H, m), 7.21 (2H, d , J = 8.6Hz), 8.1 (2H, d, J = 8.6Hz)

Example 1
2- (4-Aminobenzyl) -5-methoxycarbonyloxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-methoxycarbonyloxy-3-methyl-2- To a solution of (4-nitrobenzyl) phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.61 g) in ethyl acetate (7 mL) was added 10% palladium carbon powder (0.2 g). In addition, the mixture was stirred at room temperature for 13 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (0.58 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.67 (3H, s), 1.99 (3H, s), 2.04 (3H, s), 2.09 (3H, s), 2.17 (3H, s), 3.5 (2H, brs), 3.73 (1H, d, J = 15.4Hz), 3.8-3.95 (4H, m), 3.97 (1H, d, J = 15.4Hz), 4.1-4.2 (1H, m), 4.24 (1H, dd, J = 11.9Hz, 6.0Hz), 5.0 -5.2 (2H, m), 5.2-5.35 (2H, m), 6.5-6.6 (2H, m), 6.75-6.85 (4H, m)

Example 2
5-hydroxy-3-methyl-2- {4- [3- (3-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside 2- (4-aminobenzyl) -5-methoxycarbonyloxy-3-methyl Phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.25 g) and pyridine (0.043 mL) in methylene chloride (10 mL) in 4-nitrophenyl chloroformate (90 mg) And stirred at room temperature for 12 hours. To the reaction mixture, 3-aminomethylpyridine (0.045 mL) and triethylamine (0.11 mL) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (8 mL), sodium methoxide (28% methanol solution, 0.39 mL) was added, and the mixture was stirred at room temperature for 2 hr. After concentrating the reaction mixture under reduced pressure, the residue was purified successively by ODS solid phase extraction method (washing solvent: distilled water, elution solvent: methanol) and BOND ELUT-SCX (elution solvent: methanol) manufactured by VARIAN. 0.17 g) was obtained.

¹ H-NMR (CD ₃ OD) δ ppm:
2.11 (3H, s), 3.3-3.5 (4H, m), 3.65-3.75 (1H, m), 3.8-3.95 (2H, m), 4.07 (1H, d, J = 15.4Hz), 4.41 (2H, s), 4.8-4.9 (1H, m), 6.32 (1H, d, J = 2.2Hz), 6.56 (1H, d, J = 2.2Hz), 7.04 (2H, d, J = 8.7Hz), 7.17 ( 2H, d, J = 8.7Hz), 7.4 (1H, dd, J = 7.8Hz, 5.1Hz), 7.75-7.85 (1H, m), 8.35-8.45 (1H, m), 8.45-8.55 (1H, m )

Example 3
5-hydroxy-3-methyl-2- (4-ureidobenzyl) phenyl β-D-glucopyranoside In the same manner as in Example 2 using ammonia (2 mol / L methanol solution) instead of 3-aminomethylpyridine A compound was obtained.

¹ H-NMR (CD ₃ OD) δ ppm:
2.1 (3H, s), 3.35-3.5 (4H, m), 3.65-3.75 (1H, m), 3.8-3.95 (2H, m), 4.07 (1H, d, J = 15.3Hz), 4.8-4.9 ( 1H, m), 6.32 (1H, d, J = 2.1Hz), 6.55 (1H, d, J = 2.1Hz), 7.04 (2H, d, J = 8.5Hz), 7.1-7.2 (2H, m)

Example 4
5-Hydroxy-3-methyl-2- {4- [3- (2-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside Example using 2-aminomethylpyridine instead of 3-aminomethylpyridine The title compound was obtained in the same manner as 2.

¹ H-NMR (CD ₃ OD) δ ppm:
2.11 (3H, s), 3.3-3.5 (4H, m), 3.65-3.75 (1H, m), 3.8-3.95 (2H, m), 4.08 (1H, d, J = 15.5Hz), 4.48 (2H, s), 4.8-4.9 (1H, m), 6.32 (1H, d, J = 2.4Hz), 6.57 (1H, d, J = 2.4Hz), 7.04 (2H, d, J = 8.5Hz), 7.15- 7.25 (2H, m), 7.25-7.35 (1H, m), 7.42 (1H, d, J = 7.9Hz), 7.75-7.85 (1H, m), 8.4-8.5 (1H, m)

Example 5
5-hydroxy-2- {4- [3- (4-hydroxy-3-methoxybenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside instead of 3-aminomethylpyridine 4-hydroxy-3- The title compound was obtained in the same manner as in Example 2 using methoxybenzylamine.

¹ H-NMR (CD ₃ OD) δ ppm:
2.11 (3H, s), 3.3-3.5 (4H, m), 3.65-3.75 (1H, m), 3.8-3.95 (5H, m), 4.07 (1H, d, J = 15.2Hz), 4.26 (2H, s), 4.8-4.9 (1H, m), 6.32 (1H, d. J = 2.3Hz), 6.56 (1H, d, J = 2.3Hz), 6.7-6.8 (2H, m), 6.9 (1H, s ), 7.04 (2H, d, J = 8.5Hz), 7.15-7.20 (2H, m)

Example 6
2- (4- {3-[(S) -1-carbamoyl-2- (4-hydroxyphenyl) ethyl] ureido} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside 3-aminomethylpyridine The title compound was obtained as described above and in Example 2 using L-tyrosine amide hydrochloride instead of.

¹ H-NMR (CD ₃ OD) δ ppm:
2.11 (3H, s), 2.85 (1H, dd, J = 13.8Hz, 7.7Hz), 3.01 (1H, dd, J = 13.8Hz, 6.1Hz), 3.3-3.5 (4H, m), 3.65-3.75 ( 1H, m), 3.8-3.95 (2H, m), 4.06 (1H, d, J = 15.5Hz), 4.45 (1H, dd, J = 7.7Hz, 6.1Hz), 4.8-4.9 (1H, m), 6.32 (1H, d, J = 2.3Hz), 6.56 (1H, d, J = 2.3Hz), 6.65-6.75 (2H, m), 7.01 (2H, d, J = 8.6Hz), 7.05-7.15 (4H , m)

Reference Example 5
N-sulfamoylethylenediamine hydrochloride Triethylamine (1.5 mL) was added to a suspension of N-benzyloxycarbonylethylenediamine hydrochloride (1 g) in methylene chloride (10 mL), and the mixture was stirred at room temperature for 30 minutes. N-benzyloxycarbonylsulfamoyl chloride (1.41 g) was added to the mixture and stirred at room temperature for 2 hours. Water and 2 mol / L hydrochloric acid were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 30/1 to 10/1) to give N-benzyloxycarbonyl-N ′-[2- (benzyloxycarbonylamino) ethyl] sulfamide (1 .2 g) was obtained. The obtained N-benzyloxycarbonyl-N ′-[2- (benzyloxycarbonylamino) ethyl] sulfamide (0.61 g) was dissolved in methanol (5 mL), 2 mol / L hydrochloric acid (0.75 mL) and 10% Palladium carbon powder (0.6 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (0.26 g).

¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.85-3.0 (2H, m), 3.1-3.2 (2H, m), 6.69 (2H, brs), 6.8 (1H, t, J = 5.8Hz), 8.02 (3H, brs)

Reference Example 6
A solution of phosphoryl chloride (21.4 mL) in acetonitrile (60 mL) was added dropwise to a solution of 2,4-dihydroxy-6-methylbenzaldehyde N, N-dimethylformamide (20.8 mL) in acetonitrile (60 mL) under ice-cooling. For 1 hour. To the reaction mixture, a solution of 3,5-dihydroxytoluene (24.8 g) in acetonitrile (60 mL) was added dropwise at −20 to −15 ° C., stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for 1 hour. 1 mol / L hydrochloric acid (300 mL) was added to the reaction mixture, and the mixture was stirred at 50 ° C. for 1 hour, and then allowed to cool to room temperature. The mixture was extracted twice with diethyl ether, and the combined extracts were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane-diethyl ether, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (22.9 g).

¹ H-NMR (DMSO-d ₆ ) δ ppm:
2.45 (3H, s), 6.12 (1H, d, J = 2.3Hz), 6.15-6.25 (1H, m), 10.06 (1H, s), 10.66 (1H, s), 12.05 (1H, s)

Reference Example 7
2,4-Dibenzyloxy-6-methylbenzaldehyde 2,4-Dihydroxy-6-methylbenzaldehyde (18.3 g), benzyl bromide (31.4 mL) and potassium carbonate (49.8 g) in N, N-dimethylformamide The (200 mL) suspension was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane-diethyl ether, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (31 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.59 (3H, s), 5.09 (2H, s), 5.11 (2H, s), 6.43 (1H, d, J = 2.1Hz), 6.48 (1H, d, J = 2.1Hz), 7.3-7.45 (10H , m), 10.59 (1H, s)

Reference Example 8
4-Benzyloxy-2-hydroxy-6-methylbenzaldehyde 2,4-dibenzyloxy-6-methylbenzaldehyde (26.6 g) and magnesium bromide-diethyl ether complex (20.7 g) in toluene (175 mL) -diethyl The ether (25 mL) suspension was stirred at 70 ° C. overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes, and then the mixture was extracted with diethyl ether. The extract was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane-ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (15.4 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.53 (3H, s), 5.08 (2H, s), 6.3-6.4 (2H, m), 7.3-7.45 (5H, m), 10.09 (1H, s), 12.44 (1H, s)

Reference Example 9
1- (4-Bromophenyl) -1- (4-benzyloxy-2-hydroxy-6-methylphenyl) methanol A solution of 1,4-dibromobenzene (21.2 g) in tetrahydrofuran (200 mL) at −78 ° C., argon Under the atmosphere, n-butyl lithium (2.46 mol / L n-hexane solution, 30.5 mL) was added, and the mixture was stirred at the same temperature for 1 hour. A solution of 4-benzyloxy-2-hydroxy-6-methylbenzaldehyde (7.27 g) in tetrahydrofuran (50 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour under ice-cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane-ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (10.8 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.14 (3H, s), 2.92 (1H, d, J = 2.7Hz), 5.01 (2H, s), 6.09 (1H, d, J = 2.7Hz), 6.38 (1H, d, J = 2.5Hz), 6.43 (1H, d, J = 2.5Hz), 7.15-7.5 (9H, m), 8.3 (1H, s)

Reference Example 10
5-Benzyloxy-2- (4-bromobenzyl) -3-methylphenol 1- (4-bromophenyl) -1- (4-benzyloxy-2-hydroxy-6-methylphenyl) methanol (10.8 g) To a solution of sodium iodide (24.3 g) in acetonitrile (260 mL) was added dropwise trimethylsilyl chloride (20.6 mL) under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 mol / L aqueous sodium thiosulfate solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give the title compound (5.4 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.2 (3H, s), 3.92 (2H, s), 4.61 (1H, s), 5.01 (2H, s), 6.32 (1H, d, J = 2.3Hz), 6.47 (1H, d, J = 2.3Hz ), 7.0-7.1 (2H, m), 7.3-7.5 (7H, m)

Reference Example 11
2- (4-Bromobenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- (4-bromobenzyl)- 3-methylphenol (4.98 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α-D-glucopyranose (7.69 g) in methylene chloride (100 mL) Boron trifluoride / diethyl ether complex (0.98 mL) was added to the solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/3) to give 5-benzyloxy-2- (4-bromobenzyl) -3-methylphenyl 2,3,4,6. -Tetra-O-acetyl-β-D-glucopyranoside (9.1 g) was obtained. The resulting dimethyl sulfide (24 mL) of 5-benzyloxy-2- (4-bromobenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (8.56 g) ) -Boron trifluoride / diethyl ether complex (15.1 mL) was added to a methylene chloride (24 mL) solution, and the mixture was stirred at 35 ° C. for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/2 to 2/3) to give the title compound (5.54 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.65 (3H, s), 1.99 (3H, s), 2.04 (3H, s), 2.09 (3H, s), 2.11 (3H, s), 3.74 (1H, d, J = 16.1Hz), 3.8-3.9 (1H, m), 3.95 (1H, d, J = 16.1Hz), 4.18 (1H, dd, J = 12.0Hz, 2.5Hz), 4.27 (1H, dd, J = 12.0Hz, 6.0Hz), 4.82 ( 1H, s), 5.04 (1H, d, J = 7.4Hz), 5.1-5.15 (1H, m), 5.2-5.3 (2H, m), 6.39 (1H, d, J = 2.4Hz), 6.52 (1H , d, J = 2.4Hz), 6.85-6.9 (2H, m), 7.3-7.35 (2H, m)

Reference Example 12
2- {4-[(E) -2-carboxyvinyl] benzyl} -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 2- (4- Bromobenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (5.5 g) and acrylic acid (1.8 mL) in acetonitrile (65 mL) Triethylamine (6.1 mL), palladium (II) acetate (0.2 g) and tris (2-methylphenyl) phosphine (0.54 g) were added to the mixture, and the mixture was heated to reflux overnight under light shielding. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed successively with 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 50/1 to 30/1 to 10/1) to obtain the title compound (4.96 g).

¹ H-NMR (CD ₃ OD) δ ppm:
1.6 (3H, s), 1.95 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.08 (3H, s), 3.83 (1H, d, J = 16.2Hz), 4.0-4.1 (2H, m), 4.15 (1H, dd, J = 12.2Hz, 2.6Hz), 4.32 (1H, dd, J = 12.2Hz, 5.6Hz), 5.0-5.2 (2H, m), 5.24 (1H, d , J = 7.8Hz), 5.3-5.4 (1H, m), 6.35-6.45 (2H, m), 6.54 (1H, d, J = 2.4Hz), 7.0-7.1 (2H, m), 7.4-7.5 ( 2H, m), 7.61 (1H, d, J = 15.6Hz)

Example 7
5-hydroxy-3-methyl-2- {4-[(E) -2- (2-pyridylmethylcarbamoyl) vinyl] benzyl} phenyl β-D-glucopyranoside 2- {4-[(E) -2-carboxy Vinyl] benzyl} -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (35 mg) in N, N-dimethylformamide (1 mL) solution in 2-amino Methylpyridine (7 mg), 1-hydroxybenzotriazole (9 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (22 mg) and triethylamine (0.024 mL) were added and stirred at room temperature for 4 days. . The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: methylene chloride / methanol = 20/1) to give 5-hydroxy-3-methyl-2- {4-[(E) -2- (2-pyridylmethyl). Carbamoyl) vinyl] benzyl} phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (26 mg) was obtained. This was dissolved in methanol (2 mL), sodium methoxide (28% methanol solution, 0.01 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS solid phase extraction (washing solvent: distilled water, elution solvent: methanol) to obtain the title compound (18 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
2.11 (3H, s), 3,3-3.45 (4H, m), 3.65-3.75 (1H, m), 3.85-3.95 (1H, m), 3.96 (1H, d, J = 15.9Hz), 4.16 ( 1H, d, J = 15.9Hz), 4.6 (2H, s), 4.8-4.9 (1H, m), 6.34 (1H, d, J = 2.4Hz), 6.58 (1H, d, J = 2.4Hz), 6.62 (1H, d, J = 15.8Hz), 7.1-7.2 (2H, m), 7.25-7.35 (1H, m), 7.35-7.45 (3H, m), 7.53 (1H, d, J = 15.8Hz) , 7.75-7.85 (1H, m), 8.45-8.5 (1H, m)

Example 8
5-hydroxy-3-methyl-2- (4-{(E) -2- [3- (morpholin-4-yl) propylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside instead of 2-aminomethylpyridine The title compound was obtained in the same manner as in Example 7 using N- (3-aminopropyl) morpholine.

¹ H-NMR (CD ₃ OD) δ ppm:
1.7-1.85 (2H, m), 2.1 (3H, s), 2.3-2.55 (6H, m), 3.25-3.5 (6H, m), 3.6-3.75 (5H, m), 3.85-3.95 (1H, m ), 3.96 (1H, d, J = 15.8Hz), 4.15 (1H, d, J = 15.8Hz), 4.8-4.9 (1H, m), 6.34 (1H, d, J = 2.1Hz), 6.5 (1H , d, J = 15.8Hz), 6.58 (1H, d, J = 2.1Hz), 7.1-7.2 (2H, m), 7.35-7.45 (2H, m), 7.46 (1H, d, J = 15.8Hz)

Example 9
5-hydroxy-3-methyl-2- (4-{(E) -2- [2- (sulfamoylamino) ethylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside instead of 2-aminomethylpyridine The title compound was obtained in the same manner as in Example 7 using N-sulfamoylethylenediamine hydrochloride.

¹ H-NMR (CD ₃ OD) δ ppm:
2.1 (3H, s), 3.19 (2H, t, J = 6.2Hz), 3.3-3.45 (4H, m), 3.46 (2H, t, J = 6.2Hz), 3.71 (1H, dd, J = 12.0Hz , 4.6Hz), 3.89 (1H, dd, J = 12.0Hz, 1.5Hz), 3.96 (1H, d, J = 15.8Hz), 4.16 (1H, d, J = 15.8Hz), 4.8-4.9 (1H, m), 6.34 (1H, d, J = 2.6Hz), 6.53 (1H, d, J = 15.7Hz), 6.58 (1H, d, J = 2.6Hz), 7.15-7.2 (2H, m), 7.35- 7.45 (2H, m), 7.48 (1H, d, J = 15.7Hz)

Reference Example 13
4-Benzyloxy-2-methoxymethoxy-6-methylbenzaldehyde 4-Benzyloxy-2-hydroxy-6-methylbenzaldehyde (12.1 g) and N, N-diisopropylethylamine (17.4 mL) in methylene chloride (120 mL) To the solution was added chloromethyl methyl ether (5.7 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous citric acid solution and extracted with diethyl ether. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (11.8 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.58 (3H, s), 3.5 (3H, s), 5.1 (2H, s), 5.23 (2H, s), 6.45-6.5 (1H, m), 6.67 (1H, d, J = 2.3Hz), 7.3 -7.45 (5H, m), 10.52 (1H, s)

Reference Example 14
1- [4- (3-Benzyloxypropoxy) phenyl] -1- (4-benzyloxy-2-methoxymethoxy-6-methylphenyl) methanol benzyl 3-bromopropyl ether (4.58 g), 4-bromophenol A mixture of (3.81 g), cesium carbonate (9.77 g) and sodium iodide (0.3 g) in N, N-dimethylformamide (40 mL) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with 1 mol / L sodium hydroxide aqueous solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 4- (3-benzyloxypropoxy) -1-bromo. Benzene (6.08 g) was obtained. This was dissolved in tetrahydrofuran (100 mL), n-butyllithium (2.66 mol / L n-hexane solution, 6.2 mL) was added at −78 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a solution of 4-benzyloxy-2-methoxymethoxy-6-methylbenzaldehyde (3.15 g) in tetrahydrofuran (20 mL), and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/4 to 1/3 to 1/2) to obtain the title compound (5 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.0-2.1 (2H, m), 2.31 (3H, s), 3.2 (3H, s), 3.65 (2H, t, J = 6.2Hz), 3.79 (1H, d, J = 10.8Hz), 4.05 (2H , t, J = 6.3Hz), 4.51 (2H, s), 4.95 (1H, d, J = 6.7Hz), 5.01 (1H, d, J = 6.7Hz), 5.04 (2H, s), 5.99 (1H , d, J = 10.8Hz), 6.53 (1H, d, J = 2.2Hz), 6.67 (1H, d, J = 2.2Hz), 6.8-6.85 (2H, m), 7.15-7.2 (2H, m) , 7.25-7.45 (10H, m)

Reference Example 15
4- [4- (3-hydroxypropoxy) benzyl] -3-methoxymethoxy-5-methylphenol 1- [4- (3-benzyloxypropoxy) phenyl] -1- (4-benzyloxy-2-methoxymethoxy To a solution of (6-methylphenyl) methanol (5 g) in methanol (30 mL) -tetrahydrofuran (10 mL) was added 10% palladium carbon powder (1 g), and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to 2/3) to obtain the title compound (2.57 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.75 (1H, t, J = 5.4Hz), 1.95-2.05 (2H, m), 2.17 (3H, s), 3.37 (3H, s), 3.8-3.9 (2H, m), 3.92 (2H, s) , 4.07 (2H, t, J = 5.9Hz), 4.58 (1H, s), 5.11 (2H, s), 6.35 (1H, d, J = 2.3Hz), 6.53 (1H, d, J = 2.3Hz) , 6.75-6.8 (2H, m), 6.95-7.05 (2H, m)

Reference Example 16
5-Benzyloxy-2- [4- (3-hydroxypropoxy) benzyl] -3-methylphenol 4- [4- (3-hydroxypropoxy) benzyl] -3-methoxymethoxy-5-methylphenol (2.56 g ) And potassium carbonate (1.6 g) in N, N-dimethylformamide (40 mL) was added benzyl bromide (1.1 mL) and stirred at room temperature overnight. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL) -methanol (5 mL), concentrated hydrochloric acid (0.6 mL) was added, and the mixture was stirred at 50 ° C. for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/2 to 2/3) to obtain the title compound (1.45 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.75 (1H, t, J = 5.4Hz), 2.0-2.05 (2H, m), 2.25 (3H, s), 3.8-3.9 (2H, m), 3.91 (2H, s), 4.09 (2H, t, J = 5.9Hz), 4.66 (1H, s), 5.02 (2H, s), 6.35 (1H, d, J = 2.4Hz), 6.47 (1H, d, J = 2.4Hz), 6.75-6.85 (2H, m), 7.05-7.1 (2H, m), 7.3-7.45 (5H, m)

Reference Example 17
5-Benzyloxy-2- {4- [3- (tert-butyldiphenylsilyloxy) propoxy] benzyl} -3-methylphenol 5-benzyloxy-2- [4- (3-hydroxypropoxy) benzyl] -3 -To a solution of methylphenol (1.42 g) and imidazole (0.77 g) in N, N-dimethylformamide (10 mL) was added tert-butyldiphenylsilyl chloride (2.0 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 to 4/1) to obtain the title compound (1.53 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.03 (9H, s), 1.95-2.05 (2H, m), 2.26 (3H, s), 3.83 (2H, t, J = 5.9Hz), 3.92 (2H, s), 4.07 (2H, t, J = 6.3Hz), 4.68 (1H, s), 5.02 (2H, s), 6.36 (1H, d, J = 2.4Hz), 6.48 (1H, d, J = 2.4Hz), 6.75-6.8 (2H, m) , 7.0-7.1 (2H, m), 7.3-7.45 (11H, m), 7.6-7.65 (4H, m)

Reference Example 18
5-Benzyloxy-2- [4- (3-hydroxypropoxy) benzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- { 4- [3- (tert-Butyldiphenylsilyloxy) propoxy] benzyl} -3-methylphenol (1.5 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl Boron trifluoride / diethyl ether complex (0.31 mL) was added to a solution of -α-D-glucopyranose (1.44 g) in methylene chloride (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (25 mL), tetra (n-butyl) ammonium fluoride (0.95 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into a saturated aqueous citric acid solution and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to 2/3 to 1/2) to give the title compound (1.35 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.65 (3H, s), 1.8 (1H, t, J = 5.4Hz), 1.95-2.05 (11H, m), 2.14 (3H, s), 3.75 (1H, d, 15.7Hz), 3.8-3.85 (3H , m), 3.96 (1H, d, J = 15.7Hz), 4.06 (2H, t, J = 6.0Hz), 4.1-4.15 (1H, m), 4.19 (1H, dd, J = 12.2Hz, 5.9Hz ), 5.0-5.05 (3H, m), 5.1-5.15 (1H, m), 5.2-5.3 (2H, m), 6.56 (1H, d, J = 2.4Hz), 6.64 (1H, d, J = 2.4 Hz), 6.7-6.8 (2H, m), 6.9-6.95 (2H, m), 7.3-7.45 (5H, m)

Reference Example 19
2- [4- (3-Azidopropoxy) benzyl] -5-benzyloxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- [ 4- (3-hydroxypropoxy) benzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.5 g) and triethylamine (0.15 mL) in methylene chloride ( 5 mL) solution was added methanesulfonyl chloride (0.06 mL) and stirred at room temperature for 30 minutes. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 mL), sodium azide (92 mg) was added, and the mixture was stirred at 100 ° C. for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/2) to obtain the title compound (0.46 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.63 (3H, s), 1.95-2.05 (11H, m), 2.14 (3H, s), 3.49 (2H, t, J = 6.5Hz), 3.74 (1H, d, 15.7Hz), 3.75-3.85 (1H , m), 3.9-4.0 (3H, m), 4.1-4.15 (1H, m), 4.21 (1H, dd, J = 12.2Hz, 6.0Hz), 4.95-5.05 (3H, m), 5.05-5.15 ( 1H, m), 5.2-5.3 (2H, m), 6.56 (1H, s), 6.64 (1H, s), 6.7-6.75 (2H, m), 6.9-6.95 (2H, m), 7.3-7.45 ( 5H, m)

Example 10
2- [4- (3-Aminopropoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside 2- [4- (3-azidopropoxy) benzyl] -5-benzyloxy-3-methylphenyl Sodium methoxide (28% methanol solution, 0.03 mL) was added to a solution of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.1 g) in methanol (5 mL) -tetrahydrofuran (5 mL). The mixture was further stirred at room temperature for 1 hour. 2- [4- (3-azidopropoxy) benzyl] -5-benzyloxy-3-methylphenyl β-D-glucopyranoside (by purifying the reaction mixture with BOND ELUT-SCX (elution solvent: methanol) manufactured by VARIAN 76 mg) was obtained. This was dissolved in methanol (5 mL), 10% palladium carbon powder (30 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (61 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.85-1.95 (2H, m), 2.09 (3H, s), 2.79 (2H, t, J = 7.0Hz), 3.35-3.45 (4H, m), 3.65-3.75 (1H, m), 3.8-3.9 ( 2H, m), 3.98 (2H, t, J = 6.2Hz), 4.04 (1H, d, J = 15.5Hz), 4.8-4.9 (1H, m), 6.3 (1H, d, J = 2.1Hz), 6.53 (1H, d, J = 2.1Hz), 6.7-6.8 (2H, m), 6.95-7.05 (2H, m)

Example 11
2- [4- (3-Aminopropoxy) benzyl] -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 2- [4- (3-azido (Propoxy) benzyl] -5-benzyloxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (35 mg) in tetrahydrofuran (3 mL) in 10% palladium carbon powder (10 mg And stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (28 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.62 (3H, s), 1.85-1.95 (5H, m), 2.02 (3H, s), 2.04 (3H, s), 2.07 (3H, s), 2.8 (2H, t, J = 7.0Hz), 3.71 (1H, d, J = 15.8Hz), 3.92 (1H, d, J = 15.8Hz), 3.97 (2H, t, J = 6.2Hz), 4.0-4.05 (1H, m), 4.15 (1H, dd, J = 12.2Hz, 2.3Hz), 4.31 (1H, dd, J = 12.2Hz, 5.5Hz), 5.05-5.15 (2H, m), 5.2 (1H, d, J = 7.9Hz), 5.3-5.35 (1H , m), 6.37 (1H, d, J = 2.2Hz), 6.54 (1H, d, J = 2.2Hz), 6.7-6.8 (2H, m), 6.85-6.9 (2H, m)

Example 12
2- (4- {3- [2-cyano-3- (2-hydroxyethyl) guanidino] propoxy} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside 2- [4- (3-amino (Propoxy) benzyl] -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.29 g) in 2-propanol (3 mL) suspension in S, S′-Dimethyl-N-cyanodithioiminocarbonate (90 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to methylene chloride / methanol = 20/1) to give 2- (4- {3- [N ′-(cyano)]. -S- (Methyl) isothioureido] propoxy} benzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.25 g) was obtained. 2- (4- {3- [N ′-(cyano) -S- (methyl) isothioureido] propoxy} benzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O obtained 2-Aminoethanol (1 mL) was added to a methanol (1 mL) solution of -acetyl-β-D-glucopyranoside (0.12 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS solid phase extraction (washing solvent: distilled water, elution solvent: methanol) to obtain the title compound (63 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.95-2.05 (2H, m), 2.11 (3H, s), 3.25-3.45 (8H, m), 3.6 (2H, t, J = 5.3Hz), 3.71 (1H, dd, J = 11.9Hz, 4.9Hz ), 3.8-3.95 (2H, m), 3.99 (2H, t, J = 5.9Hz), 4.06 (1H, d, J = 15.1Hz), 4.8-4.9 (1H, m), 6.32 (1H, d, J = 2.2Hz), 6.56 (1H, d, J = 2.2Hz), 6.75-6.85 (2H, m), 7.0-7.05 (2H, m)

Reference Example 20
1- (4-Ethylphenyl) -1- (4-benzyloxy-2-methoxymethoxy-6-methylphenyl) methanol To a solution of 4-bromo-1-ethylbenzene (1.11 g) in tetrahydrofuran (10 mL) was added -78. N-Butyllithium (2.66 mol / L n-hexane solution, 2 mL) was added under an argon atmosphere at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 4-benzyloxy-2-methoxymethoxy-6-methylbenzaldehyde (0.86 g) in tetrahydrofuran (3 mL), and the mixture was stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 to 2/1) to obtain the title compound (1.15 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.19 (3H, t, J = 7.7Hz), 2.33 (3H, s), 2.6 (2H, q, J = 7.7Hz), 3.13 (3H, s), 3.76 (1H, d, J = 10.7Hz), 4.93 (1H, d, J = 6.6Hz), 5.01 (1H, d, J = 6.6Hz), 5.04 (2H, s), 6.02 (1H, d, J = 10.7Hz), 6.53 (1H, d, J = 2.3Hz), 6.65 (1H, d, J = 2.3Hz), 7.05-7.15 (2H, m), 7.15-7.25 (2H, m), 7.3-7.45 (5H, m)

Reference Example 21
4- (4-Ethylbenzyl) -3-methoxymethoxy-5-methylphenol 1- [4- (3-benzyloxypropoxy) phenyl] -1- (4-benzyloxy-2-methoxymethoxy-6-methylphenyl) It was synthesized in the same manner as in Reference Example 15 using 1- (4-ethylphenyl) -1- (4-benzyloxy-2-methoxymethoxy-6-methylphenyl) methanol instead of methanol.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.19 (3H, t, J = 7.7Hz), 2.18 (3H, s), 2.58 (2H, q, J = 7.7Hz), 3.35 (3H, s), 3.95 (2H, s), 4.55 (1H, s ), 5.11 (2H, s), 6.35 (1H, d, J = 2.5Hz), 6.53 (1H, d, J = 2.5Hz), 7.0-7.1 (4H, m)

Reference Example 22
2- (4-Ethylbenzyl) -5-benzyloxy-3-methylphenol 4- [4- (3-hydroxypropoxy) benzyl] -3-methoxymethoxy-5-methylphenol instead of 4- (4-ethyl Synthesis was performed in the same manner as in Reference Example 16 using (benzyl) -3-methoxymethoxy-5-methylphenol.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.2 (3H, t, J = 7.6Hz), 2.25 (3H, s), 2.6 (2H, q, J = 7.6Hz), 3.94 (2H, s), 4.63 (1H, s), 5.01 (2H, s ), 6.35 (1H, d, J = 2.2Hz), 6.48 (1H, d, J = 2.2Hz), 7.05-7.1 (4H, m), 7.3-7.45 (5H, m)

Example 13
2- (4-Ethylbenzyl) -5-hydroxy-3-methylphenyl β-D-galactopyranoside 2- (4-ethylbenzyl) -5-benzyloxy-3-methylphenol (0.35 g) and 1 Boron trifluoride-diethyl ether complex (0.53 mL) was added to a methylene chloride (6 mL) solution of 2,3,4,6-penta-O-acetyl-β-D-galactopyranose (1.64 g), Stir at room temperature for 3 days. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (15 mL), sodium methoxide (28% methanol solution, 1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 15/1) to give 5-benzyloxy-2- (4-ethylbenzyl) -3-methylphenyl β-D-galactopyranoside ( 0.1 g) was obtained. This was dissolved in methanol (5 mL), 10% palladium carbon powder (50 mg) was added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. Insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue is purified by reverse phase preparative column chromatography (CAPEELL PAK UG120 ODS, 5 μL, 120 mm, 20 × 50 mm, flow rate 30 mL / min linear gradient, water / methanol = 75/25 to 20/80, manufactured by Shiseido). Gave the title compound (5 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.17 (3H, t, J = 7.6Hz), 2.09 (3H, s), 2.56 (2H, q, J = 7.6Hz), 3.53 (1H, dd, J = 9.7Hz, 3.3Hz), 3.6-3.65 ( 1H, m), 3.7-3.8 (3H, m), 3.85-3.95 (2H, m), 4.1 (1H, d, J = 15.6Hz), 4.78 (1H, d, J = 7.7Hz), 6.32 (1H , d, J = 2.0Hz), 6.59 (1H, d, J = 2.0Hz), 7.0-7.05 (4H, m)

Reference Example 23
2-amino-2-methylpropionamide To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (1 g) in N, N-dimethylformamide (10 mL), 1-hydroxybenzotriazole (0.63 g), 1-ethyl -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia (2 mL) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 0.5 mol / L hydrochloric acid, water, 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-benzyloxycarbonyl. Amino-2-methylpropionamide (0.26 g) was obtained. This was dissolved in methanol (5 mL), 10% palladium carbon powder (30 mg) was added, and the mixture was stirred at room temperature for 3 hr in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.11 g).

¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.15 (6H, s), 1.9 (2H, brs), 6.83 (1H, brs), 7.26 (1H, brs)

Reference Example 24
3-Aminopropionamide To a suspension of 3- (benzyloxycarbonylamino) propionic acid (33.5 g) in tetrahydrofuran (75 mL) was added 1,1′-carbonylbis-1H-imidazole (31.6 g) at room temperature. For 30 minutes. A 28% aqueous ammonia solution (150 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (150 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed successively with water, 1 mol / L hydrochloric acid, water and diethyl ether, and dried under reduced pressure to give 3- (benzyloxycarbonylamino) propionamide (31.8 g). A mixture of the obtained 3- (benzyloxycarbonylamino) propionamide (0.11 g), 10% palladium carbon powder (25 mg) and methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (43 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
2.39 (2H, t, J = 6.6Hz), 2.91 (2H, t, J = 6.6Hz)

Reference Example 25
To a solution of (S) -2- (3-aminopropionylamino) -3-benzyloxypropionamide (S) -3-benzyloxy-2- (tert-butoxycarbonylamino) propionic acid (5 g) in tetrahydrofuran (25 mL) 1,1′-carbonylbis-1H-imidazole (3.57 g) was added and stirred at room temperature for 1 hour. A 28% aqueous ammonia solution (25 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water, 1 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added 4 mol / L hydrochloric acid (1,4-dioxane solution, 25 mL), and the mixture was stirred overnight at room temperature. Diethyl ether (50 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give (S) -2-amino-3-benzyloxypropionamide hydrochloride (3.8 g). ) To a solution of 3- (benzyloxycarbonylamino) propionic acid (2.23 g) in N, N-dimethylformamide (20 mL), (S) -2-amino-3-benzyloxypropionamide hydrochloride (2.54 g), 1 -Hydroxybenzotriazole (1.62 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.83 g) and triethylamine (5.6 mL) were added and stirred overnight at room temperature. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water, 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The solid residue was treated with n-hexane, collected by filtration, and dried under reduced pressure to obtain (S) -3-benzyloxy-2- [3- (benzyloxycarbonylamino) propionylamino] propionamide (3.35 g). . 10% palladium carbon powder (25 mg) was added to a suspension of the obtained (S) -3-benzyloxy-2- [3- (benzyloxycarbonylamino) propionylamino] propionamide (0.11 g) in methanol (3 mL). And stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (75 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
2.35-2.5 (2H, m), 2.9-3.0 (2H, m), 3.7 (1H, dd, J = 9.8Hz, 4.5Hz), 3.78 (1H, dd, J = 9.8Hz, 5.8Hz), 4.5- 4.65 (3H, m), 7.2-7.4 (5H, m)

Reference Example 26
To a solution of 2-amino-2-methylpropionic acid benzyl ester hydrochloride 2- (tert-butoxycarbonylamino) -2-methylpropionic acid (4.06 g) in N, N-dimethylformamide (40 mL) was added potassium carbonate (4 .15 g) and benzyl bromide (2.85 mL) were added and stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with n-hexane and collected by filtration, and the crystals were dried under reduced pressure to give 2- (tert-butoxycarbonylamino) -2-methylpropionic acid benzyl ester (4.44 g). 4 mol / L hydrochloric acid (1,4-dioxane solution, 15 mL) was added to the obtained 2- (tert-butoxycarbonylamino) -2-methylpropionic acid benzyl ester (4.44 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with diethyl ether and stirred for 1 hour. The insoluble material was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (3.4 g).

¹ H-NMR (DMSO-d ₆ ) δ ppm:
1.49 (6H, s), 5.25 (2H, s), 7.3-7.45 (5H, m), 8.54 (3H, brs)

Reference Example 27
N, N-diisopropylethylamine (10.5 mL) was added to a suspension of 4-nitro-3-phenoxyphenol 3-fluoro-4-nitrophenol (4.71 g) in methylene chloride (60 mL), and the mixture was stirred at room temperature for 30 minutes. did. Chloromethyl methyl ether (3.42 mL) was added to the mixture under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous citric acid solution and extracted with diethyl ether. The extract was washed successively with saturated aqueous citric acid solution, water, 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. N, N-dimethylformamide (50 mL), phenol (3.11 g) and potassium carbonate (4.98 g) were added to the residue, and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Tetrahydrofuran (30 mL), water (3 mL) and concentrated hydrochloric acid (3 mL) were added to the residue, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.3 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
6.34 (1H, d, J = 2.5Hz), 6.58 (1H, dd, J = 9.1Hz, 2.5Hz), 7.05-7.15 (2H, m), 7.15-7.25 (1H, m), 7.35-7.45 (2H , m), 8.03 (1H, d, J = 9.1Hz)

Reference Example 28
Triethylamine (5.67 mL) was added to a suspension of 4-bromo-3-phenoxyphenol 4-nitro-3-phenoxyphenol (6.27 g) in methylene chloride (50 mL), and the mixture was stirred at room temperature for 30 minutes. Pivaloyl chloride (4.34 mL) was added to the mixture under ice cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with diethyl ether. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The solid residue was suspended in n-hexane, collected by filtration, washed with n-hexane, and dried under reduced pressure to give 1-bromo-2-phenoxy-4-pivaloyloxybenzene (5.5 g). This was dissolved in a mixed solvent of methanol (15 mL) -tetrahydrofuran (10 mL), 10% palladium carbon powder (3 g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (20 mL) -48% hydrobromic acid (15 mL), a solution of sodium nitrite (1.26 g) in water (5 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 min. The above reaction mixture was added to a suspension of cuprous bromide (1.69 g) in 48% hydrobromic acid (10 mL) under ice-cooling, stirred at the same temperature for 30 minutes, and then stirred at 100 ° C. for 1 hour. The reaction mixture was returned to room temperature, diluted with water, and extracted with diethyl ether. The extract was washed successively with 1 mol / L hydrochloric acid (3 times), water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (35 mL), sodium methoxide (28% methanol solution, 10 mL) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 2 mol / L hydrochloric acid, and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6/1 to 4/1) to give the title compound (2.81 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
5.11 (1H, brs), 6.42 (1H, d, J = 2.8Hz), 6.52 (1H, dd, J = 8.7Hz, 2.8Hz), 6.95-7.05 (2H, m), 7.1-7.2 (1H, m ), 7.3-7.4 (2H, m), 7.44 (1H, d, J = 8.7Hz)

Reference Example 29
1- (4-Benzyloxy-2-methoxymethoxy-6-methylphenyl) -1- [4- (3-benzyloxypropoxy) -2-phenoxyphenyl] methanol instead of 4-bromophenol 4-bromo-3 The title compound was obtained in the same manner as in Reference Example 14 using phenoxyphenol.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.05 (2H, m), 2.27 (3H, s), 3.32 (3H, s), 3.59 (2H, t, J = 6.1Hz), 3.78 (1H, d, J = 9.5Hz), 3.95 (2H , t, J = 6.4Hz), 4.48 (2H, s), 4.95 (1H, d, J = 11.4Hz), 4.98 (1H, d, J = 11.4Hz), 5.02 (1H, d, J = 6.6Hz ), 5.1 (1H, d, J = 6.6Hz), 6.27 (1H, d, J = 9.5Hz), 6.36 (1H, d, J = 2.2Hz), 6.38 (1H, d, J = 2.2Hz), 6.61 (1H, dd, J = 9.0Hz, 2.5Hz), 6.63 (1H, d, J = 2.5Hz), 6.8-6.85 (2H, m), 7.0-7.1 (1H, m), 7.2-7.45 (13H , m)

Reference Example 30
5-Benzyloxy-2- [4- (3-benzyloxypropoxy) -2-phenoxybenzyl] -3-methyl-1- (methoxymethoxy) benzene 1- (4-benzyloxy-2-methoxymethoxy-6) To a solution of methylphenyl) -1- [4- (3-benzyloxypropoxy) -2-phenoxyphenyl] methanol (2.31 g) in methylene chloride (37 mL) at −50 ° C. with triethylsilane (2.97 mL) and trifluoride. Boron halide / diethyl ether complex (1.18 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous potassium carbonate solution and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1 to 5/1) to give the title compound (1.65 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.05 (2H, m), 2.16 (3H, s), 3.32 (3H, s), 3.6 (2H, t, J = 6.1Hz), 3.88 (2H, s), 3.96 (2H, t, J = 6.3Hz), 4.48 (2H, s), 5.03 (2H, s), 5.07 (2H, s), 6.45-6.55 (3H, m), 6.65-6.75 (2H, m), 6.95-7.1 (3H, m ), 7.2-7.5 (12H, m)

Reference Example 31
5-Benzyloxy-2- [4- (3-benzyloxypropoxy) -2-phenoxybenzyl] -3-methylphenol 5-benzyloxy-2- [4- (3-benzyloxypropoxy) -2-phenoxybenzyl Methanol (1 mL) and concentrated hydrochloric acid (0.54 mL) were added to a tetrahydrofuran (7 mL) solution of 3-methyl-1- (methoxymethoxy) benzene (1.55 g), and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give the title compound (0.54 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.95-2.05 (2H, m), 2.29 (3H, s), 3.59 (2H, t, J = 6.1Hz), 3.86 (2H, s), 3.95 (2H, t, J = 6.3Hz), 4.48 (2H , s), 5.0 (2H, s), 5.53 (1H, s), 6.37 (1H, d, J = 2.5Hz), 6.43 (1H, d, J = 2.6Hz), 6.45 (1H, d, J = 2.5Hz), 6.57 (1H, dd, J = 8.6Hz, 2.6Hz), 6.9-7.05 (3H, m), 7.05-7.15 (1H, m), 7.2-7.45 (12H, m)

Reference Example 32
5-Benzyloxy-2- [4- (3-hydroxypropoxy) -2-phenoxybenzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy 2- [4- (3-Benzyloxypropoxy) -2-phenoxybenzyl] -3-methylphenol (0.52 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetate Boron trifluoride / diethyl ether complex (0.059 mL) was added to a solution of imidoyl-α-D-glucopyranose (0.55 g) in methylene chloride (5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1 to 1/1) to give 5-benzyloxy-2- [4- (3-benzyloxypropoxy) -2-phenoxy. [Benzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.66 g) was obtained. This was dissolved in tetrahydrofuran (7 mL), 10% palladium carbon powder (130 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (4 mL), potassium carbonate (0.18 g) and benzyl bromide (0.14 mL) were added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 to 1/2) to give the title compound (0.45 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.65-1.75 (4H, m), 1.9-2.05 (11H, m), 2.1 (3H, s), 3.7-3.85 (4H, m), 3.9 (1H, d, J = 16.9Hz), 3.95-4.05 ( 2H, m), 4.09 (1H, dd, J = 12.3Hz, 2.3Hz), 4.17 (1H, dd, J = 12.3Hz, 5.5Hz), 4.95-5.05 (3H, m), 5.05-5.15 (1H, m), 5.15-5.25 (2H, m), 6.42 (1H, d, J = 2.6Hz), 6.49 (1H, dd, J = 8.6Hz, 2.6Hz), 6.55-6.65 (3H, m), 6.95- 7.05 (2H, m), 7.05-7.15 (1H, m), 7.3-7.45 (7H, m)

Example 14
2- (4- {3- [2- (carbamoyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside 5-benzyloxy-2- [4- ( 3-hydroxypropoxy) -2-phenoxybenzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.45 g) and triethylamine (0.13 mL) in methylene chloride To the (6 mL) solution, methanesulfonyl chloride (0.065 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5-benzyloxy-2- {4- [3- (methanesulfonyloxy) propoxy]- 2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.48 g) was obtained. Obtained 5-benzyloxy-2- {4- [3- (methanesulfonyloxy) propoxy] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β- D-glucopyranoside (0.17 g) was dissolved in a mixed solvent of methanol (2.5 mL) -acetonitrile (2.5 mL), 3-aminopropionamide (43 mg) and a catalytic amount of sodium iodide were added, and the mixture was dissolved at 55 ° C. Stir for days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 8/1 to 6/1) to give 5-benzyloxy-2- (4- {3- [2- (carbamoyl) ethylamino] Propoxy} -2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (60 mg) was obtained. 5-Benzyloxy-2- (4- {3- [2- (carbamoyl) ethylamino] propoxy} -2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O- obtained Acetyl-β-D-glucopyranoside (25 mg) was dissolved in tetrahydrofuran (2 mL), 10% palladium carbon powder (25 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give 2- (4- {3- [2- (carbamoyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2, 3,4,6-tetra-O-acetyl-β-D-glucopyranoside (21 mg) was obtained. This was dissolved in methanol (2 mL), sodium methoxide (0.01 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS solid phase extraction (washing solvent: distilled water, elution solvent: methanol) to obtain the title compound (12 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.85-1.95 (2H, m), 2.04 (3H, s), 2.39 (2H, t, J = 6.8Hz), 2.72 (2H, t, J = 7.0Hz), 2.81 (2H, t, J = 6.8Hz ), 3.25-3.45 (4H, m), 3.65-3.75 (1H, m), 3.75-4.0 (5H, m), 4.75-4.85 (1H, m), 6.32 (1H, d, J = 1.7Hz), 6.42 (1H, d, J = 2.2Hz), 6.5-6.6 (2H, m), 6.77 (1H, d, J = 8.9Hz), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m) , 7.25-7.4 (2H, m)

Example 15
2- (4- {3- [1-carbamoyl-1- (methyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside instead of 3-aminopropionamide The title compound was obtained in the same manner as in Example 14 using 2-amino-2-methylpropionamide.

¹ H-NMR (CD ₃ OD) δ ppm:
1.36 (6H, s), 1.9-2.0 (2H, m), 2.04 (3H, s), 2.77 (2H, t, J = 7.2Hz), 3.3-3.45 (4H, m), 3.65-3.75 (1H, m), 3.8-3.9 (2H, m), 3.9-4.0 (3H, m), 4.82 (1H, d, J = 7.4Hz), 6.33 (1H, d, J = 2.2Hz), 6.43 (1H, d , J = 2.5Hz), 6.5-6.6 (2H, m), 6.78 (1H, d, J = 9.0Hz), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.25-7.4 ( 2H, m)

Example 16
2- [4- (3- {2-[(S) -1-carbamoyl-2-hydroxyethylcarbamoyl] ethylamino} propoxy) -2-phenoxybenzyl] -5-hydroxy-3-methylphenyl β-D- Glucopyranoside 5-benzyloxy-2- [4- (3-hydroxypropoxy) -2-phenoxybenzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0. 45 g) and triethylamine (0.13 mL) in methylene chloride (6 mL) were added with methanesulfonyl chloride (0.065 mL) under ice-cooling and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5-benzyloxy-2- {4- [3- (methanesulfonyloxy) propoxy]- 2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.48 g) was obtained. Obtained 5-benzyloxy-2- {4- [3- (methanesulfonyloxy) propoxy] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β- D-glucopyranoside (0.1 g) was dissolved in a mixed solvent of methanol (1.5 mL) -acetonitrile (1.5 mL), and (S) -2- (3-aminopropionylamino) -3-benzyloxypropionamide (76 mg ) And a catalytic amount of sodium iodide, and stirred at 55 ° C. for 2 days. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1 to 8/1) to give 5-benzyloxy-2- [4- (3- {2-[(S) -2]. -Benzyloxy-1- (carbamoyl) ethylcarbamoyl] ethylamino} propoxy) -2-phenoxybenzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (42 mg) Got. This was dissolved in tetrahydrofuran (3 mL), 10% palladium carbon powder (40 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The mixture was further stirred for 8 hours at room temperature in a hydrogen atmosphere (0.35 MPa). The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 2- [4- (3- {2-[(S) -1-carbamoyl-2-hydroxyethylcarbamoyl] ethylamino} propoxy) -2-phenoxybenzyl. ] -5-Hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (30 mg) was obtained. This was dissolved in methanol (2 mL), sodium methoxide (0.01 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to ODS solid phase extraction method (washing solvent: distilled water, elution solvent: methanol) and reverse phase preparative column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 mm, 20 × The title compound (5 mg) was obtained by sequentially purifying with 50 mm, flow rate 30 mL / min linear gradient, water / methanol = 90/10 to 10/90).

¹ H-NMR (CD ₃ OD) δ ppm:
1.85-1.95 (2H, m), 2.05 (3H, s), 2.35-2.55 (2H, m), 2.75 (2H, t, J = 7.0Hz), 2.87 (2H, t, J = 6.6Hz), 3.25 -3.45 (4H, m), 3.6-4.0 (8H, m), 4.35-4.45 (1H, m), 4.75-4.9 (1H, m), 6.3-6.35 (1H, m), 6.43 (1H, d, J = 2.2Hz), 6.5-6.6 (2H, m), 6.77 (1H, d, J = 8.6Hz), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.25-7.4 (2H , m)

Reference Example 33
Of 5-benzyloxy-2- [4- (tert-butyldiphenylsilyloxy) -2-phenoxybenzyl] -3-methylphenol 4-bromo-3-phenoxyphenol (2.81 g) and imidazole (1.08 g) To a N, N-dimethylformamide (25 mL) solution was added tert-butyldiphenylsilyl chloride (3.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with diethyl ether. The extract was washed successively with water, 1 mol / L aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane to n-hexane / ethyl acetate = 20/1) to give 4- (tert-butyldiphenylsilyloxy) -2-phenoxybromobenzene (5.1 g). Got. This was dissolved in tetrahydrofuran (30 mL), n-butyllithium (2.44 mol / L n-hexane solution, 3.9 mL) was added at -78 ° C under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a solution of 4-benzyloxy-2-hydroxy-6-methylbenzaldehyde (1 g) in tetrahydrofuran (5 mL) was added, and the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was poured into saturated aqueous ammonium chloride and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 to 4/1) to give 1- (4-benzyloxy-2-hydroxy-6-methylphenyl) -1- [ 4- (tert-Butyldiphenyloxy) -2-phenoxyphenyl] methanol (1.77 g) was obtained. This was dissolved in methylene chloride (25 mL), triethylsilane (2.1 mL) and boron trifluoride / diethyl ether complex (0.84 mL) were added at −50 ° C., and the mixture was stirred for 2 hours. Water was added to the reaction mixture, and the mixture was stirred for 30 minutes. The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 to 4/1) to obtain the title compound (1.1 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.04 (9H, s), 2.23 (3H, s), 3.76 (2H, s), 4.98 (2H, s), 5.53 (1H, s), 6.28 (1H, d, J = 2.5Hz), 6.34 (1H , d, J = 2.5Hz), 6.41 (1H, d, J = 2.5Hz), 6.46 (1H, dd, J = 8.5Hz, 2.5Hz), 6.7-6.85 (3H, m), 7.0-7.1 (1H , m), 7.15-7.25 (2H, m), 7.25-7.45 (11H, m), 7.55-7.65 (4H, m)

Reference Example 34
5-Benzyloxy-2- [4- (tert-butyldiphenylsilyloxy) -2-methylbenzyl] -3-methylphenol 4-Bromo-3-methylphenol was used instead of 4-bromo-3-phenoxyphenol In the same manner as in Reference Example 33, the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.07 (9H, s), 2.13 (3H, s), 2.22 (3H, s), 3.73 (2H, s), 4.58 (1H, s), 5.0 (2H, s), 6.34 (1H, d, J = 2.4Hz), 6.37 (1H, dd, J = 8.4Hz, 2.6Hz), 6.42 (1H, d, J = 8.4Hz), 6.46 (1H, d, J = 2.4Hz), 6.68 (1H, d, J = 2.6Hz), 7.3-7.45 (11H, m), 7.65-7.75 (4H, m)

Reference Example 35
5-Benzyloxy-2- (4-hydroxy-2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- [4 -(Tert-Butyldiphenylsilyloxy) -2-phenoxybenzyl] -3-methylphenol (1.1 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetimidoyl-α Boron trifluoride / diethyl ether complex (0.11 mL) was added to a solution of -D-glucopyranose (1 g) in methylene chloride (10 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1 to 1/1) to give 5-benzyloxy-2- [4- (tert-butyldiphenylsilyloxy) -2- Phenoxybenzyl] -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (1.6 g) was obtained. This was dissolved in tetrahydrofuran (15 mL), tetra (n-butyl) ammonium fluoride (0.47 g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/2 to 1/1) to obtain the title compound (1.15 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.67 (3H, s), 1.98 (3H, s), 2.0 (3H, s), 2.04 (3H, s), 2.11 (3H, s), 3.7-3.85 (2H, m), 3.91 (1H, d, J = 16.8Hz), 4.05-4.15 (1H, m), 4.19 (1H, dd, J = 12.1Hz, 5.9Hz), 4.63 (1H, s), 4.95-5.15 (4H, m), 5.15-5.3 ( 2H, m), 6.33 (1H, d, J = 2.5Hz), 6.39 (1H, dd, J = 8.4Hz, 2.5Hz), 6.53 (1H, d, J = 8.4Hz), 6.57 (1H, d, J = 2.4Hz), 6.62 (1H, d, J = 2.4Hz), 7.0-7.15 (3H, m), 7.3-7.45 (7H, m)

Reference Example 36
5-Benzyloxy-2- (4-hydroxy-2-methylbenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- [4 Instead of-(tert-butyldiphenylsilyloxy) -2-phenoxybenzyl] -3-methylphenol, 5-benzyloxy-2- [4- (tert-butyldiphenylsilyloxy) -2-methylbenzyl] -3- The title compound was obtained in the same manner as in Reference Example 35 using methylphenol.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.41 (3H, s), 1.97 (3H, s), 1.99 (3H, s), 2.03 (3H, s), 2.08 (3H, s), 2.33 (3H, s), 3.55 (1H, d, J = 16.3Hz), 3.75-3.85 (1H, m), 3.87 (1H, d, J = 16.3Hz), 4.05-4.15 (1H, m), 4.2 (1H, dd, J = 12.2Hz, 5.9Hz), 4.48 (1H, s), 4.9-5.15 (4H, m), 5.15-5.25 (2H, m), 6.29 (1H, d, J = 8.3Hz), 6.42 (1H, dd, J = 8.3Hz, 2.6Hz) , 6.55-6.7 (3H, m), 7.3-7.5 (5H, m)

Reference Example 37
5-Benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2 -(4-Hydroxy-2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.52 g) and pyridine (0.5 mL) in methylene chloride (5 mL) To the solution was added trifluoromethanesulfonic anhydride (0.14 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 0.5 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2/1 to 3/2) to give the title compound (0.53 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.63 (3H, s), 1.98 (3H, s), 2.0 (3H, s), 2.04 (3H, s), 2.12 (3H, s), 3.75-3.9 (2H, m), 4.05 (1H, d, J = 17.3Hz), 4.1-4.15 (1H, m), 4.21 (1H, dd, J = 12.2Hz, 5.9Hz), 4.95-5.15 (4H, m), 5.15-5.3 (2H, m), 6.59 ( 1H, d, J = 2.5Hz), 6.61 (1H, d, J = 2.5Hz), 6.67 (1H, d, J = 2.3Hz), 6.74 (1H, d, J = 8.5Hz), 6.8 (1H, dd, J = 8.5Hz, 2.3Hz), 7.05-7.15 (2H, m), 7.15-7.25 (1H, m), 7.3-7.45 (7H, m)

Reference Example 38
5-Benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-methylbenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2 -(4-Hydroxy-2-phenoxybenzyl) -3-methylphenyl instead of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- (4-hydroxy- 2-Methylbenzyl) -3-methylphenyl The title compound was obtained in the same manner as in Reference Example 37 using 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.38 (3H, s), 1.96 (3H, s), 1.98 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.43 (3H, s), 3.6 (1H, d, J = 16.9Hz), 3.75-3.85 (1H, m), 3.97 (1H, d, J = 16.9Hz), 4.05-4.15 (1H, m), 4.2 (1H, dd, J = 12.4Hz, 5.9Hz), 4.98 (1H, d, J = 7.7Hz), 5.0-5.1 (3H, m), 5.15-5.25 (2H, m), 6.52 (1H, d, J = 8.6Hz), 6.59 (1H, d, J = 2.4 Hz), 6.6 (1H, d, J = 2.4Hz), 6.86 (1H, dd, J = 8.6Hz, 2.5Hz), 7.07 (1H, d, J = 2.5Hz), 7.3-7.5 (5H, m)

Reference Example 39
5-Benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β -D-glucopyranoside 5-benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0 .53 g), 3-butenoic acid (0.1 mL), triethylamine (0.42 mL), palladium (II) acetate (14 mg) and tris (2-methylphenyl) phosphine (37 mg) in acetonitrile (5 mL) in an argon atmosphere The mixture was heated under reflux overnight. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed successively with 0.5 mol / L hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2) to obtain the title compound (0.26 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
1.62 (3H, s), 1.97 (3H, s), 1.99 (3H, s), 2.03 (3H, s), 2.08 (3H, s), 3.2-3.25 (2H, m), 3.75-3.85 (2H, m), 3.97 (1H, d, J = 17.4Hz), 4.05-4.15 (1H, m), 4.19 (1H, dd, J = 12.3Hz, 5.6Hz), 4.95-5.15 (4H, m), 5.15- 5.3 (2H, m), 6.05-6.15 (1H, m), 6.3-6.4 (1H, m), 6.57 (1H, d, J = 2.4Hz), 6.6-6.7 (2H, m), 6.88 (1H, d, J = 1.6Hz), 6.94 (1H, dd, J = 8.0Hz, 1.6Hz), 6.95-7.05 (2H, m), 7.05-7.15 (1H, m), 7.3-7.5 (7H, m)

Reference Example 40
5-Benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-methylbenzyl} -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β -D-glucopyranoside instead of 5-benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside And 5-benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-methylbenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside The title compound was obtained in a similar manner to 39.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.34 (3H, s), 1.96 (3H, s), 1.98 (3H, s), 2.02 (3H, s), 2.06 (3H, s), 2.37 (3H, s), 3.25 (2H, d, J = 7.0Hz), 3.61 (1H, d, J = 17.3Hz), 3.75-3.85 (1H, m), 3.94 (1H, d, J = 17.3Hz), 4.05-4.15 (1H, m), 4.2 (1H, dd, J = 12.1Hz, 5.8Hz), 4.9-5.1 (4H, m), 5.1-5.25 (2H, m), 6.1-6.25 (1H, m), 6.35-6.45 (2H, m), 6.55-6.65 (2H, m), 6.9-7.0 (1H, m), 7.15-7.2 (1H, m), 7.25-7.5 (5H, m)

Example 17
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O— Acetyl-β-D-glucopyranoside 5-benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6- To a solution of tetra-O-acetyl-β-D-glucopyranoside (0.26 g) in N, N-dimethylformamide (4 mL) was added 2-amino-2-methylpropionic acid benzyl ester hydrochloride (81 mg), 1-hydroxybenzotriazole. (52 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.12 g) and triethylamine ( .18ML) and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 2/3) to give 5-benzyloxy-2- (4-{(1E) -3- [1-benzyl. Oxycarbonyl-1- (methyl) ethylcarbamoyl] prop-1-enyl} -2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0. 22 g) was obtained. This was dissolved in methanol (4 mL), 10% palladium carbon powder (50 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain the title compound (0.18 g).

¹ H-NMR (CD ₃ OD) δ ppm:
1.42 (6H, s), 1.57 (3H, s), 1.7-1.85 (2H, m), 1.96 (3H, s), 1.98 (3H, s), 2.02 (3H, s), 2.07 (3H, s) , 2.14 (2H, t, J = 7.4Hz), 2.52 (2H, t, J = 7.7Hz), 3.71 (1H, d, J = 16.9Hz), 3.87 (1H, d, J = 16.9Hz), 4.0 -4.1 (1H, m), 4.12 (1H, dd, J = 12.3Hz, 2.2Hz), 4.3 (1H, dd, J = 12.3Hz, 5.8Hz), 5.0-5.15 (2H, m), 5.19 (1H , d, J = 8.2Hz), 5.33 (1H, t, J = 9.5Hz), 6.38 (1H, d, J = 1.9Hz), 6.53 (1H, d, J = 1.9Hz), 6.56 (1H, d , J = 7.8Hz), 6.71 (1H, d, J = 1.4Hz), 6.81 (1H, dd, J = 7.8Hz, 1.4Hz), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m ), 7.3-7.4 (2H, m)

Example 18
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O- Acetyl-β-D-glucopyranoside 5-benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6- Instead of tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-methylbenzyl} -3-methylphenyl 2 , 3,4,6-tetra-O-acetyl-β-D-glucopyranoside was used to obtain the title compound in the same manner as in Example 17.

¹ H-NMR (CD ₃ OD) δ ppm:
1.29 (3H, s), 1.46 (6H, s), 1.75-1.9 (2H, m), 1.93 (3H, s), 1.97 (3H, s), 2.01 (3H, s), 2.09 (3H, s) , 2.16 (2H, t, J = 7.2Hz), 2.33 (3H, s), 2.51 (2H, t, J = 7.7Hz), 3.58 (1H, d, J = 16.8Hz), 3.88 (1H, d, J = 16.8Hz), 4.0-4.1 (1H, m), 4.14 (1H, dd, J = 12.3Hz, 2.0Hz), 4.31 (1H, dd, J = 12.3Hz, 5.4Hz), 5.0-5.2 (3H , m), 5.3 (1H, t, J = 9.5Hz), 6.25-6.35 (1H, m), 6.4-6.45 (1H, m), 6.5-6.6 (1H, m), 6.75-6.85 (1H, m ), 6.95-7.05 (1H, m)

Reference Example 41
2- (4-Bromo-2-methylbenzoyl) -5-hydroxyphenol 4-bromo-2-methylbenzoic acid (2 g) and N, N-dimethylformamide (3 drops) in 1,2-dichloroethane (20 mL) Thionyl chloride (0.75 mL) was added to the suspension, and the mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was cooled to room temperature, resorcinol (1.22 g) and aluminum chloride (1.24 g) were added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into 1 mol / L hydrochloric acid and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 to 5/1) to obtain the title compound (2.38 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.28 (3H, s), 5.85-6.35 (2H, m), 6.44 (1H, d, J = 2.0Hz), 7.1-7.2 (2H, m), 7.35-7.5 (2H, m), 12.58 (1H, s)

Reference Example 42
N of 5-benzyloxy-2- (4-bromo-2-methylbenzyl) phenol 2- (4-bromo-2-methylbenzoyl) -5-hydroxyphenol (2.02 g) and potassium carbonate (1.91 g) , N-dimethylformamide (10 mL) was added with benzyl bromide (1.64 mL) and stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 12/1) to give 1,5-dibenzyloxy-2- (4-bromo-2-methylbenzoyl) benzene (1.95 g). ) Diethyl ether (1.9 mL) of the obtained 1,5-dibenzyloxy-2- (4-bromo-2-methylbenzoyl) benzene (1.85 g) and magnesium dibromide-diethyl ether complex (0.98 g) ) -Toluene (14 mL) suspension was stirred at 75 ° C. overnight. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The extract was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30/1 to 5/1) to give 5-benzyloxy-2- (4-bromo-2-methylbenzoyl) phenol (1. 45 g) was obtained. The obtained 5-benzyloxy-2- (4-bromo-2-methylbenzoyl) phenol (0.67 g) and triethylamine (0.28 mL) were dissolved in tetrahydrofuran (4 mL), and methyl chloroformate ( 0.15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4.5 mL), a solution of sodium borohydride (0.26 g) in water (4.5 mL) was added under ice cooling, and the mixture was stirred for 1 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5/1) to give the title compound (0.59 g).

¹ H-NMR (CDCl ₃ ) δ ppm:
2.26 (3H, s), 3.81 (2H, s), 4.68 (1H, s), 5.01 (2H, s), 6.46 (1H, d, J = 2.5Hz), 6.5 (1H, dd, J = 8.3Hz , 2.5Hz), 6.8 (1H, d, J = 8.3Hz), 6.9 (1H, d, J = 8.1Hz), 7.24 (1H, dd, J = 8.1Hz, 2.1Hz), 7.3-7.45 (6H, m)

Reference Example 43
5-Benzyloxy-2- (4-bromo-2-methylbenzyl) phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-methoxycarbonyloxy-3-methyl-2- ( The title compound was obtained in the same manner as in Reference Example 4 except that 5-benzyloxy-2- (4-bromo-2-methylbenzyl) phenol was used in place of 4-nitrobenzyl) phenol.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.81 (3H, s), 1.99 (3H, s), 2.01 (3H, s), 2.05 (3H, s), 2.2 (3H, s), 3.7 (1H, d, J = 16.4Hz), 3.76 (1H , d, J = 16.4Hz), 3.8-3.9 (1H, m), 4.15 (1H, dd, J = 12.2Hz, 2.7Hz), 4.22 (1H, dd, J = 12.2Hz, 5.8Hz), 4.95- 5.15 (4H, m), 5.2-5.3 (2H, m), 6.58 (1H, dd, J = 8.4Hz, 2.4Hz), 6.65-6.8 (3H, m), 7.2 (1H, dd, J = 8.1Hz , 2.1Hz), 7.25-7.45 (6H, m)

Reference Example 44
5-Benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-methylbenzyl} phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-benzyloxy-2- (4-trifluoromethanesulfonyloxy-2-phenoxybenzyl) -3-methylphenyl instead of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside The title compound was obtained in the same manner as in Reference Example 39 using oxy-2- (4-bromo-2-methylbenzyl) phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. .

¹ H-NMR (CDCl ₃ ) δ ppm:
1.8 (3H, s), 1.99 (3H, s), 2.01 (3H, s), 2.04 (3H, s), 2.2 (3H, s), 3.27 (2H, d, J = 7.1Hz), 3.7-3.9 (3H, m), 4.1-4.2 (1H, m), 4.22 (1H, dd, J = 12.2Hz, 5.9Hz), 4.95-5.2 (4H, m), 5.2-5.35 (2H, m), 6.15- 6.3 (1H, m), 6.46 (1H, d, J = 16.0Hz), 6.56 (1H, dd, J = 8.5Hz, 2.6Hz), 6.65-6.75 (2H, m), 6.85 (1H, d, J = 8.0Hz), 7.05-7.2 (2H, m), 7.25-7.45 (5H, m)

Example 19
2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxyphenyl 2,3,4,6-tetra-O-acetyl-β- D-glucopyranoside 5-benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-phenoxybenzyl} -3-methylphenyl 2,3,4,6-tetra-O- 5-benzyloxy-2- {4-[(1E) -3-carboxyprop-1-enyl] -2-methylbenzyl} phenyl 2,3,4,6-tetra instead of acetyl-β-D-glucopyranoside The title compound was obtained in the same manner as in Example 17 using -O-acetyl-β-D-glucopyranoside.

¹ H-NMR (CD ₃ OD) δ ppm:
1.45 (6H, s), 1.72 (3H, s), 1.8-1.9 (2H, m), 1.97 (3H, s), 2.03 (3H, s), 2.08 (3H, s), 2.1-2.2 (5H, m), 2.55 (2H, t, J = 7.6Hz), 3.66 (1H, d, J = 16.2Hz), 3.7-3.8 (1H, m), 4.05-4.2 (2H, m), 4.33 (1H, dd , J = 12.1Hz, 5.4Hz), 5.0-5.2 (2H, m), 5.24 (1H, d, J = 8.0Hz), 5.37 (1H, t, J = 9.4Hz), 6.4 (1H, dd, J = 8.2Hz, 3.1Hz), 6.6-6.7 (2H, m), 6.73 (1H, d, J = 8.1Hz), 6.85-6.95 (1H, m), 6.95-7.0 (1H, m)

Example 20
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -3-methylphenyl β-D-glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2, To a solution of 3,4,6-tetra-O-acetyl-β-D-glucopyranoside (81 mg) in N, N-dimethylformamide (2 mL), 1- (2-hydroxyethyl) piperazine (14 mg), 1-hydroxybenzotriazole (16 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (38 mg) and tri Ethylamine The (0.07 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1 to 8/1) to give 5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxy Ethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D- Glucopyranoside (42 mg) was obtained. This was dissolved in methanol (2 mL), sodium methoxide (0.01 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS solid phase extraction (washing solvent: distilled water, elution solvent: methanol) to obtain the title compound (25 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.4 (6H, s), 1.75-1.9 (2H, m), 2.04 (3H, s), 2.14 (2H, t, J = 7.5Hz), 2.3-2.65 (8H, m), 3.25-3.45 (4H, m), 3.5-3.75 (7H, m), 3.8-3.95 (2H, m), 3.98 (1H, d, J = 16.3Hz), 4.82 (1H, d, J = 7.2Hz), 6.33 (1H, d , J = 1.9Hz), 6.55 (1H, d, J = 1.8Hz), 6.65-6.75 (1H, m), 6.75-6.85 (2H, m), 6.9-7.0 (2H, m), 7.0-7.1 ( 1H, m), 7.25-7.4 (2H, m)

Example 21
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -3-methylphenyl β-D-glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2, 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl)-instead of 3,4,6-tetra-O-acetyl-β-D-glucopyranoside 5-Hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside was used for the title compound in the same manner as in Example 20. It was obtained.

¹ H-NMR (CD ₃ OD) δ ppm:
1.42 (6H, s), 1.8-1.9 (2H, m), 2.04 (3H, s), 2.1-2.2 (2H, m), 2.37 (3H, s), 2.45-2.6 (8H, m), 3.25- 3.4 (4H, m), 3.55-3.75 (7H, m), 3.75-3.9 (2H, m), 3.99 (1H, d, J = 16.9Hz), 4.77 (1H, d, J = 7.6Hz), 6.38 (1H, d, J = 2.0Hz), 6.5 (1H, d, J = 8.0Hz), 6.58 (1H, d, J = 2.0Hz), 6.78 (1H, d, J = 8.0Hz), 6.97 (1H , s)

Example 22
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) Phenyl β-D-glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxyphenyl instead of 6-tetra-O-acetyl-β-D-glucopyranoside The title compound was obtained in the same manner as in Example 20 using 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹ H-NMR (CD ₃ OD) δ ppm:
1.43 (6H, s), 1.8-1.95 (2H, m), 2.1-2.25 (5H, m), 2.4-2.55 (6H, m), 2.57 (2H, t, J = 7.3Hz), 3.35-3.5 ( 4H, m), 3.5-3.75 (7H, m), 3.85-3.95 (3H, m), 4.8-4.9 (1H, m), 6.33 (1H, dd, J = 8.1Hz, 2.4Hz), 6.6 (1H , d, J = 8.1Hz), 6.66 (1H, d, J = 2.4Hz), 6.85-7.0 (3H, m)

Example 23
5-hydroxy-3-methyl-2- [2-phenoxy-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra- To a solution of O-acetyl-β-D-glucopyranoside (81 mg) in N, N-dimethylformamide (2 mL) was added 1- (benzyloxycarbonyl) piperazine (24 mg), 1-hydroxybenzotriazole (16 mg), 1-ethyl-3. -(3-Dimethylaminopropyl) carbodiimide hydrochloride (38 mg) and triethylamine (0.07 m ), And the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/2 to methylene chloride / methanol = 10/1) to give 2- (4- {3- [1-{[4- ( Benzyloxycarbonyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O— Acetyl-β-D-glucopyranoside (52 mg) was obtained. This was dissolved in methanol (2 mL), 10% palladium carbon powder (25 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. Insolubles were removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in methanol (2 mL), sodium methoxide (0.01 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS solid phase extraction (washing solvent: distilled water, elution solvent: methanol) to obtain the title compound (21 mg).

¹ H-NMR (CD ₃ OD) δ ppm:
1.4 (6H, s), 1.75-1.9 (2H, m), 2.04 (3H, s), 2.14 (2H, t, J = 7.8Hz), 2.54 (2H, t, J = 7.4Hz), 2.7 (4H , brs), 3.25-3.45 (4H, m), 3.5-3.75 (5H, m), 3.8-3.95 (2H, m), 3.98 (1H, d, J = 16.4Hz), 4.82 (1H, d, J = 7.1Hz), 6.33 (1H, d, J = 1.7Hz), 6.55 (1H, d, J = 1.8Hz), 6.65-6.75 (1H, m), 6.75-6.85 (2H, m), 6.9-7.0 (2H, m), 7.0-7.1 (1H, m), 7.25-7.4 (2H, m)

Example 24
5-hydroxy-3-methyl-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra- 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxy-3-methylphenyl instead of O-acetyl-β-D-glucopyranoside The title compound was obtained in the same manner as in Example 23 using 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside.

¹ H-NMR (CD ₃ OD) δ ppm:
1.42 (6H, s), 1.8-1.9 (2H, m), 2.04 (3H, s), 2.1-2.2 (2H, m), 2.37 (3H, s), 2.5-2.6 (2H, m), 2.8- 3.0 (4H, m), 3.25-3.4 (4H, m), 3.55-3.75 (5H, m), 3.75-3.9 (2H, m), 3.98 (1H, d, J = 16.8Hz), 4.77 (1H, d, J = 7.9Hz), 6.38 (1H, d, J = 2.3Hz), 6.5 (1H, d, J = 7.7Hz), 6.58 (1H, d, J = 2.3Hz), 6.78 (1H, d, J = 7.7Hz), 6.96 (1H, s)

Example 25
5-hydroxy-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D-glucopyranoside 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl 2,3,4,6-tetra-O-acetyl- 2- (4- {3- [1-carboxy-1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -5-hydroxyphenyl instead of β-D-glucopyranoside 2,3,4,6- The title compound was obtained in the same manner as in Example 23 using tetra-O-acetyl-β-D-glucopyranoside.

¹ H-NMR (CD ₃ OD) δ ppm:
1.43 (6H, s), 1.8-1.95 (2H, m), 2.1-2.25 (5H, m), 2.57 (2H, t, J = 7.4Hz), 2.65-2.8 (4H, m), 3.35-3.75 ( 9H, m), 3.85-3.95 (3H, m), 4.85-4.9 (1H, m), 6.33 (1H, dd, J = 8.3Hz, 2.2Hz), 6.59 (1H, d, J = 8.3Hz), 6.66 (1H, d, J = 2.2Hz), 6.85-7.0 (3H, m)

Test example 1
Human SGLT1 activity inhibitory action confirmation test 1) Cloning of human SGLT1 and recombination into expression vector Total RNA derived from human small intestine (Ori gene) was reverse transcribed using oligo dT as a primer to prepare a cDNA library for PCR amplification. Using this cDNA library as a template, the nucleotide sequence from No. 1 to No. 2005 of human SGLT1 (ACCESSION: M24847) reported by Hediger et al. Was amplified by PCR, and multiple cloning of pcDNA3.1 (-) (Invitrogen) was performed. Inserted into the site. The base sequence of the inserted DNA completely matched the reported base sequence.

2) Establishment of human SGLT1 stable expression strain A human SGLT1 expression vector was digested with ScaI to form a linear DNA, and then introduced into CHO-K1 cells by the lipofection method (Effectene Transfection Reagent: QIAGEN). A neomycin resistant cell line was obtained with 1 mg / mL G418 (LIFE TECNOLOGIES), and methyl-α-D-glucopyranoside uptake activity was measured by the method described later. The strain showing the strongest uptake activity was selected as CS1-5-11D, and then cultured in the presence of 200 μg / mL G418.

3) Measurement of methyl-α-D-glucopyranoside (α-MG) uptake inhibition activity CS1-5-11D was seeded at 3 × 10 ⁴ cells / well in a 96-well plate, cultured for 2 days, and subjected to an uptake experiment. . Uptake buffer (140 mM sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, 5 mM tris (hydroxymethyl) aminomethane To the buffer pH 7.4), an α-MG mixture of a non-radioactive label (Sigma) and a ¹⁴ C-labeled body (Amersham Pharmacia Biotech) was mixed and added to a final concentration of 1 mM. The test compound was dissolved in dimethyl sulfoxide, and then appropriately diluted with distilled water and added to an uptake buffer containing 1 mM α-MG to obtain a measurement buffer. A buffer for measurement containing no test compound was prepared for the control group, and a buffer for measurement of basal uptake containing 140 mM choline chloride instead of sodium chloride was prepared for the basal uptake measurement. The cultured CS1 medium was removed, 180 μL of pretreatment buffer (basic uptake buffer not containing α-MG) was added per well, and the mixture was allowed to stand at 37 ° C. for 10 minutes. After the same operation was repeated once more, the pretreatment buffer was removed, 75 μL of measurement buffer and basal uptake buffer were added per well, and the mixture was allowed to stand at 37 ° C. One hour later, the measurement buffer was removed, and washed twice with 180 μL of washing buffer (basic uptake buffer containing 10 mM non-labeled α-MG) per well. Cells were lysed with 75 μL of 0.2 mol / L sodium hydroxide per well, and the solution was transferred to a picoplate (Packard). 150 μL of micro scintillation 40 (Packard) was added and mixed, and the radioactivity was measured with a micro scintillation counter top count (Packard). Taking the value obtained by subtracting the basal uptake from the uptake of the control group as 100%, the uptake of methyl-α-D-glucopyranoside at each concentration of the test compound was calculated. The concentration at which the test compound inhibits methyl-α-D-glucopyranoside uptake by 50% (IC ₅₀ value) was calculated by logit plot. The results are shown in Table 1.

Test example 2
Test for confirming inhibitory effect on blood glucose level in rats 1) Preparation of diabetic model rats Nicotinamide (230 mg / kg) was intraperitoneally administered to 8-week-old rats, and streptozotocin (85 mg / kg) was tailed under ether anesthesia 15 minutes later. It was injected intravenously. One week after administration, the rats were fasted overnight and subjected to a glucose tolerance test (2 g / kg). An animal having a plasma glucose concentration of 300 mg / dL or more after 1 hour was selected and used for a liquid feed load test.

2) Liquid feed loading test After fasting the diabetes model rats overnight, the drug (1 mg / kg) dissolved in distilled water was orally administered to the control group and distilled water alone was orally administered to the control group. Immediately after drug administration, 17.25 kcal / kg liquid feed (Oriental Yeast Industry: No. 038, control group dextrin / maltose combination) was orally administered. Blood was collected from the tail artery immediately before drug administration and over time after drug administration, and immediately treated with heparin. After centrifugation, blood was collected and the glucose concentration was quantified with Glucose B Test Wako (Wako Pure Chemical Industries). Table 2 shows plasma glucose concentrations immediately before drug administration (0 hours) and 0.5 hours and 1 hour after drug administration. In addition, the numerical value in a table | surface is represented by the average value +/- standard error.

Claims (22)

Human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula ( IA ) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[In the formula
W ¹ is an oxygen atom or a sulfur atom ;
X ² is a C _1-6 alkylene group which may have a hydroxyl group ;
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ^8a is a C _1-6 alkyl group having 1 to 5 arbitrary groups selected from the following substituent group γ ;
R ^B , R ^D , R ^E and R ^F may be the same or different and each may have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl group; or
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
The prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by the general formula (IA). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , or any group selected from the following substituent group δ Good C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, Each of them is a hydrogen atom, a C _1-6 alkyl group optionally having 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or both are bonded together with an adjacent nitrogen atom Forming a C _2-6 cyclic amino group optionally having any group selected from the following substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] A human SGLT1 activity inhibitor comprising as an active ingredient a benzylphenol derivative represented by the following general formula (Ia) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[In the formula
W ² is a single bond ;
X ³ is a C _1-6 alkylene group or C _2-6 alkenylene group which may have a hydroxyl group;
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ^8b is an aryl group optionally having 1 to 3 arbitrary groups selected from the following substituent group α, and a hetero ring optionally having any group selected from the following substituent group β. An aryl group or a C _1-6 alkyl group optionally having 1 to 5 arbitrary groups selected from the following substituent group γ ;
R ^B , R ^D , R ^E and R ^F may be the same or different and each may have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 or an alkyl group; or together with the nitrogen atom to which Z and R ^8b is adjacent attached, any good C _2-6 cyclic amino group which may have a group selected from the following substituent group δ Forming;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
The prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by the general formula (Ia). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] Human SGLT1 activity inhibitor containing as an active ingredient a benzylphenol derivative represented by the following general formula (Ib) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X ¹ is an C _2-6 alkenylene group;
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ⁸ , R ^B , R ^D , R ^E and R ^F may be the same or different and each have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α. An aryl group, a heteroaryl group optionally having an arbitrary group selected from the following substituent group β, or 1 to 5 arbitrary groups selected from the following substituent group γ or also C _1-6 alkyl group; or Z and together with the nitrogen atom to which R ⁸ is adjacent bonded, may have any group selected from the following substituent group [delta] C _2-6 Forming a cyclic amino group;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
A prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by formula (Ib). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] A human SGLT1 activity inhibitor comprising as an active ingredient a benzylphenol derivative represented by the following general formula (Ic) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X is a C _1-6 alkylene group optionally having a hydroxyl group, a C _2-6 alkenylene group or a single bond (provided that W is a single bond in the case of a single bond);
Y ¹ is —C (═NH) —;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ⁸ , R ^B , R ^D , R ^E and R ^F may be the same or different and each have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α. An aryl group, a heteroaryl group optionally having an arbitrary group selected from the following substituent group β, or 1 to 5 arbitrary groups selected from the following substituent group γ or also C _1-6 alkyl group; or Z and together with the nitrogen atom to which R ⁸ is adjacent bonded, may have any group selected from the following substituent group [delta] C _2-6 Forming a cyclic amino group;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
The prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by the general formula (Ic). Compounds having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group [substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] A human SGLT1 activity inhibitor comprising as an active ingredient a benzylphenol derivative represented by the following general formula (Id) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X is a C _1-6 alkylene group optionally having a hydroxyl group, a C _2-6 alkenylene group or a single bond (provided that W is a single bond in the case of a single bond);
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z ¹ is —CON (R ^D ) R ^E or —C (═NR ^G ) N (R ^H ) R ^I ;
R ⁸ , R ^D, and R ^E may be the same or different and each is a hydrogen atom, an aryl group optionally having 1 to 3 arbitrary groups selected from the following substituent group α, Heteroaryl group optionally having an arbitrary group selected from substituent group β, or C _1-6 optionally having 1 to 5 arbitrary groups selected from the following substituent group γ R ^D and R ^E are combined to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom. And
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
A prodrug is a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 , to one or more arbitrary hydroxyl groups in the compound represented by formula ( Id). A compound having a group selected from an alkoxycarbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group, and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] R ² is a hydrogen atom, a C _1-6 alkyl group, a phenoxy group or a halogen atom, R ³ , R ⁴ and R ⁵ are hydrogen atoms, R ⁶ is a methyl group, R ⁷ is a hydroxyl group, C _{1 A benzylphenol} derivative according to any one of claims 1 to 5 , which is a _-6 alkyl group or a hydroxy (C _1-6 alkyl) group, a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient As a human SGLT1 activity inhibitor. The human SGLT1 activity inhibitor according to any one of claims 1 to 6 , which is a postprandial hyperglycemia inhibitor. The human SGLT1 activity inhibitor according to any one of claims 1 to 6 , which is a preventive or therapeutic agent for a disease caused by hyperglycemia. The diseases caused by hyperglycemia are diabetes, impaired glucose tolerance, fasting glucose abnormalities, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism The human SGLT1 activity inhibitor according to claim 8 , which is a disease selected from the group consisting of abnormalities, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout. The human SGLT1 activity inhibitor according to any one of claims 1 to 6 , which is an agent for inhibiting the transition to diabetes of a person with impaired glucose tolerance or an impaired fasting blood glucose level. The human SGLT1 activity inhibitor according to any one of claims 1 to 6 , which is a preventive or therapeutic agent for a disease caused by an increase in blood galactose level. Diseases caused by the increase in blood galactose value is galactosemia, claim 1 1 human SGLT1 activity inhibitor according. The human SGLT1 activity inhibitor according to any one of claims 1 to 12 , wherein the dosage form is a sustained-release preparation. Insulin sensitivity enhancer, sugar absorption inhibitor, biguanide, insulin secretagogue, SGLT2 activity inhibitor, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptidyl Peptidase IV inhibitor, protein tyrosine phosphatase-1B inhibitor, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, fructose-bisphosphatase inhibitor, pyruvate dehydrogenase inhibitor, hepatic gluconeogenesis inhibitor, D-kaileunositol, Glycogen synthase kinase-3 inhibitor, glucagon-like peptide-1, glucagon-like peptide 1-analog, glucagon-like peptide-1 agonist, amylin, amylin analog, amylin Nyst, aldose reductase inhibitor, advanced glycation endogenesis inhibitor, protein kinase C inhibitor, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N- Acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy- 1-methylhydantoin, bimoclomol , sulodexide , antipruritics , laxatives, hydroxymethylglutaryl coenzyme A reductase inhibitors, fibrate compounds, β ₃ -adrenergic receptor agonists, acylcoenzyme A: cholesterol acyltransferase inhibitors, Probucol Thyroid hormone receptor agonist, cholesterol absorption inhibitor, lipase inhibitor, microsomal triglyceride transfer protein inhibitor, lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low density lipoprotein receptor potentiator, nicotinic acid derivative , Bile acid adsorbent, sodium conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor, appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor drugs, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensives, sympatholytic agents, central antihypertensives, alpha ₂ - adrenergic receptor agonists, antiplatelet agents Uric acid production inhibitor, comprising a combination of at least one agent selected from the group consisting of uricosuric agents and uric alkalinization medicine, human SGLT1 activity inhibitor according to any one of claims 1-6. A benzylphenol derivative represented by the following general formula (Ib) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X ¹ is an C _2-6 alkenylene group;
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ⁸ , R ^B , R ^D , R ^E and R ^F may be the same or different and each have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α. An aryl group, a heteroaryl group optionally having an arbitrary group selected from the following substituent group β, or 1 to 5 arbitrary groups selected from the following substituent group γ or also C _1-6 alkyl group; or Z and together with the nitrogen atom to which R ⁸ is adjacent bonded, may have any group selected from the following substituent group [delta] C _2-6 Forming a cyclic amino group;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
A prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by formula (Ib). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] A benzylphenol derivative represented by the following general formula (Ic) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X is a C _1-6 alkylene group optionally having a hydroxyl group, a C _2-6 alkenylene group or a single bond (provided that W is a single bond in the case of a single bond);
Y ¹ is —C (═NH) —;
Z is a hydrogen atom, C _2-7 alkoxycarbonyl group, a formyl ^{group, -R B, -COR C, -SO} 2 R C, -CON (R D) R E, -CSN (R D) R E, - SO ₂ NHR ^F or —C (═NR ^G ) N (R ^H ) R ^I ;
R ^C is C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, arylsulfonylamino group, aryl optionally having 1 to 3 arbitrary groups selected from the following substituent group α A group, a heteroaryl group optionally having any group selected from the following substituent group β, or C optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _1-6 alkyl groups;
R ⁸ , R ^B , R ^D , R ^E and R ^F may be the same or different and each have 1 to 3 arbitrary groups selected from a hydrogen atom and the following substituent group α. An aryl group, a heteroaryl group optionally having an arbitrary group selected from the following substituent group β, or 1 to 5 arbitrary groups selected from the following substituent group γ or also C _1-6 alkyl group; or Z and together with the nitrogen atom to which R ⁸ is adjacent bonded, may have any group selected from the following substituent group [delta] C _2-6 Forming a cyclic amino group;
R ^D and R ^E combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
The prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by the general formula (Ic). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl) group and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group [Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] A benzylphenol derivative represented by the following general formula (Id) or a pharmacologically acceptable salt thereof, or a prodrug thereof:

[Wherein W is an oxygen atom, a sulfur atom or a single bond;
X is a C _1-6 alkylene group optionally having a hydroxyl group, a C _2-6 alkenylene group or a single bond (provided that W is a single bond in the case of a single bond);
Y is a carbonyl group, a sulfonyl group, —C (═NH) — or a single bond;
Z ¹ is —CON (R ^D ) R ^E or —C (═NR ^G ) N (R ^H ) R ^I ;
R ⁸ , R ^D, and R ^E may be the same or different and each is a hydrogen atom, an aryl group optionally having 1 to 3 arbitrary groups selected from the following substituent group α, Heteroaryl group optionally having an arbitrary group selected from substituent group β, or C _1-6 optionally having 1 to 5 arbitrary groups selected from the following substituent group γ R ^D and R ^E are combined to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom. And
R ^G , R ^H and R ^I may be the same or different and are each a hydrogen atom, a cyano group, a carbamoyl group, a C _2-6 acyl group, a C _2-7 alkoxycarbonyl group, an aryl (C _2-7 Alkoxycarbonyl) group, nitro group, C _1-6 alkylsulfonyl group, sulfamide group, carbamimidoyl group, or C ₁ optionally having 1 to 5 arbitrary groups selected from the following substituent group γ _-6 alkyl groups; or R ^G and R ^H combine to form an ethylene group;
R ^H and R ^I combine to form a C _2-6 cyclic amino group which may have an arbitrary group selected from the following substituent group δ together with the adjacent nitrogen atom;
R ² is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a phenoxy group, a phenylthio group, a phenylamino group, or a halogen atom;
R ^{3 to} R ⁵ may be the same or different and are each a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a halogen atom;
R ⁶ is a hydrogen atom or a C _1-6 alkyl group;
R ⁷ represents a hydrogen atom, a hydroxyl group, an amino group, a mono- or di (C _1-6 alkyl) amino group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy (C _1-6 alkyl) group, or a carbamoyl group. A (C _1-6 alkyl) group;
G is the formula

Or expression

A group represented by:
The prodrug has a C _2-7 acyl group, a C _1-6 alkoxy (C _2-7 acyl) group, a C _2-7 alkoxy group on one or more arbitrary hydroxyl groups in the compound represented by formula ( Id). A compound having a group selected from a carbonyl (C _2-7 acyl) group, a C _2-7 alkoxycarbonyl group and a C _1-6 alkoxy (C _2-7 alkoxycarbonyl) group;
[Substituent group α]
Halogen atom, hydroxyl group, amino group, C _1-6 alkylsulfonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkyl group, C _1-6 alkoxy group, amino (C _1-6 alkyl group) and C _2-7 alkoxycarbonyl group (substituent group β)
Halogen atom, amino group and C _1-6 alkyl group [substituent group γ]
Hydroxyl group, C _1-6 alkoxy group, C _1-6 alkylthio group, amino group, mono- or di (C _1-6 alkyl) amino group, mono- or di [hydroxy (C _1-6 alkyl)] amino group, ureido group , Sulfamide group, mono or di (C _1-6 alkyl) ureido group, mono or di (C _1-6 alkyl) sulfamide group, C _2-6 acylamino group, amino (C _2-6 acylamino) group, C _{1- 6} alkylsulfonyl group, C _1-6 alkylsulfonylamino group, carbamoyl (C _1-6 alkylsulfonylamino) group, carboxy group, C _2-7 alkoxycarbonyl group, —CON (R ^J ) R ^K , the following substituent group gamma any group which may have on the 1-3 ring aryl selected from ² (C _1-6 alkoxy) group, any group selected from the following substituent group gamma ² 1-3 Aryl (C _1-6 alkyl) optionally present on an individual ring Ruthio) group, C _3-7 cycloalkyl group, C _2-6 heterocycloalkyl group, —NHC (═N—CN) NHR ^L , and 1 to 3 arbitrary groups selected from the above substituent group α An optionally selected aryl group, a heteroaryl group optionally having an arbitrary group selected from the substituent group β, and an arbitrary group selected from the following substituent group δ. C _2-6 cyclic amino group, C _1-4 aromatic cyclic amino group and C _1-6 alkyl (C _1-4 aromatic cyclic amino) group R ^J and R ^K may be the same or different, , A hydrogen atom, a C _1-6 alkyl group which may have 1 to 3 arbitrary groups selected from the following substituent group γ ¹ , or the following together with the adjacent nitrogen atom bonded to each other Forming a C _2-6 cyclic amino group optionally having any group selected from the substituent group δ;
R ^L is a C _1-6 alkyl group or a hydroxy (C _1-6 alkyl) group.
[Substituent group γ ¹ ]
A hydroxyl group, an amino group, a mono or di (C _1-6 alkyl) amino group, a mono or di [hydroxy (C _1-6 alkyl)] amino group, a ureido group, a mono or di (C _1-6 alkyl) ureido group, C _2-6 acylamino group, C _1-6 alkylsulfonylamino group and carbamoyl group [substituent group γ ² ]
Halogen atom, hydroxyl group, amino group, C _1-6 alkyl group and C _1-6 alkoxy group
[Substituent group δ]
Hydroxyl group, carbamoyl group, C _1-6 alkyl group, oxo group, carbamoyl (C _1-6 alkyl) group, hydroxy (C _1-6 alkyl) group and C _1-6 alkylsulfonylamino (C _1-6 alkyl) group ] R ² is a hydrogen atom, a C _1-6 alkyl group, a phenoxy group or a halogen atom, R ³ , R ⁴ and R ⁵ are hydrogen atoms, R ⁶ is a methyl group, R ⁷ is a hydroxyl group, C _{1 The benzylphenol} derivative according to any one of claims 15 to 17 , which is a _-6 alkyl group or a hydroxy (C _1-6 alkyl) group, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A pharmaceutical composition comprising the benzylphenol derivative according to any one of claims 15 to 18 or a pharmacologically acceptable salt thereof, or a prodrug thereof as an active ingredient. The pharmaceutical composition according to claim 19 , wherein the dosage form is a sustained-release preparation. (A) The benzylphenol derivative or the pharmacologically acceptable salt thereof according to any one of claims 15 to 18 , or a prodrug thereof, and (B) an insulin sensitivity enhancer, a sugar absorption inhibitor, a biguanide Drugs, insulin secretagogues, SGLT2 activity inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors Drugs, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-kaileunositol, glycogen synthase kinase-3 Pesticide, glucagon-like peptide-1, glucagon-like peptide 1-analogue, glucagon-like peptide-1 agonist, amylin, amylin analogue, amylin agonist, aldose reductase inhibitor, terminal glycation endogenesis inhibitor, protein kinase C inhibition Drug, γ-aminobutyric acid receptor antagonist, sodium channel antagonist, transcription factor NF-κB inhibitor, lipid peroxidase inhibitor, N-acetylated-α-linked-acid-dipeptidase inhibitor, insulin-like growth factor- I, platelet-derived growth factor, platelet-derived growth factor analog, epidermal growth factor, nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, bimoclomol , sulodexide, antidiarrheal , laxative, hydroxymethylglutaryl Coenzyme A reductase Harm drugs, fibrate compounds, beta ₃ - adrenergic receptor agonists, acyl-coenzyme A: cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors , Lipoxygenase inhibitor, carnitine palmitoyltransferase inhibitor, squalene synthase inhibitor, low density lipoprotein receptor potentiator, nicotinic acid derivative, bile acid adsorbent, sodium-conjugated bile acid transporter inhibitor, cholesterol ester transfer protein inhibitor , Appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor Antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, exchange blockers, central antihypertensives, α ₂ -adrenoceptor agonists, antiplatelet agents, uric acid production inhibitors, uric acid excretion promoters and urinary alkali A pharmaceutical comprising a combination of at least one drug selected from the group consisting of chemicals. A compound selected from the following group:
5-hydroxy-3-methyl-2- {4- [3- (3-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-ureidobenzyl) phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- {4- [3- (2-pyridylmethyl) ureido] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (4-hydroxy-3-methoxybenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- (4- {3-[(S) -1-carbamoyl-2- (4-hydroxyphenyl) ethyl] ureido} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- {4-[(E) -2- (2-pyridylmethylcarbamoyl) vinyl] benzyl} phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-{(E) -2- [3- (morpholin-4-yl) propylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- (4-{(E) -2- [2- (sulfamoylamino) ethylcarbamoyl] vinyl} benzyl) phenyl β-D-glucopyranoside;
2- (4- {3- [2-cyano-3- (2-hydroxyethyl) guanidino] propoxy} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3-Benzylureido) benzyl] -5-hydroxy-3-methylphenyl
  β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (3,4-dimethoxybenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- {4- [3- (4-methanesulfonylbenzyl) ureido] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- {4- [3- (3-aminomethylbenzyl) ureido] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [3- (imidazol-1-yl) propyl] ureido} benzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [2- (4-hydroxyphenyl) ethyl] ureido} benzyl) -3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (2-aminoethylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (3-aminopropylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4-[(E) -2- (4-aminobutylcarbamoyl) vinyl] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- {4-[(E) -2- (2-methanesulfonylaminoethylcarbamoyl) vinyl] benzyl} -3-methylphenyl β-D-glucopyranoside;
2- (4-{(E) -2- [2- (2-aminoacetylamino) ethylcarbamoyl] vinyl} benzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- {4- [3- (2-cyano-3-methylguanidino) propoxy] benzyl} -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3-guanidinopropoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (4-guanidinobutoxy) benzyl] -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- (4- {3- [2- (carbamoyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- (4- {3- [1-carbamoyl-1- (methyl) ethylamino] propoxy} -2-phenoxybenzyl) -5-hydroxy-3-methylphenyl β-D-glucopyranoside;
2- [4- (3- {2-[(S) -1-carbamoyl-2-hydroxyethylcarbamoyl] ethylamino} propoxy) -2-phenoxybenzyl] -5-hydroxy-3-methylphenyl β-D- Glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-phenoxybenzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) -3-methylphenyl β-D-glucopyranoside;
5-hydroxy-2- (4- {3- [1-{[4- (2-hydroxyethyl) piperazin-1-yl] carbonyl} -1- (methyl) ethylcarbamoyl] propyl} -2-methylbenzyl) Phenyl β-D-glucopyranoside;
5-hydroxy-3-methyl-2- [2-phenoxy-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside;
5-hydroxy-3-methyl-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D -Glucopyranoside;
5-hydroxy-2- [2-methyl-4- (3- {1-[(piperazin-1-yl) carbonyl] -1- (methyl) ethylcarbamoyl} propyl) benzyl] phenyl β-D-glucopyranoside;
And pharmacologically acceptable salts thereof.