JP2009196985A - Medicinal composition - Google Patents

Abstract

（式中、環Ａ及び環Ｂは、置換されていてもよい、単環不飽和ヘテロ環、二環縮合不飽和ヘテロ環、またはベンゼン環、Ｘは炭素または窒素、Ｙは−（ＣＨ_２）_ｎ−（ｎは１または２）、Ｚは5−チオ−β−D−グルコピラノシル、4−フルオロ−4−デオキシ−β−D−グルコピラノシル、β−D−ガラクトピラノシル、4−フルオロ−4−デオキシ−β−D−ガラクトピラノシル等であり、ただし、環Ａが置換されていてもよい二環縮合不飽和へテロ環のとき、ＹはＸを含む環に結合し、Ｚは5−チオ−β−D−グルコピラノシル等であり、環Ａと環Ｂが置換されていてもよいベンゼンのとき、Ｚは5−チオ−β−D−グルコピラノシルである。）
【選択図】 なし
PROBLEM TO BE SOLVED: To provide a pharmaceutical composition useful for prevention / treatment of diabetes and the like.
A pharmaceutical composition comprising a compound of the following formula, or a pharmaceutically acceptable salt thereof:

(Wherein ring A and ring B are optionally substituted monocyclic unsaturated heterocycle, bicyclic fused unsaturated heterocycle, or benzene ring, X is carbon or nitrogen, Y is — (CH ₂ ) _n- (n is 1 or 2), Z is 5-thio-β-D-glucopyranosyl, 4-fluoro-4-deoxy-β-D-glucopyranosyl, β-D-galactopyranosyl, 4-fluoro-4 -Deoxy-β-D-galactopyranosyl, etc. provided that, when ring A is an optionally substituted bicyclic fused unsaturated heterocycle, Y is bonded to a ring containing X and Z is 5 Z is 5-thio-β-D-glucopyranosyl, such as -thio-β-D-glucopyranosyl and the like, wherein ring A and ring B may be substituted.
[Selection figure] None

Description

  The present invention relates to a pharmaceutical composition.

  Diet therapy and exercise therapy are essential for the treatment of diabetes, but if this alone does not provide sufficient control, insulin or oral diabetes drugs are used as needed. Currently, biguanide compounds, sulfonylurea compounds, insulin resistance improvers, and α-glucosidase inhibitors are used as antidiabetic agents. However, biguanide compounds have side effects such as lactic acidosis, sulfonylurea compounds have severe hypoglycemia, insulin resistance improvers have edema and heart failure, and α-glucosidase inhibitors have abdominal distension and diarrhea. Development of new anti-diabetic drugs without such problems is desired.

  In recent years, Glucose toxicity theory has been proposed in which hyperglycemia, which is the pathological condition of diabetes itself, is involved in the development of diabetes. Chronic hyperglycemia reduces insulin secretion and insulin sensitivity, which causes a vicious cycle in which blood glucose levels further increase (see Non-Patent Documents 1 and 2). According to this theory, correcting hyperglycemia not only suppresses various complications, but also leads to efficient treatment of diabetes by breaking the vicious circle described above.

  One method for correcting hyperglycemia is to excrete excess sugar in blood directly into urine. For example, by inhibiting the sodium-dependent glucose transporter (SGLT) present in the proximal tubule of the kidney, it inhibits glucose reabsorption in the kidney, promotes urinary excretion of sugar, and lowers blood glucose Can do. In fact, it has been confirmed that phlorizin having SGLT inhibitory action is continuously administered subcutaneously to diabetic model animals to correct hyperglycemia and to maintain normal blood glucose levels for a long period of time, thereby improving insulin secretion and insulin resistance. (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5, etc.).

  Further, by treating a diabetes model animal with an SGLT inhibitor for a long period of time, the insulin secretion response and insulin sensitivity are improved without causing any adverse effects on the kidney of the model animal or abnormalities in plasma electrolytes, and the diabetic It has been reported to suppress the onset / progress of nephropathy and neuropathy (Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8, etc.).

  From the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance and suppress the development of diabetes and diabetic complications by lowering blood glucose levels in diabetic patients.

  Patent Document 1 describes aryl O- or N-thioglucopyranoside having the following structure.

(Where Y is O or N)
Patent Document 2 describes a heterocyclyl fluoroglycoside derivative having the following structure.

  Patent Document 3 describes an aryl fluoroglycoside having the following structure.

  These compounds are described as having an SGLT inhibitory action.

  Furthermore, Patent Document 4 describes an aryl C-glycoside having the following structure.

この化合物は炎症性疾患、自己免疫疾患などの治療に有用であることが記載されている。下記構造を有するアリールＣ−グリコシド化合物が記載されている。

This compound is described as being useful for the treatment of inflammatory diseases, autoimmune diseases and the like. An aryl C-glycoside compound having the structure:

WO01 / 27128 pamphlet WO 2004/014931 US2004 / 0259819A1 US2005 / 0014704A1 WO98 / 31697

Diabetologia 28, 119 (1985) Diabetes Care, Volume 13, Page 610 (1990) Journal of Clinical Investigation (J. Clin. Invest.), 79, 1510 (1987) Journal of Clinical Investment (J. Clin. Invest.), 80, 1037 (1987) Journal of Clinical Investigation (J. Clin. Invest.), 87, 561 (1991) Journal of Medicinal Chemistry (J. Med. Chem.) Volume 42, 5311 (1999) British Journal of Pharmacology (Br. J. Pharmacol.), 132, 578 (2001) Life Sciences Vol. 76, 2655 (2005)

  The present invention provides a novel pharmaceutical composition comprising a compound having an excellent SGLT inhibitory action as an active ingredient.

  The present invention relates to a pharmaceutical composition comprising as an active ingredient a compound represented by the following formula (A) or a pharmacologically acceptable salt thereof.

  Formula (A):

(In the formula, ring A and ring B are each independently an optionally substituted monocyclic unsaturated heterocycle, an optionally substituted bicyclic fused unsaturated heterocycle, or an optionally substituted benzene. ring,
X is carbon or nitrogen,
Y is — (CH ₂ ) _n — (where n is 1 or 2),
Z is

And
put it here,
(1) When ring A is an optionally substituted bicyclic fused unsaturated heterocycle, Y is bonded to one of the bicyclic fused unsaturated heterocycles containing X, and Z is

Is;
(2) When ring A and ring B are optionally substituted benzene rings, Z is

It is. )

  The compound of the formula (A) has an inhibitory activity on a sodium-dependent glucose transporter existing in the intestine and kidney of mammals, and the pharmaceutical composition of the present invention is used as a hypoglycemic agent or as a diabetes or diabetic complication (for example, It is useful as a therapeutic / preventive agent for diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), obesity, a prophylactic / therapeutic agent for hyperglycemia (such as postprandial hyperglycemia) or a wound healing promoter.

  “Halogen” or “halo” refers to chlorine, bromine, fluorine and iodine, with chlorine or fluorine being preferred.

  “Alkyl” refers to a monovalent group of a straight or branched saturated hydrocarbon chain having 1 to 12 carbon atoms. A linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 4 carbon atoms is more preferable. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, and various branched chain isomers thereof. Furthermore, the alkyl may be independently substituted with 1 to 4 substituents as described below, if necessary.

  “Alkylene” refers to a divalent group of a straight or branched saturated hydrocarbon chain having 1 to 12 carbon atoms. A linear or branched alkylene group having 1 to 6 carbon atoms is preferable, and a linear or branched alkylene group having 1 to 4 carbon atoms is more preferable. For example, methylene, ethylene, propylene, trimethylene and the like can be mentioned. If necessary, it may be independently substituted with 1 to 4 substituents described later.

  When these alkylenes are bonded to different carbon atoms on the benzene ring, monocyclic unsaturated heterocycle, or bicyclic fused unsaturated heterocycle, a 5- to 7-membered fused together with the bonded carbon atoms. The hydrocarbon ring may be formed, and the hydrocarbon ring may be further independently substituted with 1 to 4 substituents described later.

  “Alkenyl” refers to a monovalent group of a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and having one or more double bonds, and having 2 to 6 carbon atoms. A chain alkenyl group is preferable, and a linear or branched alkenyl group having 2 to 4 carbon atoms is more preferable. For example, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl group, 3-heptenyl, 4-heptenyl, 3-octenyl, 3- Nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl and the like can be mentioned. If necessary, alkenyl may be independently substituted with 1 to 4 substituents as described below.

  “Alkenylene” refers to a divalent group of a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and having one or more double bonds, and having 2 to 6 carbon atoms. A chain alkenylene group is preferable, and a linear or branched alkenylene group having 2 to 4 carbon atoms is more preferable. For example, vinylene, propenylene, butanediylene and the like can be mentioned. If necessary, alkenylene may be independently substituted with 1 to 4 substituents described later.

  When alkenylene is bonded to different carbon atoms on the benzene ring, monocyclic unsaturated heterocycle, or bicyclic fused unsaturated heterocycle, it is fused together with the carbon atoms to which it is bonded to a 5- to 7-membered. A hydrocarbon ring may be formed, and the hydrocarbon ring may be further independently substituted with 1 to 4 substituents described later.

  “Alkynyl” refers to a monovalent group of a straight or branched hydrocarbon chain having 2 to 12 carbon atoms and having one or more triple bonds, and is a straight chain or branched chain having 2 to 6 carbon atoms Of the alkynyl group is more preferable, and a linear or branched alkynyl group having 2 to 4 carbon atoms is more preferable. For example 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-noninyl, 4 -Decynyl, 3-undecynyl, 4-dodecynyl and the like. Alkynyl may be independently substituted with 1 to 4 substituents as described below, if necessary.

  “Cycloalkyl” refers to a monovalent group of a monocyclic or bicyclic saturated hydrocarbon ring having 3 to 12 carbon atoms, preferably a monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. If necessary, these may be independently substituted with 1 to 4 substituents described later.

  “Cycloalkenyl” refers to a monovalent group of a monocyclic or bicyclic unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having one or more double bonds, and is a monocyclic group having 4 to 7 carbon atoms. Unsaturated hydrocarbon groups are preferred. Specific examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and the like. These may be optionally substituted by 1 to 4 substituents as described below.

  “Cycloalkynyl” refers to a monovalent group of a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms and having one or more triple bonds, and having 6 to 8 carbon atoms. Saturated hydrocarbon groups are preferred. Specific examples include cyclooctynyl and cyclodecynyl. Since these are substituents described later, they may be independently substituted by 1 to 4 as necessary.

  The “aryl group” refers to a monovalent group of a monocyclic or bicyclic aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples include phenyl and naphthyl (1-naphthyl, 2-naphthyl and the like). If necessary, these may be independently substituted with 1 to 4 substituents described later.

  “Monocyclic unsaturated heterocycle” means a 3- to 12-membered monocyclic unsaturated hydrocarbon having 1 to 4 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom It means a ring, preferably a 4- to 7-membered unsaturated hydrocarbon ring having 1 to 4 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 4,5-dihydrooxazole, thiazole, isothiazole, thiadiazole, tetrazole and the like. If necessary, it may be independently substituted with 1 to 4 substituents described later.

  “Bicyclic fused unsaturated heterocycle” means at least one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and at least one double or triple bond. Means a 7-12 membered bicyclic condensed hydrocarbon ring having preferably 8-10 membered having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. A condensed hydrocarbon ring is meant. Examples thereof include benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydroisoquinoline and the like.

  “Heterocyclyl” is a monovalent group of the above “monocyclic unsaturated heterocycle” or “bicyclic fused unsaturated heterocycle” or “monocyclic unsaturated heterocycle” or “bicyclic fused unsaturated heterocycle”. Refers to a monovalent group of a heterocyclic ring that occurs when saturated with. If necessary, it may be independently substituted with 1 to 4 substituents described later.

  “Alkanoyl” refers to a group formed by bonding the above “alkyl” to a carbonyl.

  “Alkoxy” refers to a group formed by bonding the above “alkyl” to an oxygen atom.

  Examples of the substituent in each of the above groups include halogen (fluorine, chlorine, bromine, iodine), nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclo Alkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynyl Carbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkyl Ruoxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, cycloalkynyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynyl Carbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono- or di-alkylamino, mono- or di- Alkanoylamino, mono- or di-alkoxy Rubonylamino, mono- or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono- or di-alkylcarbamoyl, mono- or di-arylcarbamoyl, alkylsulfuryl Phynyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkyl Sulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, etc. Can be mentioned. Each of the above groups may be further optionally substituted with these substituents as desired.

Furthermore, the terms haloalkyl, halolower alkyl, haloalkoxy, haloloweralkoxy, halophenyl, haloheterocyclyl, each represent alkyl, loweralkyl, alkoxy, loweralkoxy, phenyl or heterocyclyl substituted with one or more halogens. Refer to it. Preferred are alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl or heterocyclyl substituted with 1 to 7 halogen, more preferably alkyl, lower alkyl, alkoxy, lower alkoxy or phenyl substituted with 1 to 5 halogen. Or it is heterocyclyl. Furthermore, the terms halopyridyl, halothienyl, respectively, refer to pyridyl, or thienyl, substituted with one or more halogens (such as fluorine or chlorine). _{Specifically, CHF 2, CF 3, CHF} 2 O, CF 3 O, CF 3 CH 2, CF 3 CH 2 O, FCH 2 CH 2 O, ClCH 2 CH 2 O, FC 6 H 4, ClC 6 H ₄ , BrC ₆ H ₄ , IC ₆ H ₄ , FC ₅ H ₃ N, ClC ₅ H ₃ N, BrC ₅ H ₃ N, FC ₄ H ₂ S, ClC ₄ H ₂ S, and BrC ₄ H ₂ S It is done.

  The terms hydroxyalkyl, hydroxy lower alkyl, hydroxyalkoxy, hydroxy lower alkoxy, hydroxyphenyl, respectively, refer to alkyl, lower alkyl, alkoxy, lower alkoxy, or phenyl substituted with one or more hydroxy. Preferably it is alkyl substituted with 1-4 hydroxy, lower alkyl, alkoxy, lower alkoxy, or phenyl, more preferably alkyl substituted with 1-2 hydroxy, lower alkyl, alkoxy, lower alkoxy, or phenyl It is. Further, the terms alkoxyalkyl, lower alkoxyalkyl, alkoxy lower alkyl, lower alkoxy lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxylower alkoxy, loweralkoxyloweralkoxy, alkoxyphenyl, loweralkoxyphenyl are each one or more of Refers to alkyl, lower alkyl, alkoxy, lower alkoxy, or phenyl substituted with alkoxy or lower alkoxy. Preferably it is alkyl substituted by 1-4 alkoxy, lower alkyl, alkoxy, lower alkoxy, or phenyl, more preferably alkyl substituted by 1-2 alkoxy, lower alkyl, alkoxy, lower alkoxy, or phenyl It is.

  Similarly, “cyanophenyl” refers to a phenyl group substituted with one or more cyano groups.

  “Arylalkyl” and “arylalkoxy” refer to an alkyl or alkoxy having an aryl as a substitution, whether used alone or otherwise as part of a substitution.

  In the definition of the general formula in the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. More preferably, it means a linear or branched carbon chain having 1 to 4 carbon atoms.

  In the active ingredient of the present invention, as a preferred embodiment, ring A is an optionally substituted monocyclic unsaturated heterocycle, and Z is

It is.

In another preferred embodiment, the optionally substituted monocyclic unsaturated heterocycle is a halogen, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclo Alkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynyl Carbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynylo Cycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, cycloalkynyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyl Oxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono- or di-alkylamino, mono- or di-alkanoyl Amino, mono- or di-alkoxycarbo Ruamino, mono- or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono- or di-alkylcarbamoyl, mono- or diarylcarbamoyl, sulfamoyl, mono- or Di-alkylsulfamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl Alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl , Arylsulfonyl, and heterocyclylsulfonyl, etc. (wherein the substituent may be further substituted with one or more substituents selected from the above substituents) A good monocyclic unsaturated heterocycle,
An optionally substituted bicyclic fused unsaturated heterocycle is halogen, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, Alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclyl Carbonyl, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cyclo Alkyloxycarbonyl, cycloalkenyloxycarbonyl, cycloalkynyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyl Oxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono- or di-alkylamino, mono- or di-alkanoylamino, mono- Or di-alkoxycarbonylamino, mono-if Is di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono- or di-alkylcarbamoyl, mono- or di-arylcarbamoyl, sulfamoyl, mono- or di- Alkylsulfamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenyl Sulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl, And bicyclic condensation optionally substituted with 1 to 5 substituents selected from heterocyclylsulfonyl and the like (wherein the substituents may be further substituted with one or more substituents selected from the above substituents) An unsaturated heterocycle,
An optionally substituted benzene ring is halogen, nitro, cyano, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy , Cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl, alkenyloxy Carbonyl, alkynyloxycarbonyl, cycloalkyloxycarbo , Cycloalkenyloxycarbonyl, cycloalkynyloxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyloxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyloxy, Heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono- or di-alkylamino, mono- or di-alkanoylamino, mono- or di -Alkoxycarbonylamino, mono- or di-aryl cal Nylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono- or di-alkylcarbamoyl, mono- or di-arylcarbamoyl, sulfamoyl, mono- or di-alkylsulfamoyl, Alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, Cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl, heterocyclylsulfo 1 to 5 substituents selected from nyl, alkylene, alkyleneoxy, alkylenedioxy, alkenylene and the like (wherein the substituent may be further substituted with one or more substituents selected from the above substituents) A benzene ring optionally substituted by

  The “optionally substituted benzene ring” includes a benzene ring substituted with alkylene, that is, a benzene ring forming a hydrocarbon ring condensed with a carbon atom to which alkylene is bonded, and alkenylene. Substituted benzene rings, that is, benzene rings forming a condensed hydrocarbon ring (for example, a benzene ring) with a bonded carbon atom are also included.

  The optionally substituted monocyclic unsaturated heterocycle is preferably halogen, hydroxyl, alkoxy, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl. Oxy, aryl, aryloxy, arylalkoxy, cyano, nitro, amino, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, sulfamoyl, mono- Or di-alkylsulfamoyl, alkanoyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfinyl, al Rusuruhoniru, arylsulfonyl, monocyclic unsaturated heterocyclic ring may be substituted with a substituent having 1 to 3 selected from heterocyclyl and oxo and the like.

  The optionally substituted bicyclic fused unsaturated heterocycle is preferably halogen, hydroxyl, alkoxy, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyclo Alkyloxy, aryl, aryloxy, arylalkoxy, cyano, nitro, amino, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, sulfamoyl, mono -Or di-alkylsulfamoyl, alkanoyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfinyl, Alkylsulfonyl, arylsulfonyl, by two may be ring fused unsaturated heterocyclic ring substituted with a substituent having 1 to 3 selected from heterocyclyl and oxo and the like.

  The benzene ring which may be substituted is preferably halogen, hydroxyl, alkoxy, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyloxy, Aryl, aryloxy, arylalkoxy, cyano, nitro, amino, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, sulfamoyl, mono- or di -Alkylsulfamoyl, alkanoyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfinyl, alkyl Sulfonyl, arylsulfonyl, heterocyclyl, alkylene, alkyleneoxy, a benzene ring which may be substituted with 1-3 substituents selected from alkylenedioxy and alkenylene and the like.

In other preferred embodiments, the optionally substituted monocyclic unsaturated heterocycle is halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, Amino, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, sulfamoyl, mono- or di-alkylsulfamoyl, carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, Monocyclic unsaturated hete optionally substituted with 1-3 substituents independently selected from phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl and oxo It is a ring,
The optionally substituted bicyclic fused unsaturated heterocycle is halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkyl. Amino, alkanoylamino, alkoxycarbonylamino, sulfamoyl, mono- or di-alkylsulfamoyl, carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkanoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, A bicyclic fused unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from phenylsulfonyl, heterocyclyl and oxo;
Optionally substituted benzene rings are halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, alkanoyl Amino, alkoxycarbonylamino, sulfamoyl, mono- or di-alkylsulfamoyl, carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, A benzene ring optionally substituted with 1-3 substituents independently selected from alkylene and alkenylene;
Here, the substitution on the benzene ring, monocyclic unsaturated heterocycle, or bicyclic fused unsaturated heterocycle further includes halogen, hydroxy, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, alkylthio, 1-3 substituents independently selected from alkylsulfonyl, mono- or di-alkylamino, carboxy, alkoxycarbonyl, phenyl, alkyleneoxy, alkylenedioxy, oxo, carbamoyl, and mono- or di-alkylcarbamoyl May be substituted.

In a preferred embodiment, the optionally substituted monocyclic unsaturated heterocycle is halogen, cyano, alkyl, alkoxy, alkanoyl, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, carbamoyl. A monocyclic unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from mono- or di-alkylcarbamoyl, phenyl, heterocyclyl, and oxo;
The optionally substituted bicyclic fused unsaturated heterocycle is halogen, cyano, alkyl, alkoxy, alkanoyl, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, carbamoyl, mono- or A bicyclic fused unsaturated heterocycle optionally substituted with 1-3 substituents independently selected from di-alkylcarbamoyl, phenyl, heterocyclyl, and oxo;
Optionally substituted benzene ring is halogen, cyano, alkyl, alkoxy, alkanoyl, mono- or di-alkylamino, alkanoylamino, alkoxycarbonylamino, carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, A benzene ring optionally substituted with 1-3 substituents independently selected from phenyl, heterocyclyl, alkylene and alkenylene;
Here, the substitution on the benzene ring, monocyclic unsaturated heterocycle or bicyclic unsaturated heterocycle is further halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di- It may be substituted with 1-3 substituents independently selected from alkylamino, carboxy, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxycarbonyl, carbamoyl, and mono- or di-alkylcarbamoyl.

As another preferred embodiment,
(1) A ring A is a monocyclic unsaturated heterocycle optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, and oxo;
Ring B may each be substituted with 1-3 groups selected from the following groups, monocyclic unsaturated heterocycles, bicyclic fused unsaturated heterocycles, or benzene rings:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene, and alkenylene;
Here, the substituents of the ring A and the ring B may be further substituted with a group 1-3 selected from the following group:
Halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxyl, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxycarbonyl, carbamoyl, and mono- or di-alkylcarbamoyl;
(2) The benzene ring in which ring A may be substituted with 1-3 group selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and alkenylene;
Ring B is a monocyclic unsaturated heterocycle or bicyclic unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and oxo;
Here, the substituents of the above ring A and ring B may be substituted with 1-3 groups selected from the following group:
Halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxyl, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxycarbonyl, carbamoyl, and mono- or di-alkylcarbamoyl; Or
(3) A ring A is a bicyclic unsaturated hetero ring optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, and oxo;
Monocyclic unsaturated heterocycle, bicyclic fused unsaturated heterocycle or benzene ring optionally substituted with 1-3 substituents wherein ring B is selected:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl , Carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and oxo;
Here, the substitution of ring A and ring B is further halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxy, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxy Optionally substituted with 1-3 substituents independently selected from carbonyl, carbamoyl and mono- or di-alkylcarbamoyl;
It is.

As another preferred embodiment,
(1) Ring A is a monocyclic unsaturated heterocycle optionally substituted with halogen, lower alkyl, halolower alkyl, lower alkoxy, or oxo, and ring B is (a) halogen; cyano; Alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-alkylamino; optionally substituted by halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower alkylamino Good phenyl; and a benzene ring optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or heterocyclyl optionally substituted with mono- or di-lower alkylamino Or (b) halogen; cyano; lower alkyl; halo lower alkyl Lower alkoxy; halo lower alkoxy; mono- or di-alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, phenyl optionally substituted with mono- or di-lower alkylamino; and halogen; A monocyclic unsaturated heterocycle optionally substituted with a group selected from cyano, lower alkyl, halolower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-alkylamino, or ( c) halogen; cyano; lower alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower. Substituted with alkylamino Optionally substituted phenyl; and optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or heterocyclyl optionally substituted with mono- or di-lower alkylamino Is a ring-fused unsaturated heterocycle;
(2) Ring A is a benzene ring optionally substituted with halogen, lower alkyl, halo lower alkyl, lower alkoxy, phenyl, or lower alkenylene, and ring B is (a) halogen; cyano; lower alkyl; Halo lower alkyl; phenyl lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, mono- or di-alkylamino, Phenyl optionally substituted with carbamoyl or mono- or di-lower alkylcarbamoyl; and halogen, cyano, lower alkyl, halolower alkyl, lower alkoxy, halolower alkoxy, mono- or di-lower alkylamino, carbamoyl, Also A monocyclic unsaturated heterocycle optionally substituted with a group selected from heterocyclyl optionally substituted with mono- or di-lower alkylcarbamoyl, or (b) halogen; cyano; lower alkyl; halolower alkyl; Phenyl lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; phenyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-alkylamino And to a bicyclic fused unsaturated group optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-lower alkylamino; Is a terror ring; or (3) Ring A is A bicyclic fused-unsaturated heterocycle optionally substituted with a logene, lower alkyl, halo lower alkyl, lower alkoxy, or oxo, wherein ring B is (a) halogen; cyano; lower alkyl; halo lower alkyl; Lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or phenyl optionally substituted with mono- or di-alkylamino; and halogen A benzene ring optionally substituted with a group selected from heterocyclyl optionally substituted with cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower alkylamino, (b) halogen; Lower alkyl; halo lower alkyl; lower alkoxy; Mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, or phenyl optionally substituted with mono- or di-lower alkylamino; and halogen, cyano A monocyclic unsaturated heterocycle optionally substituted with a group selected from heterocyclyl optionally substituted with lower alkyl, halolower alkyl, lower alkoxy, mono- or di-lower alkylamino, or (c) Halo; cyano; lower alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-alkylamino Optionally substituted And bicyclic fused unsaturated groups optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-lower alkylamino Heterocycle.

In a more preferred embodiment, Y is —CH ₂ —, and X is the 1-position and is bonded to ring A at the 3-position.

As another preferred embodiment,
(1) The benzene ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; phenyl; and lower alkylene;
Ring B is a monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, halo lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo Heterocyclyl optionally substituted with lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl; and oxo;
(2) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted by lower alkoxy; lower alkoxy optionally substituted by halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B is a benzene ring optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo-lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, or halo-lower alkoxy; and lower alkylene;
(3) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B is a monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and oxo;
(4) Bicyclic fused unsaturated heterocyclic ring optionally substituted with 1-3 groups selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
A benzene ring or a monounsaturated heterocycle, wherein ring B may be substituted with 1-3 groups each selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and lower alkylene; or
(5) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted by lower alkoxy; lower alkoxy optionally substituted by halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B may be substituted with 1-3 groups each selected from the following groups, monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and oxo;
It is.

  Preferred monocyclic unsaturated heterocycles include 5- to 6-membered unsaturated heterocycles containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Specifically, furan, thiophene, oxazole, isoxazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyrazine, dihydroisoxazole, dihydropyridine, and thiazole are preferable. Preferred bicyclic fused unsaturated heterocycles include 9 to 10 membered bicyclic unsaturated heterocycles containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Specifically, indoline, isoindoline, benzothiazole, benzoxazole, indole, indazole, quinoline, isoquinoline, benzothiophene, benzofuran, thienothiophene, or dihydroisoquinoline is preferable.

  Furthermore, in the active ingredient of the present invention, as a preferable compound, ring A is

(Wherein R ^1a , R ^2a , R ^3a , R ^1b , R ^2b , and R ^3b are each independently hydrogen, halogen, hydroxyl, alkoxy, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, Alkoxyalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyloxy, phenyl, phenylalkoxy, cyano, nitro, amino, mono- or di-alkylamino, alkanoylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono- or di -Represents alkylcarbamoyl, alkanoyl, alkylsulfonylamino, phenylsulfonylamino, alkylsulfinyl, alkylsulfonyl or phenylsulfonyl.
And ring B is

(Wherein R ^4a and R ^5a are each independently hydrogen; halogen; hydroxy; alkoxy; alkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; phenylalkyl; alkoxyalkoxy; hydroxyalkoxy; alkenyl; alkynyl; Cycloalkenyl; Cycloalkenyl; Cycloalkyloxy; Phenyloxy; Phenylalkoxy; Cyano; Nitro; Amino; Mono- or Di-alkylamino; Alkanoylamino; Carboxyl; Alkylsulfonylamino; phenylsulfonylamino; alkylsulfinyl; alkylsulfonyl; phenylsulfonyl; halogen, cyano, alkyl, Phenyl optionally substituted with 1-3 groups selected from loalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy, mono- or di-alkylamino, carbamoyl, and mono- or di-alkylcarbamoyl; or R ^4a and R ^5a are heterocyclyl optionally substituted with 1-3 groups selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, carbamoyl and mono- or di-alkylcarbamoyl, Bonded to each other terminally to form an alkylene;
R ^4b , R ^5b , R ^4c and R ^5c are each independently hydrogen; halogen; hydroxyl; alkoxy; alkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; phenylalkyl; Cycloalkenyl; Cycloalkoxy; Phenyloxy; Phenylalkoxy; Cyano; Nitro; Amino; Mono- or Di-alkylamino; Alkanoylamino; Carboxyl; Alkoxycarbonyl; Carbamoyl; Mono- or Di-alkylcarbamoyl; Alkylsulfonylamino; phenylsulfonylamino; alkylsulfinyl; alkylsulfonyl; phenylsulfonyl; halogen, cyano, a Phenyl optionally substituted with 1-3 groups selected from: kill, haloalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy, and mono- or di-alkylamino; or halogen, cyano, alkyl, haloalkyl, It represents a heterocyclyl optionally substituted with 1-3 groups selected from alkoxy and haloalkoxy. )
And Z is

It is.

More preferably, in the active ingredient of the present invention, R ^1a , R ^2a , R ^3a , R ^1b , R ^2b , and R ^3b are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy, or Phenyl;
R ^4a and R ^5a are each independently hydrogen; halogen; lower alkyl; halo lower alkyl; phenyl lower alkyl; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, methylenedioxy, ethylene Phenyl optionally substituted by 1-3 groups selected from oxy, mono- or di-lower alkylamino, carbamoyl and mono- or di-lower alkylcarbamoyl; or halogen, cyano, lower alkyl, halolower alkyl , Lower alkoxy, halo lower alkoxy, mono- or di-lower alkylamino, carbamoyl, and heterocyclyl optionally substituted with 1-3 groups selected from mono- or di-lower alkylcarbamoyl, or R another ^4a and R ^5a is And combine with each other to form a lower alkylene;
R ^4b , R ^5b , R ^4c and R ^5c are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy or halo lower alkoxy.

In the active ingredient of the present invention, more preferably, ring A is
Ring A is

R ^1a is halogen, lower alkyl, or lower alkoxy, R ^2a and R ^3a are hydrogen; ring B is

And
R ^4a is from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, methylenedioxy, ethyleneoxy, mono- or di-lower alkylamino, carbamoyl, and mono- or di-lower alkylcarbamoyl. Phenyl optionally substituted with 1-3 groups selected; or selected from halogen, cyano, lower alkyl, lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl A heterocyclyl optionally substituted with 1-3 groups;
Whether R ^5a is hydrogen,
Alternatively, R ^4a and R ^5a are bonded to each other at the terminal to form an alkylene.

As an even more preferred compound in the active ingredient of the present invention, R ^1a is halogen or lower alkyl, and R ^4a is halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, mono- or di -Phenyl optionally substituted with 1-3 groups selected from lower alkylamino, carbamoyl, and mono- or di-lower alkylcarbamoyl; or halogen, cyano, lower alkyl, lower alkoxy, carbamoyl and mono- or Heterocyclyl optionally substituted with 1-3 groups selected from di-lower alkylcarbamoyl, and R ^5a is hydrogen.

More preferably, R ^4a is phenyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, or mono- or di-lower alkylamino; or halogen, cyano, Heterocyclyl optionally substituted by lower alkyl, halo lower alkyl, lower alkoxy or halo lower alkoxy.

More preferably, R ^4a is phenyl substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; or heterocyclyl substituted with halogen, cyano, lower alkyl or lower alkoxy. .

  Even more preferably, the heterocyclyl is a 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur, or 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. It is a 9-10 membered heterocyclyl contained. Specific examples include thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, thiazolyl, quinolyl, tetrazolyl, and oxazolyl.

Particularly preferably, R ^4a is phenyl substituted with halogen or cyano; or pyridyl substituted with halogen.

  In another preferred embodiment of the present invention, ring A is

R ^1a is halogen, lower alkyl, or lower alkoxy, R ^2a and R ^3a are hydrogen; ring B is

R ^4b and R ^5b are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy.

  In still another preferred embodiment, ring A is

R ⁶ is hydrogen, halogen or alkyl, and ring B is

R ^7a and R ^7b are independently of each other hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halopyridyl, thienyl, or halothienyl. Or R ^7a and R ^7b form a fused benzene ring, fused furan ring or fused dihydrofuran ring with the carbon atoms to which they are bonded, and Y is CH ₂ .

In a more preferred embodiment, R ⁶ is halogen and Z is

R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, halophenyl, cyanophenyl, pyridyl, or halopyridyl, or R ^7a and R 7b ^A condensed benzene ring, a condensed furan ring, and a condensed dihydrofuran ring are formed together with the carbon atom to which ^7b is bonded.

In a further preferred embodiment, R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or alkylthio, or condensed together with the carbon atom to which R ^7a and R ^7b are bonded. A furan ring or a condensed dihydrofuran ring is formed.

In yet another preferred embodiment, R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, or haloalkoxy, or condensed together with the carbon atom to which R ^7a and R ^7b are attached. A furan ring or a condensed dihydrofuran ring is formed.

In another preferred embodiment, R ⁶ is fluorine, chlorine or bromine, more preferably fluorine or chlorine.

In another preferred embodiment, R ⁶ is halogen, and ring B is

And R ^7a is halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or alkylthio.

More preferably, R ^7a is halogen (chlorine, bromine, iodine etc.), alkyl (methyl, ethyl etc.), cycloalkyl (cyclopropyl etc.), haloalkyl (difluoromethyl, trifluoromethyl etc.), alkoxy (methoxy, ethoxy etc.) ) Or haloalkoxy (chloroethoxy, difluoromethoxy, trifluoromethoxy, etc.). More preferably, R ^7a is halogen, alkyl, cycloalkyl, or alkoxy.

  In another preferred embodiment, ring B is

It is.

More preferably, R ⁶ is halogen and R ^7a is halogen (especially fluorine, chlorine) or alkyl (especially methyl or ethyl).

  In yet another preferred embodiment, ring B is

（式中、

(Where

Represents a single bond or a double bond)
And R ⁶ is halogen.

In another preferred embodiment, ring A is indole, chloroindole, or chlorobenzene, ring B is ethylphenyl, ethoxyphenyl, benzo [b] thiophen-2-yl, or 5-phenyl-2-thienyl, and Y is —CH. _2- and Z are 5-thio-β-D-glucopyranosyl, 4-fluoro-4-deoxy-β-D-glucopyranosyl, 4-fluoro-4-deoxy-β-D-galactopyranosyl, or 6- Fluoro-6-deoxy-β-D-glucopyranosyl.

In the pharmaceutical composition of the present invention, as a preferred active ingredient,
3- (4-Ethylphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole, 4-chloro-3- (4-ethylphenylmethyl) -1- (5-thio-β-D- Glucopyranosyl) indole, 4-chloro-3- (4-ethylphenylmethyl) -1- (4-fluoro-4-deoxy-β-D-glucopyranosyl) indole, 4-chloro-3- (4-ethoxyphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole, 3- (benzo [b] thiophen-2-ylmethyl) -4-chloro-1- (4-fluoro-4-deoxy-β-D-galacto Pyranosyl) benzene, 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (6-fluoro-6-deoxy-β-D-glucopyranosyl) benzene, or 4-chloro-3- ( 5-Phenyl-2-thienylmethyl) -1- (4- Ruoro-4- deoxy-beta-D-glucopyranosyl) benzene, or a pharmaceutically acceptable salt thereof.

  The active ingredient (I) of the present invention has an inhibitory activity on a sodium-dependent glucose transporter and exhibits an excellent hypoglycemic effect. For this reason, the pharmaceutical composition of the present invention is useful as a hypoglycemic agent. In addition, the pharmaceutical composition of the present invention comprises diabetes, diabetic complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc.), delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, high It can be suitably used as a prophylactic or therapeutic agent for fatty acidemia, hyperglycerolemia, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, metabolic syndrome, atherosclerosis, hyperglycemia or hypertension it can. In particular, as a preventive or therapeutic agent for diabetes (such as type 1 or type 2 diabetes), diabetic complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) or obesity, or hyperglycemia (especially after meals) Can be suitably used as a preventive or therapeutic agent for hyperglycemia.

  The active ingredient (A) of the present invention can be used for the purpose of the present invention either in a free form or in the form of a pharmaceutically acceptable salt thereof. Pharmacologically acceptable salts include, for example, alkali metal salts such as lithium, sodium or potassium; alkaline earth metal salts such as calcium or magnesium; and salts with zinc or aluminum; and organic bases such as ammonium, choline, diethanolamine , Lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucosamine, triethanolamine and salts with dehydroabiethylamine; hydrochloric acid, hydrobromic acid, hydroiodic acid, Salts with inorganic acids such as sulfuric acid, nitric acid, phosphoric acid; or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid Ethane sulfonic acid, Salts with organic acids such as Zensuruhon acid; or aspartic acid, salts with acidic amino acids such as glutamic acid.

  Moreover, the pharmacologically acceptable salt of the active ingredient (A) includes any of its internal salts, solvates or hydrates.

  The compound (A) which is an active ingredient of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and a pharmaceutical carrier usually used for oral or parenteral administration is used. Thus, a suitable preparation can be obtained. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants ( Examples thereof include magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrating agents (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.). In addition, in the case of oral administration, these pharmaceutical preparations may be solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as solutions, suspensions and emulsions. On the other hand, in the case of parenteral administration, for example, injection water, physiological saline, glucose aqueous solution or the like can be used as an injection, a drip infusion, or a suppository.

  The dose of the active ingredient (A) of the present invention and its pharmacologically acceptable salt varies depending on the administration method, patient age, body weight, condition or type / degree of disease, but is usually about 0 per day. 0.1 to 50 mg / kg, particularly about 0.1 to 30 mg / kg is preferable.

  The active ingredient (A) of the present invention has an SGLT inhibitory action, thereby promoting the excretion of sugar into urine and exerting a hypoglycemic action. When the active ingredient of the present invention was continuously administered to a non-insulin dependent diabetes model animal for 4 weeks, the blood glucose level was improved.

  Moreover, the compound which is an active ingredient of this invention also has the characteristics that toxicity is low.

The active ingredient of the present invention can be produced by the following method.
Manufacturing method I

(Wherein OR ⁸ is protected hydroxy, Ph is phenyl, and other symbols have the same meanings as described above.)
Step I-1:
The compound represented by the formula (I-1) is obtained by combining a compound represented by the formula (B) and benzaldehyde dimethyl acetal in an appropriate solvent (tetrahydrofuran, dioxane, dichloromethane, etc.) with an acid (hydrochloric acid, sulfuric acid, p-tosylic acid, For example, by the condensation in the presence of fluorinated boric acid.
Step I-2:
The compound represented by the formula (I-2) can be produced by protecting the hydroxy of the compound (I-1). As the hydroxy protecting group, a conventional protecting group can be used, and examples thereof include alkylsilyl groups such as benzyl group, acetyl group, and trimethylsilyl group. Alternatively, the hydroxy protecting group may form an acetal or silyl acetal together with the adjacent hydroxy. Hydroxy protection can be performed by conventional methods (see "Protecting Groups in Organic Synthesis", John Wiley & Sons).
Step I-3:
The compound represented by the formula (I-3) is obtained by reacting the compound represented by the formula (I-2) in an appropriate solvent (eg, methanol, ethanol, water, etc.), acid (eg, hydrochloric acid, acetic acid, p-toluenesulfone). Acid, methanesulfonic acid, trifluoroacetic acid, etc.).
Step I-4:
The compound represented by the formula (I-4) can be produced by protecting the hydroxy of the compound represented by the formula (I-3) in the same manner as in Step I-2.
Step I-5:
The compound represented by the formula (I-5) is obtained by converting the compound represented by the formula (I-4) into a fluorinating agent (for example, (diethylamino) sulfur trifluoride) in a suitable solvent (dichloromethane, chloroform, tetrahydrofuran, etc.). It can manufacture by processing with.
Step I-6:
The compound represented by the formula (A-1) can be produced by subjecting the compound represented by the formula (I-5) to deprotection.

  Deprotection can be carried out by conventional methods such as reduction, hydrolysis, acid treatment, fluoride treatment, etc., depending on the type of protecting group to be removed.

  In the case of reduction, for example, the treatment may be carried out using a catalyst (palladium-carbon, platinum, etc.) in a suitable solvent (methanol, ethanol, etc.) under a hydrogen atmosphere.

  In the case of hydrolysis, in a suitable solvent (eg, tetrahydrofuran, dioxane, methanol, ethanol, water, etc.), a base (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, etc.) ).

  In the case of acid treatment, treatment with an acid (for example, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, etc.) may be performed in a suitable solvent (for example, methanol, ethanol, etc.).

In the case of fluoride treatment, treatment with a fluoride (hydrogen fluoride, hydrogen fluoride-pyridine, tetrabutylammonium fluoride, etc.) in an appropriate solvent (methanol, ethanol, acetonitrile, tetrahydrofuran, etc.) may suffice.
Process II:

(In the formula, Tr is trityl (ie, triphenylmethyl), and other symbols have the same meanings as described above.)
Step II-1:
The compound represented by the formula (II-1) is prepared by combining the compound represented by the formula (B) with trityl chloride in the presence of a base (pyridine, N, N-dimethylaminopyridine, triethylamine, diisopropylethylamine, etc.) (Dimethylformamide, tetrahydrofuran, dichloromethane, etc.) can be produced by reacting under cooling to heating.
Step II-2:
The compound represented by the formula (II-2) can be produced by protecting the hydroxy of the compound represented by the formula (II-1). Protection can be carried out in the same manner as in Step I-2.
Step II-3:
The compound represented by the formula (II-3) is obtained by treating the compound represented by the formula (II-2) with an acid (acetic acid, formic acid, hydrochloric acid, etc.) in an appropriate solvent (tetrahydrofuran, methanol, ethanol, water, etc.). By doing so, it can be manufactured.
Step II-4:
The compound represented by the formula (II-4) can be produced by treating the compound represented by the formula (II-3) with a fluorinating agent. This step can be carried out in the same manner as Step I-5.
Step II-5:
The compound represented by the formula (A-2) can be produced by subjecting the compound represented by the formula (II-4) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process III:

(Wherein R ⁹ is bromine or iodine, and other symbols have the same meaning as described above.)
Step III-1:
The compound represented by the formula (III-1) is obtained by cooling the compound represented by the formula (C) in an appropriate solvent (such as tetrahydrofuran) while cooling with alkyllithium (methyllithium, n-butyllithium, t-butyllithium, etc. ) And then reacting with the compound represented by the formula (D).
Step III-2:
The compound represented by the formula (III-2) is obtained by reacting the compound represented by the formula (III-1) in a suitable solvent in the presence of Lewis acid such as boron trifluoride / diethyl ether complex or trifluoroacetic acid ( For example, it can be produced by treating with a silane compound (for example, trialkylsilanes such as triethylsilane and triisopropylsilane) at room temperature under cooling with acetonitrile, dichloromethane and the like.
Step III-3:
The compound represented by the formula (A-3) can be produced by subjecting the compound represented by the formula (III-2) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Recipe IV:

(In the formula, the symbols have the same meaning as described above.)
Step IV-1:
The compound represented by the formula (IV-1) includes a compound represented by the formula (E) and a compound represented by the formula (F) (for example, 2,3,4,6-tetra-O-benzyl-D-galactopira Nosyl chloride) can be produced by condensation under cooling to heating in the presence of a base (sodium hydride, potassium hydroxide, etc.) in a suitable solvent (tetrahydrofuran, dimethylformamide, etc.).
Step IV-2:
The compound represented by the formula (A-4) can be produced by subjecting the compound represented by the formula (IV-1) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Manufacturing method V:

(In the formula, the symbols have the same meaning as described above.)
Process V-1:
The compound represented by the formula (V-1) can be produced by treating the compound represented by the formula (C) with alkyllithium and then reacting with the compound represented by the formula (G). This step can be produced in the same manner as Step III-1.
Process V-2:
The compound represented by the formula (V-2) can be produced by reducing the compound represented by the formula (V-1). The reduction can be carried out in the same manner as in Step III-2.
Process V-3:
The compound represented by the formula (A-5) can be produced by subjecting the compound represented by the formula (V-2) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process VI:

(In the formula, the symbols have the same meaning as described above.)
Process VI-1:
The compound represented by the formula (VI-1) can be produced by condensing the compound represented by the formula (A-3) or (A-4) and benzaldehyde dimethyl acetal. The condensation can be carried out in the same manner as in Step I-1.
Process VI-2:
The compound represented by the formula (VI-2) can be produced by protecting the hydroxy of the compound represented by the formula (VI-1). Protection can be carried out in the same manner as in Step I-2.
Process VI-3:
The compound represented by the formula (VI-3) can be produced by hydrolyzing the compound represented by the formula (VI-2) with an acid. Hydrolysis can be carried out in the same manner as in Step I-3.
Process VI-4:
The compound represented by the formula (VI-4) can be produced by protecting the hydroxy of the compound represented by the formula (VI-3). Protection can be carried out in the same manner as in Step I-2.
Process VI-5:
The compound represented by the formula (VI-5) can be produced by treating the compound represented by the formula (VI-4) with a fluorinating agent. This step can be carried out in the same manner as Step I-5.
Process VI-6:
The compound represented by the formula (A-6) can be produced by subjecting the compound represented by the formula (VI-5) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process VII:

(In the formula, the symbols have the same meaning as described above.)
Step VII-1:
The compound represented by the formula (VII-1) is obtained by lithiating the compound represented by the formula (C), treating the lithiated compound with CuI, and then converting the obtained compound into a compound represented by the formula (H). It can be produced by reacting.

  Lithiation can be produced by treating with alkyllithium (methyllithium, n-butyllithium, t-butyllithium, etc.) in a suitable solvent (tetrahydrofuran, etc.) under cooling.

  The treatment with CuI can be carried out by reacting the lithiated compound with CuI in a suitable solvent (such as tetrahydrofuran) under cooling.

The reaction of the obtained compound with the compound of formula (H) can be carried out in an appropriate solvent (such as tetrahydrofuran) under cooling to room temperature.
Step VII-2:
The compound represented by the formula (VII-2) can be produced by reducing the compound represented by the formula (VII-1). The reduction can be carried out in the same manner as in Step III-2.
Step VII-3:
The compound represented by the formula (A-7) can be produced by subjecting the compound represented by the formula (VII-2) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process VIII:

(In the formula, the symbols have the same meaning as described above.)
Step VIII-1:
The compound represented by the formula (VIII-1) is produced by condensing the compound represented by the formula (E) and the compound represented by the formula (I) (see Tetrahedron Lett., 2001, 42, 1197-1200). be able to. The condensation can be carried out in the same manner as in Step IV-1.
Step VIII-2:
The compound represented by the formula (A-8) can be produced by subjecting the compound represented by the formula (VIII-1) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.

  Of the compounds represented by formula (A), ring A is

(Where R ⁶ has the same meaning as above)
And ring B is

(Here, R ^7a and R ^7b have the same meaning as described above.)
And Y is CH ₂ can be produced by the following method.
Recipe IX:

(Where Ar is

And R ⁶ , R ⁷ , R ^7b and R ⁸ have the same meaning as described above. )
Step IX-1:
The compound represented by the formula (IX-1) is obtained by catalyzing the compound represented by the formula (J) and the formula (K) (that is, 5-thio-D-glucose) in a suitable solvent (for example, methanol, ethanol, etc.). (For example, it can be produced by condensation in the presence or absence of ammonium chloride, acetic acid, etc.).
Step IX-2:
The compound represented by the formula (IX-2) can be produced by protecting the hydroxy of the compound represented by the formula (IX-1). Protection can be carried out in the same manner as in Step I-2.
Step IX-3:
The compound represented by the formula (IX-3) is obtained by reacting the compound represented by the formula (IX-2) with an oxidizing agent (2,3−) in a suitable solvent (for example, tetrahydrofuran, dioxane, dichloromethane, etc.) at room temperature or under cooling. (Dichloro-5,6-dicyano-1,4-benzoquinone, etc.).
Process IX-4:
The compound represented by the formula (IX-4) is produced by condensing the compound represented by the formula (IX-3) and the compound represented by Ar-COCl (the symbols have the same meaning as described above). Can do.

The condensation is carried out in a suitable solvent (for example, a halogenated hydrocarbon such as dichloromethane or chloroform) in the presence of a Lewis acid (for example, aluminum chloride, boron trifluoride / diethyl ether complex) under cooling to heating ( For example, it can be carried out at −30 ° C. to 60 ° C.).
Step IX-5:
The compound represented by the formula (IX-5) can be produced by reducing the compound represented by the formula (IX-4).
The reduction is carried out in a suitable solvent (for example, ethers such as tetrahydrofuran, alcohols such as methanol and ethanol), reducing agents (for example, sodium borohydride (used in the presence or absence of cerium chloride), hydrogen For example, by treatment with sodium triacetoxyborohydride, lithium aluminum hydride, diisobutylaluminum hydride) at room temperature (for example, −30 ° C. to 25 ° C.) under cooling.
Step IX-6:
The compound represented by the formula (IX-6) can be produced by reducing the compound represented by the formula (IX-5).

Reduction is performed in a suitable solvent (acetonitrile, dichloromethane, etc.), in the presence of an acid (organic acid such as trifluoroacetic acid or methanesulfonic acid, Lewis acid such as boron trifluoride / diethyl ether complex, titanium tetrachloride). It can be carried out by treating with a silane reagent (triethylsilane, triisopropylsilane, etc.) from below at room temperature (for example, -30 ° C to 25 ° C).
Step IX-7:
The compound represented by the formula (A-9) can be produced by subjecting the compound represented by the formula (IX-6) to deprotection. The deprotection can be carried out in the same manner as in Step I-6. .
Recipe X:

(In the formula, the symbols have the same meaning as described above.)
Process X-1:
The compound represented by the formula (X-1) can be produced by condensing a compound represented by the formula (XII-7) (described later in the production method XII) and benzaldehyde dimethyl acetal. The condensation can be carried out in the same manner as in Step I-1.
Process X-2:
The compound represented by the formula (X-2) can be produced by protecting the hydroxy of the compound represented by the formula (X-1). Protection can be carried out in the same manner as in Step I-2.
Process X-3:
The compound represented by the formula (X-3) can be produced by hydrolyzing the compound represented by the formula (X-2) with an acid. Hydrolysis can be carried out in the same manner as in Step I-3.
Process X-4:
The compound represented by the formula (X-4) can be produced by protecting the hydroxy of the compound represented by the formula (X-3). Protection can be carried out in the same manner as in Step I-2.
Process X-5:
The compound represented by the formula (X-5) can be produced by treating the compound represented by the formula (X-4) with a fluorinating agent. This step can be carried out in the same manner as Step I-5.
Process X-6:
The compound represented by the formula (A-10) can be produced by subjecting the compound represented by the formula (X-5) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process XI:

Wherein Ar ¹ is phenyl or thienyl, R ¹¹ is bromine or iodine, Ar ² is phenyl, halophenyl, cyanophenyl, pyridyl, halopyridyl, thienyl, or halothienyl, R ¹² is cycloalkyl, R ¹⁰ is

Where OR ⁸ is protected hydroxy and R ⁶ and Z have the same meaning as above. )
Process XI-1:
The compound represented by the formula (XI-1) is the same as the compound represented by the formula (L), Ar ² B (OH) ₂ or R ¹² B (OH) ₂ (wherein the symbols have the same meanings as described above). Can be produced by coupling.

The coupling reaction is carried out in a suitable solvent (eg, tetrahydrofuran, dioxane, water, or a mixed solvent thereof), a palladium catalyst (eg, tetrakis (triphenylphosphine) palladium, palladium acetate, etc.) and a base (eg, sodium carbonate). In the presence of potassium carbonate, etc.) from room temperature to heating (for example, 25 to 150 ° C.).
Process XI-2:
The compound represented by the formula (A-11) can be produced by subjecting the compound represented by the formula (XI-1) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.
Process XII:

(In the formula, the symbols have the same meaning as described above.)
Process XII-1:
The compound represented by the formula (XII-1) can be produced by condensing the compound represented by the formula (M) and D-galactose represented by the formula (N). The condensation can be carried out in the same manner as in Step IX-1.
Process XII-2:
The compound represented by the formula (XII-2) can be produced by protecting the hydroxy of the compound represented by the formula (XII-1). Protection can be carried out in the same manner as in Step I-2.
Process XII-3:
The compound represented by the formula (XII-3) can be produced by oxidizing the compound represented by the formula (XII-2). The oxidation can be carried out in the same manner as in Step IX-3.
Process XII-4:
The compound represented by the formula (XII-4) can be produced by condensing the compound represented by the formula (XII-3) and Ar—COCl (the symbols have the same meaning as described above). The condensation can be carried out in the same manner as in Step IX-4.
Process XII-5:
The compound represented by the formula (XII-5) can be produced by reducing the compound represented by the formula (XII-4). The reduction can be carried out in the same manner as in Step IX-5.
Process XII-6:
The compound represented by the formula (XII-6) can be produced by reducing the compound represented by the formula (XII-5). The reduction can be carried out in the same manner as in Step IX-6.
Process XII-7:
The compound represented by the formula (XII-7) can be produced by subjecting the compound represented by the formula (XII-6) to deprotection. Deprotection can be carried out in the same manner as in Step I-6.

  Compounds of formula (B), compounds of formula (C), and compounds of formula (E) are described in WO 2004/080990 or WO 2005/012326.

The compound of the formula (J) can be produced as follows.
Process XIII:

(In the formula, R ¹³ is alkyl, and other symbols have the same meaning as described above.)
First, the compound represented by the formula (O) is heated in a suitable solvent (methanol, ethanol, toluene, etc.) and in the presence of an acid (for example, zinc chloride, hydrochloric acid, polyphosphoric acid, trifluoroacetic acid, etc.) to cyclize. To produce a compound represented by the formula (XIII-1).

  Next, the compound represented by the formula (XIII-1) is used in a suitable solvent (eg, methanol, ethanol, tetrahydrofuran, water, etc.) at room temperature or under heating with a base (eg, sodium hydroxide, lithium hydroxide, etc.). A compound represented by the formula (XIII-2) is produced by hydrolysis.

  Further, the compound represented by the formula (XIII-2) is decarboxylated in an appropriate solvent (for example, quinoline) in the presence of a catalyst (for example, copper) to obtain a compound represented by the formula (XIII-3). Manufacturing.

  Then, the compound represented by the formula (XIII-3) is reacted with an acid (for example, trifluoroacetic acid, boron trifluoride / diethyl ether complex) in a suitable solvent (for example, tetrahydrofuran, dichloromethane, etc.) at room temperature or under heating. A compound represented by the formula (J) can be produced by treatment with a reducing agent (for example, triethylsilane, zinc borohydride) in the presence.

  The compound represented by the formula (O) is represented by the formula (P)

(However, the symbols have the same meaning as above)
In the presence of an acid (hydrochloric acid, acetic acid, etc.) at room temperature or under heating in a suitable solvent (acetonitrile, methanol, ethanol, water) and CH ₃ COCO ₂ R ¹³ (wherein R ¹³ is the same as above) Or the compound of formula (Q)

(However, the symbols have the same meaning as above)
Was treated with sodium nitrite in an appropriate solvent (water, methanol, ethanol) at room temperature or in the presence of an acid (for example, hydrochloric acid) at room temperature or under cooling to produce the corresponding diazonium salt compound. Then, CH ₃ COCH (CH ₃ ) CO ₂ R ¹³ (however, in the presence of a base (sodium acetate, potassium hydroxide, etc.) in a suitable solvent (eg, methanol, ethanol, water) at room temperature or under cooling R ¹³ can be produced by reacting with R) having the same meaning as described above.

The compound represented by the formula (G) can be produced as follows.
Recipe XIV:

(In the formula, Me is methyl, and other symbols have the same meaning as described above.)
The compound of formula (XIV-1) is produced by treating the compound of formula (R) with a fluorinating agent in the same manner as in Step I-5.

  A compound of formula (XIV-2) is prepared by subjecting a compound of formula (XIV-1) to a dealkylation reaction. Dealkylation is carried out in a mixture of sulfuric acid and acetic acid under heating.

  The compound of the formula (G) is produced by oxidizing the compound of the formula (XIV-2) with an oxidizing agent (such as acetic acid-dimethyl sulfoxide) in a suitable solvent (such as dichloromethane) under cooling to room temperature.

  The compound of the formula (R) can be produced by a conventional method such as the method described in Tetrahedron Lett., 2000, 41, 5547-5551.

These other starting compounds are commercially available or are easily produced by methods conventional to those skilled in the art.
Production Example 1: 3- (4-Ethylphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole (1) Penta-O-acetyl-5-thio-D-glucopyranose (813 mg) Suspended in ethanol (20 ml), sodium methoxide (28% methanol solution, 2 drops) was added thereto. The mixture was stirred at room temperature for 1 hour under an argon atmosphere, indoline (238 mg) was added to the resulting solution, and the mixture was refluxed overnight. Further acetic acid (2 drops) was added and refluxed for 7 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure to obtain crude 1- (5-thio-β-D-glucopyranosyl) indoline. This compound was used in the next step without purification.

  (2) The above compound was dissolved in chloroform (20 ml), and acetic anhydride (1.51 ml), pyridine (1.29 ml) and 4-dimethylaminopyridine (24 mg) were added. After stirring at room temperature for 2.5 days, the organic solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1), recrystallized from methanol, and 1- (2,3,4 , 6-Tetra-O-acetyl-5-thio-β-D-glucopyranosyl) indoline (321 mg) was obtained. Melting point: 163-165 ° C. APCI-Mass m / Z 466 (M + H).

(3) The above compound (310 mg) was dissolved in 1,4-dioxane (10 ml), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (159 mg) and water (3 Drop) was added. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 2: 1) to give 1- (2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl). Indole (308 mg) was obtained. APCI-Mass m / Z 481 (M + NH ₄ ).

  (4) Aluminum chloride (439 mg) was added to a solution of the above compound (305 mg) and 4-ethylbenzoyl chloride (166 mg) in dichloromethane (15 ml) at 0 ° C. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 5 hours. The mixture was poured into ice water, 1N hydrochloric acid (10 ml) was added, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 3: 1-2: 1) to give 4-ethylphenyl 1- (2,3,4,6-tetra-O-acetyl-5- Thio-β-D-glucopyranosyl) indol-3-yl ketone (354 mg) was obtained. APCI-Mass m / Z 596 (M + H).

  (5) Cerium (III) chloride pentahydrate (648 mg) and sodium borohydride (66 mg) were added to a solution of the above compound (347 mg) in ethanol (5 ml) -tetrahydrofuran (10 ml) at 0 ° C. It was. After stirring at the same temperature for 2 hours, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure to give 4-ethylphenyl 1- (2,3,4,6-tetra-O-acetyl-5-thio-β-D-glucopyranosyl) indol-3-yl. Methanol (387 mg) was obtained. This compound was used in the next step without purification.

(6) The above compound was dissolved in acetonitrile (10 ml) -dichloromethane (5 ml), and triethylsilane (0.46 ml) and boron trifluoride / diethyl ether complex salt (0.37 ml) were added at −10 ° C. in an argon atmosphere. . After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added, and the organic solvent was distilled off under reduced pressure. After extraction with ethyl acetate (25 ml) and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1) to give 3- (4-ethylphenylmethyl) -1- (2,3,4,6-tetra-O-acetyl- 5-thio-β-D-glucopyranosyl) indole (290 mg) was obtained. APCI-Mass m / Z 599 (M + NH ₄ ).

  (7) The above compound (281 mg) was dissolved in methanol (5 ml) -tetrahydrofuran (5 ml), and sodium methoxide (28% methanol solution, 2 drops) was added thereto. After stirring for 2 hours at room temperature under an argon atmosphere, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 19: 1) to give 3- (4-ethylphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole (190 mg). Obtained. APCI-Mass m / Z 414 (M + H).

Production Example 2: 4-Chloro-3- (4-ethylphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole (1) Penta-O-acetyl-5-thio-D-glucopyranose ( 1323 mg) was suspended in ethanol (30 ml), and sodium methoxide (28% methanol solution, 2 drops) was added. The mixture was stirred at room temperature under an argon atmosphere for 1 hour, 4-chloroindoline (500 mg) and ammonium chloride (174 mg) were added to the resulting solution, and the mixture was refluxed for 22 hours. After cooling to room temperature, the solvent was distilled off to obtain crude 4-chloro-1- (5-thio-β-D-glucopyranosyl) indoline. This compound was used in the next step without purification.

  (2) The above compound was dissolved in chloroform (20 ml), and acetic anhydride (2.45 ml), pyridine (2.10 ml) and 4- (dimethylamino) pyridine (40 mg) were added. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 3: 1) to give 4-chloro-1- (2,3,4,6-tetra-O-acetyl-5-thio-β- D-glucopyranosyl) indoline (1157 mg) was obtained. APCI-Mass m / Z 500/502 (M + H).

(3) By treating the above compound in the same manner as in Production Example 1- (3), 4-chloro-1- (2,3,4,6-tetra-O-acetyl-5-thio-β-D- A glucopyranosyl) indole was obtained. APCI-Mass m / Z 515/517 (M + NH ₄ ).

  (4) By treating the above compound and 4-ethylbenzoyl chloride in the same manner as in Production Example 1- (4), (5), (6) and (7), 4-chloro-3- (4-ethylphenyl) Methyl) -1- (5-thio-β-D-glucopyranosyl) indole was obtained. APCI-Mass m / Z 448/450 (M + H).

Production Example 3: 4-chloro-3- (4-ethylphenylmethyl) -1- (4-fluoro-4-deoxy-β-D-glucopyranosyl) indole (1) 4-chloroindoline (1.00 g) and D- A suspension of galactose (1.94 g) in water (3.0 ml) -ethanol (20 ml) was refluxed for 29 hours under an argon atmosphere. The solvent was distilled off under reduced pressure to obtain crude 4-chloro-1- (β-D-galactopyranosyl) indoline. This compound was used in the next step without purification.

  (2) The above compound was suspended in chloroform (20 ml), and acetic anhydride (4.92 ml), pyridine (4.21 ml) and 4- (dimethylamino) pyridine (80 mg) were added thereto. After stirring at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90: 10-60: 40) to give 4-chloro-1- (2,3,4,6-tetra-O-acetyl-β- D-galactopyranosyl) indoline (2.34 g) was obtained. APCI-Mass m / Z 484/486 (M + H).

(3) The above compound was treated in the same manner as in Production Example 1- (3) to give 4-chloro-1- (2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl). I got an indole. APCI−Mass m / Z 499/501 (M + NH ₄ ).

  (4) By treating the above compound and 4-ethylbenzoyl chloride in the same manner as in Production Example 1- (4), (5), (6) and (7), 4-chloro-3- (4-ethylphenyl) Methyl) -1- (β-D-galactopyranosyl) indole was obtained. APCI-Mass m / Z 432/434 (M + H).

  (5) The above compound (6.80 g) was suspended in chloroform (300 ml), and benzaldehyde dimethyl acetal (3.54 ml) and p-toluenesulfonic acid monohydrate (0.15 g) were added thereto. After stirring at room temperature for 40 minutes, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed and dried, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100: 0-90: 10) to give 4-chloro-3- (4-ethylphenylmethyl) -1- (4,6-O-benzylidene -Β-D-Galactopyranosyl) indole (7.12 g) was obtained. APCI-Mass m / Z 520/522 (M + H).

  (6) The above compound (7.12 g) was suspended in chloroform (300 ml), and pyridine (6.64 ml) and benzoyl chloride (4.77 ml) were added thereto at 0 ° C. The mixture was warmed to room temperature and stirred for 3 days. The mixture was diluted with ethyl acetate, washed and dried, and the solvent was evaporated under reduced pressure to give crude 4-chloro-3- (4-ethylphenylmethyl) -1- (2,3-di-O- Benzoyl-4,6-O-benzylidene-β-D-galactopyranosyl) indole was obtained. This compound was used in the next step without purification.

(7) A solution of the above compound in acetic acid (240 ml) -water (30 ml) was stirred at 70 ° C. overnight. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / ethyl acetate = 100: 0-95: 5) to give 4-chloro-3- (4-ethylphenylmethyl) -1- (2,3-di- O-benzoyl-β-D-galactopyranosyl) indole (7.06 g) was obtained. APCI−Mass m / Z 657/659 (M + NH ₄ ).

(8) The above compound (7.06 g) was suspended in 2,4,6-trimethylpyridine (70 ml), and benzoyl chloride (1.54 ml) was added thereto at −40 ° C. The mixture was warmed to 0 ° C. and stirred overnight. The reaction mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 90: 10-50: 50) and recrystallized from ethanol to give 4-chloro-3- (4-ethylphenylmethyl) -1- (2,3,6-Tri-O-benzoyl-β-D-galactopyranosyl) indole (5.17 g) was obtained. Melting point: 192-193 ° C. APCI-Mass m / Z 761/763 (M + NH ₄ ).

  (9) The above compound (700 mg) was dissolved in dichloromethane (70 ml), and (diethylamino) sulfur trifluoride (1.24 ml) was added thereto at 0 ° C. under an argon atmosphere. After stirring at room temperature for 24 hours, cold water was added and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / ethyl acetate = 100: 0-95: 5) and recrystallized from diisopropyl ether to give 4-chloro-3- (4-ethylphenylmethyl) -1 -(2,3,6-Tri-O-benzoyl-4-fluoro-4-deoxy-β-D-glucopyranosyl) indole (452 mg) was obtained. Melting point: 137-138 ° C. APCI-Mass m / Z 746/748 (M + H).

  (10) By treating the above compound in the same manner as in Production Example 1- (7), 4-chloro-3- (4-ethylphenylmethyl) -1- (4-fluoro-4-deoxy-β-D- A glucopyranosyl) indole was obtained. APCI-Mass m / Z 434/436 (M + H).

Production Example 4: 4-Chloro-3- (4-ethoxyphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole Production Example 2- (3-) 4-Chloro-1- ( 2,3,4,6-Tetra-O-acetyl-5-thio-β-D-glucopyranosyl) indole and 4-ethoxybenzoyl chloride were prepared in Preparation Examples 1- (4), (5), (6) and (7 ) To give the title compound. APCI-Mass m / Z 464/466 (M + H).

Production Example 5: 3- (Benzo [b] thiophen-2-ylmethyl) -4-chloro-1- (4-fluoro-4-deoxy-β-D-galactopyranosyl) benzene (1) 1- (benzo [B] Thiophen-2-ylmethyl) -5-bromo-2-chlorobenzene (1.00 g) was dissolved in tetrahydrofuran (8 ml) -toluene (16 ml) and cooled to −78 ° C. under an argon atmosphere. N-Butyllithium (1.59 M hexane solution, 1.86 ml) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 minutes. Toluene (10 ml) solution of 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone (see US 6,515,117; 1.26 g) was added dropwise and further stirred at the same temperature for 1.5 hours. . Methanolsulfonic acid (0.58 ml) in methanol (20 ml) was added and stirred at room temperature overnight. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After washing and drying, the residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 10: 0-9: 1) to give 3- (benzo [b] thiophen-2-ylmethyl) -4-chloro-1 -(1-α-Methoxy-β-D-glucopyranosyl) benzene (875 mg) was obtained.

(2) A solution of the above compound (1.91 g) and triethylsilane (2.03 ml) in dichloromethane (80 ml) was cooled to −78 ° C. under an argon atmosphere, and boron trifluoride / diethyl ether complex (1.61 ml) was added. It was. The temperature was raised to 0 ° C., and the mixture was stirred at the same temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 10: 0-9: 1) and recrystallized from ethyl acetate-diethyl ether to give 3- (benzo [b] thiophen-2-ylmethyl)- 4-Chloro-1- (β-D-glucopyranosyl) benzene (1.29 g) was obtained. Melting point: 153-154 ° C. APCI-Mass m / Z 438/440 (M + NH ₄ ).

(3) By treating the above compound in the same manner as in Production Example 3- (5), (6), (7) and (8), 3- (benzo [b] thiophen-2-ylmethyl) -4-chloro -1- (2,3,6-tri-O-benzoyl-β-D-glucopyranosyl) benzene was obtained. Melting point: 215-217 ° C. APCI-Mass m / Z 750/752 (M + NH ₄ ).

(4) A dichloromethane (50 ml) solution of the above compound (796 mg) and 4-dimethylaminopyridine (780 mg) was cooled to 0 ° C. under an argon atmosphere, and (diethylamino) sulfur trifluoride (0.63 ml) was added. It was. The mixture was warmed to room temperature and stirred at the same temperature for 19 hours. Thereto was added cold water under ice cooling, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1-2: 1) and recrystallized from ethyl acetate-hexane to give 3- (benzo [b] thiophen-2-ylmethyl)- 4-Chloro-1- (2,3,6-tri-O-benzoyl-4-fluoro-4-deoxy-β-D-galactopyranosyl) benzene (305 mg) was obtained. Melting point: 204-207 ° C. APCI-Mass m / Z 752/754 (M + NH ₄ ).

(5) By treating the above compound in the same manner as in Production Example 1- (7), 3- (benzo [b] thiophen-2-ylmethyl) -4-chloro-1- (4-fluoro-4-deoxy- β-D-galactopyranosyl) benzene was obtained. APCI-Mass m / Z 440/442 (M + NH ₄ ).

Production Example 6: 4-Chloro-3- (5-phenyl-2-thienylmethyl) -1- (6-fluoro-6-deoxy-β-D-glucopyranosyl) benzene (1) 5-Bromo-2-chloro- By treating 1- (5-phenyl-2-thienylmethyl) benzene in the same manner as in Production Example 5- (1) and (2), 4-chloro-3- (5-phenyl-2-thienylmethyl)- 1- (β-D-glucopyranosyl) benzene was obtained. APCI-Mass m / Z 464/466 (M + NH ₄ ).

  (2) Dissolve the above compound (1.00 g) in N, N-dimethylformamide (10 ml) and add trityl chloride (686 mg), 4-dimethylaminopyridine (14 mg) and triethylamine (0.47 ml) to it. It was. The mixture was stirred at room temperature for 6 days and diluted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 100: 1-19: 1) to give 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (6-O- Trityl-β-D-glucopyranosyl) benzene (870 mg) was obtained. ESI-Mass m / Z 711/713 (M + Na).

(3) By treating the above compound in the same manner as in Production Example 1- (2), 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (2,3,4-tri-O -Acetyl-6-O-trityl-β-D-glucopyranosyl) benzene was obtained. ESI−Mass m / Z 837/839 (M + Na)
(4) A solution of the above compound (1.45 g) in formic acid (10 ml) -diethyl ether (5 ml) was stirred at room temperature for 3.5 hours and diluted with water. After extraction with ethyl acetate, washing and drying were performed, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1-1: 1) to give 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (2,3 , 4-Tri-O-acetyl-β-D-glucopyranosyl) benzene (689 mg) was obtained. Melting point: 166-168 ° C. APCI-Mass m / Z 590/592 (M + NH ₄ ).

(5) The above compound is treated in the same manner as in Production Examples 5- (4) and 1- (7) to give 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (6-fluoro -6-Deoxy-β-D-glucopyranosyl) benzene was obtained. APCI-Mass m / Z 466/468 (M + NH ₄ ).

Production Example 7: 4-Chloro-3- (5-phenyl-2-thienylmethyl) -1- (4-fluoro-4-deoxy-β-D-glucopyranosyl) benzene (1) 5-Bromo-2-chloro- 1- (5-Phenyl-2-thienylmethyl) benzene (397 mg) was dissolved in tetrahydrofuran (10 ml) and cooled to −78 ° C. under an argon atmosphere. N-Butyllithium (1.56M hexane solution, 0.70 ml) was added dropwise thereto and stirred at the same temperature for 20 minutes. A solution of 2,3,6-tri-O-benzyl-4-fluoro-4-deoxy-D-glucono-1,5-lactone (496 mg) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was further stirred at the same temperature for 1.5 hours. Stir. Then, a saturated aqueous ammonium chloride solution was added, and the temperature was raised to room temperature. The mixture was diluted with water and extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure to give crude 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (1-hydroxy-2,3,6-tri-O. -Benzyl-4-fluoro-4-deoxy-D-glucopyranosyl) benzene was obtained. This compound was used in the next step without purification.

(2) A dichloromethane (10 ml) solution of the above compound was cooled to −78 ° C. under an argon atmosphere, and triisopropylsilane (0.68 ml) and boron trifluoride · diethyl ether complex (0.42 ml) were added thereto. After stirring at −78 ° C. for 1 hour, the temperature was raised to 0 ° C. and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 19: 1-9: 1) to give 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (2,3 , 6-tri-O-benzyl-4-fluoro-4-deoxy-β-D-glucopyranosyl) benzene (226 mg) was obtained. APCI−Mass m / Z 736/738 (M + NH ₄ ).

(3) To a solution of sodium iodide (550 mg) in acetonitrile (5 ml) was added trimethylsilyl chloride (0.47 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 20 minutes. Thereto was added acetonitrile (5 ml) of the above compound (220 mg), and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2.5 hours. A 10% aqueous sodium thiosulfate solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform / methanol = 30: 1) to give 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (4-fluoro-4-deoxy- β-D-glucopyranosyl) benzene (123 mg) was obtained. APCI−Mass m / Z 466/468 (M + NH ₄ )
Production Example 8-36
The compounds shown in Table 1 were produced in the same manner as in any of the above production examples.

（表中、Meはメチル、MeOはメトキシ、Etはエチル、EtOはエトキシをあらわし、"5−チオ−β−D−グルコピラノシル"、"4−フルオロ−4−デオキシ−β−D−グルコピラノシル"、"β−D−ガラクトピラノシル"、"4−フルオロ−4−デオキシ−β−D−ガラクトピラノシル"及び"6−フルオロ−6−デオキシ−β−D−グルコピラノシル"は、それぞれ、下式の構造を示す：

(In the table, Me represents methyl, MeO represents methoxy, Et represents ethyl, EtO represents ethoxy, “5-thio-β-D-glucopyranosyl”, “4-fluoro-4-deoxy-β-D-glucopyranosyl”, “β-D-galactopyranosyl”, “4-fluoro-4-deoxy-β-D-galactopyranosyl” and “6-fluoro-6-deoxy-β-D-glucopyranosyl” are respectively Show the structure of the formula:

Reference example 1: 4-chloroindoline
A solution of 4-chloroindole (3.15 g) and triethylsilane (8.30 ml) in trifluoroacetic acid (32 ml) was stirred at 50 ° C. for 30 minutes, and the solvent was evaporated under reduced pressure. The residue was basified with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100: 0-80: 20) to give the title compound (2.89 g). APCI-Mass m / Z 154/156 (M + H).

Reference Example 2: 1- (Benzo [b] thiophen-2-ylmethyl) -5-bromo-2-chlorobenzene (1) 5-Bromo-2-chlorobenzoic acid (10.0 g) was suspended in dichloromethane (80 ml). N, O-dimethylhydroxylamine hydrochloride (4.56 g), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (8.96 g), 1-hydroxybenzotriazole (6.31 g) and Triethylamine (8.88 ml) was added. After stirring at room temperature for 64 hours, 10% hydrochloric acid was added at 0 ° C., and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure to obtain crude 5-bromo-2-chloro-N-methoxy-N-methylbenzamide. This compound was used in the next step without purification.

  (2) A tetrahydrofuran (200 ml) solution of the above compound was cooled to −78 ° C. under an argon atmosphere, and diisobutylaluminum hydride (1.0 M toluene solution, 64 ml) was added thereto. The mixture was stirred at −78 ° C. for 30 minutes and then at 0 ° C. for 40 minutes. 10% hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 19: 1) to give 5-bromo-2-chlorobenzaldehyde (8.90 g).

  (3) n-Butyllithium (2.44M hexane solution, 15.8 ml) was added dropwise to a tetrahydrofuran (60 ml) solution of thiaphthalene (5.18 g) at −78 ° C. in an argon atmosphere at −78 ° C. for 30 minutes. The mixture was stirred at 0 ° C for 30 minutes. After cooling to −78 ° C., a solution of the above compound (8.90 g) in tetrahydrofuran (60 ml) was added, and the mixture was stirred at the same temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 15: 1) to obtain benzo [b] thiophen-2-yl 5-bromo-2-chlorophenyl methanol (12.25 g).

(4) A solution of the above compound (12.25 g) in dichloromethane (300 ml) was cooled to 0 ° C., and triethylsilane (12.17 ml) and boron trifluoride · diethyl ether complex (6.58 ml) were added. After stirring at the same temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane) to obtain 1- (benzo [b] thiophen-2-ylmethyl) -5-bromo-2-chlorobenzene (9.30 g). 1H-NMR (CDCl ₃ ) δ 4.30 (s, 2H), 7.02 (d, J = 0.9 Hz, 1H), 7.23-7.36 (m, 4H), 7.43 (m, 1H), 7.65-7.69 (m, 1H), 7.73-7.77 (m, 1H).

Reference Example 3: 5-Bromo-2-chloro-1- (5-phenyl-2-thienylmethyl) benzene (1) 5-Bromo-2-chlorobenzoic acid (55.95 g) was suspended in dichloromethane (500 ml). , Oxalyl chloride (25 ml) and N, N-dimethylformamide (5 drops) were added. After stirring overnight at room temperature, tetrahydrofuran (50 ml) was added, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and 2-phenylthiophene (34.63 g) were dissolved in dichloromethane (1000 ml), and aluminum chloride (31.70 g) was added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 18 hours. The reaction mixture was poured into ice water and extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. The residue was triturated in hexane to give 5-bromo-2-chlorophenyl 5-phenyl-2-thienyl ketone (50.22 g). Melting point: 132-134 ° C. APCI-Mass m / Z 377/379 (M + H).

  (2) Boron trifluoride-diethyl ether complex (50.18 ml) was added to a suspension of the above compound (50.00 g) and triethylsilane (63.44 ml) in dichloromethane (300 ml) -acetonitrile (300 ml) at 0 ° C. It was. After stirring at room temperature for 3 hours, aqueous sodium bicarbonate was added, and the mixture was extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure. After treatment with activated carbon, crystallization from methanol gave 5-bromo-2-chloro-1- (5-phenyl-2-thienylmethyl) benzene (42.92 g). Melting point: 80-81 ° C.

Reference Example 4: 2,3,6-Tri-O-benzyl-4-fluoro-4-deoxy-D-glucono-1,5-lactone (1) Methyl 2,3,6-tri-O-benzyl-β -D-galactopyranoside (see Sakagami et al., Tetrahedron Letters, 2000, 41, 5547-5551; 16.99 g) is dissolved in dichloromethane (172 ml) and (diethylamino) sulfur trifluoride (9.71 ml) Was added at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours and then at room temperature for 5 hours. The mixture was cooled to 0 ° C. and saturated aqueous sodium hydrogen carbonate was added. After drying the organic phase, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 100: 0-90: 10), and methyl 2,3,6-tri-O-benzyl-4-fluoro-4-deoxy-β- D-glucopyranoside (5.86 g) was obtained. APCI-Mass m / Z 484 (M + NH ₄ ).

(2) A mixture of the above compound (5.39 g) and 3M sulfuric acid (10 ml) -acetic acid (50 ml) was stirred at 90 ° C. for 5 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 4: 1) to give 2,3,6-tri-O-benzyl-4-fluoro-4-deoxy-D-glucose (2.39 g). Got. APCI-Mass m / Z 470 (M + NH ₄ ).

(3) The above compound (2.76 g) was dissolved in dimethyl sulfoxide (16 ml), and acetic anhydride (11 ml) was added at 0 ° C. under an argon atmosphere. The mixture was stirred at room temperature overnight, ice water was added at 0 ° C., and the mixture was extracted with ethyl acid. After washing and drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane / ethyl acetate = 19: 1-9: 1) to give 2,3,6-tri-O-benzyl-4-fluoro-4-deoxy-D-glucono. -1,5-lactone (2.08 g) was obtained. APCI-Mass m / Z 468 (M + NH ₄ ).

Test Example 1 Human SGLT2 Inhibitory Action Confirmation Test (1) Test Compound The compound described in the above Production Example was used.
(2) Test method
Human SGLT2 stably expressing CHOK1 cells were seeded in a 24-well plate at 40 × 10 ⁴ cells / well. After culturing in Ham's F-12 medium containing 10% fetal bovine serum, 50 IU / ml penicillin, 50 μg / ml streptomycin, 400 μg / ml geneticin for 2 days at 37 ° C. in the presence of 5% CO ₂ , methyl-α- D-glucopyranoside (α-MG) uptake experiment was conducted. Remove the medium and buffer (137 mM sodium chloride, 5 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 50 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid, After washing once with a buffer containing 20 mM tris (hydroxymethyl) aminomethane, pH 7.4), 250 μl of a buffer containing the test compound was added per well. The test compound was dissolved in dimethyl sulfoxide (DMSO) and added to the buffer (final DMSO concentration 0.5%). In addition, a buffer containing only DMSO was prepared as a control, and a buffer containing the SGLT inhibitor phlorizin (final concentration 100 μM) was prepared in the same way for measuring non-SGLT uptake. 250 μl was added. After leaving at 37 ° C. for 10 minutes, a buffer solution containing α-MG and (U- ^14C ) -α-MG (final concentration of α-MG 0.5 mM) was added at 50 μl per well, and further at 37 ° C. Let stand for 2 hours. Next, all the buffer solution added to the cells was removed, and 400 μl of ice-cold phosphate buffer was added per well and immediately removed. This washing operation was repeated two more times. Thereafter, 300 μl per well of 0.3 N NaOH was added to solubilize the cells, and the radioactivity in the solubilized solution was measured with a liquid scintillation counter. Results were corrected with protein concentration. The value obtained by subtracting SGLT non-specific uptake from control uptake was taken as 100%, and the concentration at which each test compound inhibited it by 50% (IC ₅₀ value) was determined by the probit method (logistic model).
(3) Results The results are as shown in the table below.

２．尿糖排泄促進作用確認試験
（１）被験化合物
前記製造例記載化合物を用いた。
（２）実験方法
6週齢の雄性SDラットを2日間代謝ケージで予備飼育後、実験に用いた。被験化合物（30 mg/kg）は、0.2％Tween80を含む0.2％カルボキシメチルセルロース（CMC）溶液に懸濁し、10 ml/kg宛経口投与した。対照群には、溶媒（0.2％Tween80を含む0.2％CMC溶液）のみを経口投与した。1群あたりの匹数は3匹とした。投与直後から代謝ケージにて24時間尿を採集し、グルコース脱水素酵素法にて、尿中のグルコース濃度を測定した。尿量と尿中グルコース濃度から、1日あたりの尿糖排泄量を算出した。
（３）結果
結果は下表のとおりである。なお、１日あたりの尿糖排泄量（ｍｇ）は、下式で定義されるＡまたはＢで表した。

2. Urinary glucose excretion promoting action confirmation test (1) Test compound The compound described in the above Production Example was used.
(2) Experimental method
Six-week-old male SD rats were preliminarily raised in metabolic cages for 2 days and then used for experiments. The test compound (30 mg / kg) was suspended in a 0.2% carboxymethyl cellulose (CMC) solution containing 0.2% Tween 80 and orally administered to 10 ml / kg. In the control group, only the solvent (0.2% CMC solution containing 0.2% Tween 80) was orally administered. The number of animals per group was three. Immediately after administration, urine was collected for 24 hours in a metabolic cage, and the glucose concentration in urine was measured by the glucose dehydrogenase method. The amount of urinary glucose excretion per day was calculated from the urine volume and urine glucose concentration.
(3) Results The results are as shown in the table below. The urinary glucose excretion amount (mg) per day was expressed as A or B defined by the following formula.

    A ≧ 2400> B ≧ 2000 (mg)

  The compound represented by the formula (A), which is an active ingredient of the present invention, a pharmacologically acceptable salt thereof, or has an SGLT inhibitory action and exhibits a hypoglycemic action. Therefore, the pharmaceutical composition of the present invention can be used as a hypoglycemic agent, or for the prevention / prevention of diabetes, diabetic complications (diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.), obesity, hyperglycemia, etc. It is useful as a therapeutic agent.

Claims (24)

Formula (A):

(In the formula, ring A and ring B are each independently an optionally substituted monocyclic unsaturated heterocycle, an optionally substituted bicyclic fused unsaturated heterocycle, or an optionally substituted benzene. ring,
X is carbon or nitrogen,
Y is — (CH ₂ ) _n — (where n is 1 or 2),
Z is

And
put it here,
(1) When ring A is an optionally substituted bicyclic fused unsaturated heterocycle, Y is bonded to one of the bicyclic fused unsaturated heterocycles containing X, and Z is

Is;
(2) When ring A and ring B are optionally substituted benzene rings, Z is

It is. )
Or a pharmaceutically acceptable salt thereof as an active ingredient. Ring A is an optionally substituted monocyclic unsaturated heterocycle, and Z is

The pharmaceutical composition according to claim 1. (1) A ring A is a monocyclic unsaturated heterocycle optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, and oxo;
Ring B may each be substituted with 1-3 groups selected from the following groups, monocyclic unsaturated heterocycles, bicyclic fused unsaturated heterocycles, or benzene rings:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene, and alkenylene;
Here, the substituents of the ring A and the ring B may be further substituted with a group 1-3 selected from the following group:
Halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxyl, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxycarbonyl, carbamoyl, and mono- or di-alkylcarbamoyl;
(2) The benzene ring in which ring A may be substituted with 1-3 group selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and alkenylene;
Ring B is a monocyclic unsaturated heterocycle or bicyclic unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and oxo;
Here, the substituents of the above ring A and ring B may be substituted with 1-3 groups selected from the following group:
Halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxyl, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxycarbonyl, carbamoyl, and mono- or di-alkylcarbamoyl; Or
(3) A ring A is a bicyclic unsaturated hetero ring optionally substituted with 1-3 groups selected from the following group:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl Carboxyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, and oxo;
Monocyclic unsaturated heterocycle, bicyclic fused unsaturated heterocycle or benzene ring optionally substituted with 1-3 substituents wherein ring B is selected:
Halogen, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkanoyl, alkylthio, alkylsulfonyl, alkylsulfinyl, amino, mono- or di-alkylamino, sulfamoyl, mono- or di-alkylsulfamoyl , Carboxy, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, alkylsulfonylamino, phenyl, phenoxy, phenylsulfonylamino, phenylsulfonyl, heterocyclyl, alkylene and oxo;
Here, the substitution of ring A and ring B is further halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkanoyl, mono- or di-alkylamino, carboxy, hydroxy, phenyl, alkylenedioxy, alkyleneoxy, alkoxy Optionally substituted with 1-3 substituents independently selected from carbonyl, carbamoyl and mono- or di-alkylcarbamoyl;
The pharmaceutical composition according to claim 1, wherein (1) Ring A is a monocyclic unsaturated heterocycle optionally substituted with halogen, lower alkyl, halolower alkyl, lower alkoxy, or oxo, and ring B is (a) halogen; cyano; Alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-alkylamino; optionally substituted by halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower alkylamino Good phenyl; and a benzene ring optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or heterocyclyl optionally substituted with mono- or di-lower alkylamino Or (b) halogen; cyano; lower alkyl; halo lower alkyl Lower alkoxy; halo lower alkoxy; mono- or di-alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, phenyl optionally substituted with mono- or di-lower alkylamino; and halogen; A monocyclic unsaturated heterocycle optionally substituted with a group selected from cyano, lower alkyl, halolower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-alkylamino, or ( c) halogen; cyano; lower alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower. Substituted with alkylamino Optionally substituted phenyl; and optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or heterocyclyl optionally substituted with mono- or di-lower alkylamino Is a ring-fused unsaturated heterocycle;
(2) Ring A is a benzene ring optionally substituted with halogen, lower alkyl, halo lower alkyl, lower alkoxy, phenyl, or lower alkenylene, and ring B is (a) halogen; cyano; lower alkyl; Halo lower alkyl; phenyl lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, mono- or di-alkylamino, Phenyl optionally substituted with carbamoyl or mono- or di-lower alkylcarbamoyl; and halogen, cyano, lower alkyl, halolower alkyl, lower alkoxy, halolower alkoxy, mono- or di-lower alkylamino, carbamoyl, Also A monocyclic unsaturated heterocycle optionally substituted with a group selected from heterocyclyl optionally substituted with mono- or di-lower alkylcarbamoyl, or (b) halogen; cyano; lower alkyl; halolower alkyl; Phenyl lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; phenyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-alkylamino And to a bicyclic fused unsaturated group optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-lower alkylamino; Is a terror ring; or (3) Ring A is A bicyclic fused-unsaturated heterocycle optionally substituted with a logene, lower alkyl, halo lower alkyl, lower alkoxy, or oxo, wherein ring B is (a) halogen; cyano; lower alkyl; halo lower alkyl; Lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or phenyl optionally substituted with mono- or di-alkylamino; and halogen A benzene ring optionally substituted with a group selected from heterocyclyl optionally substituted with cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-lower alkylamino, (b) halogen; Lower alkyl; halo lower alkyl; lower alkoxy; Mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, or phenyl optionally substituted with mono- or di-lower alkylamino; and halogen, cyano A monocyclic unsaturated heterocycle optionally substituted with a group selected from heterocyclyl optionally substituted with lower alkyl, halolower alkyl, lower alkoxy, mono- or di-lower alkylamino, or (c) Halo; cyano; lower alkyl; halo lower alkyl; lower alkoxy; halo lower alkoxy; mono- or di-lower alkylamino; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or mono- or di-alkylamino Optionally substituted And bicyclic fused unsaturated groups optionally substituted with a group selected from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, heterocyclyl optionally substituted with mono- or di-lower alkylamino The pharmaceutical composition according to claim 1, which is a heterocycle. Y is -CH 2 _- a, is bonded to the ring A in position 3 X as position 1, The pharmaceutical composition of claim 1. (1) The benzene ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; phenyl; and lower alkylene;
Ring B is a monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, halo lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo Heterocyclyl optionally substituted with lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl; and oxo;
(2) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted by lower alkoxy; lower alkoxy optionally substituted by halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B is a benzene ring optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo-lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo-lower alkyl, lower alkoxy, or halo-lower alkoxy; and lower alkylene;
(3) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B is a monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle, each optionally substituted with 1-3 groups selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and oxo;
(4) Bicyclic fused unsaturated heterocyclic ring optionally substituted with 1-3 groups selected from the following group:
Lower alkyl optionally substituted with halogen or lower alkoxy; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
A benzene ring or a monounsaturated heterocycle, wherein ring B may be substituted with 1-3 groups each selected from the following group:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and lower alkylene; or
(5) Monocyclic unsaturated heterocyclic ring in which ring A may be substituted with 1-3 group selected from the following group:
Lower alkyl optionally substituted by lower alkoxy; lower alkoxy optionally substituted by halogen or lower alkoxy; cycloalkyl; cycloalkoxy; and oxo;
Ring B may be substituted with 1-3 groups each selected from the following groups, monocyclic unsaturated heterocycle or bicyclic fused unsaturated heterocycle:
Halogen; lower alkyl optionally substituted with halogen, lower alkoxy or phenyl; lower alkoxy optionally substituted with halogen or lower alkoxy; cycloalkyl; cycloalkoxy; halogen, cyano, lower alkyl, halo lower alkyl, lower Phenyl optionally substituted with alkoxy, or halo lower alkoxy; heterocyclyl optionally substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; and oxo;
The pharmaceutical composition according to claim 1, wherein Ring A is

(Wherein R ^1a , R ^2a , R ^3a , R ^1b , R ^2b , and R ^3b are each independently hydrogen, halogen, hydroxyl, alkoxy, alkyl, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, Alkoxyalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyloxy, phenyl, phenylalkoxy, cyano, nitro, amino, mono- or di-alkylamino, alkanoylamino, carboxyl, alkoxycarbonyl, carbamoyl, mono- or di -Represents alkylcarbamoyl, alkanoyl, alkylsulfonylamino, phenylsulfonylamino, alkylsulfinyl, alkylsulfonyl or phenylsulfonyl.
And ring B is

(Wherein R ^4a and R ^5a are each independently hydrogen; halogen; hydroxy; alkoxy; alkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; phenylalkyl; alkoxyalkoxy; hydroxyalkoxy; alkenyl; alkynyl; Cycloalkenyl; Cycloalkenyl; Cycloalkyloxy; Phenyloxy; Phenylalkoxy; Cyano; Nitro; Amino; Mono- or Di-alkylamino; Alkanoylamino; Carboxyl; Alkylsulfonylamino; phenylsulfonylamino; alkylsulfinyl; alkylsulfonyl; phenylsulfonyl; halogen, cyano, alkyl, Phenyl optionally substituted with 1-3 groups selected from loalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy, mono- or di-alkylamino, carbamoyl, and mono- or di-alkylcarbamoyl; or R ^4a and R ^5a are heterocyclyl optionally substituted with 1-3 groups selected from halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, carbamoyl and mono- or di-alkylcarbamoyl, Bonded to each other terminally to form an alkylene;
R ^4b , R ^5b , R ^4c and R ^5c are each independently hydrogen; halogen; hydroxyl; alkoxy; alkyl; haloalkyl; haloalkoxy; hydroxyalkyl; alkoxyalkyl; phenylalkyl; Cycloalkenyl; Cycloalkoxy; Phenyloxy; Phenylalkoxy; Cyano; Nitro; Amino; Mono- or Di-alkylamino; Alkanoylamino; Carboxyl; Alkoxycarbonyl; Carbamoyl; Mono- or Di-alkylcarbamoyl; Alkylsulfonylamino; phenylsulfonylamino; alkylsulfinyl; alkylsulfonyl; phenylsulfonyl; halogen, cyano, a Phenyl optionally substituted with 1-3 groups selected from: kill, haloalkyl, alkoxy, haloalkoxy, alkylenedioxy, alkyleneoxy, and mono- or di-alkylamino; or halogen, cyano, alkyl, haloalkyl, It represents a heterocyclyl optionally substituted with 1-3 groups selected from alkoxy and haloalkoxy. )
And Z is

The pharmaceutical composition according to claim 1, wherein R ^1a , R ^2a , R ^3a , R ^1b , R ^2b , and R ^3b are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy, or phenyl;
R ^4a and R ^5a are each independently hydrogen; halogen; lower alkyl; halo lower alkyl; phenyl lower alkyl; halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, methylenedioxy, ethylene Phenyl optionally substituted by 1-3 groups selected from oxy, mono- or di-lower alkylamino, carbamoyl and mono- or di-lower alkylcarbamoyl; or halogen, cyano, lower alkyl, halolower alkyl , Lower alkoxy, halo lower alkoxy, mono- or di-lower alkylamino, carbamoyl, and heterocyclyl optionally substituted with 1-3 groups selected from mono- or di-lower alkylcarbamoyl, or R another ^4a and R ^5a is And combine with each other to form a lower alkylene;
The pharmaceutical composition according to claim 7, wherein R ^4b , R ^5b , R ^4c and R ^5c are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy or halo lower alkoxy. Ring A is

R ^1a is halogen, lower alkyl, or lower alkoxy, R ^2a and R ^3a are hydrogen; ring B is

And
R ^4a is from halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, methylenedioxy, ethyleneoxy, mono- or di-lower alkylamino, carbamoyl, and mono- or di-lower alkylcarbamoyl. Phenyl optionally substituted with 1-3 groups selected; or selected from halogen, cyano, lower alkyl, lower alkoxy, mono- or di-lower alkylamino, carbamoyl, or mono- or di-lower alkylcarbamoyl A heterocyclyl optionally substituted with 1-3 groups;
Whether R ^5a is hydrogen,
^9. The pharmaceutical composition according to claim 8, wherein R ^4a and R ^5a are bonded to each other at an end to form an alkylene. R ^1a is halogen or lower alkyl, and R ^4a is halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, mono- or di-lower alkylamino, carbamoyl, and mono- or di- Phenyl optionally substituted by 1-3 groups selected from lower alkylcarbamoyl; or 1-3 groups selected from halogen, cyano, lower alkyl, lower alkoxy, carbamoyl and mono- or di-lower alkylcarbamoyl 10. The pharmaceutical composition according to claim 9, which is heterocyclyl optionally substituted with ^R5a is hydrogen. R ^4a is halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, or phenyl optionally substituted with mono- or di-lower alkylamino; or halogen, cyano, lower alkyl, halo 11. The pharmaceutical composition according to claim 10, which is heterocyclyl optionally substituted with lower alkyl, lower alkoxy or halo lower alkoxy. ^12. R ^4a is phenyl substituted with halogen, cyano, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy; or heterocyclyl substituted with halogen, cyano, lower alkyl, or lower alkoxy. The pharmaceutical composition as described. 13. The pharmaceutical composition according to claim 12, wherein ^R4a is phenyl substituted with halogen or cyano; or pyridyl substituted with halogen. Ring A is

R ^1a is halogen, lower alkyl, or lower alkoxy, R ^2a and R ^3a are hydrogen; ring B is

8. The pharmaceutical composition according to claim 7, wherein R ^4b and R ^5b are each independently hydrogen, halogen, lower alkyl, halo lower alkyl, lower alkoxy, or halo lower alkoxy. Ring A is

R ⁶ is hydrogen, halogen or alkyl, and ring B is

R ^7a and R ^7b are independently of each other hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halopyridyl, thienyl, or halothienyl. Or R ^7a and R ^7b together with the carbon atoms to which they are bonded form a fused benzene ring, fused furan ring or fused dihydrofuran ring, wherein Y is CH ₂ . . R ⁶ is halogen and Z is

R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, phenyl, halophenyl, cyanophenyl, pyridyl, or halopyridyl, or R ^7a and R 7b The pharmaceutical composition according to claim 15, which forms a condensed benzene ring, a condensed furan ring, or a condensed dihydrofuran ring together with the carbon atom to which ^7b is bonded. R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or alkylthio, or a fused furan ring, or fused with the carbon atom to which R ^7a and R ^7b are attached. 17. A pharmaceutical composition according to claim 16, which forms a dihydrofuran ring. R ^7a and R ^7b are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, or haloalkoxy, or a condensed furan ring or a condensed dihydrofuran ring with the carbon atom to which R ^7a and R ^7b are attached. 18. The pharmaceutical composition according to claim 17, wherein R ⁶ is halogen and ring B is

17. The pharmaceutical composition according to claim 16, wherein R ^7a is halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or alkylthio. The pharmaceutical composition according to claim 19, wherein R ^7a is halogen, alkyl, cycloalkyl, or alkoxy.   The active ingredient is 3- (4-ethylphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole, 4-chloro-3- (4-ethylphenylmethyl) -1- (5-thio- β-D-glucopyranosyl) indole, 4-chloro-3- (4-ethylphenylmethyl) -1- (4-fluoro-4-deoxy-β-D-glucopyranosyl) indole, 4-chloro-3- (4- Ethoxyphenylmethyl) -1- (5-thio-β-D-glucopyranosyl) indole, 3- (benzo [b] thiophen-2-ylmethyl) -4-chloro-1- (4-fluoro-4-deoxy-β -D-galactopyranosyl) benzene, 4-chloro-3- (5-phenyl-2-thienylmethyl) -1- (6-fluoro-6-deoxy-β-D-glucopyranosyl) benzene, and 4-chloro -3- (5-Phenyl-2-thienylmethyl The pharmaceutical composition according to claim 1, which is a compound selected from) -1- (4-fluoro-4-deoxy-β-D-glucopyranosyl) benzene, or a pharmacologically acceptable salt thereof.   The pharmaceutical composition according to claim 1, which is a hypoglycemic agent.   Diabetes mellitus, diabetic complications, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerolemia, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, metabolic The pharmaceutical composition according to claim 1, which is a prophylactic or therapeutic agent for syndrome, atherosclerosis, hyperglycemia or hypertension.   The pharmaceutical composition according to claim 1, which is a preventive or therapeutic agent for diabetes, diabetic complications, or obesity.