HK1068895B - Nitrogen-containing heterocyclic derivative, medicinal composition containing the same, medicinal use thereof, and intermediate therefor - Google Patents

Description

Nitrogen-containing heterocyclic derivatives, pharmaceutical compositions containing them, their pharmaceutical use and intermediates for their preparation

Technical Field

The present invention relates to nitrogen-containing heterocyclic derivatives or pharmaceutically acceptable salts thereof, or prodrugs thereof, which are useful as medicaments, pharmaceutical compositions containing the above compounds, pharmaceutical uses thereof, and production intermediates thereof.

More specifically, the present invention relates to nitrogen-containing heterocyclic derivatives represented by the following general formula:

wherein, X¹And X³Independently represent N or CH; x²Represents N or CR²；X⁴Represents N or CR³(ii) a Provided that X is¹、X²、X³And X⁴1 or 2 of (a) represents N; r¹Represents A hydrogen atom, A halogen atom, A lower alkyl group, A lower alkoxy group, A lower alkylthio group, A lower alkoxy-substituted (lower alkyl group), A lower alkoxy-substituted (lower alkoxy group), A lower alkoxy (lower alkoxy) -substituted (lower alkyl group), A cyclic lower alkyl group, A halo (lower alkyl group) or A group represented by the general formulA HO-A-: wherein A represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r²Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group, a (lower acyl) amino group, a mono (lower alkyl) amino group or a di (lower alkyl) amino group; r³Represents a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof or a prodrug thereof, which exhibit inhibitory activity against human SGLT2 and are useful as agents for the prevention or treatment of diseases associated with hyperglycemia such as diabetes, diabetic complications or obesity, pharmaceutical compositions containing them, and their pharmaceutical use and intermediates for the production thereof.

Technical Field

Diabetes is a lifestyle-related disease that occurs due to changes in dietary habits and lack of exercise. Furthermore, when sufficient and continuous control is difficult, concurrent medication is required. Biguanides, sulfonylureas, and insulin sensitivity enhancers are now used as antidiabetic agents. However, biguanides and sulfonylureas sometimes exhibit side effects such as lactic acidosis and hypoglycemia, respectively. Insulin sensitivity enhancers sometimes exhibit side effects such as edema and are concerned about the occurrence of progressive obesity. Therefore, in order to solve these problems, development of an antidiabetic agent having a novel mechanism is desired.

In recent years, research and development of novel antidiabetic agents have been conducted which promote urinary glucose excretion and lower blood glucose levels by blocking reabsorption of excess glucose in the kidney (j.clin.invest., volume 79, page 1510-1515 (1987)). Furthermore, it has been reported that SGLT2 (Na)⁺/glucose cotransporter 2) is present in the S1 segment of the renal proximal tubule and is mainly involved in the reabsorption of glucose exuded through the glomerulus (j. clin. invest., 93, 397-. Therefore, inhibition of the activity of human SGLT2 can block reabsorption of excess glucose in the kidney, thus promoting excretion of excess glucose through urine and normalizing blood glucose levels. Therefore, rapid development of antidiabetic agents having a strong inhibitory activity against human SGLT2 and a novel mechanism is expected. In addition, since such agents promote excretion of excess glucose through urine as urine glucose excretion, thereby reducing accumulation of glucose in the body, they are also expected to have preventive or palliative effects on obesity and diuretic effects. Further, these agents are also considered to be useful for various diseases associated with the progression of diabetes or obesity due to hyperglycemia.

Summary of The Invention

The present inventors have conducted earnest studies in order to find a compound having human SGLT2 inhibitory activity. As a result, it was found that the compound represented by the above general formula (I) shows an excellent inhibitory activity against human SGLT2, and thus forms the basis of the present invention.

The present invention provides the above nitrogen-containing heterocyclic derivatives, pharmaceutically acceptable salts thereof or prodrugs thereof, which have inhibitory activity against human SGLT2 and show excellent hypoglycemic action by excreting excess glucose in urine to hinder reabsorption of glucose in the kidney, pharmaceutical compositions containing the above compounds, and their pharmaceutical uses and production intermediates thereof.

Namely, the present invention relates to a nitrogen-containing heterocyclic derivative represented by the following general formula (I):

wherein, X¹And X³Independently represent N or CH; x²Represents N or CR²；X⁴Represents N or CR³(ii) a Provided that X is¹、X²、X³And X⁴1 or 2 of (a) represents N; r¹Represents A hydrogen atom, A halogen atom, A lower alkyl group, A lower alkoxy group, A lower 0 alkylthio group, A lower alkoxy-substituted (lower alkyl group), A lower alkoxy-substituted (lower alkoxy group), A lower alkoxy (lower alkoxy) -substituted (lower alkyl group), A cyclic lower alkyl group, A halo (lower alkyl group) or A group represented by the general formulA HO-A-: wherein A represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r²Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group, a (lower acyl) amino group, a mono (lower alkyl) amino group or a di (lower alkyl) amino group; r³Represents a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof or a prodrug thereof.

The present invention also relates to a pharmaceutical composition, a human SGLT2 inhibitor and a medicament for preventing or treating diseases associated with hyperglycemia, which comprise, as an active ingredient, a nitrogen-containing heterocyclic derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The present invention relates to a method for preventing or treating a disease associated with hyperglycemia, which comprises administering an effective amount of a nitrogen-containing heterocyclic derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof.

The present invention relates to the use of a nitrogen-containing heterocyclic derivative represented by the general formula (I) above, a pharmaceutically acceptable salt thereof, or a prodrug thereof for producing a pharmaceutical composition for preventing or treating a disease associated with hyperglycemia.

The present invention relates to a pharmaceutical combination comprising (a) a nitrogen-containing heterocyclic derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof, and (B) at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, liver gluconeogenesis inhibitors, D-chiral inositol (D-chiroinositol), glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation end-product formation inhibitors, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, glucose receptor kinase inhibitors, glucose receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, Protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxy-methyl-glutaryl-coa reductase inhibitors, fibric acid (fibric acid) derivatives, β -aminobutyric acid (pbr), and combinations thereof₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitor, probcol, thyroid hormone receptor agonist, cholesterolSterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesteryl ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensive agents, sympatholytic agents, central action antihypertensive agents, alpha-glucosidase inhibitors, alpha₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

The present invention relates to a method for preventing and treating diseases associated with hyperglycemia, which comprises administering an effective amount of (a) a nitrogen-containing heterocyclic derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof, in combination with (B) at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation end-product formation inhibitors, insulin secretion enhancers, insulin inhibitors, insulin receptor agonists, insulin receptor kinase inhibitors, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-7 acylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, beta-glucosidase inhibitors, beta-glucosidase,Nerve growth factor, carnitine derivative, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxy-methyl-glutaryl-CoA reductase inhibitor, fibric acid derivative, beta-glutaryl-CoA reductase inhibitor, and pharmaceutical composition containing the same₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporters, cholesterol₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

The present invention relates to the use of (A) and (B) in pharmaceutical compositions for the prevention and treatment of diseases associated with hyperglycemia. (A) Is a nitrogen-containing heterocyclic derivative represented by the general formula (I), a pharmaceutically acceptable salt thereof, or a prodrug thereof. (B) Is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation inhibitorsEnd product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxy-methyl-glutaryl-CoA reductase inhibitors, fibric acid derivatives, β -methyl-glutaryl-CoA reductase inhibitors₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporters, cholesterol₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

Further, the present invention relates to a nitrogen-containing heterocyclic derivative represented by the following general formula (II):

wherein, X¹And X³Independently represent N or CH; x⁴Represents N or CR³；X⁵Represents N or CR⁴(ii) a Provided that X is¹、X³、X⁴And X⁵1 or 2 of (a) represents N; r⁰Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula p¹⁰-O-A-represents A group: wherein P is¹⁰Represents a hydrogen atom or a hydroxyl protecting group; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r³Represents a hydrogen atom or a lower alkyl group; r⁴Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group (which may have a protective group), a lower acyl group, a mono (lower alkyl) amino group (which may have a protective group), or a di (lower alkyl) amino group; or a salt thereof, and a nitrogen-containing heterocyclic derivative represented by the following general formula (III):

wherein, X¹And X³Independently represent N or CH; x⁴Represents N or CR³；X⁵Represents N or CR⁴(ii) a Provided that X is¹、X³、X⁴And X⁵1 or 2 of (a) represents N; r⁰Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula P¹⁰-O-A-represents A group: wherein P is¹⁰Represents a hydrogen atom or a hydroxyl protecting group; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r³Represents a hydrogen atom or a lower alkyl group; r⁴Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group (which may have a protective group), a lower acyl amino group, a mono (lower alkyl) amino group (which may have a protective group), or a di (lower alkyl)Group) amino group; or a salt thereof.

In the present invention, the term "prodrug" refers to a compound of a nitrogen-containing heterocyclic derivative represented by the above general formula (I) which can be converted into its active form in vivo. As the prodrug of the compound of the nitrogen-containing heterocyclic derivative represented by the above general formula (I) or the pharmaceutically acceptable salt thereof, for example, a compound represented by the following general formula (Ia):

wherein P represents a hydrogen atom or a group forming a prodrug; x¹And X³Independently represent N or CH; x²Represents N or CR²；X⁴Represents N or CR³(ii) a Provided that X is¹、X³、X⁴And X⁵1 or 2 of (a) represents N; r²Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyclic lower alkyl group, an amino group, a (lower acyl) amino group, a mono (lower alkyl) amino group or a di (lower alkyl) amino group; r³Represents a hydrogen atom or a lower alkyl group; r¹¹Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula P¹-O-A-represents A group: wherein P is¹Represents a hydrogen atom or a group forming a prodrug; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; provided that P and R are¹¹Contains a prodrug-forming group, or a pharmaceutically acceptable salt thereof.

As examples of the group forming a prodrug, hydroxy protecting groups generally used in prodrugs such as lower acyl, lower alkoxy-substituted (lower acyl), lower alkoxycarbonyl, and lower alkoxy-substituted (lower (alkoxycarbonyl) may be mentioned.

In the present invention, the term "lower alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, etc.; the term "lower alkoxy" means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.; the term "lower alkylthio" refers to a straight or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, hexylthio, etc. Lower "alkylene" refers to straight or branched chain alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, and the like; the term "lower alkyleneoxy" refers to a hydroxy group substituted with an alkylene group as described above; the term "alkylenethio" refers to a thiol group substituted with an alkylene group as described above. The term "cyclic lower alkyl" refers to a 3-7 membered cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylcycloheptyl and the like. The term "halogen atom" refers to a fluorine atom' chlorine atom, bromine atom or iodine atom. The term "halo (lower alkyl)" is lower alkyl substituted by only 1 to 3 different or the same halogen atoms as defined above. The term "lower acyl group" means a straight or branched chain acyl group having 2 to 7 carbon atoms or a cyclic acyl group having 4 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, cyclohexylcarbonyl, etc.; the term "lower alkoxy-substituted (lower acyl)" means a lower acyl group substituted with the above-mentioned lower alkoxy group. The term "lower alkoxy-substituted (lower alkoxy)" means the above-mentioned lower alkoxy group substituted with the above-mentioned lower alkoxy group. The term "lower alkoxy (lower alkoxy) -substituted (lower alkyl)" means the above-mentioned alkyl group substituted with the above-mentioned lower alkoxy-substituted (lower alkoxy). The term "lower alkoxycarbonyl" refers to a straight-chain or branched alkoxycarbonyl group having 2 to 7 carbon atoms or a cyclic alkoxycarbonyl group having 4 to 8 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl and cyclohexyloxycarbonyl; the term "lower alkoxycarbonyl-substituted (lower acyl)" means the above-mentioned lower acyl substituted with the above-mentioned lower alkoxycarbonyl, such as 3- (ethoxycarbonyl) propionyl; the term "lower alkoxy-substituted (lower alkoxycarbonyl)" means the above-mentioned lower alkoxycarbonyl substituted with the above-mentioned alkoxy, such as 2-methoxyethoxycarbonyl. The term "mono (lower alkyl) amino" refers to an amino group that is mono-substituted with a lower alkyl group as described above; the term "di (lower alkyl) amino" refers to the same or different lower alkyl disubstituted amino groups described above; the term "(lower acyl) amino" refers to an amino group substituted with the above lower acyl group. In various production intermediates, the term "hydroxy-protecting group" refers to a hydroxy-protecting group used in general organic synthesis, in particular, benzyl, methyl, methoxymethyl, acetyl, benzoyl, 2-trimethylsilylethoxymethyl and the like, in addition to the hydroxy-protecting group generally used for the above-mentioned prodrug. The term "amino-protecting group" refers to an amino-protecting group used in general organic synthesis, such as benzyl, p-methoxybenzyl, lower acyl, lower alkoxycarbonyl, etc., in various production intermediates.

The term "nitrogen-containing heterocyclic derivative" represented by the above-mentioned general formulae (I), (II) and (III) means a 3-benzyl-2-hydroxypyridine derivative, a 4-benzyl-3-hydroxypyridine derivative, a 3-benzyl-4-hydroxypyridine derivative, a 2-benzyl-3-hydroxypyridine derivative, a 4-benzyl-3-hydroxypyridazine derivative, a 4-benzyl-5-hydroxypyridazine derivative, a 3-benzyl-4-hydroxypyridazine derivative, a 5-benzyl-4-hydroxypyrimidine derivative, a 4-benzyl-5-hydroxypyrimidine derivative or a 2-benzyl-3-hydroxypyrazine derivative. In the case where the compounds of the present invention have tautomers, the present invention includes all tautomers.

The nitrogen-containing heterocyclic derivative represented by the above general formula (I) and a prodrug thereof of the present invention can be prepared, for example, by the reaction described in the following scheme 1:

scheme 1

Wherein P is⁰Represents a group forming a prodrug; y is¹Represents a leaving group (e.g., chlorine atom, bromine atom, etc.); x¹、X²、X³、X⁴、X⁵、R⁰、R¹The meaning of the same is as before.

Process 1

The corresponding compound represented by the above general formula (II) can be prepared as follows: the alcohol compound or its salt is glycosidated with acetylbromo-alpha-D-glucose in an inert solvent in the presence of a base (e.g., silver salts such as silver carbonate, silver oxide, etc.; potassium carbonate, sodium hydride, etc.). As the solvent used in the glycosidation reaction, for example, acetonitrile, tetrahydrofuran, dichloromethane, toluene, N-dimethylformamide, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 2 hours to 2 days, depending on the raw materials, the solvent and the reaction temperature used.

Process 2

The nitrogen-containing heterocyclic derivative of the present invention represented by the above general formula (I) can be prepared as follows: the compound represented by the above general formula (II) is subjected to alkaline hydrolysis by a conventional method. As the solvent used in the basic hydrolysis, methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof, and the like can be mentioned. As the base used, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and the like can be mentioned. The reaction temperature is usually from 0 ℃ to room temperature, and the reaction time is usually from 30 minutes to 6 hours, depending on the starting materials, the solvent and the reaction temperature used.

Process 3

A prodrug of a nitrogen-containing heterocyclic derivative represented by the general formula (I) [ for example, a prodrug represented by the above general formula (Ia) ] can be prepared as follows: the hydroxyl group-protecting group generally used for prodrugs is introduced into the hydroxyl group of the nitrogen-containing heterocyclic derivative represented by the above general formula (I) by a conventional method using, for example, a reagent for introducing a hydroxyl-protecting group represented by the above general formula (IV).

For example, the compound represented by the general formula (III) as a starting material in the above production method (scheme 1) can be prepared according to the reaction described in the following scheme 2:

scheme 2

Wherein M is¹Represents a hydroxyl protecting group; m²Represents a hydrogen atom or a hydroxyl protecting group; x⁶Represents N or CR⁵；R⁵Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group or a lower alkoxy group; r¹²Represents a hydrogen atom, a lower alkyl group or an amino-protecting group; r¹³Represents a hydrogen atom or a lower alkyl group; x¹、X³、X⁴、X⁵And R⁰With the proviso that X of the compound (V) is¹、X³、X⁴And X⁶1 or 2 of (a) represents N.

Process 4

The compound represented by the above general formula (VII) can be prepared as follows: the compound represented by the above general formula (V) is oxidized with Dess-Martin reagent in an inert solvent, and the protecting group is optionally removed in a usual manner. As the solvent used in the oxidation, for example, methylene chloride may be mentionedChloroform, or a mixed solvent thereof. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 10 minutes to 1 day, depending on the raw materials, the solvent and the reaction temperature used. When R is⁵When it is a halogen atom, the corresponding compound may optionally be derivatized as follows: the compound is substituted with an amine derivative represented by the general formula (VI) or a salt thereof in the presence or absence of a base (e.g., sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.) in the presence or absence of a solvent. As the solvent used for the substitution reaction, N-dimethylformamide, N-methylacetamide, tetrahydrofuran, tert-butanol, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from room temperature to 150 ℃ and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Process 5

The compound represented by the above general formula (III) can be prepared as follows: (1) hydrogenating a compound represented by the above general formula (VII) with a palladium catalyst (palladium carbon powder, etc.) in an inert solvent under hydrogen atmosphere in the presence or absence of an acid (such as hydrochloric acid); or (2) reducing the compound represented by the above general formula (VII) with a reducing agent. As the solvent used in (1) hydrogenation, for example, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropanol, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the raw materials, the solvent and the reaction temperature used. (2) The reduction with a reducing agent can be carried out with a reducing agent such as sodium cyanoborohydride in the presence of a Lewis acid such as trifluoroboric acid and the like in an inert solvent such as tetrahydrofuran and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Among the compounds represented by the above general formula (III) as the raw materials in the above production method (scheme 1), compounds represented by the following general formula (IIIa) can be prepared, for example, according to the reaction described in the following scheme 3:

scheme 3

Wherein M is¹、X¹、X³、X⁴、X⁶And R⁰The meaning of the same is as above.

Process 6

The compound represented by the general formula (IIIa) can be prepared as follows: the compound represented by the general formula (V) is hydrogenated with a palladium catalyst (e.g., palladium carbon powder) in the presence or absence of an acid (e.g., hydrochloric acid) in an inert solvent under a hydrogen atmosphere, and the protecting group is optionally removed by a usual method. As the solvent used in the hydrogenation, for example, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropyl alcohol, and extremely mixed solvents and the like can be mentioned. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Process 7

The compound represented by the above general formula (VIII) can be prepared as follows: removing the protecting group M of the compound represented by the above general formula (V) by a usual method¹。

Process 8

The compound represented by the above general formula (IIIa) can be prepared as follows: the compound represented by the general formula (VIII) is hydrogenated with a palladium catalyst (e.g., palladium carbon powder) in the presence or absence of an acid (e.g., hydrochloric acid) in an inert solvent under a hydrogen atmosphere, and the protecting group is optionally removed by a usual method. As the solvent used in the hydrogenation, for example, methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropyl alcohol, and extremely mixed solvents and the like can be mentioned. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting materials, the solvent and the reaction temperature used.

Among the compounds represented by the general formula (III) as the starting material in the above production method (scheme 1), compounds represented by the following general formula (IIIb) can be prepared, for example, according to the reaction described in the following scheme 4:

scheme 4

Wherein Y is²Represents a chlorine atom or a bromine atom; r⁰And R⁴The meaning of the same is as above.

Process 9

The compound represented by the above general formula (XI) can be prepared as follows: the compound represented by the above general formula (IX) is dissolved in an inert solvent, and the compound is reacted with lithium 2, 6, 6, 6-tetramethylpyridinium amide usually at-100 ℃ to-50 ℃ for 2 usually 10 minutes to 2 hours, and the resulting product is reacted with the compound represented by the above general formula (X) usually at-100 ℃ to room temperature. As the inert solvent used, there may be mentioned tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane, a mixed solvent thereof and the like. The time for the condensation reaction is usually from 30 minutes to 6 hours, and varies depending on the raw materials, the solvent and the process temperature used.

Process 10

The compound represented by the above general formula (Va) can be prepared as follows: the compound represented by the above general formula (XI) is reacted with benzyl alcohol in the presence of tris [2- (2-methoxyethoxy) ethyl ] amine in a solvent such as toluene, benzene, etc., with a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, etc. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Process 11

The compound represented by the above general formula (IIIb) can be prepared as follows: the compound represented by the above general formula (Va) is optionally deprotected in a usual manner, and then hydrogenated with a palladium catalyst (e.g., palladium carbon powder) in the presence or absence of an acid (e.g., hydrochloric acid) under a hydrogen atmosphere. As the solvent which is related to hydrogenation in years, mention may be made of, for example, jiacun, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, isopropyl alcohol, a mixed solvent thereof, and the like. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Among the compounds represented by the general formula (III) as the starting material in the above production method (scheme 1), the compounds represented by the following general formula (IIIc) can be prepared, for example, according to the reaction described in the following scheme 5:

scheme 5

Wherein R is⁶Represents a lower alkyl group; r⁷Represents lower alkyl, cyclic lower alkyl, lower alkoxy, amino (which may have a protecting group), lower acyl, mono (lower alkyl) amino (which may have a protecting group), or di (lower alkyl) amino; y is³Represents a leaving group (e.g., a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc.); r⁰And R³The meaning of the same is as above.

Process 12

The compound represented by the above general formula (XIV) can be prepared as follows: (1) condensing a compound represented by the above general formula (XII) with a benzyl derivative represented by the above general formula (XIII) in a solvent (e.g., 1, 2-dimethoxyethane, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, etc.) in the presence of a base (e.g., sodium hydride, potassium tert-butoxide, etc.); or (2) condensing the compound represented by the above general formula (XII) with a benzyl derivative represented by the above general formula (XIII) in a solvent (e.g., tetrahydrofuran, diethyl ether, N-dimethylformamide, N-dimethylacetamide, etc.) in the presence or absence of lithium bromide or lithium chloride, with a base (e.g., diisopropylethylamine, triethylamine, 1, 8-diazabicyclo [5, 4, 0] -7-undecene, etc.). In the reaction (1), the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used. Further, in the reaction (2), the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 1 hour to 1 day, and varies depending on the raw materials, the solvent and the reaction temperature used.

Process 13

The compound represented by the above general formula (IIIc) can be prepared as follows: the compound represented by the above general formula (XIV) is reacted with the compound represented by the above general formula (XV) or a salt thereof in an alcohol solvent in the presence or absence of a base (such as sodium methoxide, sodium ethoxide, or the like). As the alcohol solvent used in the reaction, for example, spring, ethanol, propanol, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 2 hours to 2 days, depending on the raw materials, the solvent and the reaction temperature used.

Among the compounds represented by the general formula (III) as the starting material in the above production method (scheme 1), compounds represented by the following general formula (IIId) can be prepared, for example, according to the reaction described in the following scheme 6:

scheme 6

Wherein R is⁰、R³And R⁶The meaning of the same is as above.

Process 14

The compound represented by the above general formula (XVII) can be prepared as follows: the compound represented by the above general formula (XVI) is reduced in an inert solvent with a reducing agent such as borane-tetrahydrofuran complex, borane-dimethylsulfide complex, etc. in an inert solvent. As the inert solvent which is used in the reduction reaction in some years, there may be mentioned, for example, tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used. Furthermore, the starting materials represented by the above general formula (XVI) can be purchased commercially or prepared according to literature procedures or methods analogous thereto, for example, J.org.chem., 37, 555-559 (1972); SYNLETT, page 137-138 (1993).

Process 15

The compound represented by the above general formula (XVIII) can be prepared as follows: is a compound represented by the above general formula (XVII) oxidized with Dess-Mart in reagent. As the solvent used for the oxidation reaction, for example, dichloromethane, chloroform, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

Process 16

The compound represented by the above general formula (IIId) can be prepared as follows: the compound represented by the above general formula (XVIII) is cyclized by reacting it with hydrazine or a hydrate thereof or a salt thereof in a solvent (e.g., methanol, ethanol, toluene, or benzene, a mixed solvent thereof, etc.), and then oxidized with selenium dioxide, etc. in an alcohol solvent (e.g., methanol, ethanol, etc.). In the cyclization reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the raw materials, the solvent and the reaction temperature used. In the oxidation reaction, the reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 2 days, depending on the raw materials, the solvent and the reaction temperature used.

The compound represented by the general formula (V) as a starting material in the above production method (scheme 2) can be prepared, for example, according to the reaction described in the following scheme 7:

scheme 7

Wherein, X¹、X³、X⁴、X⁶、R⁰And M¹The meaning of the same is as above.

Process 17

The compound represented by the above general formula (XX) can be produced by introducing a protecting group into the hydroxyl group of the compound represented by the above general formula (XIX) in a usual manner.

Process 18

The compound represented by the above general formula (V) can be prepared as follows: the compound represented by the above general formula (XX) is dissolved in an inert solvent, the compound is reacted with organolithium (e.g., t-butyllithium, n-butyllithium, etc.) usually at-100 to 0 for usually 10 minutes to 2 hours, and then the resulting compound is reacted therewith at-100 to room temperature by adding the compound represented by the above general formula (X) to the reaction mixture. As the inert solvent used for the reaction, there can be mentioned, for example, tetrahydrofuran, diethyl ether, 1, 2-dioxyethane, a mixed solvent thereof and the like. The time for the condensation reaction is usually from 30 minutes to 6 hours, and varies depending on the raw materials, the solvent and the reaction temperature used.

The compound represented by the general formula (V) as a starting material in the above production method (scheme 2) can also be produced, for example, according to the reaction described in the following scheme 8:

scheme 8

Wherein Z represents MgBr, MgCl, MgI or lithium atom; x¹、X³、X⁴、X⁶、R⁰And M¹The meaning of the same is as above.

Process 19

The compound represented by the above general formula (V) can be prepared as follows: a compound represented by the above general formula (XXI) is condensed with a compound represented by the above general formula (XXII) in an inert solvent. As the solvent in the condensation reaction, there may be mentioned, for example, tetrahydrofuran, diethyl ether, 1-dimethoxyethane, a mixed solvent thereof and the like. The reaction temperature is usually from-100 ℃ to room temperature, and the reaction time is usually from 30 minutes to 6 hours, depending on the starting materials, the solvent and the reaction temperature used.

The compound represented by the general formula (XXI) as a starting material in the above production method (scheme 8) can also be prepared, for example, according to the reaction described in the following scheme 9:

scheme 9

Wherein X⁷Represents N or CR⁸；R⁸Represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cyclic lower alkyl group or a lower alkoxy group; r⁹Represents a lower alkyl group; y is⁴Represents a leaving group (e.g., a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc.); x¹、X⁴、X⁶、R⁶And M¹The same as above, provided that in compound (XXIII) and compound (XXIV), X¹、X³、X⁴And X⁷Is N or 2.

Process 20

The compound represented by the above general formula (XXI) can be prepared as follows: the compound represented by the general formula (XX) is dissolved in an inert solvent, the compound is reacted with organolithium (e.g., t-butyllithium, N-butyllithium, etc.) at usually-100 ℃ to 0 ℃ for usually 10 minutes to 2 hours, then N, N-dimethylformamide is added, the mixture is allowed to react at usually-100 ℃ to room temperature for usually 30 minutes to 1 day, and the reaction mixture is treated with an acidic aqueous solution. As the inert solvent used, for example, tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane and a mixed solvent thereof and the like can be mentioned, and as the acidic aqueous solution, for example, an aqueous solution of acetic acid, hydrochloric acid, succinic acid, oxalic acid and the like can be mentioned. The treatment time in the acidic aqueous solution is generally 5 minutes to 30 minutes, varying depending on the acidic solvent used.

Process 21

The compound represented by the above formula (XXV) can be prepared by introducing a protecting group M into the hydroxyl group of the compound represented by the above formula (XXIII) by a conventional method¹And then the preparation. Further, optionally at R⁸In the case of a hydroxyl group, the corresponding compound can be derived by O-alkylation using a compound represented by the above formula (XXIV).

Process 22

The compound represented by the above general formula (XXI) can be prepared as follows: the compound represented by the above general formula (XXV) is subjected to a reduction reaction with a reducing agent such as diisobutylaluminum hydride or the like in an inert solvent. As the solvent used in the reaction, for example, tetrahydrofuran, dichloromethane, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from-100 ℃ to room temperature, and the reaction time is usually from 1 hour to 6 days, depending on the starting materials, the solvent and the reaction temperature used.

Process 23

The compound represented by the above formula (XXVII) can be prepared by introducing a protecting group M into the hydroxyl group of the compound represented by the above formula (XXVI) by a usual method¹And then the preparation. Further, optionally at R⁸In the case of a hydroxyl group, the corresponding compound can be derived by O-alkylation using a compound represented by the above formula (XXIV).

Process 24

The compound represented by the above general formula (XXI) can be prepared as follows: the compound represented by the above general formula (XXVII) is subjected to a reduction reaction with a reducing agent (e.g., diisobutylaluminum hydride, etc.) in an inert solvent, and then (2) to an oxidation reaction with an oxidizing agent (e.g., Dess-Martin reagent) in an inert solvent. As the solvent used in the reduction reaction, for example, tetrahydrofuran, dioxymethane, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from-10 ℃ to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used. As the solvent used in the oxidation reaction, for example, chloroform, dichloromethane, a mixed solvent thereof, and the like can be mentioned. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 1 hour to 1 day, depending on the raw materials, the solvent and the reaction temperature used.

The nitrogen-containing heterocyclic derivative represented by the above general formula (I) of the present invention and the prodrug thereof obtained by the above production process can be isolated and purified by conventional separation means such as fractional recrystallization, purification by chromatography, solvent extraction and solid phase extraction.

The nitrogen-containing heterocyclic derivatives represented by the above general formula (I) of the present invention and prodrugs thereof can be converted into their pharmaceutically acceptable salts by a usual method. Examples of such salts include acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like), acid addition salts with organic acids (e.g., formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, and the like), and salts with inorganic bases (e.g., sodium salts, potassium salts, and the like).

The nitrogen-containing heterocyclic derivatives represented by the above general formula (I) and prodrugs thereof of the present invention include solvates thereof with pharmaceutically acceptable solvents such as ethanol and water.

In the nitrogen-containing heterocyclic derivative represented by the above general formula (I) of the present invention and the prodrug thereof, there are 2 optical isomers (R-and S-isomers) in each compound having an asymmetric carbon atom (except for a glucopyranosyloxy moiety). In the present invention, both R-isomer and S-isomer can be used, and a mixture of 2 isomers can also be used.

The nitrogen-containing heterocyclic derivative represented by the above general formula (I) and the prodrug thereof of the present invention exhibit an activity of lowering blood glucose level by an excellent inhibitory activity against human SGLT 2. Therefore, they are extremely useful as drugs for preventing or treating diseases associated with hyperglycemia. Such as diabetes, diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcers, macroangiopathy), obesity, hyperinsulinemia, glucose metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, arteriosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout, and the like.

Furthermore, the compounds of the present invention are suitably combined with at least one drug other than SGLT2 inhibitors. Examples of drugs that may be used in combination with the compounds of the present invention include insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, glucose secretion enhancers, insulin receptor kinase inhibitors, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, advanced glycation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kB inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like productsGrowth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxy-methyl-glutaryl-CoA reductase inhibitors, fibric acid derivatives, beta-glutaryl-CoA reductase inhibitors₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporters, cholesterol₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

Where the compounds of the present invention are used in combination with one or more of the above drugs, the present invention includes various dosage forms such as: as a single formulation or separate formulations administered simultaneously by the same or different routes of administration, or as separate formulations administered by the same or different routes of administration at different dosing intervals. Pharmaceutical cocktails comprising a compound of the invention and one or more of the above drugs comprise 2 dosage forms for the above combination as a single formulation and separate formulations.

When suitably combined with the above drugs, the compounds of the present invention can achieve more favorable effects than additive effects in the prevention or treatment of the above-mentioned diseases. Also, the dosage administered can be reduced compared to each drug used alone; alternatively, co-administration with drugs other than SGLT2 inhibitors may avoid or reduce side effects.

Specific compounds for the above-mentioned drugs in combination and preferred diseases to be treated are exemplified below. However, the invention is not so limited, for example, specific compounds include their free compounds and their or other pharmaceutically acceptable salts.

As insulin sensitivity enhancers, there may be mentioned peroxisome proliferator-activated receptor- γ agonists (e.g., troglitazone, pioglitazone hydrochloride, rosiglitazone maleate), daglipzone sodium, GI-262570, isaglitazone, LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium and NIP-221), peroxisome proliferator-activated receptor- α agonists (e.g., GW-9578 and BM-170744), peroxisome proliferator-activated receptor- α/γ agonists (e.g., GW-268, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-MDX8), retina-like X receptor agonists (e.g., ALRT-268, KRT-268, rosiglitazone maleate, GI-2629, ciglitazone sodium and NIP-221), peroxisome proliferator-activated receptor- α agonists (e.g., GMX- α -, AGN-4204, MX-6054, AGN-194204, LG-100754 and bexarotene and other insulin sensitivity enhancers (e.g. reglixane, ONO-5816, MRX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-929, AR-H049020 and GW-501516). The insulin sensitivity enhancer is preferably used for diabetes, diabetic complications, obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder or arteriosclerosis, and more preferably for diabetes, hyperinsulinemia or glucose metabolism disorder because of improving the disorder of insulin signaling in peripheral tissues and enhancing the uptake of glucose into tissues from the blood, thereby lowering the blood glucose level.

As the glucose absorption inhibitors, there may be mentioned α -glucosidase inhibitors (e.g., acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25637, canaglibose and MDL-73945) and α -amylase inhibitors (e.g., AZM-127). The glucose absorption inhibitor is preferably used for diabetes, diabetic complications, obesity, hyperinsulinemia or glucose metabolism disorder, more preferably for diabetes or glucose metabolism disorder, because enzymatic degradation of carbohydrates contained in food in the gastrointestinal tract is inhibited, and absorption of glucose into the body is inhibited or delayed.

As biguanides, there may be mentioned phenelzine, buformin hydrochloride, metformin hydrochloride and the like. Biguanides are preferably used for diabetes, diabetic complications, hyperinsulinemia or glucose metabolism disorders, more preferably for diabetic hyperinsulinemia or glucose metabolism disorders, because blood glucose levels are reduced by an inhibitory effect on hepatic gluconeogenesis, an accelerating effect on anaerobic glycolysis in tissues or an improving effect on insulin resistance in surrounding tissues.

As the insulin secretion enhancers, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glipizide, glyburide, gliclazide, 1-butyl-3-m-aminobenzenesulfonylurea, carbutamide, glibornuride, glipizide, gliquidone, glimeperide, glithiazide, glitazole, glibutrazole, glihexanamide, glimepiride, glyburide, phenbutamide, tolcyclamide, glimepiride, nateglinide, mitiglinide calcium hydrate, repaglinide and the like may be mentioned. The insulin secretion enhancer is preferably used for diabetes, diabetic complications or glucose metabolism disorders, more preferably for diabetes or glucose metabolism disorders, because blood glucose levels are lowered by acting on pancreatic β -cells and enhancing insulin secretion.

As insulin or insulin analogs, human insulin, insulin taken from animals and human insulin analogs may be mentioned. These agents are preferably used for diabetes, diabetic complications or glucose metabolism disorders, more preferably for diabetes or glucose metabolism disorders.

As glucagon receptor antagonists, BAY-27-9955, NNC-92-1687, and the like; as the insulin receptor kinase agonists, TER-17411, L-783281, KRX-613 and the like; as the tripeptidyl peptidase II inhibitor, UCL1397 and the like; as dipeptidyl peptidase IV inhibitors, there can be mentioned NVP-DPP728A, TSL-225, P-32/98, etc.; as the protein tyrosine phosphatase 1B inhibitor, PTP-112, OC-86839, PNU-177496, etc.; as glycogen phosphorylase inhibitors, NN-4201, CP-368296 and the like; as the fructose-bisphosphatase inhibitor, there may be mentioned R-132917 and the like; as the pyruvate dehydrogenase inhibitor, AZD-7545 and the like; as the liver gluconeogenesis inhibitor, FR-225659 and the like; as the glucagon-like peptide-1 analog, exendin-4, CJC-1131 and the like; as glucagon-like peptide-1 agonists, there may be mentioned AZM-134, LY-315902 and the like; as amylase, amylase analogue or amylase agonist, pramlintide acetate and the like can be mentioned. These drugs, glucose-6-phosphatase inhibitors, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 are preferably used for diabetes, diabetic complications, hyperinsulinemia or glucose metabolism disorders, more preferably for diabetes or glucose metabolism disorders.

As aldose reductase inhibitors, there may be mentioned, for example, ascorbyl pancis-octadeca-6, 9, 12-trienoate, tolrestat, epalrestat, AND-138, BAL-ARI8, ZD-5522, ADN311, GP-1447, IDD-598, fidaresdat, sorbinil, ponarestat, risarestat, zenastat, minalstat, methosorbini, 1AL-1567, imirestat, M-16209, TAT, AD-5467, zopolstat, AS-3201, NZ-314, SG-210, JTT-811, lindolrestat AND the like. Aldose reductase inhibitors are preferred for diabetic complications because of the inhibition of aldose reductase and the reduced accumulation of intracellular sorbitol in the accelerated polyol pathway, which is in a continuous hyperglycemic state in the tissues of diabetic complications.

As the higher glycosylation end product formation inhibitors, pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride and the like can be mentioned. Inhibitors of the formation of higher glycosidation end products are preferred for diabetic complications because of the inhibition of the formation of higher glycosidation end products, which is accelerated in the continuous hyperglycemic state of diabetes, and the reduction of cell damage.

As protein kinase C inhibitors, LY-333531, midostaurin and the like can be mentioned. Protein kinase C inhibitors are preferred for diabetic complications because of the inhibition of protein kinase C activity, which is elevated in the continuous hyperglycemic state of diabetes.

As the gamma-aminobutyric acid receptor antagonist, there can be mentioned pyridate and the like; as sodium channel antagonists mexiletine hydrochloride, oxcarbazepine and the like can be mentioned; as transcription factor NF-. kappa.B inhibitors, dexlipotam and the like; as the lipid peroxidase inhibitor, tirilazad mesylate and the like; as N-acetylated- α -linked-acid-dipeptidase inhibitors, GPI-5693 and the like; as the carnitine derivative, carnitine, levacecarnitine hydrochloride, levocarnitine chloride, levocarnitine, ST-261 and the like can be mentioned. These drugs, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, neural badge factor, uridine, 5-hydroxy-1-methyl-hydantoin, EGB-761, bimoclomol, sulodexide, and Y-128 are preferably used for diabetic complications.

As hydroxymethylglutaryl-coenzyme A reductase inhibitors, there may be mentioned sodium cerivastatin, sodium pravastatin, lovastatin, cerivastatin, fluvastatin sodium, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987, pitavastatin calcium, rosuvastatin calcium, colesterone, acitrexate, dalvastatin, mevastatin, clinostatin, BMS-180431, BMY-21950, glenstastatin, arvatin, BMY-22089, bervastatin and the like. Inhibitors of hydroxymethylglutaryl-coenzyme a reductase are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder or arteriosclerosis because blood cholesterol levels are reduced by inhibiting hydroxymethylglutaryl-coenzyme a reductase.

As fibric acid derivatives, bezafibrate, beclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirfibrate, clinofibrate, bisfibrate, theofibrate, AHL-157 and the like can be mentioned. Fibric acid derivatives are preferably used for hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder or arteriosclerosis, and more preferably for hyperlipidemia or arteriosclerosis because hepatic lipoprotein lipase is activated and fatty acid oxidation is enhanced, thereby lowering blood triglyceride levels.

As the β -adrenoceptor agonist, there may be mentioned BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL37344, CP-331679, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A CL316243, AJ-9677, GW-427353, N-5984, GW-2696, YM-178 and the like. The beta-adrenergic receptor agonist is preferably used for obesity, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder, and more preferably for obesity or hyperinsulinemia, because beta-adrenergic receptors in adipose tissues are stimulated and fatty acid oxidation is enhanced, thereby inducing energy consumption.

As acyl-coenzyme a: as cholesterol acyltransferase inhibitors, NTE-122, MCC-147, PD-132201-2, DUP-129, U-73482, U-76807, RP-70676, P-06139, CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-8-434, avasimibe, CI-976, RP-64477, F-1394, eldaciibe, CS-505, CL-283546, YM-17E, lecimibide, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe and the like can be mentioned. Acyl-coenzyme a: cholesterol acyltransferase inhibitors are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorders, more preferably for hyperlipidemia or hypercholesterolemia, since by inhibiting acyl-coa: cholesterol acyltransferase reduces blood cholesterol levels.

As thyroid hormone receptor agonists, liothyronine sodium, levothyroxine sodium, KB-2611 and the like; as the cholesterol absorption inhibitor, ezetimibe, SCH-48461, etc.; as the carnitine palmitoyltransferase inhibitor, etomoxider and the like; as squalene synthetase inhibitors, there can be mentioned SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 and the like; as nicotinic acid derivatives, there may be mentioned nicotinic acid, nicotinamide, nicomol, niceritrol, acipimox, nicol, etc.; as bile acid sequestrants, there may be mentioned cholestyramine, colesevelam hydrochloride, GT-102-279, etc.; as sodium/bile acid cotransporter inhibitors, 264W94, S-8921, SD-5613, etc.; as the cholesteryl ester transfer protein inhibitor, PNU-107368E, SC-795, JTT-705CP-529414 and the like can be mentioned. These drugs, probcol, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors and low density lipoprotein receptor enhancers are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipid metabolism disorder.

As appetite suppressants there may be mentioned monoamine reuptake inhibitors, serotonin release agonists, serotonin agonists (in particular 5 HT)_2C-agonists), norepinephrine reuptake inhibitors, norepinephrine release agonists, alpha₁-adrenoceptor agonists, beta₂-adrenoceptor agonists, dopamine agonists, cannabinoids antagonists, Y-aminobutyric acid receptor antagonists H₃-histamine antagonists, L-histidine, leptin (leptin), leptin analogues, leptin receptor agonists, melanocortin receptor agonists (MC3-R agonists, MC4-R agonists), alpha-melanocyte stimulating hormones, cocaine-and amphetamine-regulated transcripts, rosellin, enterostatin agonists, calcitonin-gene-related peptides, bombesin, cholecystokinin agonists (in particular CCK-a agonists), corticotropin-releasing hormone analogues, corticotropin-releasing hormone agonists, urocortin, somatostatin analogues, somatostatin receptor agonists, pituitary adenylate cyclase-activating peptides, brain derived neuro-agonistsTrophic factors, ciliary neurotrophic factor, thyroid-releasing hormone, neurotensin, suflatin, neuropeptide Y antagonists, opioid peptide antagonists, galanin antagonists, melanin-concentrating hormone receptor antagonists, rat-related protein inhibitors, and orexin receptor antagonists. Specifically, as monoamine reuptake inhibitors, mention may be made of mazindol; as serotonin reuptake inhibitors, dexfenfluramine hydrochloride, fenfluramine, sibutramine hydrochloride, flurfosfomamide maleate, sertraline hydrochloride and the like can be mentioned; as serotonin agonists, inotriptan, (+) -norfluramine and the like; as the norepinephrine reuptake inhibitor, there can be mentioned bupropion, GW-320659, etc.; as norepinephrine-releasing agonists, rolipram, YM-992 and the like; as beta₂Adrenergic receptor agonists, there may be mentioned amphetamine, dextroamphetamine, phentermine, benzphetamine, methamphetamine, phendimetrazine, phenmetrazine, bupropion, phenylpropanolamine, chlorobenzotrimazole, etc.; as dopamine agonists, there may be mentioned ER-230, doprexin, bromocriptine maleate and the like; as cannabinoids antagonists, rimonabant, etc.; as the gamma-aminobutyric acid receptor antagonist, topiramate and the like; as H₃Histamine antagonists, GT-2394 and the like may be mentioned; as the leptin, leptin analog or leptin receptor agonist, there may be mentioned LY-355101 and the like; as cholecystokinin agonists (particularly CCK-A agonists), SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378 and the like; as neuropeptide Y antagonists, SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814 and the like; appetite suppressants are preferably used for diabetes, obesity complicated with diabetes, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, arteriosclerosis, hypertension, congestive heart failure, edema, hyperuricemia or gout, and more preferably for obesity because the activity of intracerebral monoamines or bioactive peptides in the central appetite regulating system is stimulated or inhibited and appetite is suppressed, thereby reducing appetiteThe energy uptake is obtained.

As angiotensin-converting enzyme inhibitors, captopril, enalapril maleate, alacepril, delapril hydrochloride, ramipril, lisopropril, idapril hydrochloride, benazepril hydrochloride, celepril monohydrate, cilazapril, fosinopril sodium, perindopril erbumine, mevinopril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, trandolapril, zofenopril calcium, moxapril hydrochloride, rentiopril and the like can be mentioned. Angiotensin-converting enzyme inhibitors are preferably used for diabetic complications or hypertension.

As neutral endopeptidase inhibitors, omapatrilat, MDL-100240, fasidotril, lapachalat, GW-660511X, mixanpril, SA-7060, E-4030, SLV-306, ecadotril and the like can be mentioned. Neutral endopeptidase inhibitors are preferably used for diabetic complications or hypertension.

As angiotensin II receptor antagonists, there can be mentioned candesartan cilexetil, candesartan cilexetil/hydroxychlorothiazine, losartan potassium, eprosartan maleate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmisartan, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 and the like. Angiotensin II receptor antagonists are preferably used for diabetic complications or hypertension.

As endothelin-converting enzyme inhibitors, there may be mentioned CGS-31447, CGS-35066, SM-19712 and the like; as endothelin receptor antagonists, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sitaxsentan sodium, BMS-193884, daruentan, TBC-3711, bosentan sodium, tezosentan, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, elasentan, BMS-207940 and the like can be mentioned.

These drugs are preferably used for diabetic complications or hypertension, and more preferably for hypertension.

As the diuretic, chlorthalidone, mezazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentofluthiazide, methyclothiazide, indapamide, tripamide, mefruside, azimide, ethacrynic acid, torasemide, piretanide, furosemide, bumetanide, metipram, potassium canrenoate, spironolactone, triamterene, aminophylline, cilostanin hydrochloride, LLU-alpha, PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan, conivaptan hydrochloride and the like can be mentioned. Diuretic is preferably used for diabetic complications, hypertension, congestive heart failure or edema, and more preferably for hypertension, congestive heart failure or edema, because blood pressure is reduced or edema is improved by increasing urinary excretion.

As the calcium antagonist, there may be mentioned aranidipine, efonidipine hydrochloride, nicardipine hydrochloride, barnidipine hydrochloride, binidipine hydrochloride, menidipine hydrochloride, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine besylate, pradipine, lercanidipine hydrochloride, isradipine, elidipine, azelnidipine, lacidipine, vatanidipine chloride, ledipine, diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridil hydrochloride, galopamid hydrochloride and the like; as vasodilating antihypertensive agents, indapamide, todralazine hydrochloride, hydralazine hydrochloride, cadralazine, budralazine and the like can be mentioned; as the sympathetic blocking agent, sulfamethoxazole hydrochloride, terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, doxazosin maleate, propranolol hydrochloride, atenolol, metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride, nebivolol hydrochloride, betaxolol hydrochloride, pindolol hydrochloride, terbalol hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride, bisoprolol hemifumarate, bopindoll malonate, nipropolol, penbutolol sulfate, acebutolol hydrochloride, tiliolol hydrochloride, nadolol, urapidil, indoramine, etc. may be mentioned; as antihyperlipidemic agents acting on the central nervous systemAs the compression drug, rifampicin and the like can be mentioned; as α₂Examples of the adrenergic receptor agonist include clonidine hydrochloride, methyldopa, CHF-1035, guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine, and talacrex hydrochloride. These drugs are preferably used for hypertension.

As the antiplatelet agent, ticlopidine hydrochloride, dipyridamole, cilostazol, sarpogrelate hydrochloride, dilazep dihydrochloride, trapidil, beraprost sodium, aspirin, and the like can be mentioned.

Antiplatelet agents are preferably used for arteriosclerosis or congestive heart failure.

As the uric acid synthesis inhibitor, allopurinol, oxypurinol, and the like can be mentioned; as uricosuric agents, benzbromarone, probenecid, and the like can be mentioned; as the urine alkalizer, sodium hydrogencarbonate, potassium citrate and the like can be mentioned. These drugs are preferably used for hyperuricemia or gout.

In the case of combination with a drug other than an SGLT2 inhibitor, for example, for diabetes, it is preferable to combine with at least one member of the following: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl aminopeptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, liver gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amylases, amylase analogs, amylase agonists, and appetite suppressants; more preferably in combination with at least one member of the group consisting of: insulin sensitivity enhancer, glucose absorption inhibitor, biguanide, insulin secretion enhancer, insulin or insulin analog, glucagon receptor antagonist, insulin receptor kinase stimulant, tripeptidyl peptidase II inhibitor, dipeptide machinePeptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, liver gluconeogenesis inhibitors, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amylases, amylase analogs, amylase agonists; most preferably in combination with at least one member of the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs. Also, for diabetic complications, it is preferred to use in combination with at least one member of the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, liver gluconeogenesis inhibitors, D-chiral inositols, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amylases, amylase analogs, amylase agonists, aldose reductase inhibitors, higher glycosylation end product formation inhibitors, insulin secretion enhancers, insulin receptor agonists, tripeptidyl peptidase II inhibitors, insulin receptor kinase inhibitors, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucagon-like peptide-1 analogs, Protein kinase C inhibitors, gamma-aminobutyric acid antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin receptor antagonists, and diuretics; more preferably in combination with at least one member of the group consisting of: aldose reductase inhibitor, angiotensin-converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonistAn anti-agent. Also, for obesity, it is preferred to use in combination with at least one member of the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl aminopeptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, liver gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, amylases, amylase analogs, amylase agonists, beta-agonists, and glucagon₃-adrenergic receptor agonists and appetite suppressants; more preferably in combination with at least one member of the group consisting of: beta is a₃-adrenergic receptor agonists and appetite suppressants.

When the pharmaceutical compositions of the present invention are used for actual treatment, various dosage forms may be used depending on their use. As examples of the dosage form, powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, poultices and the like can be mentioned for oral or parenteral administration.

These pharmaceutical compositions can be prepared by mixing with or diluting or dissolving in suitable pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers, solubilizers and the like, and then formulating the mixture according to their dosage forms according to conventional pharmaceutical methods. In the case of a combination of the compounds of the present invention with a drug other than an SGLT2 inhibitor, they may be prepared by formulating each active ingredient together or separately.

When the pharmaceutical composition of the present invention is used for practical treatment, the dosage of the nitrogen-containing heterocyclic derivative represented by the above-mentioned formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient is suitably determined depending on the age, sex, body weight and degree of symptoms of each patient to be treated, and is generally in the range of 0.1 to 1000 mg per day per adult when orally administered, and generally in the range of 0.01 to 300 mg per day per adult when parenterally administered, and the daily dosage may be divided into once to several times per day and suitably administered. Alternatively, where the compounds of the present invention are used in combination with a drug other than an SGLT2 inhibitor, the dose of the compounds of the present invention may be reduced based on the dose of the drug other than an SGLT2 inhibitor.

Examples

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

Reference example 1

6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one

To a solution of tert-butyllithium (1.5mol/L in hexane, 55mL) in tetrahydrofuran (150mL) was added 2-chloro-6-methoxypyridine (8.9mL) at-78 deg.C, and the mixture was stirred for 1 hour. N, N-dimethylformamide (7.6 mL) was added to the reaction mixture, the resulting mixture was stirred for 1.5 hours, acetic acid (8.6mL) was added to the reaction mixture, the temperature was raised to room temperature, a saturated aqueous sodium bicarbonate solution was added to the resulting reaction mixture, the mixture was extracted with diethyl ether, the organic layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate: 15/1-3/1) to give 6-chloro-3-formyl-2-methoxypyridine (11 g). Tert-butyllithium (1.5mol/L solution in hexane, 5.1mL) was added to a solution of 4-ethylbromobenzene (1.3g) in tetrahydrofuran (14mL) at-78 ℃ under argon atmosphere, and the mixture was stirred for 30 minutes.6-chloro-3-formyl-2-methoxypyridine (1.5 mol/L) 1.0g) was added to the reaction mixture in tetrahydrofuran (19mL) and the mixture was stirred at 0 ℃ for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-7/1) to give 6-chloro-2-methoxy-pyridin-3-yl 4-ethylphenylmethanol (1.4 g). To a solution of the obtained 6-chloro-2-methoxy-pyridin-3-yl 4-ethylphenylmethanol (0.56g) in dichloromethane (10mL) was added Dess-Martin reagent (1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benziodoxaoxolane-3-1H-one) (1.0g), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate (9mL) and 10% aqueous sodium thiosulfate (9mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 7/1) to give 6-chloro-2-methoxy-pyridin-3-yl 4-ethylphenyl ketone (0.44 g). The obtained 6-chloro-2-methoxy-pyridin-3-yl 4-ethylphenyl ketone (0.26g), benzylamine (5mL) and potassium carbonate (0.21g) were stirred at 110 ℃ for 10 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with 1mol/L hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-4/1) to give 6-benzylamino-2-methoxypyridin-3-yl 4-ethylphenyl ketone (0.24 g). To a solution of the obtained 6-benzylamino-2-methoxypyridin-3-yl 4-ethylphenyl ketone (0.24g) in ethanol (6.9mL) was added 10% palladium carbon powder (0.48g), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 2/1) to give 6-amino-3- (4-ethylbenzyl) -2-methoxypyridine (0.13 g). To the obtained 6-amino-3- (4-ethylbenzyl) -2-methoxypyridine (0.050g) was added a solution of 30% hydrobromic acid in acetic acid (1mL), and the mixture was stirred at 95 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 9/1) to give 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one (0.034 g).

¹H-NMR(CDCl₃)δppm：

1.19(3H，t，J＝7.7Hz)，1.95(3H，s)，2.58(2H，q，J＝7.7Hz)，3.69(2H，s)，6.33(1H，d，J＝7.4Hz)，7.00-7.15(5H，m)，10.41(1H，brs)

Example 1

6- (N-acetylamino) -2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-ethylbenzyl) pyridine

To a solution of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one (0.034g) in dichloromethane (2.5mL) were added acetylbromo- α -D-glucose (0.10g) and silver carbonate (0.17g), and the mixture was stirred at 50 ℃ for 3 hours in the dark. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography on preparative silica gel (developing solvent: hexane/ethyl acetate 1/2) to give 6- (N-acetylamino) -2- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy) -3- (4-ethylbenzyl) pyridine (0.081 g).

¹H-NMR(CDCl₃)δppm：

1.20(3H，t，J＝7.6Hz)，1.85(3H，s)，2.03(3H，s)，2.04(3H，s)，2.05(3H，s)，2.21(3H，s)，2.59(2H，q，J＝7.6Hz)，3.76(H，d，J＝15.3Hz)，3.85(H，d，J＝15.3Hz)，3.90-4.05(1H，m)，4.14(1H，dd，J＝2.6，12.3Hz)，4.29(1H，dd，J＝4.5，12.3Hz)，5.15-5.25(1H，m)，5.25-5.40(2H，m)，6.00-6.10(1H，m)，7.00-7.15(4H，m)，7.41(1H，d，J＝7.9Hz)，7.61(1H，brs)，7.75(1H，brd，J＝7.9Hz)

Reference example 2

6-amino-3- (4-ethylbenzyl) -1H-pyridin-2-one

To a solution of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one (0.19g) in methanol (1mL) was added 2mol/L aqueous sodium hydroxide (0.35mL), and the mixture was stirred at 80 ℃ for 22 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol-6/1) to give 6-amino-3- (4-ethylbenzyl) -1H-pyridin-2-one (0.013 g).

¹H-NMR(CDCl₃)δppm：

1.21(3H，t，J＝7.6Hz)，2.60(2H，q，J＝7.6Hz)，3.69(2H，s)，4.73(2H，brs)，5.32(1H，d，J＝7.6Hz)，7.02(1H，d，J＝7.6Hz)，7.05-7.15(4H，m)

Example 2

6-amino-2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-ethylbenzyl) pyridine

The title compound was obtained in the same manner as in example 1 using 6-amino-3- (4-ethylbenzyl) -1H-pyridin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.20(3H，t，J＝7.6Hz)，1.83(3H，s)，2.02(3H，s)，2.05(3H，s)，2.07(3H，s)，2.59(2H，q，J＝7.6Hz)3.67(1H，d，J＝15.4Hz)，3.79(1H，d，J＝15.4Hz)，3.85-4.00(1H，m)，4.05-4.35(2H，m)，5.15-5.40(3H，m)，6.00-6.15(2H，m)，7.00-7.20(5H，m)

Reference example 3

3- (4-ethylbenzyl) -4, 6-dimethyl-1H-pyridin-2-one

To a solution of 3-cyano-4, 6-dimethyl-1H-pyridin-2-one (4.6g) in dichloromethane (150mL) was added benzyl bromide (5.6mL) and silver carbonate (26g), and the mixture was stirred at 50 ℃ for 3 hours. The reaction mixture was cooled to room temperature, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-7/1) to give 2-benzyloxy-3-cyano-4, 6-dimethylpyridine (7.1 g). A solution of 2-benzyloxy-3-cyano-4, 6-dimethylpyridine (2.4g) in tetrahydrofuran (4.3mL) was added to diisobutylaluminum hydride (1.5mole/L in toluene, 8.7mL) at 0 deg.C, and the mixture was stirred at 0 deg.C for 4 hours. The reaction mixture was poured into 1mil/L hydrochloric acid (40mL) and filtered through ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4, 6-dimethylpyridine (0.90 g). Tert-butyllithium (1.5mol/L solution in hexane, 0.17mL) was added to a solution of 4-ethylbromobenzene (0.044g) in tetrahydrofuran (1.2mL) at-78 ℃ under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4, 6-dimethylpyridine (0.048g) in tetrahydrofuran (1.3mL) was added to the reaction mixture, and the mixture was stirred at 0 ℃ for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 5/1) to give 3- (4-ethylbenzyl) -4, 6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of 3- (4-ethylbenzyl) -4, 6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061g) in ethanol (3.5mL) was added 10% palladium on carbon powder (0.037g), and the mixture was allowed to script under hydrogen atmosphere at room temperature for 12 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 10/1) to give 3- (4-ethylbenzyl) -4, 6-dimethyl-1H-pyridin-2-one (0.039g)

¹H-NMR(CDCl₃)δppm：

1.19(3H，t，J＝7.6Hz)，2.14(3H，s)，2.20(3H，s)，2.59(2H，q，J＝7.6Hz)，3.90(2H，s)，5.85(1H，s)，7.00-7.10(2H，m)，7.15-7.25(2H，m)，12.71(1H，brs)

Example 3

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-ethylbenzyl) -4, 6-dimethylpyridine

The title compound was obtained in the same manner as in example 1 using 3- (4-ethylbenzyl) -4, 6-dimethyl-1H-pyridin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.17(3H，t，J＝7.6Hz)，1.70(3H，s)，2.00(3H，s)，2.04(3H，s)，2.05(3H，s)，2.18(3H，s)，2.37(3H，s)，2.56(2H，q，J＝7.6Hz)，3.81(1H，d，J＝15.3Hz)，3.90-4.05(2H，m)，4.14(1H，dd，J＝2.5，12.2Hz)，4.26(1H，dd，J＝4.8，12.2Hz)，5.10-5.40(3H，m)，6.18(1H，d，J＝8.2Hz)，6.68(1H，s)，6.90-7.10(4H，m)

Reference example 4

3- (4-methoxybenzyl) -4, 6-dimethyl-1H-pyridin-2-one

Grignard reagent (0.5mol/L solution in tetrahydrofuran) was prepared in the usual way from 4-bromoanisole, magnesium and catalytic amounts of iodine and tetrahydrofuran. The resulting Grignard solution (0.41mL) was added to a solution of 2-benzyloxy-3-formyl-4, 6-dimethylpyridine (0.019g) in tetrahydrofuran (0.8mL), and the mixture was stirred at room temperature for 80 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture and extracted with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 4/1) to give 2-methoxybenzyl-4, 6-dimethylpyridin-3-yl-4-methoxyphenylmethanol (0.014 g). To a solution of the obtained 2-methoxybenzyl-4, 6-dimethylpyridin-3-yl-4-methoxyphenylmethanol (0.014g) in ethanol (1mL) was added a catalytic amount of 10% palladium carbon powder, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 10/1) to give 3- (4-methoxybenzyl) -4, 6-dimethyl 1H-pyridin-2-one (0.010 g).

¹H-NMR(CDCl₃)δppm：

2.14(3H，s)，2.21(3H，s)，3.75(3H，s)，3.87(2H，s)，5.85(1H，s)，6.70-6.80(2H，m)，7.10-7.25(2H，m)，12.70(1H，brs)

Example 4

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) -4, 6-dimethylpyridine

The title compound was obtained in the same manner as in example 1 using 3- (4-methoxybenzyl) -4, 6-dimethyl-1H-pyridin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.75(3H，s)，2.00(3H，s)，2.04(3H，s)，2.05(3H，s)，2.17(3H，s)，2.37(3H，s)，3.74(3H，s)，3.79(1H，d，J＝15.3Hz)，3.90-4.00(2H，m)，4.14(1H，dd，J＝2.3，12.3Hz)，4.25(1H，dd，J＝4.8，12.3Hz)，5.10-5.40(3H，m)，6.19(1H，d，J＝8.0Hz)，6.67(1H，s)，6.70-6.80(2H，m)，6.90-7.00(2H，m)

Reference example 5

3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethyl-1H-pyridin-2-one

Tert-butyllithium (1.5mol/L in hexane, 2.0mL) was added to a solution of 4- (2-methoxymethoxyethyl) bromobenzene (0.60g) in tetrahydrofuran (6mL) at-78 ℃ under an argon atmosphere, and the mixture was stirred for 30 minutes. Then, a solution of 2-benzyloxy-3-formyl-4, 6-dimethylpyridine (0.49g) in tetrahydrofuran was added to the reaction mixture, and stirred at 0 ℃ for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with dimethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate ═ 5/1) to give 2-benzyloxy-4, 6-dimethylpyridin-3-yl 4- (2-methoxymethoxyethyl) phenylmethanol (0.74 g). 10% Palladium carbon powder (0.065g) was added to the resulting solution of 2-benzyloxy-4, 6-dimethylpyridin-3-yl 4- (2-methoxymethoxyethyl) phenylmethanol (0.11g) in ethanol (5.3mL), and the mixture was stirred at room temperature for 11 hours under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 10/1) to give 3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethyl-1H-pyridin-2-one (0.074 g).

¹H-NMR(CDCl₃)δppm：

2.13(3H，s)，2.21(3H，s)，2.84(2H，t，J＝7.2Hz)，3.29(3H，s)，3.72(2H，t，J＝7.2Hz)，3.91(2H，s)，4.60(2H，s)，5.85(1H，s)，7.05-7.15(2H，m)，7.15-7.25(2H，m)，12.53(1H，brs)

Example 5

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethylpyridine

The title compound was obtained in the same manner as in example 1 using 3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethyl-1H-pyridin-2-one in place of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.72(3H，s)，2.00(3H，s)，2.04(3H，s)，2.05(3H，s)，2.15(3H，s)，2.37(3H，s)，2.83(2H，t，J＝7.0Hz)，3.28(3H，s)，3.70(2H，t，J＝7.0Hz)，3.81(1H，d，J＝15.6Hz)，3.90-4.15(2H，m)，4.14(1H，dd，J＝2.3，12.3Hz)，4.26(1H，dd，J＝4.7，12.3Hz)，4.59(2H，s)，5.10-5.40(3H，m)，6.181H，d，J＝8.0Hz)，6.67(1H，s)，6.90-7.10(4H，m)

Example 6

2- (beta-D-glucopyranosyloxy) -3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethylpyridine

2mol/L aqueous sodium hydroxide (0.50mL) was added to a solution of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (2-methoxymethoxyethyl) benzyl ] -4, 6-lutidine (0.13g) in methanol (4.0mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 9/1) to give 2- (. beta. -D-glucopyranosyloxy) -3- [4- (2-methoxymethyloxyethyl) benzyl ] -4, 6-dimethylpyridine (0.086 g).

¹H-NMR(CD₃OD)δppm：

2.17(3H，s)，2.36(3H，s)，2.80(2H，t，J＝7.0Hz)，3.23(3H，s)，3.30-3.55(4H，m)，3.60-3.75(3H，m)，3.84(1H，dd，J＝2.3，12.0Hz)，3.95(1H，d，J＝15.2Hz)，4.06(1H，d，J＝15.2Hz)，4.56(2H，s)，5.85-5.95(1H，m)，6.73(1H，s)，7.05-7.15(4H，m)

Reference example 6

6-methoxy-3- (4-methoxybenzyl) -4-methyl-1H-pyridin-2-one

Diisobutylaluminum hydride (1.5mol/L in toluene, 0.53mL) was added to a solution of 3-cyano-2, 6 dimethoxy-4-methylpyridine (0.11g) in tetrahydrofuran (3mL) at 0 ℃. The temperature was allowed to rise to room temperature and the reaction solution was stirred for 5 days. 1mol/L hydrochloric acid was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate-9/1) to give 3-formyl-2, 6-dimethoxy-4-methylpyridine (0.034 g). Grignard reagent (0.5mol/L solution in tetrahydrofuran 0.72mL) prepared in the usual manner from 4-bromoanisole, magnesium, catalytic amount of iodine and tetrahydrofuran was added to the resulting solution of 3-formyl-2, 6-dimethoxy-4-methylpyridine (0.033g) in tetrahydrofuran (1.2mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 5/1) to give 2, 6-dimethoxy-4-methyl-pyridin-3-yl 4-methoxyphenylmethanol (0.053 g). Dess-Martin reagent (1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benziodoxaoxolane-3-1H-one) (0.093g) was added to the resulting solution of 2, 6-dimethoxy-4-methyl-pyridin-3-yl 4-methoxyphenylmethanol (0.053g) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 45 minutes. Saturated aqueous sodium bicarbonate (1mL) and 10% sodium thiosulfate (1mL) were added to the reaction mixture and extracted with ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 6/1) to give 2, 6-dimethoxy-4-methylpyridin-3-ylmethoxyphenyl ketone (0.043 g). Boron trichloride (1mol/L solution in methylene chloride, 0.44mL) was added to the resulting solution of 2, 6-dimethoxy-4-methylpyridin-3-ylmethoxyphenyl ketone (0.042g) in methylene chloride (1.5mL) at 0 ℃. The temperature was raised to room temperature and the reaction mixture was stirred for 30 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 1/2) to give 2-hydroxy-6-methoxy-4-methylpyridin-3-yl 4-methoxyphenylketone (0.023 g). Sodium cyanoborohydride (0.011g) was added to the resulting solution of 2-hydroxy-6-methoxy-4-methylpyridin-3-yl 4-methoxyphenylketone (0.022g) and boron trifluoride diethyl etherate (0.041mL) in tetrahydrofuran (1.6mL), and the reaction mixture was stirred at 65 ℃ for 2 hours. The reaction mixture was cooled to room temperature and extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 1/2) to give 6-methoxy-3- (4-methoxybenzyl) -4-methyl-1H-pyridin-2-one (0.008 g).

¹H-NMR(CDCl₃)δppm：

2.15(3H，s)，3.76(3H，s)，3.80(3H，s)，3.87(2H，s)，5.52(1H，s)，6.70-6.80(2H，m)，7.10-7.20(2H，m)，10.50-11.50(1H，br)

Example 7

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -6-methoxy-3- (4-methoxybenzyl) -4-methylpyridine

The title compound was obtained in the same manner as in example 1 using 6-methoxy-3- (4-methoxybenzyl) -4 methyl-1H-pyridin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.75(3H，s)，2.01(3H，s)，2.04(3H，s)，2.04(3H，s)，2.17(3H，s)，3.70-3.80(4H，m)，3.80-3.95(5H，m)，4.12(1H，dd，J＝2.1，12.3Hz)，4.25(1H，dd，J＝5.1，12.3Hz)，5.10-5.20(1H，m)，5.25-5.40(2H，m)，6.05(1H，d，J＝7.8Hz)，6.29(1H，s)，6.70-6.80(2H，m)，6.90-7.00(2H，m)

Reference example 7

4- (4-ethoxybenzyl) -3-hydroxypyridine

Sodium hydride (60%, 0.44g) and [2- (chloromethoxy) ethyl ] trimethylsilyl (2.1mL) were added to a solution of 3-hydroxypyridine (0.95g) in 1, 2-dimethoxyethane (20mL), and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate ═ 2/1) to give 3- { [2- (trimethylsilyl) ethyl ] oxymethoxy } pyridine (0.89 g). Tert-butyllithium (1.51mol L in pentane, 0.86mL) was added to the resulting solution of 3- { [2- (trimethylsilyl) ethyl ] oxymethoxy } pyridine (0.23g) in tetrahydrofuran (6mL) at-78 deg.C, and the mixture was stirred for 40 minutes. A solution of 4-ethoxybenzaldehyde (0.18g) in diethyl ether (6mL) was added to the reaction mixture, and the mixture was stirred at-78 ℃ for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate ═ 1/1) to give 4-ethoxyphenyl-3- { [2- (trimethylsilyl) and ] oxymethoxy } pyridin-4-ylcarbinol (0.28 g). To a solution of the obtained 4-ethoxyphenyl-3- { [2- (trimethylsilyl) and ] oxymethoxy } pyridin-4-ylmethanol (0.27g) in tetrahydrofuran (7mL) and water (0.3mL) was added p-toluenesulfonic acid monohydrate (0.68g), and the mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was cooled to room temperature and saturated sodium bicarbonate (12mL) was added. Insoluble matter was removed by filtration, and the mixture was extracted with a mixed solvent of methylene chloride and methanol (10: 1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol ═ 10/1) to give 4-ethoxyphenyl-3-hydroxypicolinomethanol (0.16 g). To a solution of the obtained 4-ethoxyphenyl-3-hydroxypicolinemethanol (0.13g) in acetic acid (5.3mL) was added 10% palladium carbon powder (0.13g), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration. The resulting crystals were dried under reduced pressure to give 4- (4-ethoxybenzyl) -3-hydroxypyridine (0.095 g).

¹H-NMR(CD₃OD)δppm：

1.36(3H，t，J＝7.0Hz)，3.89(2H，s)，3.99(2H，q，J＝7.0Hz)，6.75-6.90(2H，m)，7.00(1H，d，J＝4.9Hz)，7.05-7.20(2H，m)，7.87(1H，d，J＝4.9Hz)，7.99(1H，s)

Example 8

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -4- (4-ethoxybenzyl) -pyridine

The title compound was obtained in the same manner as in example 1 using 4- (4-ethoxybenzyl) -3-hydroxypyridine instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.40(3H，t，J＝7.0Hz)，1.96(3H，s)，2.04(3H，s)，2.06(3H，s)，2.09(3H，s)，3.80-3.95(3H，m)，4.00(2H，q，J＝7.0Hz)，4.17(1H，dd，J＝2.3，12.4Hz)，4.30(1H，dd，J＝5.7，12.4Hz)，5.10-5.25(2H，m)，5.25-5.40(2H，m)，6.75-6.85(2H，m)，6.95(1H，d，J＝4.7Hz)，7.00-7.10(2H，m)，8.22(1H，d，J＝4.7Hz)，8.36(1H，s)

Reference example 8

3- (4-MethoxyEditing) -1H-pyridin-2-one

Tert-butyllithium (1.48mol/L solution in pentane, 5.3mL) was added to a solution of mesitylene bromide (0.77g) in tetrahydrofuran at-78 ℃ under argon and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of 2-methoxypyridine (0.33g) in tetrahydrofuran (3mL) and the mixture was stirred for 1 hour with the temperature raised to 0 ℃. The temperature was raised to room temperature and stirred for another 1 hour. To the reaction mixture was added a solution of 4-methoxybenzaldehyde (0.57g) in tetrahydrofuran (4.2mL), and the mixture was stirred for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-3/1-2/1) to give 4-methoxyphenyl-2-methoxypyridin-3-ylcarbinol (0.43 g). To a solution of the obtained 4-methoxyphenyl-2-methoxypyridin-3-ylmethanol (0.41g) in acetic acid (2.1mL) was added 10% palladium carbon powder (0.21g), and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. Insoluble materials are filtered out, and the filtrate is concentrated by the domestic duck. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 5/1-4/1) to give 2-methoxy-3- (4-methoxybenzyl) -pyridine (0.29 g). To the resulting solution of 2-methoxy-3- (4-methoxybenzyl) -pyridine (0.023g) in dichloromethane (0.5mL) was added boron trichloride (1mol/L solution in dichloromethane, 0.06mL) at 0 ℃.

The temperature was raised to room temperature and the mixture was stirred for 1 hour. Boron trichloride (1mol/L solution in methylene chloride, 0.06mL) was added to the reaction mixture and stirred for an additional 15 hours. Water was added to the mixture, and the mixture was extracted with a mixture of methylene chloride and ethanol (10/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by functional thin layer chromatography) developing solvent: dichloromethane/methanol-8/1) to give 3- (4-methoxy-edited) -1H-pyridin-2-one (0.0017 g).

¹H-NMR(CDCl₃)δppm：

3.80(3H，s)，3.83(2H，s)，6.10-6.25(1H，m)，6.89-6.95(2H，m)，7.00-7.35(4H，m)，12.30(1H，brs)

Example 9

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) -pyridine

The title compound was obtained in the same manner as in example 1 using 3- (4-methoxybenzyl) -1H-pyridin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.88(3H，s)，2.03(3H，s)，2.05(3H，s)，2.06(3H，s)，3.78(3H，s)，3.75-3.90(2H，m)，3.90-4.00(1H，m)，4.12(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.5，12.4Hz)，5.15-5.45(3H，m)，6.15-6.25(1H，m)，6.75-6.85(2H，m)，6.91(1H，dd，J＝4.9，7.3Hz)，7.00-7.15(2H，m)，7.34(1H，dd，J＝1.9，7.3Hz)，8.00(1H，dd，J＝1.9，4.9Hz)

Reference example 9

5- (4-methoxybenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one

A suspension of methyl acetoacetate (3.2mL), 4-methoxybenzyl chloride (4.1mL), lithium bromide (2.6g) and diisopropylethylamine (5.2mL) in tetrahydrofuran (60mL) was heated at reflux for 15 h. The reaction mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution was added thereto, followed by extraction with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 2- (4-methoxybenzyl) acetoacetate. To a suspension of acetamidine hydrochloride (2.0g) in methanol (60mL) was added sodium methoxide (28% methanol solution, 2.6mL), and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added a solution of methyl 2- (4-methoxybenzyl) acetoacetate in methanol (6mL), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and dried to give 5- (4-methoxybenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one (0.54 g).

¹H-NMR(DMSO-d₆)δppm：

2.14(3H，s)，2.21(3H，s)，3.67(2H，s)，3.69(3H，s)，6.75-6.85(2H，m)，7.05-7.15(2H，m)，12.29(1H，brs)

Example 10

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -5- (4-methoxybenzyl) -2, 6-dimethylpyrimidine

To a solution of 5- (4-methoxybenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one (0.30g) in acetonitrile (6mL) were added acetylbromo-alpha-D-glucose (0.76g) and potassium carbonate (0.27g), and the mixture was stirred at 60 ℃ for 17 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: hexane/ethyl acetate ═ 1/1) and by silica gel column chromatography (eluent: hexane/ethyl acetate ═ 1/1-1/2) to give 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5- (4-methoxybenzyl) -2, 6-dimethylpyrimidine (0.24 g).

¹H-NMR(CDCl₃)δppm：

1.78(3H，s)，2.01(3H，s)，2.05(3H，s)，2.06(3H，s)，2.41(3H，s)，2.56(3H，s)，3.76(3H，s)，3.79(1H，d，J＝15.6Hz)，3.85-4.00(2H，m)，4.15(1H，dd，J＝2.2，12.4Hz)，4.26(1H，dd，J＝4.8，12.4Hz)，5.10-5.40(3H，m)，6.20(1H，d，J＝8.1Hz)，6.70-6.80(2H，m)，6.95-7.05(2H，m)

Reference example 10

4- [4- (2-benzoyloxyethyl) benzyl ] -3-hydroxypyridine

Magnesium dioxide (12g) was added to a solution of 4- (2-benzoyloxyethyl) benzyl alcohol (1.2g) in dichloromethane (50mL), and the mixture was stirred at room temperature for 23 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to give 4- (2-benzoyloxyethyl) benzaldehyde (0.87 g). Tert-butyllithium (1.52mol/L in pentane, 1.2mL) was added at-78 ℃ to a solution of 3- (methoxymethoxy) pyridine (0.20g) in diethyl ether (20 mL). The mixture was stirred for 30 minutes. To the reaction mixture was added a solution of 4- (2-benzoyloxyethyl) benzaldehyde (0.44g) in diethyl ether (4 mL). The temperature was raised to room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane and ethyl acetate were added to the residue, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 4- (2-benzoyloxyethyl) phenyl-3- (methoxymethoxy) pyridin-4-yl-methanol (0.30 g). To a solution of the obtained 4- (2-benzoyloxyethyl) phenyl-3- (methoxymethoxy) pyridin-4-yl-methanol (0.28g) in ethanol (4.8mL) was added a mixture of concentrated hydrochloric acid (0.6mL) and the mixture was heated under reflux for 10 minutes. Concentrated under reduced pressure, and ethyl acetate was added to the residue. The precipitated crystals were collected by filtration and dried to give 4- (2-benzoyloxyethyl) -phenyl-3-hydroxypyridin-4-ylcarbinol hydrochloride (0.28 g). To a solution of the obtained 4- (2-benzoyloxyethyl) -phenyl-3-hydroxypyridin-4-ylcarbinol hydrochloride (0.27g) in ethanol (6.9mL) was added 10% palladium carbon powder (0.27g), and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, and the precipitated crystals were collected by filtration. To the crystals obtained, a saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ether, the organic layer was washed with brine, dried over anhydrous sodium sulfate to a young state, and concentrated under reduced pressure. To the residue was added diethyl ether, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 4- [4- (2-benzoyloxyethyl) benzyl ] -3-hydroxypyridine (0.12 g).

¹H-NMR(CDCl₃)δppm：

3.06(2H，t，J＝7.0Hz)，4.01(2H，s)，4.52(2H，t，J＝7.0Hz)，7.00(1H，d，J＝4.8Hz)，7.15-7.30(4H，m)，7.35-7.45(2H，m)，7.50-7.60(1H，m)，7.95-8.05(3H，m)，8.27(1H，s)

Example 11

2- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -4- [4- (2-benzoyloxyethyl) -benzyl ] pyridine

The title compound was obtained in the same manner as in example 1 using 4- [4- (2-benzoyloxyethyl) -benzyl ] -3-hydroxypyridine instead of 6- (N-acetylamino) -3- (4-ethylbenzyl) -1H-pyridin-2-one.

¹H-NMR(CDCl₃)δppm：

1.93(3H，s)，2.03(3H，s)，2.06(3H，s)，2.09(3H，s)，3.05(2H，t，J＝6.9Hz)，3.85-3.95(3H，m)，4.17(1H，dd，J＝2.2，12.2Hz)，4.30(1H，dd，J＝5.7，12.2Hz)，4.51(2H，t，J＝6.9Hz)，5.10-5.25(2H，m)，5.25-5.40(2H，m)，6.95(1H，d，J＝4.6Hz)，7.05-7.15(2H，m)，7.15-7.25(2H，m)，7.35-7.50(2H，m)，7.50-7.60(1H，m)，7.9 5-8.05(2H，m)，8.22(1H，d，J＝4.6Hz)，8.37(1H，s)

Reference example 11

5- (4-ethylsulfanylbenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one

Triethylamine (3.0mL) and methanesulfonyl chloride (1.7mL) were added to a solution of 4-ethylsulfanylbenzyl alcohol (3.7g) in tetrahydrofuran (80mL) at 0 ℃ and the mixture was stirred for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was added to a suspension of sodium hydride (60%, 0.88g) and methyl acetoacetate (2.4mL) in 1, 2-dimethoxyethane (1900mL), and the mixture was heated under reflux for 4 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 2- (4-ethylsulfanylbenzyl) acetoacetate (6.1 g). To a suspension of acetamidine hydrochloride (0.80g) in methanol (15mL) was added sodium methoxide (28% methanol solution, 1.7mL), and the mixture was stirred at room temperature for 5 minutes. A solution of methyl 2- (4-ethylsulfanylbenzyl) acetoacetate (1.5g) in methanol (5mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration and dried to give 5- (4-ethylsulfanylbenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one (0.33g).

¹H-NMR(DMSO-d₆)δppm：

1.19(3H，t，J＝7.3Hz)，2.15(3H，s)，2.22(3H，s)，2.91(2H，q，J＝7.3Hz)，3.71(2H，s)，7.05-7.30(4H，m)，12.30(1H，brs)

Example 12

4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -5- (4-ethylsulfanylbenzyl) -2, 6-dimethylpyrimidine

The title compound was prepared in the same manner as in example 10 using 5- (4-ethylsulfanylbenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one instead of 5- (4-methoxybenzyl) -2, 6-dimethyl-3H-pyrimidin-4-one.

¹H-NMR(CDCl₃)δppm：

1.20-1.35(3H，m)，1.77(3H，s)，2.01(3H，s)，2.06(3H，s)，2.06(3H，s)，2.40(3H，s)，2.57(3H，s)，2.80-2.95(2H，m)，3.75-4.00(3H，m)，4.00-4.30(2H，m)，5.10-5.40(3H，m)，6.15-6.25(1H，m)，6.95-7.05(2H，m)，7.15-7.25(2H，m)

Reference example 12

3- (4-butylbenzyl) -2, 6-dimethyl-1H-pyridin-4-one

To a solution of 3-ethoxycarbonyl-2, 6-dimethyl-1H-pyridin-4-one (9.7g) in dichloromethane (200mL) were added benzyl bromide (8.9mL) and silver carbonate (41g), and the mixture was stirred at 50 ℃ for 2 hours in the dark. The reaction mixture was cooled to room temperature, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate-1/1) to give 4-benzyloxy-3-ethoxycarbonyl-2, 6-dimethylpyridine (8.6 g). To a solution of the obtained 4-benzyloxy-3-ethoxycarbonyl-2, 6-dimethylpyridine (8.6g) in tetrahydrofuran (60mL) was added diisobutylaluminum hydride (1.5mol/L in toluene, 50mL) at 0 ℃. The temperature was raised to room temperature and the mixture was stirred for a further 40 minutes. The mixture was poured into 2mol/L hydrochloric acid (68mL), 2mol/L aqueous sodium hydroxide solution (130mL) was added to the mixture, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-benzyloxy-3-hydroxymethyl-2, 6-lutidine (7.2 g). To a solution of the obtained 4-benzyloxy-3-hydroxymethyl-2, 6-dimethylpyridine (7.2g) in methylene chloride (120mL) was added Dess-Martin reagent (15g), and the mixture was stirred at room temperature for 6.5 hours. To the mixture were added saturated aqueous sodium bicarbonate (150mL) and 10% sodium thiosulfate (150mL), extracted with ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 1/2) to give 4-benzyloxy-3-formyl-2, 6-dimethylpyridine (5.3 g). To a solution of 4-butyl-bromobenzene (0.052g) in tetrahydrofuran (1.2mL) at-78 deg.C under argon was added tert-butyllithium (1.5mol/L solution in hexane, 0.20 mL). The mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of 4-benzyloxy-3-formyl-2, 6-dimethylpyridine (0.048g) in tetrahydrofuran (1.3mL), and the mixture was stirred at 0 ℃ for 50 minutes. To the mixture was added saturated aqueous ammonium chloride solution, extracted with diethyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was 4-benzyloxy-2, 6-dimethylpyridin-3-yl 4-butylphenyl methanol (0.043 g). To a solution of the obtained 4-benzyloxy-2, 6-dimethylpyridin-3-yl 4-butylphenyl methanol (0.043g) in ethanol (2.3mL) was added 10% palladium carbon powder (0.085g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 8/1) to give 3- (4-butylbenzyl) -2, 6-dimethyl-1H-pyridin-4-one (0.027 g).

¹H-NMR(CDCl₃)δppm：

0.89(3H，t，J＝7.3Hz)，1.20-1.35(2H，m)，1.45-1.60(2H，m)，2.13(3H，s)，2.17(3H，s)，2.49(2H，t，J＝7.7Hz)，3.83(2H，s)，6.08(1H，s)，6.90-7.05(4H，m)，12.54(1H，brs)

Example 13

4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-butylbenzyl) -2, 6-dimethylpyridine

The title compound was prepared in the same manner as in example 1 using 3- (4-butylbenzyl) -2, 6-dimethyl-1H-pyridin-4-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl-1H-pyridin-4-one.

¹H-NMR (CDCl₃)δppm：

0.89(3H，t，J＝7.3Hz)，1.20-1.40(2H，m)，1.45-1.60(2H，m)，1.58(3H，s)，2.00(3H，s)，2.06(3H，s)，2.10(3H，s)，2.38(3H，s)，2.45-2.60(5H，m)，3.75(1H，d，J＝15.7Hz)，3.90-4.00(1H，m)，4.06(1H，d，J＝15.7Hz)，4.15-4.35(2H，m)，5.05-5.35(4H，m)，6.68(1H，s)，6.85-6.95(2H，m)，6.95-7.10(2H，m)

Reference example 13

3- (4-methoxybenzyl) -1H-pyridin-4-one

2, 2, 6, 6-tetramethylpyridine (0.57mL) was added to a solution of n-butyllithium (1.57mol/L in tetrahydrofuran, 2.0mL) in tetrahydrofuran at-78 ℃. The temperature rose to 0 ℃. The mixture was stirred for 30 minutes. The reaction mixture was cooled to-78 ℃, 2-chloropiperazine (0.22mL) was added, and stirred at the same temperature for 1 hour. 4-methoxybenzaldehyde (0.35mL) was added to the reaction mixture, and the mixture was stirred for an additional 1.5 hours. Concentrated hydrochloric acid (1.2mL) and tetrahydrofuran (4.8mL) were added to the reaction mixture and the temperature was raised to room temperature. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate ═ 3/2) to give 2-chloropiperazin-3-yl 4-methoxyphenylmethanol (0.31 g). To a suspension of the resulting 2-chloropyrazin-3-yl 4-methoxyphenylmethanol (0.13g), sodium hydroxide (0.12g) and potassium carbonate (0.072g) in toluene (1mL) were added benzyl alcohol (0.080mL) and tris [2- (2-methoxyethoxy) ethyl ] amine (0.017mL), and the mixture was stirred at 120 ℃ for 2 hours. Water was added to the reaction mixture, which was extracted with diethyl ether, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 1/1) to give 2-benzyloxy-3- (4-methoxybenzyl) piperazine (0.025 g). To a solution of the obtained 2-benzyloxy-3- (4-methoxybenzyl) piperazine (0.025g) in ethanol (1mL) was added 10% palladium carbon powder (0.0099g), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate ═ 1/3) to give 3- (4-methoxybenzyl) -1H-pyridin-4-one (0.0055 g).

¹H-NNR(CDCl₃)δppm：

3.77(3H，s)，4.07(2H，s)，6.80-6.90(2H，m)，7.09(1H，d，J＝4.1Hz)，7.20-7.35(2H，m)，7.39(1H，d，J＝4.1Hz)，12.75(1H，brs)

Example 14

4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) piperazine

The title compound was prepared in the same manner as in example 1 using 3- (4-methoxybenzyl) -1H-piperazin-2-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl-1H-pyridin-4-one.

¹H-NMR(CDCl₃)δppm：

1.89(3H，s)，2.04(3H，s)，2.05(6H，s)，3.76(3H，s)，3.85-4.00(1H，m)，4.02(1H，d，J＝14.1Hz)，4.05-4.15(2H，m)，4.28(1H，dd，J＝4.5，12.5Hz)，5.15-5.45(3H，m)，6.10(1H，d，J＝8.2Hz)，6.75-6.85(2H，m)，7.15-7.25(2H，m)，7.95(1H，d，J＝2.7Hz)，8.20(1H，d，J＝2.7Hz)

Reference example 14

4-benzyl-2H-pyridazin-3-ones

Borane tetrahydrofuran complex (0.93mol/L solution in tetrahydrofuran, 3.8mL) was added to a solution of 1-methyl 2-succinate (0.78g) in tetrahydrofuran (12mL) at 0 ℃. The temperature was raised to room temperature and the mixture was stirred for 15 hours. Water and sodium carbonate were added to the mixture, and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20mL), Dess-Martin reagent (1.2g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (5mL), hydrazine monohydrate (0.14mL) was added, and the mixture was heated under reflux for 30 min. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate 2/1-1/1) to give 4-benzyl-3, 4-dihydro-2H-pyridazin-3-one (0.31 g). To a solution of the obtained 4-benzyl-3, 4-dihydro-2H-pyridazin-3-one (0.16g) in ethanol (5mL) was added selenium dioxide (0.48g), and the mixture was heated under reflux for 41 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and dried to give 4-benzyl-2H-pyridazin-3-one (0.083 g).

¹H-NMR(DMSO-d₆)δppm：

3.77(2H，s)，7.05(1H，d，J＝4.0Hz)，7.15-7.40(5H，m)，7.77(1H，d，J＝4.0Hz)，13.0(1H，brs)

Example 15

4- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -4-benzyl-pyridazine

The title compound was prepared in the same manner as in example 1 using 4-benzyl-2H-pyridazin-3-one instead of 6- (N-acetylamino) -3- (4-ethylbenzyl-1H-pyridin-4-one.

¹H-NMR(CDCl₃)δppm：

1.92(3H，s)，2.04(3H，s)，2.06(3H，s)，2.06(3H，s)，3.85-3.95(2H，m)，3.95-4.05(1H，m)，4.05-4.20(1H，m)，4.34(1H，dd，J＝4.4，12.6Hz)，5.15-5.45(3H，m)，6.44(1H，d，J＝8.1Hz)，7.05-7.10(1H，m)，7.10-7.20(2H，m)，7.20-7.35(3H，m)，8.77(1H，d，J＝4.7Hz)

Example 16

6- (N-acetylamino) -3- (4-ethylbenzyl) -2- (. beta. -D-glucopyranosyloxy) -4-pyridines

The title compound was prepared in the same manner as in example 6 using 6-amino-2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) 3- (4-ethylbenzyl) pyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

1.20(3H，t，J＝7.6Hz)，2.13(3H，s)，2.59(2H，q，J＝7.6Hz)，3.30-3.60(4H，m)，3.66(1H，dd，J＝5.6，11.8Hz)，3.75-4.00(3H，m)，5.89(1H，d，J＝7.8Hz)，7.00-7.20(4H，m)，7.35(1H，d，J＝8.2Hz)，7.62(1H，brd，J＝8.2Hz)

Example 17

6-amino-3- (4-ethylbenzyl) -2- (beta-D-glucopyranosyloxy) -4-pyridine

The title compound was prepared in the same manner as in example 6 using 6-amino-2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) 3- (4-ethylbenzyl) pyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

1.19(3H，t，J＝7.6Hz)，2.58(2H，q，J＝7.6Hz)，3.30-3.55(4H，m)，3.60-3.95(4H，m)，5.75-5.85(1H，m)，6.12(1H，d，J＝8.0Hz)，7.00-7.20(5H，m)

Example 18

3- (4-ethylbenzyl) -2- (beta-D-glucopyranosyloxy) -4, 6-dimethylpyridine

The title compound was prepared in the same manner as in example 6 using 6-amino-2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) 3- (4-ethylbenzyl) -4, 6-dimethylpyridine instead of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

1.17(3H，t，J＝7.5Hz)，2.17(3H，s)，2.36(3H，s)，2.56(2H，q，J＝7.5Hz)，3.30-3.55(4H，m)，3.68(1H，dd，J＝5.2，12.0Hz)，3.84(1H，dd，J＝2.2，12.0Hz)，3.94(1H，d，J＝15.3Hz)，4.05(1H，d，J＝15.3Hz)，5.85-5.95(1H，m)，6.72(1H，s)，7.00-7.15(4H，m)

Example 19

2- (beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) -4, 6 lutidine

The title compound was prepared in the same manner as in example 6 using 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) 3- (4-methoxybenzyl) -4, 6-dimethylpyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

2.17(3H，s)，2.35(3H，s)，3.30-3.55(4H，m)，3.68(1H，dd，J＝5.3，12.0Hz)，3.72(3H，s)，3.84(1H，dd，J＝2.2，12.0Hz)，3.91(1H，d，J＝15.1Hz)，4.02(1H，d，J＝15.1Hz)，5.85-5.95(1H，m)，6.72(1H，s)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Example 20

2- (beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) -4, 6 lutidine

-23 ℃ (3 to a solution of 2- (β -D-glucopyranosyloxy) -3- [4- (2-methoxymethoxyethyl) benzyl ] -4, 6-lutidine (0.054g) in dichloromethane (1.2mL) was added trimethylbromomonosilane (0.061mL), the mixture was stirred for 10 minutes, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (developing solvent: dichloromethane/methanol ═ 6/1) to give 2- (β -D-glucopyranosyloxy) -3- (4-methoxybenzyl) -4, 6-lutidine (0.008 g).

¹H-NMR(CD₃OD)δppm：

2.17(3H，s)，2.36(3H，s)，2.74(2H，t，J＝7.1Hz)，3.30-3.60(4H，m)，3.60-3.75(3H，m)，3.83(1H，dd，J＝2.3，12.1Hz)，3.94(1H，d，J＝15.5Hz)，4.06(1H，d，J＝15.5Hz)，5.85-5.95(1H，m)，6.72(1H，s)，7.00-7.20(4H，m)

Example 21

2- (beta-D-glucopyranosyloxy) -6-methoxy-3- (4-methoxybenzyl) -4-methylpyridine

The title compound was prepared in the same manner as in example 6 using 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -6-methoxy-3- (4-methoxybenzyl) -4-methylpyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

2.15(3H，s)，3.30-3.55(4H，m)，3.67(1H，dd，J＝5.5，12.1Hz)，3.72(3H，s)，3.80-3.90(5H，m)，3.90-4.05(1H，m)，5.80-5.90(1H，m)，6.26(1H，s)，6.70-6.80(2H，m)，7.05-7.15(2H，m)

Example 22

4- (4-ethoxybenzyl) -3- (beta-D-glucopyranosyloxy) pyridine

The title compound was prepared in the same manner as in example 6 using 3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -4- (4-ethoxybenzyl) pyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

1.36(3H，t，J＝6.9Hz)，3.30-3.60(4H，m)，3.71(1H，dd，J＝5.6，12.2Hz)，3.89(1H，dd，J＝2.1，12.2Hz)，3.95-4.10(4H，m)，4.99(1H，d，J＝7.6Hz)，6.75-6.90(2H，m)，7.08(1H，d，J＝5.2Hz)，7.10-7.20(2H，m)，8.08(1H，d，J＝5.2Hz)，8.39(1H，s)

Example 23

2- (beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) pyridine

The title compound was prepared in the same manner as in example 6 using 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- (4-methoxybenzyl) pyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

3.35-3.60(4H，m)，3.69(1H，dd，J＝4.9，12.1Hz)，3.76(3H，s)，3.80-4.00(3H，m)，5.87(1H，d，J＝7.6Hz)，6.80-6.90(2H，m)，6.93(1H，dd，J＝5.0，7.3Hz)，7.10-7.20(2H，m)，7.30-7.45(1H，m)，7.97(1H，dd，J＝1.6，5.0Hz)，

Example 24

4- (beta-D-glucopyranosyloxy) -5- (4-methoxybenzyl) -2, 6-dimethylpyrimidine

To a solution of 4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5- (4-methoxybenzyl) -2, 6-dimethylpyrimidine (0.24g) in methanol (4mL) was added sodium methoxide (28% methanol solution, 0.040mL), and the mixture was stirred at room temperature for 50 minutes. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol-7/1) to give 4- (. beta. -D-glucopyranosyloxy) -5- (4-methoxybenzyl) -2, 6-dimethylpyrimidine (0.11 g).

¹H-NMR(CD₃OD)δppm：

2.34(3H，s)，2.52(3H，s)，3.30-3.55(4H，m)，3.68(1H，dd，J＝5.5，11.9Hz)，3.73(3H，s)，3.85(1H，dd，J＝2.1，11.9Hz)，3.90(1H，d，J＝15.1Hz)，4.00(1H，d1，J＝15.1Hz)，6.00-6.10(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)，

Example 25

3- (beta-D-glucopyranosyloxy) -4- [4- (2-hydroxyethyl) benzyl ] -pyridine

To a solution of 3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -4- [4- (2-benzoyloxyethyl) benzyl ] -pyridine (0.086g) in methanol (1mL) was added sodium methoxide (28% methanol solution, 0.008mL), and the mixture was stirred at 25 ℃ for 23 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol-4/1), 3- (. beta. -D-glucopyranosyloxy) -4- [4- (2-hydroxyethyl) benzyl ] -pyridine (0.044 g).

¹H-NMR(CD₃OD)δppm：

2.78(2H，t，J＝7.2Hz)，3.30-3.60(4H，m)，3.60-3.80(3H，m)，3.89(1H，dd，J＝2.0，12.2Hz)，4.03(1H，d，J＝15.1Hz)，4.11(1H，d，J＝15.1Hz)，4.99(1H，d，J＝7.6Hz)，7.09(1H，d，J＝5.0Hz)，7.10-7.25(4H，m)，8.08(1H，d，J＝5.0Hz)，8.39(1H，s)

Example 26

5- (4-ethylsulfanylbenzyl) -4- (. beta. -D-glucopyranosyloxy) -2, 6-dimethylpyrimidine

The title compound was prepared in the same manner as in example 24 using 4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5- (4-ethylthiobenzyl) -2, 6-dimethyl) pyrimidine in place of 4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5- (4- (methoxybenzyl) -2, 6-dimethylpyrimidine.

¹H-NMR(CD₃OD)δppm：

1.23(3H，t，J＝7.3Hz)，2.34(3H，s)，2.52(3H，s)，2.87(2H，q，J＝7.3Hz)，3.30-3.60(4H，m)，3.69(1H，dd，J＝5.2，12.1Hz)，3.85(1H，dd，J＝2.2，12.1Hz)，3.93(1H，d，J＝15.5Hz)，4.02(1H，d，J＝15.5Hz)，6.00-6.10(1H，m)，7.10-7.30(4H，m)

Example 27

The title compound was prepared in the same manner as in example 6 using 3- (4-butylbenzyl) -4- (. beta. -D-glucopyranosyloxy) -2, 6-dimethylpyridine and 4- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- (4-butylbenzyl) -2, 6-dimethyl) pyridine in place of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (2-methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

0.91(3H，t，J＝7.3Hz)，1.25-1.40(2H，m)，1.45-1.60(2H，m)，2.37(3H，s)，2.47(3H，s)，2.50-2.60(2H，m)，3.30-3.60(4H，m)，3.68(1H，dd，J＝6.2，12.1Hz)，3.91(1H，dd，J＝2.1，12.1Hz)，3.94(1H，d，J＝15.4Hz)，4.15(1H，d，J＝15.4Hz)，5.05-5.15(1H，m)，6.95-7.10(5H，m)

Example 28

2- (beta-D-glucopyranosyloxy) -3- (4-methoxybenzyl) piperazine

The title compound was prepared in the same manner as in example 6 using 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- (4-methoxybenzyl) piperazine instead of 2- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -3- [4- (2-methoxymethoxyethyl) benzyl ] -4, 6-dimethylpyridine.

¹H-NMR(CD₃OD)δppm：

3.3 5-3.60(4H，m)，3.66(1H，dd，J＝4.8，12.1Hz)，3.74(3H，s)，3.81(1H，dd，J＝1.9，12.1Hz)，4.06(1H，d，J＝14.2Hz)，4.17(1H，d，J＝14.2Hz)，5.89(1H，d，J＝8.0Hz)，6.75-6.85(2H，m)，7.15-7.30(2H，m)，8.03(1H，d，J＝2.8Hz)，8.10(1H，d，J＝2.8Hz)

Example 29

4-benzyl-3- (. beta. -D-glucopyranosyloxy) pyridazines

To a solution of 3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -4-benzylpyridazine (0.055g) in methanol (2mL) was added sodium methoxide (28% methanol solution, 0.010mL), and the mixture was stirred at room temperature for 30 minutes. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol-7/1) to give 4-benzyl-3- (. beta. -D-glucopyranosyloxy) pyridazine (0.032 g).

¹H-NMR(CD₃OD)δppm：

3.30-3.65(4H，m)，3.71(1H，dd，J＝5.0，12.1Hz)，3.84(1H，dd，J＝1.5，12.1Hz)，3.95-4.10(2H，m)，6.09(1H，d，J＝8.2Hz)，7.1 5-7.40(6H，m)，8.70(1H，d，J＝4.7Hz)

Example 30

3- (4-methoxybenzyl) -2- (6-O-methoxycarbonyl) -beta-D-glucopyranosyloxy) -4, 6-dimethylpyridine

To a solution of 2- (. beta. -D-glucopyranosyloxy) -3- (4-methoxybenzyl) -4, 6-lutidine (0.32g) in 2, 4, 6-collidine (3.8mL) at-40 ℃ was added a solution of potassium chloroformate (0.18mL) in dichloromethane (0.4 mL). The temperature rose to room temperature. The mixture was stirred for 7 hours. To the reaction mixture was added 10% aqueous citric acid solution (12mL), and the mixture was extracted with ethyl acetate, and the organic layer was washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3- (4-methoxybenzyl) -2- (6-O-methoxycarbonyl) - β -D-glucopyranosyloxy) -4, 6-lutidine (0.27 g).

¹H-NMR(CD₃OD)δppm：

2.15(3H，s)，2.35(3H，s)，3.30-3.55(3H，m)，3.55-3.65(1H，m)，3.67(3H，s)，3.72(3H，s)，3.83(1H，d，J＝15.2Hz)，4.06(1H，d，J＝15.2Hz)，4.28(1H，dd，J＝5.7，11.7Hz)，4.40(1H，dd，J＝2.1，11.7Hz)，5.90-6.00(1H，m)，6.71(1H，s)，6.70-6.80(2H，m)，7.05-7.15(2H，m)

Test example 1

Determination of the inhibitory Effect on human SGLT2 Activity

(1) Construction of a plasmid vector expressing human SGLT2

A cDNA library for PCR amplification was prepared by reverse-transcribing all RNAs obtained from human kidney (Ori gene) using oligo dT as a primer using SUPERSCRIPT preamplification System (Gibco-BRL: LIFE TECHNOLOGIES). A DNA fragment encoding human SGLT2 was amplified by PCR reaction using Pfu DNA polymerase (produced by Stratagene) wherein the above-mentioned human kidney cDNA library was used as a template, and the following oligonucleotides 0702F and 0712R (designated as SEQ ID Nos. 1 and 2, respectively) were used as primers. The amplified DNA fragments were ligated into pCR-Blunt (Invitrogen) according to standard methods of kits, which is a vector for cloning. Coli HB101 competent cells (manufactured by TOYOBO co., ltd.) were transformed according to a usual method, and then transformants were selected on LB agar medium (containing 50 μ g/mL kanamycin). After plasmid DNA was extracted and purified from one of the transformants, amplification of a DNA fragment encoding human SGLT2 was performed by PCR reaction with Pfu DNA polymerase (manufactured by Srtatagene), in which the following oligonucleotides 0714F and 0715R (denoted as sequence nos. 3 and 4, respectively) were used as primers. The amplified DNA fragment was digested with restriction enzymes Xho I and Hind III, and then purified with Wizard purification system (Promega). The purified DNA fragment was inserted into the corresponding site of pcDNA3.1(-) Myc/His-A (Invitrogen), a vector for expressing the fusion protein. Coli HB101 competent cells (from TOYOBO Co., Ltd.) were transformed according to a usual method, and then transformants were selected on LB agar medium (containing 50. mu.g/mL of ampicillin). After plasmid DNA was extracted and purified from one of the transformants, the base sequence of the DNA fragment inserted into the multi-cloning site of the vector pcDNA3.1(-) Myc/His-A was analyzed. This clone has single base substitutions (ATC encoding isoleucine-433 substituted with GTC) compared to human SGLT2 reported by Wells et al (am. J. Physiol., 263, 459-465 (1992)). Subsequently, a clone in which isoleucine-433 was substituted with valine was obtained. The plasmid vector expressing human SGLT2 (in which the peptide was designated as sequence No. 5 and fused to the carboxy-terminal alanine residue) was designated KL 29.

Serial number 1ATGGAGGAGCACACAGAGGC

Serial number 2GGCATAGAAGCCCCAGAGGA

Serial number 3AACCTCGAGATGGAGGAGCACACAGAGGC

Serial number 4AACAAGCTTGGCATAGAAGCCCCAGAGGA

Serial number 5KLGPEQKLISEEDLNSAVDHHHHHH

(2) Preparation of cells transiently expressing human SGLT2

KL29 (plasmid encoding human SGLT 2) was transfected into COS-7 cells (RIKEN CELL BANKRCB0539) by electroporation. Electroporation was carried out with GENE PULSER II (Bio-Rad Laboratories) under the following conditions: 0.29kV, 975. mu.F, 2X 10⁶COS-7 cells and 20. mu.g KL29 were cultured in 500. mu.L OPTI-MEMI medium (Gibco-BRL: LIFE TECHNOLOGIES) in a 0.4cm format sample chamber. After gene transfer, the cells were harvested by centrifugation and resuspended in OPTI-MEM I medium (1 mL/sample chamber). 125 μ L of the cell suspension was added to each well of a 96-well plate. 5% CO at 37 ℃₂After overnight incubation in China, 125. mu.L of DMEM medium [ containing 10% fetal bovine serum (Sanko Junyaku), 100 units/mL penicillin G sodium (Gibco-BRL: LIFETECHNOLOGIES) and 1 OO. mu.g/mL streptomycin sulfate (Gibco-BRL: LIFE TECHNOLOGIES)]. These cells were cultured for the next day, and then used to measure the inhibitory activity on α -D-glucopyranoside uptake.

(3) Measurement of inhibitory Activity on uptake of alpha-D-glucopyranoside

After removing the medium of COS-7 cells transiently expressing human SGLT2, 200. mu.L of a pretreatment buffer (pH7.4 buffer containing 140mM choline chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM 2- [4- (2-hydroxyethyl) -1-piperazinyl) was added to each well]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminomethane) and then incubating the cells at 37 ℃ for 10 minutes. Buffers for uptake measurements were prepared as follows: mu.L of alpha-D- (U-14C) glucopyranoside (Amersham Pharmacia Biotech) was added to 525. mu.L of uptake buffer (pH7.4 buffer containing 140mM sodium chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 5mM alpha-D-glucopyranoside, 10mM10mM 2- [4- (2-hydroxyethyl) -1-piperazinyl) containing at least one test sample]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminomethane) and mixed. As a control, a measurement buffer without any test sample was prepared. To estimate the basal uptake in the absence of test sample and sodium, a measurement buffer for basal uptake was similarly prepared, which replaced sodium chloride with 140mM choline chloride. After removing the pretreatment buffer, 75. mu.L of each buffer was added to each wellCells were incubated at 37 ℃ for 2 hours. After removing the measurement buffer, 200. mu.L of a washing buffer (pH7.4 buffer containing 140mM choline chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10 mM. alpha. -D-glucopyranoside, 10mM 2- [4- (2-hydroxyethyl) -1-piperazinyl) was added to each well]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminomethane) and immediately removed. After 2 additional washes, 75 μ L0.2N sodium hydroxide solution was added to each well to lyse the cells. Cell lysates were transferred to picoplate (Packard) and 150 μ L microScint (Packard) was added to each well and radioactivity was measured using a microplate scintillation counter topcount (Packard). The difference in uptake was obtained as a 100% value by subtracting the basal uptake radioactivity of the control, and then the concentration at which uptake was 50% Inhibited (IC) was calculated from the concentration-inhibition curve by the least squares method₅₀). The results are shown in Table 1.

TABLE 1

Test compounds	IC(nM)
		Example 18	41
Example 19	45
		Example 20	45
Example 21	55

Industrial applicability

Since they show excellent inhibitory activity against human SGLT2, the nitrogen-containing heterocyclic derivatives represented by the above general formula (I), pharmaceutically acceptable salts thereof and prodrugs thereof of the present invention show excellent blood glucose-lowering effect by preventing reabsorption of glucose in the kidney, excreting excess glucose into urine. The present invention can provide a medicament for preventing or treating diseases associated with hyperglycemia such as diabetes, diabetic complications, obesity and the like. Further, since the compound represented by the above general formula (II) or (III) or a salt thereof is important as an intermediate for producing the nitrogen-containing heterocyclic derivative represented by the above general formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof of the present invention, the present invention can be easily prepared by these compounds.

[ sequence listing other than text ]

Sequence number 1: synthetic DNA primers

Sequence number 2: synthetic DNA primers

Sequence number 3: synthetic DNA primers

Sequence number 4: synthetic DNA primers

Sequence number 5: peptide fused to the carboxy-terminal alanine residue of human SGLT2

Sequence listing

<110> orange crude drug Industrial Co., Ltd (Kissei PHARMACEUTICAL CO., LTD.)

Western village Junyang (NISHIMIURA, Toshihiro)

Rattan-cabin elegance era (FUJIKURA, Hideki)

Vogue-press mail-book (FUSHIMI, Nobuhiko)

Tianhe (TATANI, Kazuya)

Sheng Ye Jian Zi (KATSUNO, Kenji)

Yizozhi Zhenghe (ISAJI, Masayuki)

<120> nitrogen-containing heterocyclic derivative, pharmaceutical composition containing the same, pharmaceutical use thereof, and intermediate for production thereof

<130>PCT-A0218

<140>

<141>

<150>JPP2001-187368

<151>2001-06-20

<160>5

<170>PatentIn Ver.2.1

<210>1

<211>20

<212>DNA

<213> Artificial sequence

<220>

<223> synthetic DNA primer

<400>1

atggaggagc acacagaggc 20

<210>2

<211>20

<212>DNA

<213> Artificial sequence

<220>

<223> synthetic DNA primer

<400>2

ggcatagaag ccccagagga 20

<210>3

<211>29

<212>DNA

<213> Artificial sequence

<220>

<223> synthetic DNA primer

<400>3

aacctcgaga tggaggagca cacagaggc 29

<210>4

<211>29

<212>DNA

<213> Artificial sequence

<220>

<223> synthetic DNA primer

<400>4

aacaagcttg gcatagaagc cccagagga 29

<210>5

<211>25

<212>PRT

<213> Artificial sequence

<220>

<223> peptide fused to carboxy-terminal alanine residue of human SGLT2

<400>5

Lys Leu Gly Pro Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Ser

1 5 10 15

Ala Val Asp His His His His His His

20 25

Claims (26)

1. A nitrogen-containing heterocyclic derivative represented by the following general formula:

wherein, X¹And X³Independently represent N or CH; x²Represents N or CR²；X⁴Represents N or CR³(ii) a Provided that X is¹、X²、X³And X⁴1 or 2 of (a) represents N; r¹Represents A hydrogen atom, A halogen atom, A lower alkyl group, A lower alkoxy group, A lower alkylthio group, A lower alkoxy-substituted (lower alkyl group), A lower alkoxy-substituted (lower alkoxy group), A lower alkoxy (lower alkoxy) -substituted (lower alkyl group), A cyclic lower alkyl group, A halo (lower alkyl group) or A group represented by the general formulA HO-A-: wherein A represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r²Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group, a (lower acyl) amino group, a mono (lower alkyl) amino group or a di (lower alkyl) amino group; r³Represents a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof or a prodrug thereof.

2. The nitrogen-containing heterocyclic derivative according to claim 1, having the following general formula:

wherein P represents a hydrogen atom or a group forming a prodrug; r¹¹Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula P¹-O-A-represents A group: wherein P is¹Represents a hydrogen atom or a group forming a prodrug; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is represented by the formula

Wherein the content of the first and second substances,X¹and X³Independently represent N or CH; x²Represents N or CR²；X⁴Represents N or CR³(ii) a Provided that X is¹、X²、X³And X⁴1 or 2 of (a) represents N; r¹Represents A hydrogen atom, A halogen atom, A lower alkyl group, A lower alkoxy group, A lower alkylthio group, A lower alkoxy-substituted (lower alkyl group), A lower alkoxy-substituted (lower alkoxy group), A lower alkoxy (lower alkoxy) -substituted (lower alkyl group), A cyclic lower alkyl group, A halo (lower alkyl group) or A group represented by the general formulA HO-A-: wherein A represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r²Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group, a (lower acyl) amino group, a mono (lower alkyl) amino group or a di (lower alkyl) amino group; r³Represents a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof.

4. The nitrogen-containing heterocyclic derivative according to claim 2, wherein P or R¹¹Has a prodrug-forming group, or a pharmaceutically acceptable salt thereof.

5. The nitrogen-containing heterocyclic derivative according to claim 4, wherein P and P¹Each of which is a lower acyl group, a lower alkoxy-substituted (lower acyl group), a lower alkoxycarbonyl group or a lower alkoxy-substituted (lower alkoxycarbonyl group), or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 5 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the composition is a human SGLT2 inhibitor.

8. The pharmaceutical composition according to claim 6 or 7, wherein the composition is a medicament for preventing or treating a disease associated with hyperglycemia.

9. The pharmaceutical composition of claim 8, wherein the disease associated with hyperglycemia is selected from diabetes, diabetic complications, obesity, hyperinsulinemia, glucose metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorders, arteriosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout.

10. The pharmaceutical composition of claim 9, wherein the disease associated with hyperglycemia is diabetes.

11. The pharmaceutical composition of claim 9, wherein the disease associated with hyperglycemia is a diabetic complication.

12. The pharmaceutical composition of claim 9, wherein the disease associated with hyperglycemia is obesity.

13. Use of the nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 5 for the production of a pharmaceutical composition for the prophylaxis or treatment of a disease associated with hyperglycemia.

14. A pharmaceutical combination comprising (a) a nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 5, and (B) at least one member selected from the group consisting of: insulin sensitivity enhancer, glucose absorption inhibitor, biguanide, pancreasInsulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, glucagon receptor agonists, glucose receptor kinase inhibitors, glucose dehydrogenase inhibitors, glucose metabolism inhibitors, transcription factor NF-kB inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl-glutaryl-CoA reductase inhibitors, fibric acid derivatives, beta-glutaryl-CoA reductase inhibitors₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporters, cholesterol₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

15. The pharmaceutical combination according to claim 14 for use in the prevention or treatment of diseases associated with hyperglycemia.

16. The pharmaceutical combination of claim 15, wherein component (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, and appetite suppressants, wherein the disease associated with hyperglycemia is diabetes.

17. The pharmaceutical combination of claim 16, wherein component (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, and dextrin agonists.

18. The pharmaceutical combination of claim 17, wherein component (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, and insulin or insulin analogs.

19. The pharmaceutical combination of claim 15, wherein component (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation end-product formation inhibitors, insulin secretion enhancers, insulin inhibitors, insulin receptor agonists, insulin receptor kinase inhibitors, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- κ B inhibitors, lipid peroxidase inhibitors, N-acetylated- α -linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist and a diuretic, and the hyperglycemia-related disease is a diabetic complication.

20. The pharmaceutical combination of claim 19, wherein component (B) is at least one member selected from the group consisting of: aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors and angiotensin II receptor antagonists.

21. The pharmaceutical combination of claim 15, wherein component (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, beta 3-adenosyladrenergic receptor agonists, and appetite suppressants, and the disease associated with hyperglycemia is obesity.

22. The pharmaceutical combination of claim 21, wherein component (B) is at least one member selected from the group consisting of: beta is a₃-agonists of adrenergic receptors on the glands and appetite suppressants.

23. The pharmaceutical combination of claim 22, wherein the appetite suppressant is an agent selected from the group consisting of: monoamine reuptake inhibitors, serotonin release agonists, serotonin agonists, norepinephrine reuptake inhibitors, norepinephrine release agonists, alpha₁-adrenoceptor agonists, beta₂-adrenoceptor agonists, dopamine agonists, cannabinoids, gamma-aminobutyric acid receptor antagonists, H₃-histamine antagonists, L-histidine, leptin analogues, leptin receptor agonists, melanocortin receptor agonists, alpha-melanocyte stimulating hormone, cocaine-and amphetamine-regulated transcripts, rosewood protein, enterostatin agonists, calcitonin-gene-related peptide, and derivatives thereof,Bombesin, cholecystokinin agonists, corticotropin-releasing hormone analogs, corticotropin-releasing hormone agonists, urocortin, somatostatin analogs, somatostatin receptor agonists, pituitary adenylate cyclase-activating peptide, brain-derived neurotrophic factor, ciliary neurotrophic factor, thyroid stimulating hormone-releasing hormone, neurotensin, suwawayatide, neuropeptide Y antagonists, opioid peptide antagonists, galanin antagonists, melanin-concentrating hormone receptor antagonists, rat-related protein inhibitors, and orexin receptor antagonists.

Use of (a) and (B) for the preparation of a pharmaceutical composition for the prevention or treatment of a disease associated with hyperglycemia, wherein (a) is a nitrogen-containing heterocyclic derivative, a pharmaceutically acceptable salt thereof, or a prodrug thereof according to any one of claims 1 to 5, and (B) is at least one member selected from the group consisting of: insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin or insulin analogs, glucagon receptor antagonists, insulin receptor kinase agonists, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiral inositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycation end-product formation inhibitors, insulin secretion enhancers, insulin inhibitors, insulin receptor agonists, insulin receptor kinase inhibitors, tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6 phosphatase inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor-I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylhydantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl-pentanediol, hydroxyurea, hydroxydiacyl-CoA reductase inhibitor, fibric acid derivative, beta-reductase inhibitor₃-adrenoceptor agonists, acyl-coa: cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesterol ester transfer protein inhibitors, appetite suppressants, angiotensin-converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin-converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilatory antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low density lipoprotein receptor enhancers, nicotinic acid derivatives, bile acid sequestrants, sodium/bile acid cotransporters, cholesterol₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalizing agents.

25. A nitrogen-containing heterocyclic derivative represented by the following general formula:

wherein, X¹And X³Independently represent N or CH; x⁴Represents N or CR³；X⁵Represents N or CR⁴(ii) a Provided that X is¹、X³、X⁴And X⁵1 or 2 of (a) represents N; r⁰Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula P¹⁰-O-A-represents A group: wherein P is¹⁰Represents a hydrogen atom or a hydroxyl protecting group; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r³Represents a hydrogen atom or a lower alkyl group; r⁴Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group (which may have a protective group), a lower acyl group, a mono (lower alkyl) amino group (which may have a protective group), or a di (lower alkyl) amino group; or a salt thereof.

26. A nitrogen-containing heterocyclic derivative represented by the following general formula:

wherein, X¹And X³Independently represent N or CH; x⁴Represents N or CR³；X⁵Represents N or CR⁴(ii) a Provided that X is¹、X³、X⁴And X⁵1 or 2 of (a) represents N; r⁰Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group or a lower alkoxy-substituted (lower alkyl group), a lower alkoxy-substituted (lower alkoxy group), a lower alkoxy (lower alkoxy) -substituted (lower alkyl group), a cyclic lower alkyl group, a halo (lower alkyl group) or a group represented by the general formula P¹⁰-O-A-represents A group: wherein P is¹⁰Represents a hydrogen atom or a hydroxyl protecting group; a represents a lower alkylene group, a lower alkyleneoxy group or a lower alkylenethio group; r³Represents a hydrogen atom or a lower alkyl group; r⁴Represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyclic lower alkyl group, a lower alkoxy group, an amino group (which may have a protective group), a lower acyl group, a mono (lower alkyl) amino group (which may have a protective group), or a di (lower alkyl) amino group; or a salt thereof.