HK1099556B - Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof - Google Patents

Description

Fused heterocyclic derivative, pharmaceutical composition comprising same, and pharmaceutical use thereof

Technical Field

The present invention relates to a fused heterocyclic derivative and a pharmaceutically acceptable salt thereof or a prodrug thereof useful as a medicament, a pharmaceutical composition comprising the fused heterocyclic derivative and the pharmaceutically acceptable salt thereof or the prodrug thereof, and a pharmaceutical use thereof.

More particularly, the present invention relates to a fused heterocyclic derivative having an inhibitory effect on human SGLT activity, a pharmaceutically acceptable salt thereof or a prodrug thereof, which is useful as an agent for the prophylaxis or treatment of diseases associated with hyperglycemia such as diabetes, impaired glucose tolerance, diabetic complications or obesity; a pharmaceutical composition comprising the fused heterocyclic derivative, a pharmaceutically acceptable salt thereof or a prodrug thereof; and pharmaceutical applications thereof.

Background

Diabetes is a lifestyle disease with a background of dietary changes and lack of exercise. Thus, diet therapy and exercise therapy are performed in patients with diabetes. In addition, when its adequate control and continued implementation are difficult, medication is performed at the same time. In addition, it has been confirmed by large-scale clinical trials that it is necessary to strictly control blood glucose levels for a long period of time in order to prevent diabetic patients from developing and developing diabetic complications by receiving treatment (see, for example, references 1 and 2 below). In addition, many epidemiological studies on impaired glucose tolerance and macroangiopathy (macroangiopathy) indicate that impaired glucose tolerance, which is a borderline type, is also a risk factor for macroangiopathy as well as diabetes. Therefore, the need for improvement of postprandial hyperglycemia has been focused (for example, see the following reference 3).

In recent years, development of different therapeutic agents for diabetes has been carried out in an environment where diabetic patients have proliferated. For example, diabetes therapeutic agents such as biguanides, sulfonylureas, insulin sensitivity enhancers, α -glucosidase inhibitors, and the like have been used. However, biguanides and sulfonylureas occasionally exhibit side effects, such as lactic acidosis and hypoglycemia, respectively. Insulin sensitivity enhancers occasionally exhibit side effects such as edema, and concerns about their promotion of obesity. In addition, alpha-glucosidase inhibitors that delay carbohydrate digestion and absorption in the small intestine are useful for improving postprandial hyperglycemia. Acarbose (acarbose), an α -glucosidase inhibitor, has also been reported to have an effect of preventing or delaying the onset of diabetes by applying it to patients suffering from impaired glucose tolerance (for example, see reference 4 below). However, since α -glucosidase inhibitors do not affect the elevated glucose caused by the uptake of glucose monosaccharides (for example, see reference 5 below), with the change in sugar composition in the recent diet, a wider range of carbohydrate absorption inhibitory activity has been required.

In recent years, research and development of a novel therapeutic agent for diabetes, which promotes urinary glucose excretion and lowers blood glucose level by preventing reabsorption of excess glucose in the kidney, have been conducted (for example, see the following reference 6). In addition, SGLT2 (sodium-dependent glucose transporter 2) is reported to be present in the S1 segment of the proximal tubule (proximal tubule) of the kidney and is mainly involved in the reabsorption of glucose filtered through the glomerulus (for example, see reference 7 below). Therefore, inhibition of human SGLT2 activity prevents reabsorption of excess glucose in the kidney, subsequently promotes excretion of excess glucose through urine, and normalizes blood glucose level. In addition, since the urine sugar excretion-promoting drugs excrete excessive blood sugar through urine, and thus sugar accumulation in the body is reduced, they are also expected to have a preventive or alleviating effect on obesity and a diuretic effect. In addition, the drug is considered to be useful for various associated diseases that appear with the progression of diabetes or obesity caused by hyperglycemia.

Furthermore, SGLT1 (sodium-dependent glucose transporter 1) is known to be present in the small intestine that controls carbohydrate absorption. It has also been reported that glucose and galactose malabsorption occurs in patients with dysfunction caused by congenital abnormality of human SGLT1 (for example, see the following references 8 to 10). In addition, SGLT1 has been confirmed to be involved in the absorption of glucose and galactose (for example, see the following references 11 and 12). Furthermore, it has been confirmed that mRNA and protein of SGLT1 are increased and absorption of glucose is promoted in OLETF rats and rats having streptozotocin-induced diabetic symptoms (for example, see the following references 13 and 14). Generally, in diabetic patients, digestion and absorption of carbohydrates is increased. For example, it has been confirmed that mRNA and protein of SGLT1 are highly increased in the human small intestine (for example, see the following reference 15). Therefore, blocking human SGLT1 activity inhibits absorption of carbohydrates such as glucose in the small intestine, and consequently can prevent an increase in blood glucose level. In particular, delaying sugar absorption based on the above mechanism is considered to be effective for normalizing postprandial hyperglycemia.

Therefore, it has been desired to rapidly develop a therapeutic agent for diabetes having a novel mechanism of action with an inhibitory effect on human SGLT activity to improve or solve the above-mentioned problems.

The fused heterocyclic derivative provided by the invention is a novel compound. These derivatives have not been reported to have SGLT1 and/or SGLT2 inhibitory activity and to inhibit the absorption of glucose and galactose in the small intestine, or to be useful as a medicament for inhibiting the reabsorption of excess glucose in the kidney.

Reference 1: the Diabetes Control and compatibility Trial research group, N.Engl.J.Med., 1993.9, Vol.329, No.14, pp.977-986;

reference 2: UK reactive Diabetes Study Group, Lancet, 1998.9, Vol.352, No.9131, pp.837-853;

reference 3: makoto ToMINAGA, Endocrinology & diabetes, 2001.11, Vol.13, No.5, pp.534-542;

reference 4: Jean-Louis Chiasson et al, Lancet, 2002.6, Vol.359, No.9323, pp.2072-2077;

reference 5: hiroyuki ODAKA et al, Journal of Japanese society of Nutrition and Food Science, 1992, Vol.45, p.27;

reference 6: five people, Luciano Rossetti et al, J.Clin.Invest., 1987.5, Vol.79, pp.1510-1515;

reference 7: yoshikatsu Kanai et al, J.Clin.Invest., 1994.1, Vol.93, pp.397-404;

reference 8: tadao BABA et al, Supplementary volume of Nippon Rinsho, Ryoikibietsu Shokogoun, 1998, No.19, pp.552-554;

reference 9: michihiro KasaHARA et al, Saishin Igaku, 1996.1, Vol.51, No.1, pp.84-90;

reference 10: tomofusa TSUCHIYA et al, Nippon Rinsho, 1997.8, Vol.55, No.8, pp.2131-2139;

reference 11: yoshikatsu KANAI, Kidney and analysis, 1998.12, Vol.45, extra edition, pp.232-237;

reference 12: turk et al, Nature, 1991.3, Vol.350, pp.354-356;

reference 13: Y.Fujita et al, Diabetologia, 1998, Vol.41, pp.1459-1466;

reference 14: six people, dye et al, Biochemical Society Transactions, 1997, Vol.25, p.479S;

reference 15: five of Dyer et al, American Journal of Physiology, 2002.2, Vol.282, No.2, pp.G241-G248.

DISCLOSURE OF THE INVENTION

The present inventors have conducted earnest studies to find a compound having an inhibitory effect on human SGLT activity. As a result, it was found that certain fused heterocyclic derivatives represented by the following general formula (I) exhibit human SGLT1 and/or SGLT2 inhibitory activity as described below and are excellent drugs having an inhibitory effect on the increase in blood glucose level or an inhibitory effect on the decrease in blood glucose level, thereby forming the basis of the present invention.

The present invention provides novel compounds exhibiting inhibitory effects on human SGLT activity, pharmaceutical compositions comprising the compounds, and pharmaceutical uses thereof.

That is, the present invention relates to:

[1] a fused heterocyclic derivative represented by the following general formula (I):

wherein

R¹And R⁴One represents a group represented by the following general formula:

[ in the formula, R⁵And R⁶Independently represent a hydrogen atom, a hydroxyl group, a halogen atom, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_2-6Alkenyloxy radical, C_1-6Alkylthio radical, C_2-6Alkenylthio, halo (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, halo (C)_1-6Alkylthio) group, hydroxy (C)_1-6Alkyl) group, hydroxy (C)_2-6Alkenyl) group, hydroxy (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkylthio) group, carboxyl group (C)_1-6Alkyl) group, carboxyl (C)_2-6Alkenyl) group, carboxyl (C)_1-6Alkoxy) group, carboxyl (C)_1-6Alkylthio) radical, C_2-7Alkoxycarbonyl group, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) groups, a,C_2-7Alkoxycarbonyl (C)_2-6Alkenyl) group, C_2-7Alkoxycarbonyl (C)_1-6Alkoxy) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkylthio) radical, C_1-6Alkylsulfinyl radical, C_1-6Alkylsulfonyl, -U-V-W-N (R)⁷) -Z, or any of the following substituents (i) to (xxviii) which may have 1 to 3 substituents on the ring selected from the following substituent group α;

(i)C_6-10aryl group, (ii) C_6-10aryl-O-, (iii) C_6-10aryl-S-, (iv) C_6-10Aryl radical (C)_1-6Alkyl) group, (v) C_6-10Aryl radical (C)_1-6Alkoxy) group, (vi) C_6-10Aryl radical (C)_1-6Alkylthio) groups, (vii) heteroaryl, (viii) heteroaryl-O-, (ix) heteroaryl-S-, (x) heteroaryl (C)_1-6Alkyl) group, (xi) heteroaryl (C)_1-6Alkoxy) group, (xii) heteroaryl (C)_1-6Alkylthio) groups, (xiii) C_3-7Cycloalkyl, (xiv) C_3-7cycloalkyl-O-, (xv) C_3-7cycloalkyl-S-, (xvi) C_3-7Cycloalkyl (C)_1-6Alkyl) group, (xvii) C_3-7Cycloalkyl (C)_1-6Alkoxy) group, (xviii) C_3-7Cycloalkyl (C)_1-6Alkylthio) groups, (xix) heterocycloalkyl, (xx) heterocycloalkyl-O-, (xxi) heterocycloalkyl-S-, (xxii) heterocycloalkyl (C)_1-6Alkyl) group, (xxiii) heterocycloalkyl (C)_1-6Alkoxy) groups, (xxiv) heterocycloalkyl (C)_1-6Alkylthio) group, (xxv) aromatic cyclic amino group, (xxvi) aromatic cyclic amino group (C)_1-6Alkyl) group or (xxvii) aromatic cyclic amino (C)_1-6Alkoxy) group, (xxviii) aromatic cyclic amino group (C)_1-6An alkylthio) group, a mercapto group,

u represents-O-, -S-or a single bond, (provided that when U is-O-or-S-, at least one of V and W is not a single bond);

v represents C which may have a hydroxyl group_1-6Alkylene radical, C_2-6Alkenylene or a single bond;

w represents-CO-, -SO₂-, -C (═ NH) -, or a single bond;

z independently represents a hydrogen atom, C_2-7Alkoxycarbonyl group, C_6-10Aryl radical (C)_2-7Alkoxycarbonyl) radical, formyl radical, -R^A、-COR^B、-SO₂R^B、-CON(R^C)R^D、-CSN(R^C)R^D、-SO₂NHR^Aor-C (═ NR)^E)N(R^F)R^G；

R⁷、R^A、R^CAnd R^DIndependently represents a hydrogen atom, C which may have 1 to 5 substituents selected from the following substituent group beta_1-6Alkyl, or any of the following substituents (xxix) to (xxxii) which may have 1 to 3 substituents selected from the following substituent group α;

(xxix)C_6-10aryl, (xxx) heteroaryl, (xxxi) C_3-7Cycloalkyl or (xxxii) heterocycloalkyl,

or Z and R⁷An aliphatic cyclic amino group which may have 1 to 3 substituents selected from the following substituent group α, in combination with an adjacent nitrogen atom;

or R^CAnd R^DAn aliphatic cyclic amino group which may have 1 to 3 substituents selected from the following substituent group α, in combination with an adjacent nitrogen atom;

R^Bis represented by C_2-7Alkoxycarbonyl group, C_1-6Alkylsulfonylamino group, C_6-10Arylsulfonylamino group, C which may have 1 to 5 substituents selected from the following substituent group beta_1-6Alkyl, or any of the following substituents (xxxiii) to (xxxvi) which may have 1 to 3 substituents selected from the following substituent group α;

(xxxiii)C_6-10aryl, (xxxiv) heteroaryl, (xxxv) C_3-7Cycloalkyl or (xxxvi) heterocycloalkyl,

R^E、R^Fand R^GIndependently represents a hydrogen atom, a cyano group, a carbamoyl group, C_2-7Acyl radical, C_2-7Alkoxycarbonyl group, C_6-10Aryl radical (C)_2-7Alkoxycarbonyl) radical, nitro radical, C_1-6Alkylsulfonyl, sulfonamide group, amidino group, or C having 1 to 5 substituents selected from the following substituent group beta_1-6An alkyl group;

or R^EAnd R^FTaken together to form an ethylene group;

or R^FAnd R^GAn aliphatic cyclic amino group which may have any substituent selected from the following substituent group α is formed in combination with an adjacent nitrogen atom;

q represents-C_1-6Alkylene-, -C_2-6Alkenylene radical-, -C_2-6Alkynylene-, -C_1-6alkylene-O-, -C_1-6alkylene-S-, -O-C_1-6Alkylene-, -S-C_1-6Alkylene-, -C_1-6alkylene-O-C_1-6Alkylene-, -C_1-6alkylene-S-C_1-6Alkylene-, -CON (R)⁸)-、-N(R⁸)CO-、-C_1-6alkylene-CON (R)⁸) -or-CON (R)⁸)-C_1-6Alkylene-;

R⁸represents a hydrogen atom or C_1-6An alkyl group;

ring A represents C_6-10Aryl or heteroaryl radicals]

R¹And R⁴The other one of (A) and (B) represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxyl, C_2-7Alkoxycarbonyl, carbamoyl, mono-or di (C)_1-6Alkyl) amino, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) group, cyano (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carbamoyl (C)_1-6Alkyl) group, amino (C)_1-6Alkyl) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkyl) groups, a,Halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkoxy) group, carboxyl (C)_1-6Alkoxy) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkoxy) group, carbamoyl (C)_1-6Alkoxy) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkoxy) radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkoxy, C_3-7Cycloalkyl (C)_1-6Alkyl) group, or C_3-7Cycloalkyl (C)_1-6Alkoxy) groups;

R²and R³Independently represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxyl, C_2-7Alkoxycarbonyl, carbamoyl, mono-or di (C)_1-6Alkyl) amino, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) group, cyano (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carbamoyl (C)_1-6Alkyl) group, amino (C)_1-6Alkyl) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkoxy) group, carboxyl (C)_1-6Alkoxy) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkoxy) group, carbamoyl (C)_1-6Alkoxy) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkoxy) radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkoxy, C_3-7Cycloalkyl (C)_1-6Alkyl) group, or C_3-7Cycloalkyl (C)_1-6Alkoxy) groups;

A¹denotes O, S or NR⁹；

A²Represents CH or N;

R⁹represents a hydrogen atom or C_1-6An alkyl group;

g represents a group of the formula:

or a group of the formula

；

E¹Represents a hydrogen atom, a fluorine atom or a hydroxyl group;

E²represents a hydrogen atom, a fluorine atom, a methyl group or a hydroxymethyl group;

[ substituent group α ]

Halogen atom, hydroxy group, amino group, C_1-6Alkyl radical, C_1-6Alkoxy, halo (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkoxy) group, amino (C)_1-6Alkyl) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Amino group, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylsulfonylamino (C)_1-6Alkyl) group, carboxyl group, C_2-7Alkoxycarbonyl, sulfamoyl and-CON (R)^H)R^I，

[ substituent group β ]

Halogen atom, hydroxy group, amino group, C_1-6Alkoxy radical, C_1-6Alkylthio, halo (C)_1-6Alkoxy) group, halo (C)_1-6Alkylthio) groups,Hydroxy (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkylthio) group, amino (C)_1-6Alkoxy) group, amino (C)_1-6Alkylthio) groups, mono-or di (C)_1-6Alkyl) amino, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Amino, ureido, sulfonamide, mono-or di (C)_1-6Alkyl) ureido, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Ureido, mono-or di (C)_1-6Alkyl) sulfonamido, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Sulfonamide, C_2-7Acylamino, amino (C)_2-7Acylamino) group, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, carbamoyl group (C)_1-6Alkylsulfonylamino) group, carboxyl group, C_2-7Alkoxycarbonyl, -CON (R)^H)R^IAnd any of the following substituents (xxxvii) to (xxxxviii) which may have 1 to 3 substituents selected from the above substituent group α;

(xxxvii)C_6-10aryl, (xxxviii) C_6-10aryl-O-, (xxxix) C_6-10Aryl radical (C)_1-6Alkoxy) radicals, (xxxx) C_6-10Aryl radical (C)_1-6Alkylthio) groups, (xxxxxxi) heteroaryl, (xxxxii) heteroaryl-O-, (xxxxiii) C_3-7Cycloalkyl, (xxxxiv) C_3-7cycloalkyl-O-, (xxxxv) heterocycloalkyl, (xxxxvi) heterocycloalkyl-O-, (xxxxvii) aliphatic cyclic amino or (xxxxviii) aromatic cyclic amino

R^HAnd R^IIndependently represents a hydrogen atom or C which may have 1 to 3 substituents selected from the following substituent group γ_1-6An alkyl group;

or R^HAnd R^IBoth of which combine together with the adjacent nitrogen atom to form an aliphatic cyclic amino group which may have 1 to 3 substituents selected from the following substituent group δ;

[ substituent group. gamma ]

Halogen atom, hydroxy group, amino group, C_1-6Alkoxy, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkoxy) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Amino, ureido, sulfonamide, mono-or di (C)_1-6Alkyl) ureido, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Ureido, mono-or di (C)_1-6Alkyl) sulfonamido, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Sulfonamide, C_2-7Acylamino, amino (C)_2-7Acylamino) group, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, carbamoyl group (C)_1-6Alkylsulfonylamino) group, carboxyl group, C_2-7Alkoxycarbonyl, sulfamoyl and-CON (R)^J)R^K，

[ substituent group Delta ]

Halogen atom, hydroxy group, amino group, C_1-6Alkyl radical, C_1-6Alkoxy, halo (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkoxy) group, amino (C)_1-6Alkyl) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino, mono-or di [ hydroxy (C)_1-6Alkyl radical)]Amino group, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylsulfonylamino (C)_1-6Alkyl) group, carboxyl group, C_2-7Alkoxycarbonyl, sulfamoyl and-CON (R)^J)R^K，

R^JAnd R^KIndependently represents a hydrogen atom or C which may have any 1 to 3 substituents_1-6Alkyl, said substituent being selected from hydroxy, amino, mono-or di (C)_1-6Alkyl) amino, C_2-7Alkoxycarbonyl and carbamoyl;

or R^JAnd R^KBoth of which are bonded together with the adjacent nitrogen atom to form an aliphatic cyclic amino group which may have any 1 to 3 substituents selected from the group consisting of hydroxy, amino, mono-or di (C)_1-6Alkyl) amino, C_1-6Alkyl, hydroxy (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl group, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) groups and carbamoyl groups,

or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[2] a fused heterocyclic derivative as described in the above [1], or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

wherein Q represents a methylene group, an ethylene group or-OCH group₂-、-CH₂O-、-SCH₂-or-CH₂S-；

[3] A fused heterocyclic derivative described in the above [2], wherein Q represents an ethylene group;

[4] a fused heterocyclic derivative described in the above [2], wherein Q represents a methylene group;

[5]above-mentioned [1]The fused heterocyclic derivative described in (1), or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R⁵And R⁶Independently represent a hydrogen atom, a hydroxyl group, a halogen atom, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_2-6Alkenyloxy radical, C_1-6Alkylthio radical, C_2-6Alkenylthio, halo (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, halo (C)_1-6Alkylthio) group, hydroxy (C)_1-6Alkyl) group, hydroxy (C)_2-6Alkenyl) group, hydroxy (C)_1-6Alkoxy) groups or hydroxy (C)_1-6Alkylthio) groups;

[6] a fused heterocyclic derivative as described in any one of the above [1] to [5], wherein ring a represents a benzene ring or a pyridine ring;

[7] a fused heterocyclic derivative as described in any one of the above [1] to [6], or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein G represents a group of the formula:

[8] a pharmaceutical composition comprising the fused heterocyclic derivative described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient;

[9] a human SGLT inhibitor comprising as an active ingredient a fused heterocyclic derivative as described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[10] the human SGLT inhibitor of [9] above, wherein the SGLT is SGLT1 and/or SGLT 2;

[11] the human SGLT inhibitor described in the above [9], which is a postprandial hyperglycemia-inhibiting agent;

[12] the human SGLT inhibitor described in the above [9], which is a medicament for the prophylaxis or treatment of a disease associated with hyperglycemia;

[13] the human SGLT inhibitor as described in the above [12], wherein the disease associated with hyperglycemia is a disease selected from the group consisting of: diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout;

[14] the human SGLT inhibitor described in the above [9], which is an agent for inhibiting the progression of impaired glucose tolerance to diabetes in a subject;

[15] the pharmaceutical composition according to the above [8], wherein the dosage form is a sustained-release preparation;

[16] the human SGLT inhibitor as described in the above [9], wherein the dosage form is a sustained-release preparation;

[17] a method for inhibiting postprandial hyperglycemia, which comprises administering an effective amount of the fused heterocyclic derivative described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[18] a method for preventing or treating a disease associated with hyperglycemia, which comprises administering an effective amount of the fused heterocyclic derivative described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[19] the method for the prophylaxis or treatment according to the above [18], wherein the disease associated with hyperglycemia is a disease selected from the group consisting of: diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout;

[20] a method for inhibiting the development of impaired glucose tolerance into diabetes in a subject, which comprises administering an effective amount of a fused heterocyclic derivative as described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof;

[21] use of a fused heterocyclic derivative as described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof for the production of a pharmaceutical composition for inhibiting postprandial hyperglycemia;

[22] use of a fused heterocyclic derivative as described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof for the production of a pharmaceutical composition for the prophylaxis or treatment of a disease associated with hyperglycemia;

[23] the use according to [22] above, wherein the disease associated with hyperglycemia is a disease selected from the group consisting of: diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout;

[24] use of a fused heterocyclic derivative as described in any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, or a prodrug thereof for the production of a pharmaceutical composition for inhibiting the development of impaired glucose tolerance into diabetes in a subject;

[25]above-mentioned [8]The pharmaceutical composition comprising in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilizers, starch insolubilizer analogs, starch insolubilizer agonists, aldose reductase inhibitors, advanced glycation end product formation inhibitors (advanced glycation end product formation inhibitors), Protein kinase C inhibitors, gamma-aminobutyric receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide (sulodexide), Y-128, antidiarrheal agents, laxatives, hydroxyglutaryl-coa reductase inhibitors, fibrates, β -aminobutyric receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol (probcol), thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transporter inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesteryl ester transporter inhibitorsPreparation, appetite suppressant, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, diuretic, calcium antagonist, vasodilating antihypertensive, sympathetic blocker, central antihypertensive, alpha-alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[26]above-mentioned [9]The human SGLT inhibitor comprises at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, HMG-CoA reductase inhibitors, fibrates, beta-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor₃-adrenoceptor agonists, acyl-CoA cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer eggsA leukocyte inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl transferase inhibitor, a squalene synthetase inhibitor, a low density lipoprotein receptor enhancer, a nicotinic acid derivative, a bile acid sequestrant, a sodium/bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite suppressant, an angiotensin converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic, a calcium antagonist, a vasodilating antihypertensive, a sympatholytic, a central antihypertensive, an alpha-alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[27]above [17]]The method of inhibiting postprandial hyperglycemia, comprising administering in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, hydroxyglutarylCoenzyme A reductase inhibitor, fibrate compound, beta₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensive agents, sympatholytic agents, central antihypertensive agents, pro-active compounds, pro-, Alpha is alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[28]above [18]]The method for preventing or treating a disease associated with hyperglycemia, which comprises administering in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kB inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase aprotininFormulations, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methyl acetylurea, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, HMG-CoA reductase inhibitors, fibrates, beta-agonists, and pharmaceutically acceptable salts thereof₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensive agents, sympatholytic agents, central antihypertensive agents, pro-active compounds, pro-, Alpha is alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[29]above [19]]The method of inhibiting the development of impaired glucose tolerance into diabetes in a subject comprising administering in combination with at least one agent selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubilizers, starch derivatives, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitorsInsoluble hormone analogues, amylin agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-. kappa.B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogues, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheal, laxative, HMG-CoA reductase inhibitors, fibrates, beta-glycosylate compounds, beta-glycosylate inhibitors, beta-glycosyl₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensive agents, sympatholytic agents, central antihypertensive agents, pro-active compounds, pro-, Alpha is alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[30](A) and (B) in the production of a pharmaceutical composition for inhibiting postprandial hyperglycemia, wherein (A) is the above [1]To [7]]A fused heterocyclic derivative as described in any one of (a), (B) is at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitionAgents, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinsitol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amylin analogs, amylin agonists, aldose reductase inhibitors, advanced glycation end product formation inhibitors, protein kinase C inhibitors, gamma aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, glucose-phosphatase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, glycogen synthase inhibitors, aldose reductase inhibitors, advanced glycation end product formation inhibitors, protein kinase C inhibitors, gamma aminobutyric acid receptor antagonists, sodium channel antagonists, transcription, Insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheal, laxative, HMG-CoA reductase inhibitor, fibrate, beta₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensive agents, sympatholytic agents, central antihypertensive agents, pro-active compounds, pro-, Alpha is alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[31](A) and (B) in the manufacture of a medicament for the prevention or treatment of diseases associated with hyperglycemiaThe use in a pharmaceutical composition, wherein (A) is the above [1]]To [7]]A fused heterocyclic derivative as described in any one of (a), (B) is at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, HMG-CoA reductase inhibitors, fibrates, beta-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitorsAgents, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilating antihypertensive agents, sympatholytic agents, central antihypertensive agents, alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs;

[32](A) and (B) in the manufacture of a pharmaceutical composition for inhibiting the progression of impaired glucose tolerance to diabetes in a subject, wherein (A) is [1] above]To [7]]A fused heterocyclic derivative as described in any one of (a), (B) is at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, HMG-CoA reductase inhibitors, fibrates, beta-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor₃-adrenoceptor agonists, acyl-CoA cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceridesTransporter inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite suppressants, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympathetic blockers, central antihypertensives, alpha-alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs; and the like.

In the present invention, the term "C_1-6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like; the term "C_1-6Alkylene "or" -C_1-6Alkylene- "means a straight or branched chain alkylene group having 1 to 6 carbon atoms such as methylene, 1, 2-ethylene, 1, 3-propylene, 1, 4-butylene, propylene, 1-dimethylethylene, etc.; and the term "C_1-4Alkylene "or" -C_1-4Alkylene- "means a straight or branched chain alkylene group having 1 to 4 carbon atoms such as methylene, ethylene, 1, 3-propylene, 1, 4-butylene, propylene, 1-dimethylethylene and the like. The term "hydroxy (C)_1-6Alkyl) group "means the above-mentioned C substituted by hydroxy_1-6An alkyl group; the term "dihydroxy (C)_1-6Alkyl) radical "means the above-mentioned C substituted by two hydroxy groups_1-6Alkyl groups such as 2, 3-dihydroxypropyl, 1, 3-dihydroxy-2-propyl, and the like; the term "amino (C)_1-6Alkyl) group "means the above C substituted by amino_1-6Alkyl groups such as aminomethyl, 2-aminoethyl, and the like; the term "carbamoyl group (C)_1-6Alkyl) group "means the above-mentioned C substituted by carbamoyl_1-6An alkyl group; and the term "carboxy (C)_1-6Alkyl) group "means the above-mentioned C substituted by carboxyl_1-6An alkyl group.

The term "C_1-6The "alkoxy group" means a straight or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy and the like; the term "hydroxy (C)_1-6Alkoxy) radical "means the abovementioned C substituted by hydroxy_1-6An alkoxy group; the term "carboxy (C)_1-6Alkoxy) radical "means the abovementioned C substituted by carboxyl_1-6An alkoxy group; the term "carbamoyl group (C)_1-6Alkoxy) radical "means the abovementioned C substituted by carbamoyl_1-6An alkoxy group; and the term "amino (C)_1-6Alkoxy) radical "means the abovementioned C substituted by amino_1-6An alkoxy group. The term "C_1-6Alkylthio "means a straight or branched chain alkylthio having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio, etc.; the term "hydroxy (C)_1-6Alkylthio) group "means the above-mentioned C substituted by hydroxy_1-6An alkylthio group; the term "carboxy (C)_1-6Alkylthio) group "means the above-mentioned C substituted by carboxyl_1-6An alkylthio group; and the term "amino (C)_1-6Alkylthio) radical "means the abovementioned C substituted by ammonia_1-6An alkylthio group.

The term "C_2-6Alkenyl "means a straight or branched alkenyl group having 2 to 6 carbon atoms such as vinyl (vinyl), allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-methylallyl, etc.; the term "C_2-6Alkenylene "or" -C_2-6Alkenylene- "means a straight or branched alkenylene group having 2 to 6 carbon atoms, such as vinylene, propenylene, etc.; the term "C_2-4Alkenylene "means a straight or branched chain alkenylene group having 2 to 4 carbon atoms, such as ethyleneAlkenyl, propenylene, and the like; the term "hydroxy (C)_2-6Alkenyl) group "means the above-mentioned C substituted by hydroxy_2-6An alkenyl group; the term "carboxy (C)_2-6Alkenyl) group "means the above-mentioned C substituted by carboxyl_2-6An alkenyl group; the term "cyano (C)_2-6Alkenyl) group "means the above-mentioned C substituted by cyano_2-6An alkenyl group; the term "C_2-6The alkenyloxy group "means a linear or branched alkenyloxy group having 2 to 6 carbon atoms such as vinyloxy group, allyloxy group, 1-propenyloxy group, isopropenyloxy group, 1-butenyloxy group, 2-methallyloxy group and the like; the term "C_2-6Alkenylthio "means a straight or branched alkenylthio group having 2 to 6 carbon atoms such as vinylthio, allylthio, 1-propenylthio, isopropenylthio, 1-butenylthio, 2-methylallylthio and the like; the term "C_2-6Alkynyl "means a straight or branched chain alkynyl group having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, etc.; and the term "-C_2-4Alkynylene- "means a straight or branched chain alkynylene group having 2 to 4 carbon atoms such as ethynylene, propynyl, etc.

The term "mono-or di (C)_1-6Alkyl) amino "means substituted by C as described above_1-6Alkyl monosubstituted or substituted by the same or different C as defined above_1-6Alkyl-disubstituted amino; the term "mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkyl) group "means substituted with the above-mentioned mono-or di (C)_1-6Alkyl) amino substituted C as described above_1-6An alkyl group; the term "mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkoxy) group "means a group substituted with the above-mentioned mono-or di (C)_1-6Alkyl) amino substituted C as described above_1-6An alkoxy group; the term "mono-or di [ hydroxy (C)_1-6Alkyl radical)]Amino "means substituted with the above-mentioned hydroxy (C)_1-6Alkyl) radical monosubstituted or substituted by any of the above-mentioned hydroxy (C)_1-6Alkyl) amino disubstituted with a group; the term "mono-or di (C)_1-6Alkyl) ureido "means substituted by C as defined above_1-6Alkyl monosubstituted or substituted by any of the above C_1-6An alkyl disubstituted ureido group; the term "mono-or di [ hydroxy (C)_1-6Alkyl radical)]Ureido "means substituted by a hydroxy group (C) as defined above_1-6Alkyl) radical monosubstituted or substituted by any of the above-mentioned hydroxy (C)_1-6Alkyl) a ureido group disubstituted; the term "mono-or di (C)_1-6Alkyl) sulfonamido "means substituted by C as defined above_1-6Alkyl monosubstituted or substituted by any of the above C_1-6An alkyl disubstituted sulfonamide group; the term "mono-or di [ hydroxy (C)_1-6Alkyl radical)]The "sulfonamide group" is defined by the above-mentioned hydroxyl group (C)_1-6Alkyl) radical monosubstituted or substituted by any of the above-mentioned hydroxy (C)_1-6Alkyl) a sulfonamide group disubstituted with a group; the term "C_2-7The "acyl group" means a straight or branched chain 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 term "C_2-7Acylamino "means substituted by C_2-7Acyl-substituted amino; and the term "amino (C)_2-7Acylamino) group "means the above-mentioned C substituted by amino_2-7Acylamino groups such as 2-aminoacetylamino, 3-aminopropionylamino and the like. The term "C_1-6Alkylsulfinyl "means a straight or branched alkylsulfinyl group having 1 to 6 carbon atoms, such as methylsulfinyl, ethylsulfinyl, etc.; the term "C_1-6Alkylsulfonyl "means a straight or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl and the like; the term "C_1-6Alkylsulfonylamino "means substituted by C_1-6An alkylsulfonyl-substituted amino group; the term "carbamoyl group (C)_1-6Alkylsulfonylamino) group "means the above-mentioned C substituted by carbamoyl_1-6Alkylsulfonylamino such as carbamoylmethylsulfonylamino and the like; and the term "C_1-6Alkylsulfonylamino (C)_1-6Alkyl) radical "means substituted by C as defined above_1-6Alkylsulfonylamino substituted C as described above_1-6An alkyl group.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom; the term "halo (C)_1-6Alkyl) radical "means the abovementioned C substituted by any 1 to 3 halogen atoms as defined above_1-6An alkyl group; the term "halo (C)_1-6Alkoxy) radical "means the abovementioned C substituted by any 1 to 3 halogen atoms as defined above_1-6An alkoxy group; and the term "halo (C)_1-6Alkylthio) group "means the above-mentioned C substituted by any 1 to 3 halogen atoms as defined above_1-6An alkylthio group. The term "C_2-7Alkoxycarbonyl "means a straight-chain or branched alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.; the term "C_2-7Alkoxycarbonyl (C)_1-6Alkyl) radical "means substituted by C as defined above_2-7Alkoxycarbonyl substituted by the above-mentioned C_1-6An alkyl group; the term "C_2-7Alkoxycarbonyl (C)_1-6Alkoxy) radical "means substituted by C as defined above_2-7Alkoxycarbonyl substituted by the above-mentioned C_1-6An alkoxy group; the term "C_2-7Alkoxycarbonyl (C)_1-6Alkylthio) radicals "are meant to be substituted by C_2-7Alkoxycarbonyl substituted by the above-mentioned C_1-6An alkylthio group; and the term "C_2-7Alkoxycarbonyl (C)_2-6Alkenyl) group "means substituted with C as described above_2-7Alkoxycarbonyl substituted by the above-mentioned C_2-6An alkenyl group.

The term "C_3-7Cycloalkyl radicals "or" C_3-7Cycloalkyl- "means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; the term "C_3-7Cycloalkoxy "means substituted by C_3-7Cycloalkyl-substituted hydroxy; the term "C_3-7Cycloalkyl (C)_1-6Alkyl) radical "means substituted by C as defined above_3-7Cycloalkyl-substituted C as described above_1-6An alkyl group; the term "C_3-7Cycloalkyl (C)_1-6Alkoxy) radical "means substituted by C as defined above_3-7Cycloalkyl-substituted C as described above_1-6An alkoxy group; and the term "C_3-7Cycloalkyl (C)_1-6Alkylthio) radicals "are meant to be substituted by C_3-7Cycloalkyl-substituted C as described above_1-6An alkylthio group. The term "heterocycloalkyl" or "heterocycleAlkyl- "refers to a 3-7 membered aliphatic heterocyclic group containing any 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms at positions other than the binding position in the ring, derived from morpholine, thiomorpholine, tetrahydrofuran, tetrahydropyran, aziridine, azetidine, pyrrolidine, imidazolidine, dihydrocarb, and dihydrocarb,An oxazoline, piperidine, piperazine, pyrazolidine, pyrroline, imidazoline, or the like, or a 5-or 6-membered aliphatic heterocyclic group fused with a 6-membered ring containing any 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom at positions other than the binding position in the ring, which is derived from indoline, isoindoline, tetrahydroindoline, tetrahydroisoindoline, hexahydroindole, hexahydroisoindoline, and the like. The term "heterocycloalkyl (C)_1-6Alkyl) group "means the above-mentioned C substituted by the above-mentioned heterocycloalkyl group_1-6An alkyl group; the term "heterocycloalkyl (C)_1-6Alkoxy) group "means the above-mentioned C substituted by the above-mentioned heterocycloalkyl group_1-6An alkoxy group; and the term "heterocycloalkyl (C)_1-6Alkylthio) group "means the above-mentioned C substituted by the above-mentioned heterocycloalkyl group_1-6An alkylthio group.

The term "C_6-10Aryl "or" C_6-10Aryl- "means an aromatic cyclic hydrocarbon group having 6 or 10 carbon atoms, such as phenyl, naphthyl, and the like; the term "C_6-10Aryl radical (C)_1-6Alkyl) radical "means substituted by C as defined above_6-10Aryl substituted C as described above_1-6An alkyl group; the term "C_6-10Aryl radical (C)_1-6Alkoxy) radical "means substituted by C as defined above_6-10Aryl substituted C as described above_1-6An alkoxy group; and the term "C_6-10Aryl radical (C)_1-6Alkylthio) radicals "are meant to be substituted by C_6-10Aryl substituted C as described above_1-6An alkylthio group. The term "C_6-10Arylsulfonylamino "means having the above-mentioned C_6-10Sulfonylamino groups of aryl groups such as benzenesulfonylamino and the like; the term "C_6-10Aryl radical (C)_2-7Alkoxycarbonyl) radical "means substituted by C as defined above_6-10Aryl substituted C as described above_2-7Alkoxy radicalAn alkylcarbonyl group; and the term "heteroaryl" or "heteroaryl-" refers to a 5 or 6-membered aromatic heterocyclic group containing any 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, other than the binding position, in the ring, which is derived from thiazole,oxazole, isothiazole, isoOxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, thiophene, imidazole, pyrazole,Oxadiazoles, thiadiazoles, tetrazoles, furazans and the like, or 5-or 6-membered aromatic heterocyclic groups fused to a 6-membered aromatic ring containing any 1 or 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms at positions other than the binding position in the ring, derived from indole, isoindole, benzofuran, isobenzofuran, benzothiophene, benzoquinoneOxazoles, benzothiazoles, indazoles, benzimidazoles, quinolines, isoquinolines, 2, 3-naphthyridines, quinoxalines, quinazolines, 1, 2-naphthyridines, indolizines, 1, 5-naphthyridines, pteridines, and the like. The term "heteroaryl (C)_1-6Alkyl) group "means the above-mentioned C substituted by the above-mentioned heteroaryl group_1-6An alkyl group; the term "heteroaryl (C)_1-6Alkoxy) group "means the above-mentioned C substituted by the above-mentioned heteroaryl_1-6An alkoxy group; and the term "heteroaryl (C)_1-6Alkylthio) group "means the above-mentioned C substituted by the above-mentioned heteroaryl group_1-6An alkylthio group.

The term "aliphatic cyclic amino group" means a 5-or 6-membered aliphatic cyclic amino group which may contain in the ring one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom other than the nitrogen atom at the bonding position, such as morpholino, thiomorpholino, 1-aziridine, 1-azetidine, 1-pyrrolidinyl, piperidino, 1-imidazolidineA group such as a 1-piperazinyl group and a pyrazolidinyl group; the term "aromatic cyclic amino group" refers to a 5-membered aromatic cyclic amino group which may contain 1 to 3 nitrogen atoms in the ring other than the nitrogen atom at the binding site, such as 1-imidazolyl, 1-pyrrolyl, pyrazolyl, 1-tetrazolyl, etc.; the term "aromatic cyclic amino group (C)_1-6Alkyl) group "means the above-mentioned C substituted with the above-mentioned aromatic cyclic amino group_1-6An alkyl group; the term "aromatic cyclic amino group (C)_1-6Alkoxy) group "means the above-mentioned C substituted with the above-mentioned aromatic cyclic amino group_1-6An alkoxy group; and the term "aromatic cyclic amino group (C)_1-6Alkylthio) group "means the above-mentioned C substituted by the above-mentioned aromatic cyclic amino group_1-6An alkylthio group.

The term "hydroxy-protecting group" means a hydroxy-protecting group used in general organic synthesis, such as methyl, benzyl, methoxymethyl, acetyl, pivaloyl, benzoyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, allyl, etc.; the term "amino-protecting group" means an amino-protecting group used in general organic synthesis, such as benzyloxycarbonyl, t-butoxycarbonyl, benzyl, acetyl, trifluoroacetyl, etc.; and the term "carboxy-protecting group" means a carboxy-protecting group used in general organic synthesis, such as methyl, ethyl, benzyl, t-butyldimethylsilyl, allyl, etc. In addition, in the substituent group Q, the left bond means a bond to the nitrogen-containing condensed ring, and the right bond means a bond to the ring a.

The compound represented by the above general formula (I) of the present invention can be produced according to the following method or a method analogous thereto, or by other methods described in the literature or a method analogous thereto.

In the formula, E^1aRepresents a hydrogen atom, a fluorine atom or a benzyloxy group; e^2aRepresents a hydrogen atom, a fluorine atom, a methyl group or a benzyloxymethyl group；L¹Represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom; m represents a benzyl group; g¹A group represented by the formula:

or a group of the formula

M, E therein^1aAnd E^2aHave the same meanings as described above; g²The above G having a hydroxyl group protected by a benzyl group; r¹To R⁴、A¹、A²And G has the same meaning as described above, provided that in the case where each compound has a hydroxyl group, an amino group and/or a carboxyl group, a compound having a protecting group can be suitably used.

Process 1

The compound of the above general formula (III) can be prepared by subjecting the compound of the above general formula (II) to lithiation using a lithiating agent such as n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, or the like in an inert solvent. As the solvent used, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from-100 ℃ to room temperature, and the reaction time is usually from 1 minute to 3 hours, depending on the starting materials, the solvent and the reaction temperature used.

Process 2

The compound of the above general formula (IV) can be prepared by subjecting the compound of the above general formula (III) to condensation with a sugar lactone of the above general formula (Ga) or (Gb) in an inert solvent. As the solvent used, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from-100 ℃ to room temperature, and the reaction time is usually from 5 minutes to 5 hours, depending on the starting materials, the solvent and the reaction temperature used.

Process 3

The compound of the above general formula (V) can be prepared by subjecting the compound of the above general formula (IV) to reduction using a reagent such as triethylsilane, triisopropylsilane, etc. in the presence of boron trifluoride-diethyl ether complex in an inert solvent to remove the hydroxyl group at the anomeric position. As the solvent used, for example, acetonitrile, dichloromethane, 1, 2-dichloroethane, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from-20 ℃ to room temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting materials, the solvent and the reaction temperature used.

Process 4

The compound of the above general formula (I) of the present invention can be prepared by subjecting the compound of the above general formula (V) to the following reaction: 1) catalytic hydrogenation using a palladium catalyst such as palladium-carbon powder or the like in an inert solvent, or 2) treatment with a reagent such as ethanethiol in the presence of an acid such as boron trifluoride-diethyl ether complex in an inert solvent to remove benzyl groups. As the solvent used for the catalytic hydrogenation, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 1 hour to 2 days, which varies depending on the starting materials, the solvent and the reaction temperature used. As the solvent used for the acid treatment, there may be exemplified methylene chloride, 1, 2-dichloroethane, acetonitrile, a mixed solvent thereof and the like. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 2 days, which varies depending on the starting materials, the solvent and the reaction temperature used.

The starting materials for the above production methods may be prepared according to the methods described in the literature or similar methods thereto. Further, among the compounds of the above general formula (II), compounds of the following general formula (IIa), (IIb) or IIc) can also be prepared according to the following procedures 5 to 9.

In the formula, L²And L³One represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; l is⁴represents-P (═ O) (OR)⁰)₂or-P⁺(PPh₃)₃X^-；R⁰Is represented by C_1-6An alkyl group; ph represents a phenyl group; x represents a chlorine atom, a bromine atom or an iodine atom; r¹⁰And R¹¹One represents a group of the general formula:

and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; r¹²And R¹³One represents a group of the general formula:

and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; r¹⁴And R¹⁵One represents a formyl group and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; r¹⁶And R¹⁷One represents a group of the general formula:

and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; q¹Represents a vinyl group or an ethynyl group; q²Represents a single bond, -C_1-4Alkylene-, -C_2-4Alkenylene radical-, -C_2-4Alkynylene-, -C_1-4alkylene-O-, -C_1-4alkylene-S-, -C_1-4alkylene-O-C_1-6alkylene-or-C_1-4alkylene-S-C_1-6Alkylene-; q³Represents an ethenylene group or an ethynylene group; and R²、R³、R⁵、R⁶、A¹、A²And ring A has the same meaning as described above.

Process 5

The compound of the above general formula (IIa) can be prepared by subjecting the compound of the above general formula (VI) to Heck reaction or Sonogashira reaction with the compound of the above general formula (VII) in the presence or absence of a ligand such as tris (2-methylphenyl) phosphine, triphenylphosphine and the like in an inert solvent in the presence or absence of a base such as triethylamine, N-diisopropylethylamine, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium fluoride and the like in the presence or absence of copper (I) iodide using a palladium catalyst such as palladium-carbon powder, palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium dichloride and the like. As the solvent used, for example, acetonitrile, toluene, tetrahydrofuran, triethylamine, N-diisopropylethylamine, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, and varies depending on the starting materials, the solvent and the reaction temperature used.

Process 6

The compound of the above general formula (IIb) of the present invention can be prepared by subjecting the compound of the above general formula (IIa) to the following reaction: 1) catalytic hydrogenation using a palladium catalyst such as palladium-carbon powder and the like in an inert solvent, or 2) diimide reduction using a reagent such as 2, 4, 6-triisopropylbenzenesulfonylhydrazide and the like in an inert solvent in the presence or absence of a base such as triethylamine, N-diisopropylethylamine and the like. As the solvent used for the catalytic hydrogenation, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 1 hour to 2 days, which varies depending on the starting materials, the solvent and the reaction temperature used. As the solvent used for the diimide reduction, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 3 days, varying depending on the starting materials, the solvent and the reaction temperature used.

Process 7

The compound of the above general formula (VIII) can be prepared by subjecting the compound of the above general formula (VI) to the following reaction: 1) lithiation with a base such as N-butyllithium, sec-butyllithium, tert-butyllithium or the like in an inert solvent in the presence or absence of an additive such as N, N' -tetramethylethylenediamine, hexamethylphosphoramide or the like or preparation of a grignard reagent with magnesium in an inert solvent in the presence of an additive such as iodine, 1, 2-dibromoethane or the like, followed by 2) formylation with N, N-dimethylformamide. As the solvent used, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature of the reaction 1) is usually from-100 ℃ to reflux temperature, the reaction temperature of the reaction 2) is usually from-100 ℃ to room temperature, the reaction time of the reaction 1) is usually from 1 minute to 1 hour, and the reaction time of the reaction 2) is usually from 30 minutes to 1 day, which vary depending on the starting materials, the solvent and the reaction temperature used.

Process 8

The compound of the above general formula (IIc) can be prepared by subjecting the compound of the above general formula (VIII) to Wittig reaction or Horner-Emmons reaction with the compound of the above general formula (IX) in an inert solvent in the presence of a base such as sodium hydride, sodium hydroxide, potassium tert-butoxide, n-butyllithium, tert-butyllithium or the like. As the solvent used for the reaction, for example, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 1 day, which varies depending on the starting materials, the solvent and the reaction temperature used.

Process 9

The compound of the above general formula (IIb) can be prepared by subjecting a compound of the above general formula (IIc) to the following reaction: 1) catalytic hydrogenation using a palladium catalyst such as palladium-carbon powder or the like in an inert solvent, or 2) diimide reduction using a reagent such as 2, 4, 6-triisopropylbenzenesulfonylhydrazide or the like in an inert solvent in the presence or absence of a base such as triethylamine, N-diisopropylethylamine or the like. As the solvent used for the catalytic hydrogenation, for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 1 hour to 2 days, which varies depending on the starting materials, the solvent and the reaction temperature used. As the solvent used for the diimide reduction, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 3 days, varying depending on the starting materials, the solvent and the reaction temperature used.

For the compounds of the above general formula (II), wherein A¹Is a sulfur atom, A²Is a carbonyl atom, and L¹The compound which is a hydrogen atom can also be produced according to the following procedures 10 to 11 or 12 to 15.

In the formula, L⁵Represents a chlorine atom, a bromine atom or an iodine atom; r represents methyl or ethyl, or two R are combined together to form ethylene or 1, 3-propylene; r¹⁸Represents a methyl or ethyl group; and R¹To R⁴Have the same meanings as described above.

Process 10

The compound of the above general formula (XII) can be produced by subjecting the compound of the above general formula (X) to S-alkylation using the compound of the above general formula (XI) in the presence of a base such as potassium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine, etc. in an inert solvent. Examples of the solvent used include N, N-dimethylformamide, acetone, dichloromethane, and a mixed solvent thereof. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 1 day, which varies depending on the starting materials, the solvent and the reaction temperature used.

Process 11

The benzothiophene derivative of the above general formula (IId) can be produced by subjecting the compound of the above general formula (XII) to cyclization in the presence of polyphosphoric acid in an inert solvent. Examples of the solvent used include benzene, chlorobenzene, and toluene. The temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, varying depending on the starting materials, the solvent and the reaction temperature used.

Process 12

The compound of the above general formula (XIV) can be prepared by subjecting a compound of the above general formula (XIII) to the following reaction: 1) lithiation using a base such as N-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, etc. in the presence or absence of an additive such as N, N' -tetramethylethylenediamine, hexamethylphosphoramide, etc. in an inert solvent, followed by 2) formylation using N, N-dimethylformamide. As the solvent used, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like can be illustrated. The reaction temperature of the reaction 1) is usually from-100 ℃ to 0 ℃, the reaction temperature of the reaction 2) is usually from-100 ℃ to room temperature, the reaction time of the reaction 1) is usually from 30 minutes to 5 hours, and the reaction time of the reaction 2) is usually from 30 minutes to 1 day, which vary depending on the starting materials, solvents and reaction temperatures used.

Process 13

The benzothiophene derivative of the above general formula (XVI) can be prepared by subjecting the compound of the above general formula (XIV) to cyclization in an inert solvent using a mercaptoacetate of the above general formula (XV) in the presence of a base such as triethylamine, N-diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydride or the like. Examples of the solvent used include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, and N-butanol. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, and varies depending on the starting materials, the solvent and the reaction temperature used.

Process 14

The carboxylic acid derivative of the above general formula (XVII) can be prepared by subjecting the compound of the above general formula (XVI) to hydrolysis in the presence of a basic substance such as sodium hydroxide, potassium hydroxide or the like. As the solvent used, for example, methanol, ethanol, isopropanol, tetrahydrofuran, water, a mixed solvent thereof, and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, and varies depending on the starting materials, the solvent and the reaction temperature used.

Process 15

The compound of the above general formula (IId) can be prepared by subjecting the compound of the above general formula (XVII) to decarboxylation in an inert solvent using a catalyst such as copper powder or the like. As the solvent used, quinoline and the like can be exemplified. The reaction temperature is usually from 100 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting materials, the solvent and the reaction temperature used.

For the compounds of the above general formula (II), wherein L¹Is a hydrogen atom; r¹And R⁴One being a chlorine atom, a bromine atom or an iodine atom and the other being a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; and R⁹Is C_1-6Alkyl compounds may also be prepared according to the following procedures 16 to 18.

In the formula, L⁴And L⁵One represents a chlorine atom, a bromine atom or an iodine atom, and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; l is⁶And L⁷One of them represents MgCl, MgBr or MgI, and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; q⁴Represents a single bond, -C_1-5Alkylene-, -C_2-5Alkenylene radical-, -C_2-5Alkynylene-, -C_1-5alkylene-O-, -C_1-5alkylene-S-, -C_1-5alkylene-O-C_1-6Alkylene-, -C_1-5alkylene-S-C_1-6alkylene-or-C_1-5alkylene-CON (R)⁶)-；R¹⁸And R¹⁹One represents a group of the general formula:

and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; r²⁰And R²¹One represents a group of the general formula:

and the other represents a hydrogen atom, a halogen atom, C_1-6Alkyl, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) radical, dihydroxy (C)_1-6Alkyl) radical, C_1-6Alkoxy radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_3-7Cycloalkyl or C_3-7Cycloalkyl (C)_1-6Alkyl) groups; and ring A, A¹、A²、R²、R³、R⁵、R⁶And R⁸Have the same meanings as described above.

Process 16

The Grignard reagent of the above general formula (XIX) can be prepared by reacting the above general formula (XVIII) with magnesium metal in an inert solvent in the presence of an activating agent such as a catalytic amount of iodine or the like. As the solvent used, for example, diethyl ether, tetrahydrofuran, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 1 day, which varies depending on the starting materials, the solvent and the reaction temperature used.

Process 17

The alcohol derivative of the above general formula (XX) can be prepared by reacting a compound of the above general formula (XXI) with a Grignard reagent of the above general formula (XIX) in an inert solvent. As the solvent used, for example, diethyl ether, tetrahydrofuran and the like can be illustrated. The reaction temperature is usually from-20 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting materials, the solvent and the reaction temperature used.

Process 18

The benzothiophene derivative of the above general formula (IIe) can be prepared by subjecting the compound of the above general formula (XX) to reduction in the presence of iodotrimethylsilane in an inert solvent. As the solvent used, for example, acetonitrile and the like can be illustrated. The reaction temperature is usually from-20 ℃ to reflux temperature, and the reaction time is usually from 15 minutes to 1 day, depending on the starting materials, the solvent and the reaction temperature used.

For the compound of the above general formula (II), the compound of the following general formula (IIf) can also be prepared according to the following procedure 19.

In the formula, R²²And R²³One represents a group of the general formula:

wherein Q⁵represents-C_1-6Alkylene-; q⁶Represents an oxygen atom, a sulfur atom, -O-C_1-6alkyl-or-S-C_1-6Alkyl-; r⁵、R⁶And ring A has the same meaning as above, and R²²And R²³The other represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxyl, C_2-7Alkoxycarbonyl, carbamoyl, mono-or di (C)_1-6Alkyl) amino, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) group, cyano (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carbamoyl (C)_1-6Alkyl) group, amino (C)_1-6Alkyl) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkoxy) group, carboxyl (C)_1-6Alkoxy) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkoxy radicalRadical), carbamoyl radical (C)_1-6Alkoxy) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkoxy) radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkoxy, C_3-7Cycloalkyl (C)_1-6Alkyl) group or C_3-7Cycloalkyl (C)_1-6Alkoxy) groups; r²⁴And R²⁵One represents a group of the general formula:

-Q⁵-L⁸

wherein L is⁸Represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or a toluenesulfonyloxy group; q⁵Has the same meaning as above, and R²⁴And R²⁵The other represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, carboxyl, C_2-7Alkoxycarbonyl, carbamoyl, mono-or di (C)_1-6Alkyl) amino, halo (C)_1-6Alkyl) group, hydroxy (C)_1-6Alkyl) group, cyano (C)_1-6Alkyl) group, carboxyl (C)_1-6Alkyl) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkyl) group, carbamoyl (C)_1-6Alkyl) group, amino (C)_1-6Alkyl) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkyl) group, halo (C)_1-6Alkoxy) group, hydroxy (C)_1-6Alkoxy) group, carboxyl (C)_1-6Alkoxy) radical, C_2-7Alkoxycarbonyl (C)_1-6Alkoxy) group, carbamoyl (C)_1-6Alkoxy) group, amino (C)_1-6Alkoxy) group, mono-or di (C)_1-6Alkyl) amino (C)_1-6Alkoxy) radical, C_3-7Cycloalkyl radical, C_3-7Cycloalkoxy, C_3-7Cycloalkyl (C)_1-6Alkyl) group or C_3-7Cycloalkyl (C)_1-6Alkoxy) groups; and A¹、A²、R²And R³Have the same meanings as described above.

Process 19

The compound of the above formula (IIf) can be prepared by subjecting a compound of the above formula (XXI) to condensation with a compound of the above formula (XXII) in an inert solvent in the presence of a base such as sodium hydride, potassium hydroxide, potassium tert-butoxide, cesium carbonate or the like. As the solvent used for the condensation reaction, for example, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, acetone, methanol, a mixed solvent thereof and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 1 hour to 1 day, and varies depending on the starting materials, the solvent and the reaction temperature used.

If the compounds in the above-mentioned processes have hydroxyl groups, amino groups and/or carboxyl groups, they may also be used for the respective reactions after any protecting groups have been conventionally introduced as necessary. The protecting group may be selectively removed in any subsequent reaction as is customary.

The compound of the above general formula (I) of the present invention obtained by the above production method can be isolated and purified by a conventional separation apparatus, such as fractional recrystallization, purification using chromatography, solvent extraction and solid phase extraction.

The fused heterocyclic derivatives of the above general formula (I) of the present invention can be converted into their pharmaceutically acceptable salts by a usual method. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic 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, and the like; salts with inorganic bases such as sodium salts, potassium salts, etc.; salts with organic bases such as N-methyl-D-glucamine, N' -dibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) aminomethane, arginine, lysine, and the like.

The compounds of the above general formula (I) of the present invention include their solvates with pharmaceutically acceptable solvents such as water and ethanol.

In the fused heterocyclic derivative of the above general formula (I) of the present invention and a prodrug thereof, there are two geometric isomers, cis (Z) -isomer and trans (E) -isomer, in each compound having an unsaturated bond. In the present invention, any isomer may be used.

In the fused heterocyclic derivative of the above general formula (I) of the present invention and a prodrug thereof, in each compound having an asymmetric carbon atom other than the sugar moiety, there are two optical isomers, R-isomer and S-isomer. In the present invention, either one of the optical isomers may be used, and a mixture of both optical isomers may also be used.

The prodrug of the above-mentioned compound of the general formula (I) of the present invention can be prepared by introducing an appropriate group for forming a prodrug into any one or more groups selected from the group consisting of a hydroxyl group, an amino group and a cyclic amino group such as a pyrazole ring, a piperazine ring and the like of the above-mentioned compound of the general formula (I) using a corresponding reagent to conventionally produce a prodrug such as a halogenated compound and the like, and then conventionally carrying out appropriate isolation and purification as occasion demands. As the prodrug-forming group used in a hydroxyl group or an amino group, for example, C_2-7Acyl radical, C_1-6Alkoxy (C)_2-7Acyl) group, C_2-7Alkoxycarbonyl (C)_2-7Acyl) group, C_2-7Alkoxycarbonyl group, C_6-10Aryl radical (C)_2-7Alkoxycarbonyl) radical, C_1-6Alkoxy (C)_2-7Alkoxycarbonyl) groups, and the like. As the prodrug-forming group used in the cyclic amino group, for example, C_2-7Acyl radical, C_1-6Alkoxy (C)_2-7Acyl) group, C_2-7Alkoxycarbonyl (C)_2-7Acyl) group, C_2-7Alkoxycarbonyl group, C_6-10Aryl radical (C)_2-7Alkoxycarbonyl) radical, C_1-6Alkoxy (C)_2-7Alkoxycarbonyl) radical, (C)_2-7Acyloxy) methyl, 1- (C)_2-7Acyloxy) ethyl group, (C)_2-7Alkoxycarbonyl) oxymethyl, 1- [ (C)_2-7Alkoxycarbonyl) oxy]Ethyl group, (C)_3-7Cycloalkyl) oxycarbonyloxymethyl, 1- [ (C)_3-7Cycloalkyl) oxycarbonyloxy]Ethyl, and the like. The term "C_1-6Alkoxy (C)_2-7Acyl) group "means substituted by C as defined above_1-6Alkoxy-substituted C as described above_2-7An acyl group; the term "C_2-7Alkoxycarbonyl (C)_2-7Acyl) group "means substituted by C as defined above_2-7Alkoxycarbonyl substituted by the above-mentioned C_2-7An acyl group; the term "C_1-6Alkoxy (C)_2-7Alkoxycarbonyl) radical "means substituted by C as defined above_1-6Alkoxy-substituted C as described above_2-7An alkoxycarbonyl group. Term "(C)_2-7Acyloxy) methyl "means substituted by C_2-7Hydroxymethyl with O-substitution of acyl; the term "1- (C)_2-7Acyloxy) ethyl "means substituted by C_2-71-hydroxyethyl with the acyl group O-substituted; term "(C)_2-7Alkoxycarbonyl) oxymethyl "means substituted by C_2-7Hydroxymethyl O-substituted with alkoxycarbonyl; the term "1- [ (C)_2-7Alkoxycarbonyl) oxy]Ethyl "means substituted by C_2-71-hydroxyethyl with O-substitution of alkoxycarbonyl; term "(C)_3-7Cycloalkyl) oxycarbonyl "means having C as defined above_3-7Cyclic alkoxycarbonyl of cycloalkyl; term "(C)_3-7Cycloalkyl) oxycarbonyloxymethyl "means substituted by (C) as defined above_3-7Cycloalkyl) oxycarbonyl with O-substituted hydroxymethyl; and the term "1- [ (C)_3-7Cycloalkyl) oxycarbonyloxy]The ethyl group is defined by the above-mentioned (C)_3-7Cycloalkyl) oxycarbonyl for O-substituted 1-hydroxyethyl. Examples of the group forming a prodrug include glucopyranosyl (glucopyranosyl) and galactopyranosyl (galactopyranosyl). For example, these groups are preferably introduced into the hydroxyl group at the 4-or 6-position of glucopyranosyl or galactopyranosyl, and more preferably introduced into the hydroxyl group at the 4-or 6-position of glucopyranosyl.

The fused heterocyclic derivative of the above general formula (I) of the present invention exhibits a potent inhibitory effect on human SGLT1 or SGLT2 activity in, for example, a human SGLT1 or SGLT2 inhibitory activity confirmation test as described below. Therefore, the fused heterocyclic derivative of the general formula (I) of the present invention can exhibit an excellent inhibitory activity of SGLT1 in the small intestine or an excellent inhibitory activity of SGLT2 in the kidney, and can significantly inhibit the increase in blood glucose level or significantly reduce the blood glucose level. Therefore, the fused heterocyclic derivative of the above general formula (I), pharmaceutically acceptable salts and prodrugs thereof of the present invention are very useful drugs for inhibiting postprandial hyperglycemia, inhibiting the development of diabetes in patients with impaired glucose tolerance, and preventing or treating diseases associated with hyperglycemia such as diabetes, Impaired Glucose Tolerance (IGT), diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout, and the like, which involve SGLT1 activity in the small intestine and SGLT2 activity in the kidney.

Further, the compound of the present invention may be suitably used in combination with at least one drug selected from the following. Examples of drugs that can be used in combination with the compounds of the present invention include: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-. kappa.B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor (PDGF) analogs (e.g., PDGF-AA, PDGF-BB, PDGF-AB), Epidermal Growth Factor (EGF), Nerve Growth Factor (NGF)Factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, an antidiarrheal, a laxative, a HMG-CoA reductase inhibitor, a fibrate, beta₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probucol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyl transferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transporter inhibitors, appetite inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator antihypertensive agents, sympatholytic agents, central antihypertensive agents, pro-active compounds, pro-, Alpha is alpha₂-adrenoceptor agonists, antiplatelet drugs, uric acid synthesis inhibitors, uric acid excretion promoters and urine alkalizing drugs.

In the case where the compound of the present invention is used in combination with one or more of the above-mentioned drugs, the present invention includes dosage forms which are administered simultaneously as a single preparation, or simultaneously administered as separate preparations by the same or different administration routes, and administered at different administration intervals as separate preparations by the same or different administration routes. Pharmaceutical combinations comprising a compound of the invention and a drug as described above include dosage forms for the combined single and separate formulations as described above.

The compound of the present invention can obtain more advantageous additional effects of the pharmacological effects than when the compound of the present invention is appropriately used in combination with one or more drugs described above for the prevention or treatment of the above-mentioned diseases. In addition, the dosage administered may be reduced as compared to administration of the drug alone, or side effects of co-administered drugs may be avoided or reduced.

Specific compounds for the combined medicaments and preferred diseases to be treated are exemplified below. However, the present invention is not limited thereto, and specific compounds include their free compounds, and their or other pharmaceutically acceptable salts.

As the insulin sensitivity enhancers, there are exemplified peroxisome proliferator-activated receptor- γ agonists such as troglitazone, pioglitazone hydrochloride, rosiglitazone maleate, daglipzone sodium, GI-262570, isaglitazone (isaglitazone), LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium and NIP-221; peroxisome proliferator activated receptor- α agonists such as GW-9578 and BM-170744; peroxisome proliferator activated receptor- α/γ agonists such as GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158, and DRF-MDX 8; vitamin A receptor agonists such as ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754 and Bexarotene; and other insulin sensitivity enhancers such as reglixane, 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, LY-510929, AR-H049020, and GW-501516. The insulin sensitivity enhancer is preferably used for diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, more preferably for diabetes, impaired glucose tolerance or hyperinsulinemia, because of improving the interference of insulin signal transduction in peripheral tissues and enhancing the uptake of glucose from the blood into tissues, resulting in a decrease in blood glucose level.

As the sugar absorption inhibitor, for example, α -glucosidase inhibitors such as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25, 637, cagoglobose and MDL-73, 945; alpha-amylase inhibitors such as AZM-127, SGLT1 inhibitors described in the publications of International publications WO 02/098893 and WO 2004/014932, and the like. The glucose absorption inhibitor is preferably used for diabetes, impaired glucose tolerance, diabetic complications, obesity or hyperinsulinemia, and more preferably for impaired glucose tolerance, because of the inhibition of gastrointestinal enzymatic digestion of carbohydrates contained in foods, and the inhibition or delay of glucose absorption into the body.

Examples of biguanides include phenformin, buformin hydrochloride, and metformin hydrochloride. Biguanides are preferably used for diabetes, impaired glucose tolerance, diabetic complications or hyperinsulinemia, and more preferably for diabetes, impaired glucose tolerance or hyperinsulinemia, because of lowering blood glucose by an inhibitory effect on hepatic gluconeogenesis, an accelerating effect on anaerobic glycolysis in tissues or an improving effect on insulin tolerance in peripheral tissues.

As the insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glipizide, glyburide (glyburide), gliclazide, 1-butyl-3-m-aminobenzenesulfonylurea, carbutamide, glibornuride, glipizide, gliquidone, glimeperide, glybuthiazol, glibutrazole, glyhexamide, glymeperidine sodium, glimepiride, phenbutamide, tolcyclamide, glimeperide, nateglinide, mitiglinide calcium hydrate (mitiglinide calcium hydrate), repaglinide (repaglinide), and the like are exemplified. In addition, insulin secretion enhancers include glucokinase activators such as RO-28-1675. Since the blood glucose level is lowered by acting on pancreatic β -cells and enhancing insulin secretion, the insulin secretion enhancer is preferably used for diabetes, impaired glucose tolerance or diabetic complications, more preferably for diabetes or impaired glucose tolerance.

As SGLT2 inhibitors, T-1095 and compounds described in Japanese patent laid-open Nos. Hei 10-237089 and 2001-288178, and International patent publications WO01/16147, WO01/27128, WO01/68660, WO01/74834, WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/53573, WO03/000712, WO03/020737 and the like are illustrated. Since the blood glucose level is lowered by inhibiting the reabsorption of glucose in the renal proximal tubule, the SGLT2 inhibitor is preferably used for diabetes, impaired glucose tolerance, diabetic complications, obesity or hyperinsulinemia, more preferably for diabetes, impaired glucose tolerance, obesity or hyperinsulinemia.

As the insulin or insulin analog, human insulin, animal-derived insulin, human or animal-derived insulin analog, and the like are exemplified. These preparations are preferably used for diabetes, impaired glucose tolerance or diabetic complications, and more preferably for diabetes or impaired glucose tolerance.

As the glucagon receptor antagonist, BAY-27-9955, NNC-92-1687, etc.; as the insulin receptor kinase agonists, TER-17411, L-783281, KRX-613 and the like are exemplified; for tripeptide peptidase II inhibitors, UCL-1397 and the like are exemplified; for dipeptidyl peptidase IV inhibitors, for example, NVP-DPP728A, TSL-225, P-32/98, and the like; as the protein tyrosine phosphatase 1B inhibitor, for example, PTP-112, OC-86839, PNU-177496 and the like; as glycogen phosphorylase inhibitors, for example, NN-4201, CP-368296 and the like; examples of the fructose bisphosphatase inhibitor include R-132917 and the like, and examples of the pyruvate dehydrogenase inhibitor include AZD-7545 and the like; examples of hepatic gluconeogenesis inhibitors include FR-225659 and the like; as glucagon-like peptide-1 analogues, exendin-4, CJC-1131, etc., are exemplified; as glucagon-like peptide 1 agonists, for example, AZM-134, LY-315902, and the like; and for amylin, amylin analogs, or amylin agonists, such as pramlintide acetate, for example. These drugs, glucose-6-phosphatase inhibitors, D-chiroinsitol, glycogen synthase kinase-3 inhibitors and glucagon-like peptide-1 are preferably used for diabetes, impaired glucose tolerance, diabetic complications or hyperinsulinemia, more preferably for diabetes or impaired glucose tolerance.

As the aldose reductase inhibitor, ascorbyl gamolenate, tolrestat, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat (fidarestat), sorbinil, ponalrestat, salidastat-like, zenarestat, minnarrestat, methosorbini, AL-1567, imirestat, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, lindolrestat and the like are illustrated. Aldose reductase inhibitors are preferred for diabetic complications due to inhibition of aldose reductase and reduction of excess intracellular accumulation of sorbitol in polyol pathways that are exacerbated under conditions of persistent hyperglycemia in tissues that are subject to diabetic complications.

As the advanced glycation end product formation inhibitor, for example, pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride and the like are illustrated. Because of inhibiting the formation of advanced glycosylation endproducts that are accelerated in the persistent hyperglycemic condition of diabetes and reducing cell damage, inhibitors of advanced glycosylation endproduct formation are preferred for diabetic complications.

As protein kinase C inhibitors, LY-333531, midostaurin and the like are exemplified. Protein kinase C inhibitors are preferred for diabetic complications due to inhibition of protein kinase C activity which is potentiated under the persistent hyperglycemic condition of diabetes.

Examples of gamma-aminobutyric acid receptor antagonists include topiramate and the like; for sodium channel antagonists, e.g., mexiletine hydrochloride, oxcarbazepine, and the like; as the transcription factor NF-. kappa.B inhibitor, for example, dexlipotam and the like; as the lipid peroxidase inhibitor, for example, scalolazine mesylate (tiralazad mesylate) and the like; for N-acetylated- α -linked-acid-dipeptidase inhibitors, GPI-5693 and the like are exemplified; as the carnitine derivative, carnitine, levacecarnitine hydrochloride, levocarnitine chloride, levocarnitine, ST-261 and the like are exemplified. Preferably, these drugs, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide and Y-128 are used for diabetic complications.

As the antidiarrheal or laxative, calcium polycarbophil, albumin tannate, bismuth subnitrate, etc. are exemplified. These drugs are preferably used for diabetes and the like accompanied by diarrhea, constipation and the like.

As the HMG-CoA reductase inhibitor, for example, 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, coleptone, dalvastatin, acitinite, mevastatin, crivastatin, BMS-180431, BMY-21950, glavastatin, carvastatin (carvastat), BMY-22089, bervastatin and the like are exemplified. Since the blood cholesterol level is lowered by inhibiting hydroxymethylglutaryl-coa reductase, hydroxymethylglutaryl-coa reductase inhibitors are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder or atherosclerosis, more preferably for hyperlipidemia, hypercholesterolemia or atherosclerosis.

As the fibrate compound, bezafibrate, beclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirfibrate, clinofibrate, bisfibrate, etitheofibrate, AHL-157 or the like is exemplified.

For beta₃-adrenoceptor agonists, such as for example 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. Due to stimulation of beta in adipose tissue₃Adrenergic receptors and enhances the induction of energy expenditure by fatty acid oxidation, beta₃-adrenoceptor agonists are preferably used for obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, more preferably for obesity or hyperinsulinemia.

As the acyl-coenzyme A cholesterol acyltransferase inhibitor, NTE-122, MCC-147, PD-132301-2, 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, lecifibrate, C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe and the like are illustrated. Acyl-coa cholesterol acyltransferase is preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder, more preferably for hyperlipidemia or hypercholesterolemia, since blood cholesterol level is lowered by inhibiting acyl-coa cholesterol acyltransferase.

For thyroid hormone receptor agonists, for example, meiodoxam sodium, levothyroxine sodium, KB-2611 and the like; as the cholesterol absorption inhibitor, for example, ezetimibe, SCH-48461, etc.; as the lipase inhibitor, orlistat, ATL-962, AZM-131, RED-103004 and the like are exemplified; for carnitine palmitoyl transferase inhibitors, such as, for example, etomoxider, etc.; as the squalene synthetase inhibitor, SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856, TAK 475, etc. are exemplified; as the nicotinic acid derivative, for example, nicotinic acid, nicotinamide, nicorandite, acipimox, nicorandil and the like; as the bile acid sequestrant, there are exemplified cholestyramine, colesevelam hydrochloride, GT-102-279 and the like; as sodium/bile acid cotransporter inhibitors, 264W94, S-8921, SD-5613, etc.; as the cholesteryl ester transfer protein inhibitor, PNU-107368E, SC-795, JTT-705, CP-529414 and the like are exemplified. These drugs, probucol, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors and low density lipoprotein receptor enhancers are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or dyslipidemia.

As appetite suppressants, monoamine reuptake inhibitors, serotonin release agonists, serotonin agonists (in particular 5 HT) are exemplified_2C-agonists), norepinephrine reuptake inhibitors, norepinephrine releaseRelease stimulant, alpha₁-adrenoceptor agonists, beta₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptor antagonists, gamma-aminobutyric acid receptor antagonists, H₃Histamine antagonists, L-histidine, leptin (leptin), leptin analogues, leptin receptor agonists, melanocortin (melanocortin) receptor agonists (in particular MC3-R agonists, MC4-R agonists), alpha-melanocortin, cocaine-and amphetamine-regulated transcription, mahogany protein, enterostatin (enterostatin) agonists, calcitonin gene-related peptide, bombesin, cholecystokinin agonists (in particular CCK-a agonists), corticotropin releasing hormone analogues, corticotropin releasing hormone agonists, urocortin (urocortin), somatostatin analogues, somatostatin receptor agonists, pituitary adenylate cyclase activating peptide, brain derived neurotrophic factor, ciliary neurotrophic factor, melanocortin-alpha-melanocortin, melanocortin-beta-gamma-, Thyrotropin-releasing hormone, neurotensin, frog skin antihypertensive peptide, neuropeptide Y antagonist, opioid peptide antagonist, galanin (galanin) antagonist, melanin concentrating hormone receptor antagonist, guinea pig related protein inhibitor and orexin (orexin) receptor antagonist. Specifically, as monoamine reuptake inhibitors, for example, mazindol and the like; as the serotonin reuptake inhibitor, for example, dexfenfluramine hydrochloride, fenfluramine, sibutramine hydrochloride, flupentoxamine maleate, sertraline hydrochloride and the like; for serotonin agonists, for example, inotriptan, (+) -norfenfluramine and the like; as the norepinephrine reuptake inhibitor, bupropion, GW-320659, etc.; as norepinephrine-releasing stimulants, rolipram, YM-992 and the like are exemplified; for beta 2-adrenoceptor agonists, for example, amphetamine, dextroamphetamine, phentermine, benzphetamine, methamphetamine, phendimetrazine, phenmetrazine, diethylpropion, phenylpropanolamine, chlorobenzylrex, and the like; for dopamine agonists, for example, ER-230, doprexin, bromocriptine mesylate, etc.; for the cannabis receptor antagonists, for example, rimonabant (rimonabant) and the like; as gamma-aminobutyric acid receptor antagonists, topiramate is exemplifiedEtc.; for H3-histamine antagonists, GT-2394, etc. are exemplified; for leptin, leptin analogs, or leptin receptor agonists, LY-355101 and the like are exemplified; for cholecystokinin agonists (particularly CCK-A agonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378, and the like are exemplified; as neuropeptide Y antagonists, 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 are exemplified. Preferably, the appetite suppressant is used for diabetes, impaired glucose tolerance, diabetic complications, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia or gout, more preferably for obesity, due to stimulation or inhibition of the activity of intracerebral monoamines or bioactive peptides within the central appetite regulating system and suppression of appetite, resulting in decreased energy intake.

As the angiotensin converting enzyme inhibitor, captopril, enalapril maleate, alacepril, delapril hydrochloride, ramipril, lisinopril, imidapril hydrochloride, benazepril hydrochloride, ceronapril monohydrate, cilazapril, fosinopril sodium, perindopril (perindopril erbumine), mevinopril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calcium, moexipril hydrochloride, zolapril and the like are illustrated. Angiotensin converting enzyme inhibitors are preferably used for diabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240, fasidotril, Shanpatra, GW-660511X, mixanpril, SA-7060, E-4030, SLV-306, ecadotril and the like are illustrated. Preferably, neutral endopeptidase inhibitors are used for diabetic complications or hypertension.

As angiotensin II receptor antagonists, candesartan cilexetil (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 are illustrated. Angiotensin II receptor antagonists are preferred for diabetic complications or hypertension.

As the endothelin converting enzyme inhibitor, for example, CGS-31447, CGS-35066, SM-19712 and the like; as endothelin receptor antagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sertraline sodium (sodium sitaxsentan), BMS-193884, darussentan (daursentan), TBC-3711, bosentan, tezosentan sodium, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, Enlasutan (Enlasentan), BMS-207940 and the like are exemplified. Preferably these drugs are used for diabetic complications or hypertension, more preferably for hypertension.

As the diuretic, chlorothiazide, metolazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentofluthiazide, mechlorthiazide, indapamide, tripamide, mefoside, azoxan, ethacrynic acid, torasemide, piretanide, furosemide, bumetanide, metipran, potassium canrenoate (potassiumcannoate), spironolactone, triamterene, aminophylline, cilostanin hydrochloride, LLU-alpha, PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan, conivaptan hydrochloride (conceivaptan), and the like are exemplified. Since blood pressure is lowered or edema is improved by increasing urinary excretion, diuretic drugs are preferably used for diabetic complications, hypertension, congestive heart failure or edema, and more preferably for hypertension, congestive heart failure or edema.

As the calcium antagonist, there are exemplified, for example, aranidipine, efonidipine hydrochloride, nicardipine hydrochloride, barnidipine hydrochloride, benidipine hydrochloride, manidipine hydrochloride, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besylate, prasudipine, lercanidipine hydrochloride, isradipine, and eidigipineFlat, azelnidipine, lacidipine, vatanidipine hydrochloride, ledipine, diltiazem hydrochloride, clentiam maleate (clentizem), verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridil hydrochloride, gallopamil hydrochloride, and the like; as the vasodilating antihypertensive agents, indapamide, todralazine hydrochloride, hydralazine hydrochloride, cadralazine, budralazine and the like are exemplified; for the sympathetic blocking agent, for example, amisulolol hydrochloride, terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol, metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride, nebivolol, betaxolol hydrochloride, pindolol hydrochloride, terbalol hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride, bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutolol sulfate, acebutolol hydrochloride, tililol hydrochloride, nadolol, urapidil, indopipamide, etc.; for central antihypertensive agents, for example, reserpine and the like; for alpha₂Adrenergic receptor agonists, such as clonidine hydrochloride, methyldopa, CHF-1035, guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine, talacrex hydrochloride, and the like. Preferably these drugs are used for hypertension.

For antiplatelet drugs, ticlopidine hydrochloride, dipyridamole, cilostazol, ethyl hexacosane pentaenoate, sarpogrelate hydrochloride, delazipride dihydrochloride, trapidil, beraprost sodium, aspirin, and the like are exemplified. Antiplatelet agents are preferably used for atherosclerosis or congestive heart failure.

As the uric acid synthesis inhibitor, allopurinol, oxypurinol, and the like are exemplified; for uric acid excretion promoters, for example, benzbromarone, probenecid, etc.; examples of the urine alkalifying agent include sodium hydrogen carbonate, potassium citrate, and sodium citrate. Preferably these drugs are used for hyperuricemia or gout.

In the case of use in combination with the compound of the present invention, for example, in diabetes, it is preferably used in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists; most preferably in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists; most preferably in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs. Similarly, when used for diabetic complications, it is preferably used in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, insulin resistance enhancers, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, antidiarrheals, laxatives, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics; more preferably in combination with at least one drug selected from the group consisting of: aldose reductase inhibitors, angiotensin II receptor antagonists, neutral endopeptidase inhibitors and angiotensin II receptor antagonists.

Further, in the case of obesity, it is preferably used in combination with at least one drug selected from the group consisting of: insulin sensitivity enhancers, sugar absorption inhibitors, biguanides, insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, starch insolubilines, starch insolubiline analogs, starch insolubiline agonists, beta-insulin secretion enhancers, SGLT2 inhibitors, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic₃-adrenoceptor agonistsAnd appetite suppressants; more preferably in combination with at least one drug selected from the group consisting of: sugar absorption inhibitor, SGLT2 inhibitor, beta₃-adrenergic receptor agonists and appetite suppressants.

When the pharmaceutical compositions of the present invention are used for actual treatment, different dosage forms are used depending on their applications. As examples of the dosage form, powders, granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, pastes (poultices) for oral or parenteral administration are exemplified. The pharmaceutical composition of the present invention also includes sustained-release preparations including gastrointestinal muco-adsorptive preparations (e.g., International patent publication Nos. WO99/10010, WO99/26606, and Japanese patent publication No. 2001-2567).

These pharmaceutical compositions can be prepared by mixing with or diluting and dissolving with appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers, dissolution aids, and the like, and formulating the mixture according to a conventional method. In the case where the compounds of the present invention are used in combination with other drugs, they may be prepared by formulating the respective active ingredients together or separately in a similar manner as defined above.

In the case where the pharmaceutical composition of the present invention is used for practical treatment, the dose of the above-mentioned compound of the general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient is appropriately determined depending on the age, sex, body weight, symptoms and the degree of treatment of each patient, which is about 0.1 to 1,000mg per day per adult in the case of oral administration, about 0.01 to 300mg per day per adult in the case of parenteral administration, and the daily dose may be divided into one to several doses per day for appropriate administration. In addition, in the case where the compound of the present invention is used in combination with other drugs, the dose of the compound of the present invention may be reduced depending on the dose of the drug.

Examples

The present invention is further illustrated in more detail by the following reference examples, and test examples. However, the present invention is not limited by these examples.

Reference example 1

2-bromo-6-fluorobenzaldehyde

To a solution of diisopropylamine (2.65mL) in tetrahydrofuran (30mL) at-78 ℃ under an argon atmosphere was added n-butyllithium (2.44mol/L n-hexane solution, 7.03mL) and the mixture was stirred at the same temperature for 5 minutes. 3-bromofluorobenzene (3g) was added to the reaction mixture and the mixture was stirred at the same temperature for 1 hour. N, N-dimethylformamide (1.45mL) was added to the reaction mixture and the mixture was stirred at the same temperature for 10 minutes, then a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred under ice-cooling for 5 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (3.43 g).

¹H-NMR(CDCl₃)δppm：7.1-7.2(1H，m)，7.35-7.45(1H，m)，7.45-7.55(1H，m)，10.36(1H，s)

Reference example 2

4-bromobenzo [ b]Thiophene(s)

To a suspension of sodium hydride (55%, 1.11g) in dimethyl sulfoxide (20mL) was added methyl thioglycolate (1.53mL) at room temperature, and the mixture was stirred for 15 minutes. A solution of 2-bromo-6-fluorobenzaldehyde (3.43g) in dimethyl sulfoxide (4mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into ice water and the precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-methoxycarbonyl-4-bromobenzo [ b ] thiophene (1.52 g). This material was suspended in a mixed solvent of methanol (20mL) and water (10mL) and sodium hydroxide (0.91g) was added to the suspension. The mixture was stirred at 50 ℃ for 5 hours. The reaction mixture was cooled with an ice bath and acidified by adding 2mol/L hydrochloric acid to the reaction mixture. The precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-carboxybenzo [ b ] thiophene (1.27 g). To this material was added copper powder (0.42g) and quinoline (10mL) and the mixture was stirred at 190 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, 2mol/L hydrochloric acid (40mL) and ethyl acetate (20mL) were added to the reaction mixture and the mixture was stirred for 15 minutes. Insoluble materials in the mixture were removed by filtration and the organic layer of the filtrate was separated. The aqueous layer of the filtrate was extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was washed with 2mol/L hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.55 g).

¹H-NMR(CDCl₃)δppm：7.15-7.25(1H，m)，7.45-7.6(3H，m)，7.82(1H，d，J＝8.2Hz)

Reference example 3

7-bromo-benzo [ b ]]Thiophene(s)

To a mixture of 2-bromothiophenol (5g) and 2-bromomethyl-1, 3-dioxolane (2.98mL) in N, N-dimethylformamide (50mL) was added potassium carbonate (5.48g) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed successively with water, 1mol/L aqueous sodium hydroxide solution, water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-bromophenylthiomethyl) -1, 3-dioxolane (7.25 g). To a mixture of polyphosphoric acid (20g) and chlorobenzene (40mL) was added a solution of (2-bromophenylthiomethyl) -1, 3-dioxolane (7.25g) in chlorobenzene (20mL) and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and the supernatant was collected by decantation. Toluene was added to the residue and after stirring the mixture, the supernatant was collected by decantation. The supernatants were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (2.27 g).

¹H-NMR(CDCl₃)δppm：7.25(1H，t，J＝7.8Hz)，7.44(1H，d，J＝5.6Hz)，7.45-7.55(2H，m)，7.77(1H，d，J＝7.8Hz)

Reference example 4

4- [ (E) -2-Phenylethenyl]Benzo [ b ]]Thiophene(s)

A mixture of 4-bromobenzo [ b ] thiophene (0.55g), styrene (0.89mL), triethylamine (1.81mL), palladium (II) acetate (59mg), and tris (2-methylphenyl) phosphine (0.16g) in acetonitrile (10mL) was refluxed overnight under argon atmosphere. The reaction mixture was diluted with ether and the insoluble material was removed by filtration. The filtrate was washed successively with 1mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane-n-hexane/ethyl acetate 5/1) to give the title compound (0.56 g).

¹H-NMR(CDCl₃)δppm：7.2-7.45(6H，m)，7.51(1H，d，J＝5.5Hz)，7.55-7.7(4H，m)，7.81(1H，d，J＝7.8Hz)

Reference example 5

7- [ (E) -2-Phenylethenyl]Benzo [ b ]]Thiophene(s)

The title compound was prepared in a similar manner to that described in reference example 4 using 7-bromobenzo [ b ] thiophene in place of 4-bromobenzo [ b ] thiophene.

¹H-NMR(CDCl₃)δppm：7.25-7.45(7H，m)，7.5(1H，d，J＝5.7Hz)，7.55-7.65(3H，m)，7.77(1H，dd，J＝7.9Hz，1.1Hz)

Reference example 6

4- (2-phenylethyl) benzo [ b]Thiophene(s)

To a solution of 4- [ (E) -2-phenylvinyl ] benzo [ b ] thiophene (0.56g) and triethylamine (2.63mL) in tetrahydrofuran (25mL) was added 2, 4, 6-triisopropylbenzenesulfonylhydrazide (5g), and the mixture was refluxed overnight under an argon atmosphere. After the reaction mixture was cooled to room temperature, 2mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give a mixture of the starting material and the title compound (0.43 g). The mixture was dissolved in triethylamine (2.04g) and tetrahydrofuran (18mL), and 2, 4, 6-triisopropylbenzenesulfonylhydrazide (3.28g) was added to the solution, and the mixture was refluxed overnight under an argon atmosphere. The reaction mixture was cooled to room temperature and 2mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.4 g).

¹H-NMR(CDCl₃)δppm：3.0-3.05(2H，m)，3.2-3.3(2H，m)，7.1-7.35(7H，m)，7.4-7.5(2H，m)，7.75(1H，d，J＝8.0Hz)

Reference example 7

7- (2-phenylethyl) benzo [ b]Thiophene(s)

The title compound was prepared in a similar manner to that described in reference example 6 using 7- [ (E) -2-phenylvinyl ] benzo [ b ] thiophene instead of 4- [ (E) -2-phenylvinyl ] benzo [ b ] thiophene.

¹H-NMR(CDCl₃)δppm：3.05-3.15(2H，m)，3.15-3.25(2H，m)，7.1-7.35(7H，m)，7.38(1H，d，J＝5.4Hz)，7.44(1H，d，J＝5.4Hz)，7.7(1H，d，J＝7.9Hz)

Reference example 8

2- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -4- (2-phenylethyl) benzo [ b]Thiophene(s)

To a solution of 4- (2-phenylethyl) benzo [ b ] thiophene (0.4g) in tetrahydrofuran (15mL) at-78 ℃ under an argon atmosphere was added n-butyllithium (2.44mol/L n-hexane solution, 0.69mL) and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of 2, 3, 4, 6-tetra-O-benzyl-D-glucono-1, 5-lactone (0.82g) in tetrahydrofuran (3mL), and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the mixture was extracted with diethyl ether. The extract was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate-4/1) to give 2, 3, 4, 6-tetra-O-benzyl-1- [4- (2-phenylethyl) benzo [ b ] thiophen-2-yl ] -D-glucopyranose (1.02 g). This material was dissolved in acetonitrile (13mL) and triethylsilane (0.42mL) was added to the solution. Boron trifluoride-diethyl ether complex (0.18mL) was added to the solution at-20 ℃ and the mixture was stirred at room temperature for 1 hour. Saturated aqueous potassium carbonate solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 8/1) to give the title compound (0.58 g).

¹H-NMR(CDCl₃)δppm：2.9-3.05(2H，m)，3.1-3.25(2H，m)，3.6-3.7(2H，m)，3.75-3.9(4H，m)，4.11(1H，d，J＝10.4Hz)，4.55-4.75(5H，m)，4.88(1H，d，J＝10.7Hz)，4.92(1H，d，J＝11.0Hz)，4.96(1H，d，J＝11.0Hz)，6.9-7.0(2H，m)，7.05-7.4(25H，m)，7.47(1H，s)，7.7(1H，d，J＝8.1Hz)

Reference example 9

2- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -7- (2-phenylethyl) benzo [ b]Thiophene(s)

The title compound was prepared in a similar manner to that described in reference example 8 using 7- (2-phenylethyl) benzo [ b ] thiophene instead of 4- (2-phenylethyl) benzo [ b ] thiophene.

¹H-NMR(CDCl₃)δppm：3.0-3.2(4H，m)，3.6-3.7(2H，m)，3.75-3.9(4H，m)，4.11(1H，d，J＝10.3Hz)，4.5-4.75(5H，m)，4.87(1H，d，J＝10.7Hz)，4.92(1H，d，J＝11.0Hz)，4.97(1H，d，J＝11.0Hz)，6.95-7.0(2H，m)，7.1-7.45(26H，m)，7.62(1H，d，J＝7.8Hz)

Example 1

2- (beta-D-glucopyranosyl) -4- (2-phenylethyl) benzo [ b]Thiophene(s)

To a solution of 2- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl) -4- (2-phenylethyl) benzo [ b ] thiophene (0.58g) and ethanethiol (1.13mL) in dichloromethane (10mL) at room temperature was added boron trifluoride-diethyl ether complex (1.43mL), and the mixture was stirred for 3 hours. To the reaction mixture was added saturated aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give the title compound (94 mg).

¹H-NMR(CD₃OD)δppm：2.95-3.05(2H，m)，3.15-3.25(2H，m)，3.35-3.55(4H，m)，3.72(1H，dd，J＝12.1Hz，6.0Hz)，3.92(1H，dd，J＝12.1Hz，2.1Hz)，4.55(1H，d，J＝8.8Hz)，7.06(1H，d，J＝6.8Hz)，7.1-7.3(6H，m)，7.54(1H，s)，7.66(1H，d，J＝8.3Hz)

Example 2

2- (beta-D-glucopyranosyl) -7- (2-phenylethyl) benzo [ b]Thiophene(s)

The title compound was prepared in analogy to the methods described in example 1 using 2- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl) -7- (2-phenylethyl) benzo [ b ] thiophene instead of 2- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl) -4- (2-phenylethyl) benzo [ b ] thiophene.

¹H-NMR(CD₃OD)δppm：3.0-3.1(2H，m)，3.1-3.2(2H，m)，3.35-3.55(4H，m)，3.73(1H，dd，J＝12.1Hz，5.8Hz)，3.93(1H，dd，J＝12.1Hz，2.0Hz)，4.54(1H，d，J＝8.6Hz)，7.06(1H，d，J＝6.5Hz)，7.1-7.3(6H，m)，7.41(1H，s)，7.55-7.65(1H，m)

Example 3

Process 1

Benzo [ b ]]Thiophen-7-yl-p-methylbenzyl alcohol

Grignard reagent was prepared according to the general procedure using 7-bromobenzo [ b ] thiophene (1.0g), magnesium (0.13g), catalytic amounts of iodine and tetrahydrofuran (3 mL). To the Grignard reaction solution was added a solution of 4-methylbenzaldehyde (0.62g) in tetrahydrofuran (5mL) at 0 ℃ under an argon atmosphere. The reaction mixture was stirred at room temperature overnight and aqueous ammonium chloride solution was added to the mixture. The mixture was extracted with ether, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). Further purification by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 6/1) gave the title compound (0.68g) as a yellow oil.

¹H-NMR(CDCl₃)δppm：2.32(3H，s)，2.38(1H，d，J＝3.6Hz)，6.11(1H，d，J＝3.4Hz)，7.10-7.20(2H，m)，7.30-7.45(5H，m)，7.45-7.50(1H，m)，7.70-7.80(1H，m)

Process 2

7- (4-methylbenzyl) benzo [ b ]]Thiophene(s)

To a suspension of sodium iodide (2.0g) in acetonitrile was added chlorotrimethylsilane (1.5g) at room temperature, and after the mixture was stirred at room temperature for minutes, benzo [ b ] thiophen-7-yl-p-methylbenzyl alcohol (0.68g) was added to the mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, and the mixture was extracted with hexane. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.57g) as a colorless oil.

¹H-NMR(CDCl₃)δppm：2.31(3H，s)，4.20(2H，s)，7.05-7.14(3H，m)，7.14-7.20(2H，m)，7.25-7.45(3H，m)，7.65-7.75(1H，m)

Process 3

2, 3, 4, 6-tetra-O-benzyl-1- [7- (4-methylbenzyl) benzo [ b ]]Thien-2-yl]-D-glucopyranose

To a solution of 7- (4-methylbenzyl) benzo [ b ] thiophene (0.57g) in tetrahydrofuran (10mL) at-78 ℃ under an argon atmosphere was added n-butyllithium (2.71mol/L tetrahydrofuran solution, 0.88 mL). The mixture was stirred at the same temperature for 30 minutes and a solution of 2, 3, 4, 6-tetra-O-benzyl-D-glucono-1, 5-lactone (1.2g) in tetrahydrofuran (5mL) was added to the mixture. The reaction mixture was warmed to 0 ℃ and stirred for 10 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 4/1) to give the title compound (1.2 g).

Process 4

2- (2, 3, 4, 6-tetra-O-benzyl-beta-D-glucopyranosyl) -7- (4-methylbenzyl) benzo [ b]Thiophene(s)

To a solution of 2, 3, 4, 6-tetra-O-benzyl-1- [7- (4-methylbenzyl) benzo [ b ] thiophen-2-yl ] -D-glucopyranose (1.2g) and triethylsilane (0.49mL) in acetonitrile (15mL) at-20 deg.C was added boron trifluoride-diethyl ether complex (2.0mL) and the mixture was stirred for 1 hour. Saturated aqueous potassium carbonate solution was added to the mixture and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 6/1) to give the title compound (0.95 g).

¹H-NMR(CDCl₃)δppm：2.28(3H，s)，3.55-3.70(2H，m)，3.75-3.85(4H，m)，4.09(1H，d，J＝10.5Hz)，4.15-4.20(2H，m)，4.52(1H，d，J＝10.4Hz)，4.56-4.62(2H，m)，4.62-4.72(2H，m)，6.90-7.00(2H，m)，7.00-7.40(25H，m)，7.55-7.65(1H，m)

Process 5

2- (beta-D-glucopyranosyl) -7- (4-methylbenzyl) benzo [ b]Thiophene(s)

To a solution of 2- (2, 3, 4, 6-tetra-O-benzyl- β -D-glucopyranosyl) -7- (4-methylbenzyl) benzo [ b ] thiophene (0.95g) and ethanethiol (1.8mL) in dichloromethane (15mL) at room temperature was added boron trifluoride-diethyl ether complex (2.1 mL). The reaction mixture was stirred at room temperature for 3 hours, and a saturated aqueous potassium carbonate solution was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give the title compound (0.16 g).

¹H-NMR(CD₃OD)δppm：2.27(3H，s)，3.30-3.50(4H，m)，3.69(1H，dd，J＝5.9，12.1Hz)，3.90(1H，dd，J＝2.0，12.1Hz)，4.10-4.15(2H，m)，4.50(1H，d，J＝9.0Hz)，7.00-7.15(5H，m)，7.25-7.35(1 H，m)，7.35-7.40(1H，m)，7.55-7.70(1H，m)

Example 4 example 11

The compounds described in table 1 or 2 were prepared in a similar manner to that described in example 3 using the corresponding starting materials.

[ Table 1]

[ Table 2]

Example 12-example 16

The compounds described in table 3 or 4 were prepared in a similar manner to that described in example 1 using the corresponding starting materials.

[ Table 3]

Example numbering

Chemical structure

1H-NMR(CDOD)δppm

[ Table 4]

Compound 5 described in the table can be prepared according to a method similar to that described in the above examples or reference examples.

[ Table 5]

Test example 1

Confirmation test for inhibitory Effect on human SGLT1 Activity

1) Cloning and construction of vectors expressing human SGLT1

A cDNA library was prepared for PCR amplification by reverse transcription from total RNA derived from human small intestine (ori gene) using oligo-dT as a primer. Using this cDNA library as a template, a DNA fragment from 1 to 2005bp of human SGLT1 (ACCESSION: M24847) reported by Hediger et al was amplified by the PCR method and inserted into the multiple cloning site of pcDNA3.1(-) (Invitrogen). The inserted DNA sequence completely conforms to the previously reported sequence.

2) Establishment of cell line stably expressing human SGLT1

The expression vector of human SGLT1 was digested with Sca I to form a linear DNA. The linear DNA was transfected into CHO-K1 cells by lipofection (efficiency Transfection Reagent: QIAGEN). The activity on uptake of methyl- α -D-glucopyranoside was measured by culturing the selected neomycin-resistant cell line in a medium containing G418(1mg/mL, LIFE tecnologes) and then by the method described below. The cell line exhibiting the greatest uptake activity was selected and designated CS 1-5-11D. CS1-5-11D cells were cultured in the presence of 200. mu.g/mL of G418.

3) Measurement of inhibitory Activity on uptake of methyl- α -D-glucopyranoside (α -MG)

CS1-5-11D cells at 3X 10⁴The density of individual cells/well was seeded in 96-well culture plates and cultured for 2 days, which were used for uptake assays. Unlabeled (Sigma) and¹⁴a mixture of C-labeled α -MG (Amersham Pharmacia Biotech) was added at a final concentration of 1mM to an uptake buffer (pH 7.4; containing 140mM sodium chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM 2- [4- (2-hydroxyethyl) -1-piperazinyl)]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminomethane). The test compound was dissolved in dimethyl sulfoxide, and then appropriately diluted with distilled water. The test compound solution was added to an uptake buffer containing 1mM α -MG and designated as the measurement buffer. For the control group, a measurement buffer without any test compound was prepared. To measure the basal uptake, a basal uptake measurement buffer containing 140mM choline chloride instead of sodium chloride was prepared. After removing the culture medium of CS1-5-11D cells, 180. mu.L of pretreatment buffer (basal uptake buffer without. alpha. -MG) was added to each well and incubated at 37 ℃ for 10 minutes. After repeating the same treatment, the pre-treatment buffer was removed. To each well, 75. mu.L of measurement buffer or basal uptake buffer was added and incubated at 37 ℃ for 1 hour. After removal of the measurement buffer, the cells were washed twice with 180 μ L per well of wash buffer (basal uptake buffer containing 10mM unlabeled α -MG). Cells were lysed by adding 75. mu.L of 0.2mol/L NaOH to each well. The cell lysate was transferred to PicoPlates (Packard) and 150. mu.L of MicroScint-40(Packard) was added and mixed. Radioactivity was measured by a micro scintillation counter, topcount (packard). Comparing the uptake in the control group with the basal uptakeThe difference between was set to 100%, and the uptake of methyl- α -D-glucopyranoside at each drug concentration was calculated. Drug concentration (IC) for 50% inhibition of methyl-alpha-D-glucopyranoside uptake was calculated using a log (logit) plot₅₀Value). The results are shown in Table 6.

[ Table 6]

Test compounds	ICValue (nM)
		Example 1	220

Test example 2

Confirmation test for inhibitory Effect on human SGLT2 Activity

1) Cloning and construction of vectors expressing human SGLT2

A cDNA library was prepared for PCR amplification by reverse transcription from total RNA (ori gene) derived from human kidney using oligo-dT as a primer. Using this cDNA library as a template, a DNA fragment from 2 to 2039bp (ACCESSION: M95549, M95299) of human SGLT2 reported by R.G.Wells et al was amplified by the PCR method and inserted into the multiple cloning site of pcDNA3.1(-) (Invitrogen). The inserted DNA sequence completely conforms to the previously reported sequence.

2) Establishment of cell line stably expressing human SGLT2

The expression vector of human SGLT2 was digested with Sca I to form a linear DNA. The linear DNA was transfected into CHO-K1 cells by lipofection (efficiency Transfection Reagent: QIAGEN). The activity on uptake of methyl- α -D-glucopyranoside was measured by culturing the selected neomycin-resistant cell line in a medium containing G418(1mg/mL, LIFE tecnologes) and then by the method described below. The cell line exhibiting the greatest uptake activity was selected and designated CS 2-5E. CS2-5E cells were cultured in the presence of 200. mu.g/mL of G418.

3) Measurement of inhibitory Activity on uptake of methyl- α -D-glucopyranoside (α -MG)

CS2-5E cells at 3X 10⁴The density of individual cells/well was seeded in 96-well culture plates and cultured for 2 days, which were used for uptake assays. Unlabeled (Sigma) and¹⁴a mixture of C-labeled α -MG (Amersham Pharmacia Biotech) was added at a final concentration of 1mM to an uptake buffer (pH 7.4; containing 140mM sodium chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM 2- [4- (2-hydroxyethyl) -1-piperazinyl)]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminomethane). The test compound was dissolved in dimethyl sulfoxide, and then appropriately diluted with distilled water. The test compound solution was added to an uptake buffer containing 1mM α -MG and designated as the measurement buffer. For the control group, a measurement buffer without any test compound was prepared. To measure basal uptake, a basal uptake measurement buffer containing 140mM chorine chloride instead of sodium chloride was prepared. After removing the culture medium of CS2-5E cells, 180. mu.L of pretreatment buffer (basal uptake buffer without. alpha. -MG) was added to each well and incubated at 37 ℃ for 10 minutes. After repeating the same treatment, the pre-treatment buffer was removed. To each well, 75. mu.L of measurement buffer or basal uptake buffer was added and incubated at 37 ℃ for 1 hour. After removal of the measurement buffer, the cells were washed twice with 180 μ L per well of wash buffer (basal uptake buffer containing 10mM unlabeled α -MG). Cells were lysed by adding 75. mu.L of 0.2mol/L NaOH to each well. The cell lysate was transferred to PicoPlates (packard) and 150. mu.L was addedMicroScint-40(Packard) and mixed. Radioactivity was measured by a micro scintillation counter, topcount (packard). The difference between the uptake and the basal uptake in the control group was set as 100%, and the uptake of methyl- α -D-glucopyranoside at each drug concentration was calculated. Drug concentration (IC) for 50% inhibition of uptake of methyl-alpha-D-glucopyranoside was calculated using a pair plot₅₀Value). The results are shown in Table 7.

[ Table 7]

Test compounds	ICValue (nM)
		Example 1	58
Example 2	130
		Example 3	2.0

Industrial applicability

The fused heterocyclic derivative of the above general formula (I), a pharmaceutically acceptable salt thereof and a prodrug thereof of the present invention have an inhibitory effect on human SGLT activity and can be used for inhibiting an increase in blood glucose level or lowering blood glucose level by inhibiting the absorption of carbohydrates such as glucose in the small intestine or by inhibiting the reabsorption of glucose in the kidney. Therefore, the present invention can provide an excellent drug for preventing or treating diseases associated with hyperglycemia such as diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic complications, obesity and the like.

Claims (14)

1. A fused heterocyclic derivative represented by the following general formula (I):

wherein

R¹And R⁴One represents a group represented by the following general formula, and the other represents a hydrogen atom,

in the formula, R⁵And R⁶Independently represent a hydrogen atom, a hydroxyl group, a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6An alkylthio group;

q represents a methylene group or an ethylene group;

ring A represents a benzene ring;

R²and R³Represents a hydrogen atom;

A¹represents S;

A²represents CH;

g represents a group of the formula:

E¹represents a hydroxyl group;

E²represents a hydrogen atom;

or a pharmaceutically acceptable salt thereof.

2. A fused heterocyclic derivative as described in claim 1, wherein Q represents ethylene, or a pharmaceutically acceptable salt thereof.

3. A fused heterocyclic derivative as described in claim 1, wherein Q represents a methylene group, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the fused heterocyclic derivative as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

5. A human SGLT activity inhibitor comprising the fused heterocyclic derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.

6. A human SGLT inhibitor as claimed in the claim 5, wherein the SGLT is SGLT1 and/or SGLT 2.

7. A human SGLT inhibitor as described in the claim 5, which is a postprandial hyperglycemia-inhibiting drug.

8. A human SGLT inhibitor as described in the claim 5, which is a medicament for the prophylaxis or treatment of diabetes or obesity.

9. A human SGLT inhibitor as described in the claim 5, which is an agent for inhibiting the progression of impaired glucose tolerance into diabetes in a subject.

10. The pharmaceutical composition of claim 4, wherein the dosage form is a sustained release formulation.

11. A human SGLT inhibitor as described in the claim 5, wherein the dosage form is a sustained release formulation.

12. Use of a fused heterocyclic derivative as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for inhibiting postprandial hyperglycemia.

13. Use of a fused heterocyclic derivative as described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for the prophylaxis or treatment of diabetes or obesity.

14. Use of a fused heterocyclic derivative as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for inhibiting the progression of impaired glucose tolerance to diabetes in a subject.