HK1062914B

HK1062914B - Glucopyranosyloxypyrazole derivatives and use thereof in medicines

Info

Publication number: HK1062914B
Application number: HK04105809.6A
Authority: HK
Inventors: 藤仓秀纪; 伏见信彦; 西村俊洋; 中林毅司; 伊佐治正幸
Original assignee: 橘生药品工业株式会社
Priority date: 2000-12-28
Filing date: 2001-12-25
Publication date: 2006-05-04

Description

Glucopyranosyloxypyrazole derivatives and their use in medicaments

Technical Field

The present invention relates to glucopyranosyloxypyrazole derivatives or pharmaceutically acceptable salts thereof which are useful as a medicament and to the use thereof in medicine.

More particularly, the present invention relates to glucopyranosyloxypyrazole derivatives represented by the following general formula: wherein R represents a hydrogen atom, a lower alkyl group or a group forming a prodrug; one of Q and T represents a group represented by the following general formula:

(wherein P represents a hydrogen atom or a group forming a prodrug), and the other represents a lower alkyl group or a halo (lower alkyl) group; r²Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halo (lower alkyl) group or a halogen atom; provided that when R represents a hydrogen atom or a lower alkyl group, P does not represent a hydrogen atom, or a pharmaceutically acceptable salt thereof, are effective as a drug for preventing or treating diseases associated with hyperglycemia such as diabetes,An agent for diabetic complications and obesity, wherein a glucopyranosyloxypyrazole derivative having inhibitory activity to human SGLT2 is represented by the following general formula:

wherein R is⁰Represents a hydrogen atom or a lower alkyl group; q⁰And T⁰One represents a group represented by the following general formula

And the other represents lower alkyl or halo (lower alkyl); r²Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halo (lower alkyl) group or a halogen atom, is in an activated form, and relates to a pharmaceutical use thereof.

Background

Diabetes is a lifestyle-related disease that is associated with eating habits and lack of exercise. Therefore, patients with diabetes have undergone dietary and exercise treatments. In addition, when it is difficult to sufficiently control and continue, medication is simultaneously performed. Biguanides, sulfonylureas, and insulin sensitivity enhancers have now been used as antidiabetic agents. However, occasionally biguanides and sulfonylureas have adverse effects such as lactic acidosis and hypoglycemia, respectively. When an insulin sensitivity enhancer is used, adverse effects such as edema are sometimes observed, and it is also associated with progressive obesity. Therefore, in order to solve these problems, development of an antidiabetic agent having a new mechanism is required.

In recent years, novel antidiabetic agents have been developed which promote glucose excretion from urine and lower blood glucose levels by preventing reabsorption of excess glucose in the kidney (j.clin.invest., vol. 79)1510-1515 (1987)). Further, it is reported that SGLT2 (Na)⁺Glucose cotransporter 2) is present in the S1 segment of the kidney proximal tubule and is primarily involved in the reabsorption of glucose across the glomerulus (j. clin. invest., volume 93, page 397-. Therefore, inhibition of human SGLT2 activity prevents reabsorption of excess glucose in the kidney, promotes excretion of excess glucose through the urine, and normalizes blood glucose levels. It is therefore desirable to develop antidiabetic agents that have potential inhibitory activity against human SGLT2 and have novel mechanisms. Also, since these agents promote the excretion of excess glucose through urine to reduce the accumulation of glucose in the body, it is also desirable to prevent or reduce the effects on obesity and the effects of urination. In addition, these agents are considered to be effective for various diseases associated with the progression of diabetes or obesity due to hyperglycemia.

As a compound containing a pyrazole moiety, WAY-123783 is known to increase the amount of glucose excreted by normal mice. However, its effect on the human body has never been described (j.med. chem., volume 30, pages 3920-.

Disclosure of Invention

The present inventors have conducted extensive studies and found a compound having an inhibitory activity against human SGLT 2. As a result, we have found that the compounds represented by the above general formula (I) are converted in vivo into glucopyranosyloxypyrazole derivatives represented by the above general formula (II) as active forms thereof, and they have excellent inhibitory activity against human SGLT2 as shown below, thereby constituting the basis of the present invention.

The present invention provides glucopyranosyloxypyrazole derivatives or pharmaceutically acceptable salts thereof which exert an inhibitory activity against human SGLT2 in vivo and show an excellent hypoglycemic action by preventing reabsorption of glucose in the kidney to excrete excessive glucose in urine, and pharmaceutical uses thereof.

That is, the present invention relates to glucopyranosyloxypyrazole derivatives represented by the following general formula:

wherein R represents a hydrogen atom, a lower alkyl group or a group forming a prodrug; one of Q and T represents a group represented by the following general formula:

(wherein P represents a hydrogen atom or a group forming a prodrug), and the other represents a lower alkyl group or a halo (lower alkyl) group; r²Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogeno (lower alkyl) group or a halogen atom; provided that P does not represent a hydrogen atom when R represents a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof.

Meanwhile, the present invention relates to a pharmaceutical composition, a human SGLT2 inhibitor and an agent for preventing or treating diseases associated with hyperglycemia, which comprises a glucopyranosyloxypyrazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

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

The present invention relates to the use of glucopyranosyloxypyrazole derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prophylaxis or treatment of diseases associated with hyperglycemia.

Further, the present invention relates to a pharmaceutical composition comprising (A) a glucopyranosyloxypyrazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and (B) at least one compound selected from the group consisting of insulin sensitivityEnhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiroinstol, 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, insulin preparations, glucagon receptor antagonists, glucose receptor kinase inhibitors, glucose dehydrogenase inhibitors, glucose synthase kinase inhibitors, glucose-1B inhibitors, glucose synthase kinase inhibitors, 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, hydroxymethyl-glutaryl-CoA reductase inhibitors, fibric acid derivatives, β -glutaryl-CoA reductase inhibitors₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, esterase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, palmitoyl carnitine transferase inhibitors, squalene synthase 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, vasodilator antihypertensive agents, sympatholytic agents, centrally acting antihypertensive agents, vasopressin inhibitors, alpha is alpha₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric acidDrugs and urine alkalinizing agents.

The present invention relates to a method for preventing or treating a disease associated with hyperglycemia, which comprises administering an effective amount of (A) a glucopyranosyloxypyrazole derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof in combination with (B) at least one selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, an insulin preparation, a glucagon receptor antagonist, an insulin receptor kinase stimulator, a tripeptide peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinositol, a glycogen synthase kinase-3 inhibitor, a glucagon-like peptide-1, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic glucon, Glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF- 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-methylidantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl-glutaryl-CoA reductase inhibitors, fibric acid derivative, beta₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, esterase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, palmitoyl carnitine transferase inhibitors, squalene synthase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesteryl ester transfer protein inhibitors, appetite suppressants, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, vascular endothelial cell proliferation inhibitors, vascular endothelialAngiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator-inducing antihypertensive agents, sympatholytic agents, centrally acting antihypertensive agents, alpha₂-agents for adrenoreceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalinizing agents.

The present invention relates to (A) a glucopyranosyloxypyrazole derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, and (B) at least one member selected from the group consisting of an insulin sensitivity enhancer, a glucose absorption inhibitor, a biguanide, an insulin secretion enhancer, an insulin preparation, a glucagon receptor antagonist, an insulin receptor kinase stimulator, a tripeptide peptidase II inhibitor, a dipeptidylpeptidase IV inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroisinitol, a glycogen synthase kinase-3 inhibitor, a glucagon-like peptide-1 analog, a glucagon-like peptide-1 agonist, a glucose-like, Dextrins, dextrin analogs, dextrin agonists, aldose reductase inhibitors, advanced glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-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-methylidantoin, EGB-761, bimoclomol, sulodexide, Y-128, hydroxymethyl-glutaryl-CoA reductase inhibitors, fibric derivatives, beta-glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor I, platelet-derived growth factor analogs, epidermal growth₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, esterase inhibitors, microsomal triglyceride transporter inhibitors, lipoxygenase inhibitors, palmitoyl carnitine transferase inhibitors, squalene synthase inhibitors, low density lipoprotein lipase inhibitors, alpha-glucosidase inhibitors, beta-glucosidaseLipoprotein receptor potentiators, 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, vasodilator-inducing antihypertensives, sympatholytic agents, centrally acting antihypertensives, alpha-beta-agonists, alpha-agonists, beta-agonists₂-agents of adrenergic receptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urine alkalinizing agents, for the manufacture of a medicament for the prevention or treatment of diseases associated with hyperglycemia.

In the present invention, the term "prodrug" means a glucopyranosyloxypyrazole derivative represented by the above-mentioned general formula (II) which is converted in vivo into its active form. As examples of the group forming a prodrug, provided that such a group is located at a hydroxyl group, hydroxyl protecting groups commonly used as prodrugs such as lower acyl, lower alkoxy-substituted (lower acyl), lower alkoxycarbonyl, and lower alkoxy-substituted (lower alkoxycarbonyl) are exemplified, and provided that such a group is on the nitrogen atom, amino protecting groups commonly used as prodrugs such as lower acyl, lower alkoxycarbonyl, lower acyloxymethyl, and lower alkoxycarbonyloxymethyl are exemplified.

Examples of the glucopyranosyloxypyrazole derivative represented by the above general formula (I) include compounds represented by the general formula:

a compound of wherein R¹Represents a hydrogen atom, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a lower acyloxymethyl group or a lower alkoxycarbonyloxymethyl group; q¹And T¹One represents a group represented by the following general formula

(wherein P is¹Represents a hydrogen atom, a lower acyl group, a lower alkoxy-substituted (lower acyl group), a lower alkoxycarbonyl group or a lower alkoxy-substituted (lower alkoxycarbonyl group), and the other represents a lower alkyl group or a halo (lower alkyl group); r²Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a halogeno (lower alkyl) group or a halogen atom; with the proviso that when R¹P represents a hydrogen atom or a lower alkyl group¹And does not represent a hydrogen atom.

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 and the like; the term "lower alkylthio" means 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. The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom; the term "halo (lower alkyl)" refers to a lower alkyl group as defined above substituted with 1 to 3 different or identical halogen atoms as defined herein. The term "lower acyl" refers to straight, branched or cyclic acyl groups having 2 to 7 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl and cyclohexylcarbonyl; the term "lower alkoxy-substituted (lower acyl)" means the above-mentioned lower acyl group substituted with the above-mentioned lower alkoxy group. The term "lower alkoxycarbonyl" refers to a straight, branched or cyclic alkoxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl and cyclohexyloxycarbonyl; the term "lower alkoxycarbonyl-substituted (lower acyl)" means the above lower acyl substituted with the above 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. Furthermore, the term "lower acyloxymethyl" refers to hydroxymethyl substituted with the aforementioned lower acyl group O-; the term "lower alkoxycarbonyloxymethyl" refers to hydroxymethyl substituted with the aforementioned lower alkoxycarbonyl group O-.

In the substituent R, a hydrogen atom or a straight chain or branched alkyl group having 1 to 3 atoms is preferable; hydrogen atom, ethyl group, propyl group or isopropyl group is more preferable; isopropyl is most preferred for its metabolic stability in the S9 fragment of human liver. At the substituent R²Among them, a straight or branched alkyl group having 1 to 4 carbon atoms, a straight or branched alkoxy group having 1 to 3 carbon atoms or a straight or branched alkylthio group having 1 to 3 carbon atoms is preferable; ethyl, ethoxy, isopropoxy, methoxy or methylthio are more preferred. Among the substituents Q and T, it is preferable that the substituent Q is lower alkyl or halo (lower alkyl). Among them, lower alkyl is preferable; straight or branched chain alkyl eucalyptus with 1 to 3 carbon atoms is more preferred; methyl is most preferred. Among the substituents P, lower acyl and lower alkoxycarbonyl are preferred; lower alkoxycarbonyl is more preferred; straight or branched chain alkoxycarbonyl groups having 2 to 5 carbon atoms are most preferred. Specifically, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group or an isobutoxycarbonyl group is preferable.

As the compound of the present invention, 4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) methyl ] -3 Yl) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-ethylphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-ethoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -3- (6-O-isopropoxycarbonyl-. beta. -D-isopropyloxy) -glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -3- (6-O-isobutoxycarbonyl- β -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 1-isopropyl-3- (6-O-methoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -1-isopropyl-4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-Isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl -5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole, 3- (6-O-isopropoxycarbonyl- β -D-glucopyranosyloxy) -1-isopropyl-5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole, 3- (6-O-isobutoxycarbonyl- β -D-glucopyranosyloxy) -1-isopropyl-5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole and the like are preferable; 4- [ (4-Isopropoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -4-, [ solution of ] or a salt thereof (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole and the like are more preferable; 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole and the like are most preferred.

The compound of the present invention represented by the above general formula (I) can be prepared by introducing a hydroxyl-and/or amino-protecting group, which is generally useful as a prodrug, into a hydroxyl group and/or nitrogen atom of a glucopyranosyloxypyrazole derivative represented by the above general formula (II) by a conventional method.

For example, the compound of the invention can be produced from glucopyranosyloxypyrazole derivatives represented by the above general formula (II) by the following method or a method similar thereto:

wherein P is⁰Represents a hydroxy-protecting group such as lower acyl, lower alkoxy-substituted (lower acyl), lower alkoxycarbonyl, lower alkoxy-substituted (lower alkoxycarbonyl) or benzyloxycarbonyl; p³Represents lower acyl or lower alkoxycarbonyl; p⁴Represents a lower acyl group; p⁵Represents lower alkoxycarbonyl; r¹³Represents lower acyl or lower alkoxycarbonyl; r¹⁴Represents lower alkoxymethyl or lower acyloxycarbonyloxymethyl; r¹⁵Represents an amino-protecting group such as lower alkyl, lower acyl, lower alkoxy-substituted (lower acyl), lower alkoxycarbonyl, lower alkoxy-substituted (lower alkoxycarbonyl) or benzyloxycarbonyl; q⁶And T⁶One of them represents a compound represented by the general formula:

a group of (wherein P is⁰Having the same definition as above) and the other represents lower alkyl or halo (lower alkyl); q⁷And T⁷One of them represents a compound represented by the general formula:

a group of (wherein P is³Having the same definition as above) and the other represents lower alkyl or halo (lower alkyl); x¹And X²Represents a leaving group such as a bromine atom or a chlorine atom; r⁰、R²、Q⁰And T⁰Having the same definitions as above.

Method 1

The nitrogen atom of the glucopyranosyloxypyrazole derivative represented by the above general formula (II) may be protected with the fatty acid anhydride represented by the above general formula (III) usually in a fatty acid such as acetic acid at 0 ℃ to reflux temperature for 30 minutes to 1 day, or the nitrogen atom of the glucopyranosyloxypyrazole derivative represented by the above general formula (II) may be protected with the succinimide derivative represented by the above general formula (IV) usually in an inert solvent such as tetrahydrofuran at room temperature to reflux temperature for 1 hour to 1 day to prepare the prodrug represented by the above general formula (Ib). The reaction time may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 2

The compound represented by the above general formula (V) can be prepared by introducing a hydroxymethyl group into a nitrogen atom of the glucopyranosyloxypyrazole derivative represented by the above general formula (II) with formaldehyde in various solvents. Examples of the solvent used in the reaction include water, methanol, ethanol, tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, acetonitrile, and a mixed solvent thereof. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 3

The hydroxymethyl group of the compound represented by the above general formula (V) may be protected with a protecting agent represented by the above general formula (VI) in the presence of a base such as pyridine, triethylamine, triamine, N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine, 1, 2, 2, 6, 6-pentamethylpiperidine or 1, 4-diazabicyclo [2.2.2] octane in an inert solvent or without any solvent, to thereby prepare a prodrug represented by the above general formula (Ic). Examples of the inert solvent used for the reaction include dichloromethane, acetonitrile, ethyl acetate, diisopropyl ether, chloroform, tetrahydrofuran, 1, 2-dimethylethane, 1, 4-dioxane, acetone, tert-butanol, a mixed solvent thereof, and the like. The reaction temperature is usually from-40 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 2 days, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 4

The hydroxymethyl group, or the nitrogen atom and the hydroxymethyl group, of the glucopyranosyloxypyrazole derivative represented by the above general formula (II) can be protected with the protecting agent represented by the above general formula (VII) in the presence of a base such as pyridine, triethylamine, N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine, 1, 2, 2, 6, 6-pentamethylpiperidine or 1, 4-diazabicyclo [2.2.2] octane in an inert solvent or without any solvent, to thereby prepare a prodrug represented by the above general formula (Id). Examples of the inert solvent used for the reaction include dichloromethane, acetonitrile, ethyl acetate, diisopropyl ether, chloroform, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, acetone, tert-butanol, a mixed solvent thereof, and the like. The reaction temperature is usually from-40 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 2 days, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 5

The compound represented by the above general formula (Id) may be deacylated in an alcohol solvent such as methanol or ethanol in the presence of a weak base such as sodium hydrogencarbonate, sodium carbonate or potassium carbonate to prepare a prodrug represented by the above general formula (Ie) or an analog thereof. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 15 minutes to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 6

The nitrogen atom of the compound represented by the above formula (Ie) may be protected with the fatty acid anhydride represented by the above formula (III) usually at 0 ℃ to reflux temperature in a fatty acid such as acetic acid for 30 minutes to 1 day, or may be protected with the succinimide derivative represented by the above formula (IV) usually at room temperature to reflux temperature in an inert solvent such as tetrahydrofuran for 1 hour to 1 day, or may be protected with the succinimide derivative represented by the above formula (IV) usually at room temperature to reflux temperature in an inert solvent such as dichloromethane, acetonitrile, ethyl acetate, diisopropyl ether, chloroform, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 4-dioxane, acetone, tert-butanol or a mixed solvent thereof usually at-40 ℃ to reflux temperature, or in the absence of any solvent in a base such as pyridine, triethylamine, N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine, a, Protecting with a protecting agent represented by the above general formula (VI) in the presence of 1, 2, 2, 6, 6-pentamethylpiperidine or 1, 4-diazabicyclo [2.2.2] octane for 30 minutes to 2 days, to thereby prepare a prodrug represented by the above general formula (If) or an analog thereof. The reaction time may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 7

The compound represented by the above general formula (VIII) can be produced by introducing a hydroxymethyl group into a nitrogen atom of the compound represented by the above general formula (Ie) with formaldehyde in various solvents. Examples of the solvent used in the reaction include water, methanol, ethanol, tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, acetonitrile, and a mixed solvent thereof. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 8

The hydroxymethyl group of the compound represented by the above general formula (VIII) may be protected with a protecting agent represented by the above general formula (VI) in the presence of a base such as pyridine, triethylamine, N-diisopropylethylamine, picoline, lutidine, collidine, quinuclidine, 1, 2, 2, 6, 6-pentamethylpiperidine or 1, 4-diazabicyclo [2.2.2] octane in an inert solvent or without any solvent to prepare a prodrug represented by the above general formula (Ig) or an analog thereof. Examples of the inert solvent used for the reaction include dichloromethane, acetonitrile, ethyl acetate, diisopropyl ether, chloroform, tetrahydrofuran, 1, 2-dimethylethane, 1, 4-dioxane, acetone, tert-butanol, a mixed solvent thereof, and the like. The reaction temperature is usually from-40 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 2 days, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method 9

The compound represented by the above general formula (Ig) may be catalytically hydrogenated in an inert solvent in the presence of a palladium catalyst such as palladium carbide to prepare a prodrug represented by the above general formula (Ih). The inert solvent used for the reaction includes methanol, ethanol, tetrahydrofuran, ethyl acetate, a mixed solvent thereof, and the like. The reaction temperature is usually from 0 ℃ to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

For example, the compound represented by the above general formula (II) used as a starting material in the above production process can be produced according to the following method:

wherein X³And Y represents a leaving group such as a halogen atom, a methanesulfonyloxy group or a toluenesulfonyloxy group; r³Represents lower alkyl or halo (lower alkyl); r⁴Represents methyl or ethyl; r⁵Represents lower alkyl; q⁸And T⁸One represents a 2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy group and the other represents lower alkyl or halo (lower alkyl); and R is⁰、R²、Q⁰And T⁰Having the same definitions as above.

Method A

The benzyl derivative represented by the above general formula (IX) and the ketoacetate represented by the above general formula (X) may be condensed in an inert solvent in the presence of a base such as sodium hydride or potassium tert-butoxide to prepare the compound represented by the above general formula (XI). As the inert solvent used for the reaction, 1, 2-dimethoxyethane, tetrahydrofuran, 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 1 hour to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Method B

The pyrazolone derivative represented by the above general formula (XII) can be produced by condensing a compound represented by the above general formula (XI) with hydrazine or hydrazine monohydrate in an inert solvent. As the inert solvent used for the reaction, toluene, tetrahydrofuran, chloroform, 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 1 hour to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used. The pyrazolone derivative represented by the above general formula (XII) obtained by the conventional method can be converted into a salt by a general method and then used in the method C.

Method C

When R in the pyrazolone derivative represented by the above general formula (XII)³Is a lower alkyl group, the corresponding pyrazolone derivative represented by the above general formula (XII) can be glycosidated with acetyl bromide-. alpha. -D-glucose in the presence of a base such as silver carbonate in an inert solvent, and the resulting compound can be N-alkylated with an alkylating agent represented by the above general formula (XIII) in an inert solvent in the presence of a base such as potassium carbonate as required to prepare the corresponding compound represented by the above general formula (XIV). Tetrahydrofuran is a solvent used in glycosidation reactionsAnd 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, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used. The solvent used in the N-alkylation reaction may be acetonitrile, N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof, or 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, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

When R in the pyrazolone derivative represented by the above general formula (XII)³Is a halo (lower alkyl group), the corresponding pyrazolone derivative represented by the above general formula (XII) can be glycosidated with acetyl bromide-. alpha. -D-glucose in the presence of a base such as potassium carbonate in an inert solvent, and the resulting compound can be N-alkylated with an alkylating agent represented by the above general formula (XIII) in an inert solvent in the presence of a base such as potassium carbonate as required to prepare the corresponding compound represented by the above general formula (XIV). Solvents used for the glycosidation reaction include acetonitrile, 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, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used. The solvent used in the N-alkylation reaction may be acetonitrile, N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof, or 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, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

Among the compounds represented by the above general formula (XII) as the starting material, there are the following three tautomers, which may vary depending on the reaction conditions:

wherein R is²And R³Having the same definitions as above.

The obtained pyrazolone derivative represented by the above general formula (XIV) can be converted into a salt by a conventional method and then used in Process D.

Method D

The compound represented by the above general formula (XIV) can be hydrolyzed to prepare glucopyranosyloxypyrazole represented by the above general formula (II). The solvent used in the reaction may be methanol, ethanol, tetrahydrofuran, water, a mixture thereof or the like, and sodium hydroxide, sodium ethoxide or the like is used as the base. The reaction temperature is usually from 0 ℃ to room temperature, and the reaction time is usually from 30 minutes to 6 hours, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

In the compound represented by the above general formula (II) which can also be used as a starting material in the production process mentioned later, substituted R⁰The compound which is a lower alkyl group can also be produced by the following method:

wherein R is²、R⁵、Q⁰、T⁰And X³Having the same definitions as above.

Method E

The compound represented by the above general formula (IIa) can be prepared by N-alkylating the compound represented by the above general formula (IIb) with an N-alkylating agent in an inert solvent in the presence of a base such as potassium carbonate or cesium carbonate, and occasionally a catalytic amount of sodium iodide. As the inert solvent used for the reaction, N-dimethylformamide, 1, 2-dimethoxyethane, dimethylsulfoxide, tetrahydrofuran, ethanol, a mixed solvent thereof, etc. can be mentioned. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 10 minutes to 1 day, and may be appropriately changed depending on the starting materials, the solvent and the reaction temperature used.

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

The glucopyranosyloxypyrazole derivative of the invention represented by the above general formula (I) can be converted into a pharmaceutically acceptable salt thereof by a general method. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, adipic acid, oleic acid, stearic acid and the like, and salts with inorganic bases such as sodium, potassium, calcium, magnesium and the like.

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

The compounds of the present invention represented by the above general formula (I) have two optical isomers, R-isomer and S-isomer, each having asymmetric carbon atoms except glucopyranose oxygen moiety. In the present invention, either the R-isomer or the S-isomer may be used, and a mixture of both isomers may also be used.

The prodrug of the present invention represented by the above general formula (I) can be converted in vivo into a glucopyranosyloxypyrazole derivative represented by the above general formula (II) which is an active form thereof and has a significant inhibitory activity against human SGLT 2. On the other hand, WAY-123783 is insufficient as an effective human SGLT2 inhibitor because it has very weak inhibitory activity against human SGLT 2. In addition, the prodrug of the present invention represented by the above general formula (I) has improved oral absorbability, and at the same time, a pharmaceutical composition containing the prodrug as an active ingredient is a very effective oral preparation. Therefore, the prodrug of the present invention is a very effective agent for preventing or treating diseases associated with hyperglycemia such as diabetes, diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcer, macroangiopathy), obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy, arteriosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout, and the like.

In addition, the compounds of the present invention may be used in combination 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 preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, 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, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, glucose dehydrogenase inhibitors, glucose receptor kinase inhibitors, glucose uptake inhibitors, insulin secretion enhancers, insulin preparations, insulin inhibitors, insulin receptor antagonists, glucose receptor, Advanced glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-. kappa.B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor I, platelet-derived growth factor (PDGF) analogs (e.g., PDGF-AA, PDGF-BB, PDGF-AB), Epidermal Growth Factor (EGF), nerve growth factor, carnitine derivatives, uridine, 5-hydroxy-1-methylidantoin, EGB-761, bimolomol, sulfoximine, Y-128, hydroxymethyl-glutaryl-CoA reductase inhibitors, fibric acid derivatives, beta-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factors NF-. kappa.B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor I, platelet-derived growth factor (PDGF) analogs, and₃-adrenoceptor agonists, acyl-coa cholesterol acyltransferase inhibitors, probcol, thyroid hormone receptor agonists, cholesterol absorption inhibitors, esterase inhibitors, microsomal triglyceride transfer protein inhibitors, lipoxygenase inhibitors, palmitoyl carnitine transferase inhibitors, squalene synthase inhibitors, low density lipoprotein receptor enhancers, niacin derivatives, bile acid sequestrants, sodium/bile acid cotransporter inhibitors, cholesteryl ester transfer protein inhibitors, appetite suppressants, angiotensin converting enzyme inhibitors, neutral endopeptidaseInhibitors, angiotensin II receptor antagonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, diuretics, calcium antagonists, vasodilator-inducing antihypertensive agents, sympatholytic agents, centrally acting antihypertensive agents, alpha₂-adrenoceptor agonists, antiplatelet agents, uric acid synthesis inhibitors, uricosuric agents and urinary alkalizing agents.

When the compound of the present invention is used in combination with one or more of the above-mentioned drugs, the present invention includes dosage forms which are administered simultaneously as a single preparation or separate preparations of the same or different routes of administration, or dosage forms which are administered at different dosing intervals as separate preparations of the same or different routes of administration. Combinations comprising a compound of the invention and one or more of the agents described above include single agents and separate agents as noted above for the combination.

When used in combination with the above drugs, the compounds of the present invention are much more effective in preventing or treating the above diseases than the additive agents. At the same time, the dosage can be reduced compared to either drug alone, or the side effects associated with the concurrent administration of drugs other than SGLT2 inhibitors can be avoided or reduced.

Specific compounds and diseases which can be preferably treated as the above-mentioned drugs for combined use are listed below. However, the invention is not limited thereto, for example, the specific compounds include their free compounds and their or other pharmaceutically acceptable salts.

Examples of insulin sensitivity enhancers are peroxisome proliferator-activated receptor-gamma agonists such as 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-alpha agonists such as GW-9578 and BM-170744, peroxisome proliferator-activated receptor-alpha/gamma agonists such as GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 and DRF-MDX8, retinoid X receptor agonists such as ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754 and bexarotene, and other insulin sensitivity enhancers such as reglixane, 0N0-5816, MBX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-929, AR-H049020 and GW-501516. Insulin sensitivity enhancers are preferably used for diabetes, diabetic complications, obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, and most preferably for diabetes, hyperinsulinemia or glucose metabolism disorder because of improving the disturbance of insulin signal transduction in surrounding tissues and enhancing glucose uptake of tissues from blood, thereby lowering blood glucose levels.

Examples of glucose uptake inhibitors are alpha-glucosidase inhibitors such as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25, 637, cagelibose and MDL-73, 945, alpha-amylase inhibitors such as AZM-127. Glucose absorption inhibitors are preferably used for diabetes, diabetic complications, obesity, hyperinsulinemia or glucose metabolism disorders, most preferably for diabetes or glucose metabolism disorders, because they inhibit the enzymatic hydrolysis of carbohydrates in food by the gastrointestinal enzymes and inhibit or delay the absorption of glucose by the body.

Examples of biguanides are phenformin, buformin hydrochloride, metformin hydrochloride and the like. Biguanides are preferably used for diabetes, diabetic complications, hyperinsulinemia or glucose metabolism disorders, most preferably for diabetes, hyperinsulinemia or glucose metabolism disorders, because the inhibitory effect on hepatic gluconeogenesis lowers blood glucose levels, promotes the effect on anaerobic glycolysis in the tissue or improves the effect on insulin resistance in the surrounding tissue.

Examples of insulin secretion enhancers are tolbutamide, chlorpropamide, tolazamide, acetylbenzenesulfonylcyclohexamide, glyburide, glibenclamide, gliclazide, 1-butyl-3-metanilide, sulfabutamide, glibornuride, glipizide, gliquidone, glimepiride, glisoxepid, glithiazide, glitazole, glibutrazole, glyhexamide, glimepiride, glyburide, phenylbutamide, tolcyclamide, glimepiride, nateglinide, mitiglinide calnium hydrate, repaglinide, and the like. The insulin secretion enhancer is preferably used for diabetes, diabetic complications or glucose metabolism disorders, and most preferably for diabetes or glucose metabolism disorders, because blood glucose levels are lowered and insulin secretion is enhanced by acting on pancreatic β -cells.

Examples of insulin preparations are human insulin, human insulin analogues, insulin lacking from animals, and the like. The insulin preparation is preferably used for diabetes, diabetic complications or glucose metabolism disorders, most preferably for diabetes or glucose metabolism disorders.

Examples of glucagon receptor antagonists are BAY-27-9955, NNC-92-1687, and the like; examples of the insulin receptor kinase stimulators are TER-17411, L-783281, KRX-613 and the like; examples of tripeptide peptidase II inhibitors include UCL-1397; examples of dipeptidylpeptidase IV inhibitors are NVP-DPP728A, TSL-225, P-32/98, etc.; examples of the protein tyrosine phosphatase-1B inhibitors include PTP-112, 0C-86839, PNU-177496, etc.; examples of glycogen phosphorylase inhibitors include NN-4201, CP-368296 and the like; examples of fructose-bisphosphatase inhibitors include R-132917 and the like; examples of pyruvate dehydrogenase inhibitors are AZD-7545 and the like; examples of the hepatic gluconeogenesis inhibitors include FR-225659 and the like; examples of glucagon-like peptide-1 analogs are exendin-4, CJC-1131, etc.; examples of glucagon-like peptide-1 agonists are AZM-134, LY-315902, and the like; examples of dextrins, dextrin analogues, dextrin agonists are pramlintide acetate and the like. Of these drugs, glucose-6-phosphatase inhibitors, D-chiroinositol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 are preferably used for diabetes, diabetic complications, hyperinsulinemia or glucose metabolism disorders, and most preferably for diabetes or glucose metabolism disorders.

Examples of aldose reductase inhibitors are asc or byl gamolenate, tolrestat, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat, sorbinil, ponalrestat, risarestat, zenarestat, minalrestat, methos or binil, AL-1567, miristat, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, lindolrestat, and the like. Aldose reductase inhibitors are preferred for diabetic complications because they inhibit aldose reductase and reduce the extracellular accumulation of excessive sorbitol in the acelylated polyhydroxy pathway, which sustains a hyperglycemic state in the tissues in diabetic complications.

Examples of the advanced glycation end product formation inhibitor are pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride and the like. The advanced glycation end product formation inhibitor is preferably used for diabetic complications because it inhibits the formation of advanced glycation end products, it sustains a hyperglycemic state in diabetes, and can alleviate damage to cells.

Examples of protein kinase C inhibitors are LY-333531, midostaurin, and the like. Protein kinase C inhibitors are preferred for diabetic complications because they inhibit the activity of protein kinase C, which sustains a hyperglycemic state in diabetes.

Examples of gamma-aminobutyric acid receptor antagonists are topiramate and the like; examples of sodium channel antagonists are mexiletine hydrochloride, oxcarbazepine, and the like; examples of transcription factor NF-. kappa.B inhibitors are dexlipotam and the like; examples of lipid peroxidase inhibitors are tiriazad mesyl ester and the like; examples of N-acetylated- α -linked-acid-dipeptidase inhibitors include GPI-5693 and the like; examples of carnitine derivatives are carnitine, l-carnitine hydrochloride, l-carnitine chloride, l-carnitine, ST-261, etc. Among these drugs, insulin-like growth factor I, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, uridine, 5-hydroxy-1-methylidantoin, EGB-761, bimoclomol, sulodexide, and Y-128 are preferably used for diabetic complications.

Examples of hydroxymethyl-glutaryl-CoA reductase inhibitors are cerivastatin sodium, pravastatin sodium, lovastatin, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, SC-45355, SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987, calceium pitavastatin, calceium rosuvastatin, colepsy, colesterone, dalvastatin, acitate, mevastatin, pravastatin, BMS-180431, BMY-21950, glavastatin, carvastatin, BMY-22089, bervastatin and the like. The hydroxymethyl-glutaryl-coa reductase inhibitor is preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, and most preferably for hyperlipidemia, hypercholesterolemia or arteriosclerosis, because it inhibits hydroxymethyl glutaryl-coa reductase to thereby lower blood cholesterol level.

Examples of fibric acid derivatives are bezafibrate, benzclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, aluminum clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirfibrate, clinofibrate, bisfibrate, theofibrate, AHL-157 and the like. The Fibric acid derivative is preferably used for hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, and most preferably for hyperlipidemia, hypertriglyceridemia or arteriosclerosis because it can activate lipoprotein lipase of the liver and enhance the oxidation of fatty acid, thereby lowering the triglyceride level of blood.

β₃Examples of the-adrenoceptor agonist are BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, GW-2696 and the like. Beta is a₃-adrenoceptor agonists are preferably used for obesity, hyperinsulinemia, hyperlipidemia, hypertensionCholesterolemia, hypertriglyceridemia or lipodystrophy, most preferably obesity or hyperinsulinemia, because it stimulates beta in adipose tissue₃Adrenergic receptors and enhance the oxidation of fatty acids, thereby consuming energy.

Examples of acyl-coenzyme A cholesterol acyltransferase inhibitors are NTE-122, MCC-147, PD-132301-2, DUP-129, U-73482, U-76807, RP-70676, P-06139, CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755, FCE-28654, YIC-8-434, avasimibe, CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E, lexifibrate, 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe and the like. The acyl-coenzyme a cholesterol acyltransferase inhibitor is preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy, and most preferably for hyperlipidemia or hypercholesterolemia, because it inhibits acyl-coenzyme a cholesterol acetyltransferase to lower blood cholesterol levels.

Examples of thyroid hormone receptor agonists are liothyronine sodium, levothyroxine sodium, KB-2611, and the like; examples of cholesterol absorption inhibitors are ezetimibe, SCH-48461, etc.; examples of esterase inhibitors are orlistat, ATL-962, AZM-131, RED-103004, etc.; examples of microsomal triglyceride transfer protein inhibitors are etomoxider, etc.; examples of squalene synthase inhibitors are SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 and the like; examples of nicotinic acid derivatives are nicotinic acid, nicotinamide, nicormol, niceritrol, acipimox, nicorandil, etc.; examples of bile acid sequestrants are cholestyramine, colesevelam hydrochloride, GT-102-279, and the like; examples of sodium/bile acid cotransporter inhibitors are 264W94, S-8921, SD-5613, etc.; examples of cholesteryl ester transfer protein inhibitors are PNU-107368E, SC-795, JTT-705, CP-529414, and the like. Of these drugs, probcol, lipoxygenase inhibitors, palmitoyl carnitine transferase inhibitors, low density lipoprotein receptor enhancers are preferably used for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy.

Examples of appetite suppressants are monoamine reuptake inhibitors, serotonin release stimulators, serotonin agonists (especially 5 HT)_2C-agonists), norepinephrine reuptake inhibitors, norepinephrine release stimulators, alpha₁-adrenoceptor agonists, beta₂-adrenoceptor agonists, dopamine agonists, cannabinoid receptor antagonists, gamma-aminobutyric acid receptor antagonists, H₃-histamine antagonists, L-histamine, leptin analogues, leptin receptor agonists, melanocortin receptor agonists (especially MC3-R agonists, MC4-R agonists), alpha-melanocyte stimulating hormone, cocaine and amphetamine controlled transcripts, mahogany protein, enterostatin agonists, calcitonin, peptides related to the calcitonin gene, xenopus peptides, cholecystokinin agonists (especially CCK-a agonists), corticotropin releasing hormone analogues, corticotropin releasing hormone agonists, urocortin, somatostatin analogues, somatostatin receptor agonists, pituitary adenylate cyclase activating peptides, brain derived neurotrophic factors, ciliary neurotrophic factors, thyrotropin releasing hormone, thyroid stimulating hormone, and methods of using the same, Neurotensin, bombesin, neuropeptide Y antagonists, opioid peptide antagonists, galanin antagonists, melanin concentrating hormone antagonists, guinea pig related protein inhibitors, orexin receptor antagonists, and the like. Specifically, examples of monoamine reuptake inhibitors include mazindol; examples of serotonin reuptake inhibitors are dexfenfluramine hydrochloride, fenfluramine, sibutramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride and the like; examples of serotonin agonists are inotriptan, (+) -norfenfluramine and the like; examples of norepinephrine reuptake inhibitors are bupropion, GW-320659, etc.; examples of norepinephrine are release stimulants, rolipram, YM-992, and the like; beta is a₂Examples of adrenoceptor agonists are amphetamine, dexamphetamineAmphetamine, phentermine, benzphetamine, methamphetamine, phendimetrazine, phendimethomorph, bupropion, phenylpropanolamine, clobenzyl amphetamine, and the like; examples of dopamine agonists are ER-230, doprexin, bromocriptine mesylate, and the like; examples of cannabinoid receptor antagonists are rimonabant et al; examples of gamma-aminobutyric acid receptor antagonists are topiramate and the like; h₃Examples of histamine antagonists are GT-2394, etc.; examples of leptin are leptin analogs or leptin receptor agonists, LY-355101, and the like; examples of cholecystokinin agonists (especially CCK-A agonists) are SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378, etc.; examples of neuropeptide Y antagonists are 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, diabetic complications, obesity, glucose metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy, arteriosclerosis, hypertension, congestive heart failure, edema, hyperuricemia or gout, and most preferably for obesity because it can activate or inhibit monoamines within the brain or bioactive peptides in the central appetite control system and suppress appetite, thereby reducing energy intake.

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

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

Examples of angiotensin II receptor antagonists are candesartan cilexetil, candesartan cilexetil/thiazine hydrochloride, losartan potassium, eprosartan mesyl ester, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Angiotensin II receptor antagonists are preferably used for diabetic complications or hypertension.

Examples of endothelin converting enzyme inhibitors are CGS-31447, CGS-35066, SM-19712, etc.; examples of endothelin receptor antagonists are L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sodium sitaxsentan, 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, enalsentan, BMS-207940, and the like. Of these drugs, use for diabetic complications or hypertension is preferred, and use for hypertension is most preferred.

Examples of diuretics are chlorthalidone, mezazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentofluthiazide, methyclothiazide, indapamide, tripamide, mefuside, azosemide, edenic acid, torasemide, piretanide, furosemide, bumetanide, metipran, potassium canrenoate, spironolactone, triamterene, aminophylline, chlorambucil hydrochloride, LLU-alpha, PNU-80873A, isosorbide, D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide, methazine, FR-179544, OPC-31260, lixivaptan, conivaptan hydrochloride and the like. Diuretics are preferred for diabetic complications, hypertension, congestive heart failure or edema, and most preferred for hypertension, congestive heart failure or edema because it increases urination thereby lowering blood pressure or reducing edema.

Examples of calcium antagonists are aranidipine, efonidipine hydrochloride, nicardipine hydrochloride, barnidipine hydrochloride, benidipine hydrochloride, and maleopidipine hydrochlorideNifedipine, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine ethanesulfonate, pradipine, lercanidipine hydrochloride, isradipine, elidipine, azelnidipine, lacidipine, vataniipine hydrochloride, ledipine, diltiazem hydrochloride, clentiazem maleate, verapamil hydrochloride, S-verapamil, fasudil hydrochloride, bepridil hydrochloride, galopamid hydrochloride, and the like; examples of antihypertensive agents which cause vasodilation are indapamide, todralazine hydrochloride, hydralazine hydrochloride, cadralazine, budralazine and the like; examples of the sympathetic blocking agent are amisulalol hydrochloride, terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, doxazosin mesylate, propranolol hydrochloride, atenolol, metoprolol tartrate, carvedilol, nipradilol, celiprolol hydrochloride, nebivolol, betaxolol hydrochloride, propranolol hydrochloride, terbinalol hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride, bisoprolol hemifumarate, bopindolol malonate, nipradilol, penbutolol sulfate, acebutolol hydrochloride, tiliolol hydrochloride, sodalol, urapidil, ind, or amin, etc.; examples of antihypertensive agents acting on the central nerve are blood level and the like; alpha is alpha₂Examples of-adrenoceptor agonists are clonidine hydrochloride, methyldopa, CHF-1035, guanabenz acetate, guanfacine hydrochloride, moxonidine, lofexidine, talcixol hydrochloride and the like. These drugs are preferably used for hypertension.

Examples of antiplatelet agents are ticlopidine hydrochloride, dipyridamole, cilostazol, ethyl icosatenate, sarpogrelate hydrochloride, dilazep dihydrochloride, trapidil, beraprost sodium, aspirin and the like. Antiplatelet agents are preferably used in atherosclerosis or congestive heart failure.

Examples of the uric acid synthesis inhibitor include allopurinol, oxypurinol and the like; examples of uricosuric agents are benzbromarone, probenecid, etc.; examples of the urine alkalifying agent include sodium hydrogen carbonate, potassium citrate, sodium citrate and the like. These drugs are preferably used for hyperuricemia or gout.

When used in combination with a drug other than an SGLT2 inhibitor, such as for diabetes, a cocktail consisting of at least one agent selected from the group consisting of insulin sensitivity enhancers, glucose uptake inhibitors, biguanides, insulin secretion enhancers, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinstol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, and appetite suppressors is preferred; more preferred are cocktails with at least one agent selected from the group consisting of insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, gluconeogenesis inhibitors, D-chiroinstitol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, and dextrin agonists; a combination with at least one agent selected from the group consisting of insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers and insulin preparations is most preferred. Similarly, in the case of diabetic complications, the inhibitor is administered in combination with at least one member selected from the group consisting of insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitorsPyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, 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 glycosylation end product formation inhibitors, protein kinase C inhibitors, gamma-aminobutyric acid receptor antagonists, sodium channel antagonists, transcription factor NF-kappa B inhibitors, lipid peroxidase inhibitors, N-acetylated-alpha-linked-acid-dipeptidase inhibitors, insulin-like growth factor I, platelet-derived growth factor, platelet growth factor analogs, epidermal growth factor, nerve growth factor, carnitine derivatives, uridine, glucose oxidase inhibitors, A mixture of 5-hydroxy-1-methylihidantoin, 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 is preferred; a combination with at least one agent selected from the group consisting of aldose reductase inhibitors, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors and angiotensin II receptor antagonists is more preferable. In addition, when used for obesity, it is combined with at least one compound selected from the group consisting of insulin sensitivity enhancers, glucose absorption inhibitors, biguanides, insulin secretion enhancers, insulin preparations, glucagon receptor antagonists, insulin receptor kinase stimulators, tripeptide peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose-bisphosphatase inhibitors, pyruvate dehydrogenase inhibitors, hepatic gluconeogenesis inhibitors, D-chiroisinitol, glycogen synthase kinase-3 inhibitors, glucagon-like peptide-1 analogs, glucagon-like peptide-1 agonists, dextrins, dextrin analogs, dextrin agonists, beta-glucosidase inhibitors, glucose receptor kinase inhibitors, tripeptide peptidase II inhibitors, tripeptide peptidase IV inhibitors, protein tyrosine phosphatase-1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, fructose bisphosphatase inhibitors, pyruvate₃-a combination of an adrenergic receptor agonist and an appetite suppressant is preferred; and at least one kind selected from beta₃A combination of an adrenergic receptor agonist and an appetite suppressant is more preferred.

When the pharmaceutical composition of the present invention is used for practical treatment, various dosage forms can be used depending on its use. Examples of such dosage forms are powders, granules, fine powders, dry syrups, tablets, capsules, injections, solvents, ointments, suppositories, plasters and the like, which are administered orally or parenterally.

These pharmaceutical compositions can be prepared by mixing with suitable pharmaceutical additives or by diluting and dissolving suitable additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, antibacterial and antiseptic agents, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers and the like, and conventionally processing the mixture. When the compound of the present invention is used in combination with a drug other than SGLT2 inhibitors, the various active ingredients may be formulated together or separately to prepare a pharmaceutical composition.

When the pharmaceutical composition of the present invention is used for practical treatment, the dose of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be appropriately determined depending on the age, sex, body weight and symptoms of each patient and the degree of treatment, and the dose is about 0.1 to 1,000mg per day per adult in the case of oral administration, about 0.01 to 300mg per day per adult in the case of parenteral administration, and the daily dose can be divided into once or several times per day and administered at appropriate times. Meanwhile, when the compound of the present invention is used in combination with a drug other than SGLT2 inhibitor, the dose of the compound of the present invention can be appropriately reduced, which generally depends on the dose of the drug other than SGLT2 inhibitor.

The present invention will be described in further detail below based on the following reference examples, examples and test examples. However, the present invention is not limited thereto.

Reference example 1

1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one

To a solution of 4-isopropoxybenzyl alcohol (0.34g) in tetrahydrofuran (6mL) were added triethylamine (0.28mL) and methanesulfonyl chloride (0.16mL), and the mixture was stirred at room temperature for 30 minutes. The resulting insoluble matter was removed by filtration. The resulting tetrahydrofuran solution of 4-isopropoxybenzyl methanesulfonate was added to a suspension of sodium hydride (60%, 81mg) and methyl acetoacetate (0.20mL) in 1, 2-dimethoxyethane (10mL), and the mixture was stirred at 80 ℃ overnight. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in toluene (5 mL). To this solution was added anhydrous hydrazine (0.19mL), and the mixture was stirred at 80 ℃ overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one (95 mg).

¹H-NMR(DMSO-d₆)δppm：

1.22(6H，d，J＝6.0Hz)，1.99(3H，s)，3.45(2H，s)，4.40-4.60(1H，m)，6.65-6.80(2H，m)，6.95-7.10(2H，m)

Reference example 2

1, 2-dihydro-5-methyl-4- [ (4-propylphenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4-propylbenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

0.75-0.95(3H，m)，1.45-1.65(2H，m)，1.99(3H，s)，2.40-2.55(2H，m)，3.32(2H，s)，6.95-7.10(4H，m)

Reference example 3

1, 2-dihydro-4- [ (4-isobutylphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4-isobutylbenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

0.83(6H，d，J＝6.6Hz)，1.70-1.85(1H，m)，1.99(3H，s)，2.30-2.45(2H，m)，3.50(2H，s)，6.90-7.10(4H，m)

Reference example 4

1, 2-dihydro-5-methyl-4- [ (4-propoxyphenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4-propoxybenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

0.95(3H，t，J＝7.4Hz)，1.60-1.75(2H，m)，1.98(3H，s)，3.46(2H，s)，3.75-3.90(2H，m)，6.70-6.85(2H，m)，6.95-7.10(2H，m)

Reference example 5

4- [ (4-ethoxyphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4-ethoxybenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

1.20-1.35(3H，m)，1.98(3H，s)，3.46(2H，s)，3.85-4.05(2H，m)，6.70-6.85(2H，m)，6.95-7.10(2H，m)

Reference example 6

1, 2-dihydro-5-methyl-4- [ (4-trifluoromethylphenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared by analogous method as described in reference example 1 using 4-trifluoromethylbenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

2.02(3H，s)，3.64(2H，s)，7.30-7.45(2H，m)，7.55-7.70(2H，m)

Reference example 7

4- [ (4-tert-butylphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 1 using 4-tert-butylbenzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

1.24(9H，s)，2.01(3H，s)，3.49(2H，s)，7.00-7.15(2H，m)，7.15-7.30(2H，m)

Reference example 8

4- [ (4-butoxyphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4-butoxyphenylmethanol instead of 4-isopropoxybenzylalcohol.

¹H-NMR(DMSO-d₆)δppm：

0.91(3H，t，J＝7.4Hz)，1.30-1.50(2H，m)，1.55-1.75(2H，m)，1.98(3H，s)，3.46(2H，s)，3.80-3.95(2H，m)，6.70-6.85(2H，m)，6.95-7.10(2H，m)

Reference example 9

1, 2-dihydro-5-methyl-4- [ (4-methylthiophenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4- (methylthio) benzyl alcohol instead of 4-isopropoxybenzyl alcohol.

¹H-NMR(DMSO-d₆)δppm：

1.99(3H，s)，2.42(3H，s)，3.50(2H，s)，7.05-7.20(4H，m)

Reference example 10

5-ethyl-1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared in a similar manner to that described in reference example 1 using 4- (methylthio) benzyl alcohol instead of 4-isopropoxybenzyl alcohol and methyl 3-oxopentanoate instead of methyl acetoacetate.

¹H-NMR(DMSO-d₆)δppm：

1.02(3H，t，J＝7.6Hz)，2.39(2H，q，J＝7.6Hz)，2.42(3H，s)，3.51(2H，s)，7.05-7.20(4H，m)

Reference example 11

1, 2-dihydro-4- [ (4-isopropylphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one

To a suspension of 1, 2-dimethoxyethane (1mL) in sodium hydride (60%, 40mg) was added methyl acetoacetate (0.11mL), 4-isopropylbenzyl chloride (0.17g) and a catalytic amount of sodium iodide, and the mixture was stirred at 80 ℃ overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in toluene (1 mL). To this solution was added anhydrous hydrazine (0.094mL), and the mixture was stirred at 80 ℃ overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give 1, 2-dihydro-4- [ (4-isopropylphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one (0.12 g).

¹H-NMR(DMSO-d₆)δppm：

1.16(6H，d，J＝6.9Hz)，2.01(3H，s)，2.70-2.90(1H，m)，3.49(2H，s)，6.95-7.20(4H，m)

Reference example 12

4- [ (4-ethylphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 11 using 4-ethylbenzyl chloride instead of 4-isopropylbenzyl chloride.

¹H-NMR(DMSO-d₆)δppm：

1.13(3H，t，J＝7.6Hz)，2.00(3H，s)，2.45-2.60(2H，m)，3.49(2H，s)，7.00-7.15(4H，m)

Reference example 13

1, 2-dihydro-5-methyl-4- [ (4-methylphenyl) methyl ] -3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 11 using 4-methylbenzyl bromide instead of 4-isopropylbenzyl chloride.

¹H-NMR(DMSO-d₆)δppm：

1.98(3H，s)，2.23(3H，s)，3.48(2H，s)，6.95-7.10(4H，m)

Reference example 14

4-benzyl-1, 2-dihydro-5-trifluoromethyl-3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 11 using trifluoro-ethylacetoacetate instead of methyl acetoacetate and benzyl bromide instead of 4-isopropylbenzyl chloride.

¹H-NMR(DMSO-d₆)δppm：

3.73(2H，s)，7.05-7.35(5H，m)，12.50-13.10(1H，brs)

Reference example 15

1, 2-dihydro-4- [ (4-methoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 11 using 4-methoxybenzyl bromide instead of 4-isopropylbenzyl chloride.

¹H-NMR(DMS0-d₆)δppm：

1.99(3H，s)，3.47(2H，s)，3.69(3H，s)，6.75-6.85(2H，m)，7.00-7.10(2H，m)，8.70-11.70(2H，br)

Reference example 16

4-benzyl-1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

The title compound was prepared in analogy to the procedure described for reference example 11 using benzyl bromide instead of 4-isopropylbenzyl chloride.

¹H-NMR(DMSO-d₆)δppm：

2.00(3H，s)，3.54(2H，s)，7.05-7.30(5H，s)

Reference example 17

4- [ (4-Isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

To a suspension of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one (46mg), acetyl bromide- α -D-glucose (99mg) and 4A molecular sieve in tetrahydrofuran (3mL) was added silver carbonate (66mg), and the mixture was stirred overnight at 65 ℃ under the exclusion of light. The reaction mixture is purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran). Further purification by preparative thin layer chromatography on silica gel (developing solvent: ethyl acetate/hexane ═ 2/1) gave 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-0-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole (42 mg).

¹H-NMR(CDCl₃)δppm：

1.25-1.35(6H，m)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.05(3H，s)，2.10(3H，s)，3.45-3.65(2H，m)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，4.40-4.55(1H，m)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，6.70-6.80(2H，m)，6.95-7.05(2H，m)。

Reference example 18

5-methyl-4- [ (4-propylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-5-methyl-4- [ (4-propylphenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

0.91(3H，t，J＝7.3Hz)，1.50-1.65(2H，m)，1.86(3H，s)，2.01(3H，s)，2.03(3H，s)，2.05(3H，s)，2.10(3H，s)，2.45-2.55(2H，m)，3.55(1H，d，J＝15.8Hz)，3.63(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.3，12.4Hz)，4.30(1H，dd，J＝3.9，12.4Hz)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，7.00-7.20(4H，m)

Reference example 19

4- [ (4-isobutylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-4- [ (4-isobutylphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

0.87(6H，d，J＝6.6Hz)，1.70-1.85(1H，m)，1.87(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.10(3H，s)，2.40(2H，d，J＝7.2Hz)，3.56(1H，d，J＝15.8Hz)，3.63(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，4.14(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，6.95-7.10(4H，m)

Reference example 20

5-methyl-4- [ (4-propoxyphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was synthesized in a similar manner to that described in reference example 17 using 1, 2-dihydro-5-methyl-4- [ (4-propoxyphenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one

¹H-NMR(CDCl₃)δppm：

1.01(3H，t，J＝7.4Hz)，1.70-1.85(2H，m)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.10(3H，s)，3.53(1H，d，J＝15.7Hz)，3.59(1H，d，J＝15.7Hz)，3.80-3.95(3H，m)，4.14(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，6.70-6.80(2H，m)，6.95-7.10(2H，m)。

Reference example 21

4- [ (4-ethoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 4- [ (4-ethoxyphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.38(3H，t，J＝7.0Hz)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.10(3H，s)，3.53(1H，d，J＝15.8Hz)，3.59(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，3.98(2H，q，J＝7.0Hz)，4.13(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4)，5.15-5.30(3H，m)，5.50-5.60(1H，m)，6.70-6.80(2H，m)，6.95-7.10(2H，m)

Reference example 22

5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -4- [ (4-trifluoromethylphenyl) methyl ] -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-5-methyl-4- [ (4-trifluoromethylphenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.85(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.14(3H，s)，3.65(1H，d，J＝15.9Hz)，3.71(1H，d，J＝15.9Hz)，3.80-3.90(1H，m)，4.14(1H，dd，J＝2.4，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.40(3H，m)，5.55-5.65(1H，m)，7.20-7.30(2H，m)，7.45-7.55(2H，m)

Reference example 23

4- [ (4-tert-butylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 4- [ (4-tert-butylphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.27(9H，s)，1.84(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.14(3H，s)，3.56(1H，d，J＝15.8Hz)，3.64(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.30(3H，m)，5.50-5.60(1H，m)，7.00-7.10(2H，m)，7.20-7.30(2H，m)

Reference example 24

4- [ (4-butoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 4- [ (4-butoxyphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

0.96(3H，t，J＝7.4Hz)，1.40-1.55(2H，m)，1.65-1.80(2H，m)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.10(3H，s)，3.52(1H，d，J＝15.8Hz)，3.59(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，3.91(2H，t，J＝6.5Hz)，4，13(1H，dd，J＝2.3，12.4Hz)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.30(3H，m)，5.50-5.60(1H，m)，6.70-6.80(2H，m)，6.95-7.10(2H，m)

Reference example 25

5-methyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-5-methyl-4- [ (4-methylthiophenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.07(3H，s)，2.12(3H，s)，2.44(3H，s)，3.50-3.65(2H，m)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.4，12.4Hz)，4.31(1H，dd，J＝4.1，12.4Hz)，5.15-5.30(3H，m)，5.55-5.65(1H，m)，7.00-7.10(2H，m)，7.10-7.20(2H，m)，8.65-8.85(1H，brs)

Reference example 26

5-Ethyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 5-ethyl-1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.13(3H，t，J＝7.6Hz)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.44(3H，s)，2.45-2.55(2H，m)，3.50-3.70(2H，m)，3.80-3.90(1H，m)，4.05-4.20(1H，m)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.35(3H，m)，5.55-5.65(1H，m)，7.00-7.10(2H，m)，7.10-7.20(2H，m)，8.80-9.20(1H，brs)

Reference example 27

4- [ (4-isopropylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-4- [ (4-isopropylphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.20(6H，d，J＝6.9Hz)，1.85(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.13(3H，s)，2.75-2.90(1H，m)，3.56(1H，d，J＝15.8Hz)，3.63(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，4.05-4.20(1H，m)，4.31(1H，dd，J＝4.0，12.4Hz)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，7.00-7.15(4H，m)，8.70-9.30(1H，brs)

Reference example 28

4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

To a solution of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one (2.0g) in acetonitrile (100mL) were added acetyl bromide-. alpha. -D-glucose (3.1g) and potassium carbonate (1.1g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate ═ 1/1) to give 4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole (2.0 g).

¹H-NMR(CDCl₃)δppm：

1.91(3H，s)，2.03(3H，s)，2.04(3H，s)，2.09(3H，s)，2.45(3H，s)，3.73(2H，s)，3.75-3.90(1H，m)，4.15-4.35(2H，m)，5.15-5.65(4H，m)，7.00-7.20(4H，m)

Reference example 29

4-benzyl-3- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 28 using 4-benzyl-1, 2-dihydro-5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.89(3H，s)，2.02(3H，s)，2.04(3H，s)，2.08(3H，s)，3.70-3.90(3H，m)，4.15-4.30(2H，m)，5.10-5.50(4H，m)，7.10-7.30(5H，m)

Reference example 30

4- [ (4-methoxyphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 28 using 1, 2-dihydro-4- [ (4-methoxyphenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.93(3H，s)，2.03(3H，s)，2.05(3H，s)，2.09(3H，s)，3.65-3.75(2H，m)，3.77(3H，s)，3.75-3.90(1H，m)，4.15-4.35(2H，m)，5.10-5.45(4H，m)，6.75-6.85(2H，m)，7.00-7.15(2H，m)

Reference example 31

4- [ (4-methoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-4- [ (4-methoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.89(3H，s)，2.02(3H，s)，2.03(3H，s)，2.05(3H，s)，2.10(3H，s)，3.45-3.65(2H，m)，3.76(3H，s)，3.80-3.90(1H，m)，4.11(1H，dd，J＝2.2，12.4Hz)，4.30(1H，dd，J＝4.0，12.4Hz)，5.15-5.35(3H，m)，5.50-5.60(1H，m)，6.70-6.85(2H，m)，7.00-7.10(2H，m)

Reference example 32

4-benzyl-5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-beta-D-glucopyranosyloxy) -1H-pyrazole

The title compound was prepared in a similar manner to that described in reference example 17 using 4-benzyl-1, 2-dihydro-5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one.

¹H-NMR(CDCl₃)δppm：

1.86(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.11(3H，s)，3.59(1H，d，J＝15.8Hz)，3.66(1H，d，J＝15.8Hz)，3.80-3.90(1H，m)，4.11(1H，dd，J＝2.3，12.4Hz)，4.30(1H，dd，J＝4.0，12.4Hz)，5.15-5.30(3H，m)，5.50-5.65(1H，m)，7.05-7.30(5H，m)，8.75-9.55(1H，brs)

Reference example 33

4- [ (4-methoxyphenyl) methyl ] -1, 5-dimethyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) pyrazole

4- [ (4-methoxyphenyl) methyl group in acetonitrile (2mL)]A suspension of-5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole (18mg), potassium carbonate (14mg) and iodomethane (4.7mg) was stirred at 75 ℃ overnight. Passing through celite^*The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: benzene/acetone ═ 2/1) to give 4- [ (4-methoxyphenyl) methyl group]-1, 5-dimethyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) pyrazole (4 mg).

¹H-NMR(CDCl₃)δppm：

1.90(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.07(3H，s)，3.45-3.60(2H，m)，3.60(3H，s)，3.76(3H，s)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.4，12.4Hz)，4.29(1H，dd，J＝4.1，12.4Hz)，5.15-5.30(3H，m)，5.50-5.60(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Reference example 34

1-methyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole

4- [ (4-Methylthiophenyl) methyl group in tetrahydrofuran (1mL)]A suspension of (E) -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole (30mg), potassium carbonate (8.0mg) and iodomethane (8.2mg) was stirred at 75 ℃ overnight. Passing through celite^*The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/ethyl acetate ═ 5/1) to give 1-methyl-4- [ (4-methylthiophenyl) methyl group]-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole (13 mg).

¹H-NMR(CDCl₃)δppm：

1.89(3H，s)，2.02(3H，s)，2.04(3H，s)，2.07(3H，s)，2.44(3H，s)，3.65-3.95(6H，m)，4.14(1H，dd，J＝2.3，12.4Hz)，4.29(1H，dd，J＝4.3，12.4Hz)，5.15-5.35(3H，m)，5.50-5.65(1H，m)，7.00-7.20(4H，m)

Reference example 35

1-Ethyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described in reference example 34 using ethyl iodide instead of methyl iodide.

¹H-NMR(CDCl₃)δppm：

1.40(3H，t，J＝7.2Hz)，1.90(3H，s)，2.02(3H，s)，2.04(3H，s)，2.06(3H，s)，2.44(3H，s)，3.72(2H，s)，3.80-3.90(1H，m)，4.05-4.20(3H，m)，4.27(1H，dd，J＝4.5，12.4Hz)，5.10-5.35(3H，m)，5.55-5.65(1H，m)，7.00-7.10(2H，m)，7.10-7.20(2H，m)

Reference example 36

4- [ (4-methylthiophenyl) methyl ] -1-propyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole

The title compound was prepared in a similar manner to that described in reference example 34 using 1-iodopropane instead of methyl iodide.

¹H-NMR(CDCl₃)δppm：

0.92(3H，t，J＝7.4Hz)，1.75-1.90(2H，m)，1.89(3H，s)，2.02(3H，s)，2.04(3H，s)，2.06(3H，s)，2.44(3H，s)，3.72(2H，s)，3.80-3.90(1H，m)，3.90-4.05(2H，m)，4.12(1H，dd，J＝2.3，12.4Hz)，4.27(1H，dd，J＝4.5，12.4Hz)，5.10-5.35(3H，m)，5.55-5.65(1H，m)，7.00-7.10(2H，m)，7.10-7.20(2H，m)

Reference example 37

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole

To a solution of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole (61mg) in ethanol (3mL) was added 1mol/L aqueous sodium hydroxide solution (0.53mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole (39 mg).

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝5.9Hz)，2.05(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.90(1H，m)，4.45-4.60(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.15(2H，m)

Reference example 38

3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-propylphenyl) methyl ] -1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 5-methyl-4- [ (4-propylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.91(3H，t，J＝7.5Hz)，1.50-1.65(2H，m)，2.05(3H，s)，2.45-2.60(2H，m)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.83(1H，d，J＝11.9Hz)，5.00-5.10(1H，m)，7.00-7.15(4H，m)

Example 39

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isobutylphenyl) methyl ] -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-isobutyl-phenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.87(6H，d，J＝6.6Hz)，1.70-1.90(1H，m)，2.04(3H，s)，2.41(2H，d，J＝7.1Hz)，3.25-3.45(4H，m)，3.55-3.90(4H，m)，5.00-5.10(1H，m)，6.95-7.15(4H，m)

Reference example 40

3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-propoxyphenyl) methyl ] -1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 5-methyl-4- [ (4-propoxyphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.02(3H，t，J＝7.4Hz)，1.65-1.80(2H，m)，2.05(3H，s)，3.25-3.45(4H，m)，3.60-3.75(3H，m)，3.80-3.90(3H，m)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 41

4- [ (4-ethoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-ethoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.34(3H，t，J＝7.0Hz)，2.05(3H，s)，3.25-3.45(4H，m)，3.60-3.75(3H，m)，3.80-3.90(1H，m)，3.97(2H，q，J＝7.0Hz)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 42

3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-trifluoromethylphenyl) methyl ] -1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -4- [ (4-trifluoromethylphenyl) methyl ] -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.08(3H，s)，3.20-3.40(4H，m)，3.67(1H，dd，J＝5.0，11.9Hz)，3.75-3.90(3H，m)，5.00-5.10(1H，m)，7.30-7.45(2H，m)，7.45-7.60(2H，m)

Reference example 43

4- [ (4-tert-butylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-tert-butylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.28(9H，s)，2.06(3H，s)，3.25-3.45(4H，m)，3.60-3.90(4H，m)，5.00-5.10(1H，m)，7.05-7.15(2H，m)，7.20-7.30(2H，m)

Reference example 44

4- [ (4-butoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-1-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-butoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.97(3H，t，J＝7.4Hz)，1.40-1.55(2H，m)，1.65-1.80(2H，m)，2.05(3H，s)，3.30-3.45(4H，m)，3.60-3.75(3H，m)，3.83(1H，d，J＝12.0Hz)，3.91(2H，t，J＝6.4Hz)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 45

3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-methylthiophenyl) methyl ] -1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 5-methyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.06(3H，s)，2.42(3H，s)，3.20-3.45(4H，m)，3.55-3.75(3H，m)，3.80-3.90(1H，m)，5.00-5.10(1H，m)，7.05-7.20(4H，m)

Reference example 46

5-Ethyl-3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methylthiophenyl) methyl ] -1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 5-ethyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.06(3H，t，J＝7.6Hz)，2.42(3H，s)，2.47(2H，q，J＝7.6Hz)，3.25-3.45(4H，m)，3.60-3.80(3H，m)，3.80-3.90(1H，m)，5.00-5.10(1H，m)，7.10-7.20(4H，m)

Reference example 47

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropylphenyl) methyl ] -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-isopropyl-phenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.20(6H，d，J＝6.9Hz)，2.05(3H，s)，2.75-2.90(1H，m)，3.25-3.45(4H，m)，3.55-3.90(4H，m)，5.00-5.10(1H，m)，7.00-7.15(4H，m)

Reference example 48

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.42(3H，s)，3.25-3.50(4H，m)，3.69(1H，dd，J＝4.9，12.0Hz)，3.75-3.90(3H，m)，4.90-5.10(1H，m)，7.10-7.20(4H，m)

Reference example 49

4-benzyl-3- (. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4-benzyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

3.25-3.45(4H，m)，3.67(1H，dd，J＝5.3，12.0Hz)，3.80-3.95(3H，m)，4.97(1H，d，J＝7.4Hz)，7.05-7.25(5H，m)

Reference example 50

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-trifluoromethyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methoxyphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

3.25-3.45(4H，m)，3.67(1H，d，J＝5.4，12.1Hz)，3.73(3H，s)，3.75-3.90(3H，m)，4.90-5.00(1H，m)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 51

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.04(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.73(3H，s)，3.80-3.90(1H，m)，5.00-5.10(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 52

4-benzyl-3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4-benzyl-5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.05(3H，s)，3.25-3.45(4H，m)，3.60-3.90(4H，m)，5.00-5.10(1H，m)，7.05-7.25(5H，m)

Reference example 53

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -1, 5-dimethylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methoxyphenyl) methyl ] -1, 5-dimethyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.06(3H，s)，3.25-3.45(4H，m)，3.55-3.70(6H，m)，3.73(3H，s)，3.75-3.90(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.05-7.15(2H，m)

Reference example 54

3- (. beta. -D-glucopyranosyloxy) -1-methyl-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 1-methyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.42(3H，s)，3.30-3.50(4H，m)，3.69(1H，dd，J＝4.7，12.0Hz)，3.75-3.90(6H，m)，5.25-5.35(1H，m)，7.05-7.20(4H，m)

Reference example 55

1-ethyl-3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 1-ethyl-4- [ (4-methylthiophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.38(3H，t，J＝7.1Hz)，2.42(3H，s)，3.30-3.50(4H，m)，3.60-3.75(1H，m)，3.75-3.90(3H，m)，4.14(2H，q，J＝7.1Hz)，5.25-5.35(1H，m)，7.05-7.20(4H，m)

Reference example 56

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methylthiophenyl) methyl ] -1-propyl-5-trifluoromethylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methylsulfanyl-phenyl) methyl ] -1-propyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethylpyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.90(3H，t，J＝7.4Hz)，1.75-1.90(2H，m)，2.42(3H，s)，3.30-3.50(4H，m)，3.69(1H，dd，J＝4.9，12.0Hz)，3.75-3.90(3H，m)，4.00-4.10(2H，m)，5.25-5.35(1H，m)，7.05-7.20(4H，m)

Reference example 57

3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-methylphenyl) methyl ] -1H-pyrazole

5-methyl-4- [ (4-methylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole was prepared in a similar manner to that described in reference example 17 using 1, 2-dihydro-5-methyl-4- [ (4-methylphenyl) methyl ] -3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 5-methyl-4- [ (4-methylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.04(3H，s)，2.26(3H，s)，3.25-3.45(4H，m)，3.55-3.90(4H，m)，5.00-5.10(1H，m)，6.95-7.15(4H，m)

Reference example 58

4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

4- [ (4-ethylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole was prepared in a similar manner to that described in reference example 17 using 4- [ (4-ethylphenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 4- [ (4-ethylphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.18(3H，t，J＝7.6Hz)，2.04(3H，s)，2.57(2H，q，J＝7.6Hz)，3.25-3.45(4H，m)，3.55-3.90(4H，m)，5.00-5.10(1H，m)，6.95-7.20(4H，m)

Reference example 59

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methylphenyl) methyl ] -5-trifluoromethyl-1H-pyrazole

4- [ (4-methylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in reference example 28 using 1, 2-dihydro-4- [ (4-methylphenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 4- [ (4-methylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

2.25(3H，s)，3.20-3.45(4H，m)，3.55-3.70(1H，m)，3.70-3.90(3H，m)，4.80-4.95(1H，m)，6.90-7.15(4H，m)

Reference example 60

4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

4- [ (4-ethylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in reference example 28 using 4- [ (4-ethylphenyl) methyl ] -1, 2-dihydro-5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 4- [ (4-ethyl-phenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.18(3H，t，J＝7.6Hz)，2.50-2.60(2H，m)，3.15-3.40(4H，m)，3.55-3.65(1H，m)，3.70-3.90(3H，m)，4.80-4.95(1H，m)，6.95-7.15(4H，m)

Reference example 61

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropylphenyl) methyl ] -5-trifluoromethyl-1H-pyrazole

4- [ (4-isopropylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in reference example 28 using 1, 2-dihydro-4- [ (4-isopropylphenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 4- [ (4-isopropylphenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

1.20(6H，d，J＝6.9Hz)，2.75-2.85(1H，m)，3.15-3.40(4H，m)，3.55-3.65(1H，m)，3.70-3.90(3H，m)，4.80-4.95(1H，m)，7.00-7.15(4H，m)

Reference example 62

4- [ (4-chlorophenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole

4- [ (4-chlorophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole was prepared in a similar manner to that described in reference example 28 using 4- [ (4-chlorophenyl) methyl ] -1, 2-dihydro-5-trifluoromethyl-3H-pyrazolin-3-one instead of 1, 2-dihydro-4- [ (4-methylthiophenyl) methyl ] -5-trifluoromethyl-3H-pyrazolin-3-one. The title compound was then prepared in analogy to the procedure described for reference example 37 using 4- [ (4-chlorophenyl) methyl ] -3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole instead of 4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

3.20-3.40(4H，m)，3.55-3.70(1H，m)，3.75-3.90(3H，m)，4.80-4.95(1H，m)，7.10-7.25(4H，m)

Reference example 63

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1-propylpyrazole

To a suspension of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole (50mg) and cesium carbonate (0.20g) in N, N-dimethylformamide (1mL) at 50 ℃ was added 1-iodopropane (0.036mL), and the mixture was stirred overnight. Water was added to the reaction mixture, and the resulting mixture was purified by solid-phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The resulting semi-purified material was further purified by column chromatography on silica gel (eluent: dichloromethane/methanol 8/1) to give 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1-propylpyrazole (28 mg).

¹H-NMR(CD₃OD)δppm：

0.87(3H，t，J＝7.4Hz)，1.26(6H，d，J＝6.0Hz)，1.65-1.80(2H，m)，2.07(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.95(3H，m)，4.40-4.60(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Reference example 64

1-ethyl-3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropylphenyl) methyl ] -5-methylpyrazole

The title compound was prepared in a similar manner to that described in reference example 63 using iodoethane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝6.0Hz)，1.29(3H，t，J＝7.2Hz)，2.08(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.90(1H，m)，3.96(2H，q，J＝7.2Hz)，4.40-4.60(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Reference example 65

1-ethyl-3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole and iodoethane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

1.29(3H，t，J＝7.1Hz)，2.07(3H，s)，3.20-3.45(4H，m)，3.55-3.75(6H，m)，3.82(1H，dd，J＝2.0，12.OHz)，3.90-4.05(2H，m)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.05-7.15(2H，m)

Reference example 66

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methyl-1-propylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.87(3H，t，J＝7.5Hz)，1.65-1.80(2H，m)，2.07(3H，s)，3.35-3.45(4H，m)，3.60-3.75(3H，m)，3.73(3H，s)，3.75-3.85(1H，m)，3.85-3.95(2H，m)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.00-7.15(2H，m)

Reference example 67

1-ethyl-4- [ (4-ethoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 4- [ (4-ethoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole and iodoethane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

1.28(3H，t，J＝7.4Hz)，1.34(3H，t，J＝7.2Hz)，2.07(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.90-4.00(4H，m)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.00-7.15(2H，m)

Reference example 68

4- [ (4-ethoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1-propylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 4- [ (4-ethoxyphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.87(3H，t，J＝7.6Hz)，1.34(3H，t，J＝7.1Hz)，1.65-1.80(2H，m)，2.07(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.81(1H，dd，J＝2.1，12.1Hz)，3.85-4.05(4H，m)，5.00-5.10(1H，m)，6.70-6.85(2H，m)，7.00-7.15(2H，m)

Reference example 69

1-ethyl-4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole and iodoethane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

1.17(3H，t，J＝7.6Hz)，1.28(3H，t，J＝7.2Hz)，2.06(3H，s)，2.56(2H，q，J＝7.6Hz)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.90-4.00(2H，m)，5.00-5.10(1H，m)，7.00-7.15(4H，m)

Reference example 70

4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1-propylpyrazole

The title compound was prepared in analogy to the procedure described for reference example 63 using 4- [ (4-ethylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole instead of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole.

¹H-NMR(CD₃OD)δppm：

0.87(3H，t，J＝7.4Hz)，1.17(3H，t，J＝7.6Hz)，1.65-1.80(2H，m)，2.06(3H，s)，2.56(2H，q，J＝7.6Hz)，3.25-3.45(4H，m)，3.60-3.95(6H，m)，5.00-5.10(1H，m)，7.00-7.15(4H，m)

Reference example 71

1-butyl-3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole

The title compound was prepared in a similar manner to that described in reference example 63 using 1-bromobutane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

0.92(3H，t，J＝7.4Hz)，1.20-1.40(8H，m)，1.60-1.75(2H，m)，2.07(3H，s)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.81(1H，dd，J＝2.1，12.0Hz)，3.91(2H，t，J＝7.2Hz)，4.45-4.55(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Reference example 72

3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole

The title compound was prepared in a similar manner to that described in reference example 63 using 2-bromopropane instead of 1-iodopropane.

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝6.0Hz)，1.30-1.40(6H，m)，2.08(3H，s)，3.15-3.45(4H，m)，3.55-3.75(3H，m)，3.78(1H，dd，J＝2.3，12.0Hz)，4.35-4.45(1H，m)，4.45-4.55(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Reference example 73

4- [ (4-ethylthiophenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one

Methanesulfonyl chloride (3.8mL) was added to a solution of 4-ethylthiobenzyl alcohol (8.3g) and triethylamine (6.9mL) in tetrahydrofuran (200mL) at 0 deg.C, and the mixture was stirred for 1 hour. Insoluble matter was removed by filtration. To the resulting tetrahydrofuran solution of 4-ethylthiobenzyl methanesulfonate were added a suspension of sodium hydride (60%, 2.2g) and methyl acetoacetate (5.3mL) in 1, 2-dimethoxyethane (200mL), and the mixture was stirred at 80 ℃ overnight. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue dissolved in toluene (150mL) was added hydrazine monohydrate (7.2mL), and the mixture was stirred at 80 ℃ for 1 hour. The reaction mixture was cooled to 0 ℃ and stirred for a further 1 hour. The resulting precipitate was collected by filtration and washed with water and hexane to give 4- [ (4-ethylthiophenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one (1.5 g).

¹H-NMR(DMSO-d₆)δppm：

1.19(3H，t，J＝7.3Hz)，2.00(3H，s)，2.90(2H，q，J＝7.3Hz)，3.51(2H，s)，7.05-7.15(2H，m)，7.15-7.25(2H，m)

Reference example 74

4- [ (4-Ethiophenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole

To a suspension of 4- [ (4-ethylthiophenyl) methyl ] -1, 2-dihydro-5-methyl-3H-pyrazolin-3-one (1.6g) and acetyl bromide-. alpha. -D-glucose (2.9g) in tetrahydrofuran (30mL) was added silver carbonate (2.1g), and the mixture was stirred overnight at 60 ℃ under dark conditions. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) and column chromatography on silica gel (eluent: hexane/ethyl acetate: 1/3) was performed to give 4- [ (4-ethylthiophenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl- β -D-glucopyranosyloxy) -1H-pyrazole (1.4 g).

¹H-NMR(CDCl₃)δppm：

1.28(3H，t，J＝7.4Hz)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.11(3H，s)，2.89(2H，q，J＝7.4Hz)，3.56(1H，d，J＝15.9Hz)，3.62(1H，d，J＝15.9Hz)，3.80-3.90(1H，m)，4.13(1H，dd，J＝2.3，12.6Hz)，4.31(1H，dd，J＝3.9，12.6Hz)，5.15-5.35(3H，m)，5.55-5.65(1H，m)，7.00-7.10(2H，m)，7.15-7.25(2H，m)，8.79(1H，brs)

Reference example 75

4- [ (4-ethinylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

To a solution of 4- [ (4-ethylthiophenyl) methyl ] -5-methyl-3- (2, 3, 4, 6-tetra-O-acetyl-. beta. -D-glucopyranosyloxy) -1H-pyrazole (1.3g) in methanol (10mL) was added sodium methoxide (28% methanol solution, 0.13mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-5/1) to give 4- [ (4-ethylthiophenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole (0.87 g).

¹H-NMR(CD₃OD)δppm：

1.24(3H，t，J＝7.3Hz)，2.06(3H，s)，2.88(2H，q，J＝7.3Hz)，3.30-3.45(4H，m)，3.60-3.80(3H，m)，3.80-3.90(1H，m)，5.00-5.10(1H，m)，7.10-7.30(4H，m)

Reference example 76

1- (benzyloxycarbonyl) -3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole

To a solution of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole (1.3g) in tetrahydrofuran (30mL) was added N- (benzyloxycarbonyloxy) succinimide (1.6g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give 1- (benzyloxycarbonyl) -3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole (1.3 g).

¹H-NMR(CDCl₃)δppm：

1.27(6H，d，J＝6.3Hz)，2.35(3H，s)，3.45-3.70(6H，m)，3.76(1H，dd，J＝4.5，12.0Hz)，3.85(1H，dd，J＝2.8，12.0Hz)，4.40-4.50(1H，m)，5.30-5.40(2H，m)，5.48(1H，d，J＝8.0Hz)，6.70-6.80(2H，m)，6.95-7.05(2H，m)，7.25-7.50(5H，m)

Reference example 77

1- (benzyloxycarbonyl) -3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole

To a solution of 1- (benzyloxycarbonyl) -3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole (0.20g) in 2, 4, 6-trimethylpyridine (4mL) was added ethyl chloroformate (0.092mL), and the mixture was stirred at room temperature for 1 day. Water and citric acid monohydrate were added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol ═ 10/1) to give 1- (benzyloxycarbonyl) -3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole (0.17 g).

¹H-NMR(CD₃OD)δppm：

1.19(3H，t，J＝7.1Hz)，1.26(6H，d，J＝6.0Hz)，2.36(3H，s)，3.30-3.50(3H，m)，3，50-3.75(3H，m)，4.10(2H，q，J＝7.1Hz)，4.25-4.35(1H，m)，4.35-4.45(1H，m)，4.45-4.60(1H，m)，5.35-5.45(2H，m)，5.45-5.60(1H，m)，6.70-6.85(2H，m)，7.00-7.15(2H，m)，7.30-7.55(5H，m)

Reference example 78

1- (benzyloxycarbonyl) -4- [ (4-isopropoxyphenyl) methyl ] -3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole

The title compound was prepared in a similar manner to that described in reference example 77 using methyl chloroformate instead of ethyl chloroformate.

¹H-NMR(CDCl₃)δppm：

1.30(6H，d，J＝6.4Hz)，2.43(3H，s)，3.45-3.70(6H，m)，3.78(3H，s)，4.39(1H，dd，J＝2.2，1 1.8Hz)，4.40-4.55(2H，m)，5.38(2H，s)，5.40-5.50(1H，m)，6.70-6.85(2H，m)，7.00-7.10(2H，m)，7.30-7.50(5H，m)

Example 1

3- (6-O-ethoxycarbonyl-beta-D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole

To a solution of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole (0.10g) in 2, 4, 6-trimethylpyridine (1mL) was added ethyl chloroformate (0.072g), and the mixture was stirred at room temperature overnight. Citric acid monohydrate (3.3g) and water were added to the reaction mixture, and the resulting mixture was purified by ODS solid-phase extraction (washing solvent: distilled water, eluent: methanol). Purification by column chromatography on silica gel (eluent: dichloromethane/methanol ═ 10/1) and recrystallization (recrystallization solvent: ethyl acetate/hexane ═ 1/3) gave 3- (6-O-ethoxy-carbonyl- β -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole (0.084 g).

¹H-NMR(CD₃OD)δppm：

1.23(3H，t，J＝7.0Hz)，1.26(6H，d，J＝5.8Hz)，1.30-1.40(6H，m)，2.07(3H，s)，3.25-3.45(4H，m)，3.60-3.70(2H，m)，4.12(2H，q，J＝7.0Hz)，4.21(1H，dd，J＝5.4，11.6Hz)，4.34(1H，dd，J＝1.7，11.6Hz)，4.35-4.45(1H，m)，4.45-4.55(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Examples 2 to 14

The compounds listed in table 1 were prepared from the corresponding starting materials in analogy to the procedure described in example 1.

[ Table 1]

Examples	R	R²	Q
Examples	R	R²	Q	2	Methyl radical	Methoxy radical	Methyl radical
3	Methyl radical	Methylthio group	Trifluoromethyl radical	2	Methyl radical	Methoxy radical	Methyl radical
3	Methyl radical	Methylthio group	Trifluoromethyl radical	4	Ethyl radical	Methylthio group	Trifluoromethyl radical
5	Propyl radical	Methylthio group	Trifluoromethyl radical	4	Ethyl radical	Methylthio group	Trifluoromethyl radical
5	Propyl radical	Methylthio group	Trifluoromethyl radical	6	Propyl radical	Isopropoxy group	Methyl radical
7	Ethyl radical	Isopropoxy group	Methyl radical	6	Propyl radical	Isopropoxy group	Methyl radical
7	Ethyl radical	Isopropoxy group	Methyl radical	8	Ethyl radical	Methoxy radical	Methyl radical
9	Propyl radical	Methoxy radical	Methyl radical	8	Ethyl radical	Methoxy radical	Methyl radical
9	Propyl radical	Methoxy radical	Methyl radical	10	Ethyl radical	Ethoxy radical	Methyl radical
11	Propyl radical	Ethoxy radical	Methyl radical	10	Ethyl radical	Ethoxy radical	Methyl radical
11	Propyl radical	Ethoxy radical	Methyl radical	12	Ethyl radical	Ethyl radical	Methyl radical
13	Propyl radical	Ethyl radical	Methyl radical	12	Ethyl radical	Ethyl radical	Methyl radical
13	Propyl radical	Ethyl radical	Methyl radical	14	Butyl radical	Isopropoxy group	Methyl radical

Example 15

4- [ (4-Isopropoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole

The title compound was prepared in a similar manner as described in example 1 using methyl chloroformate instead of ethyl chloroformate.

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝6.1Hz)，1.30-1.40(6H，m)，2.07(3H，s)，3，25-3.45(4H，m)，3.60-3.70(2H，m)，3.71(3H，s)，4.22(1H，dd，J＝5.2，11.7Hz)，4.35(1H，dd，J＝2.1，11.7Hz)，4.35-4.45(1H，m)，4.45-4.60(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Example 16

3- (6-O-isobutoxycarbonyl-beta-D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole

The title compound was prepared in analogy to the procedure described in example 1 using isobutyl chloroformate instead of ethyl chloroformate.

¹H-NMR(CD₃OD)δppm：

0.90(6H，d，J＝6.7Hz)，1.26(6H，d，J＝5.9Hz)，1.30-1.40(6H，m)，1.80-2.00(1H，m)，2.07(3H，s)，3.25-3.50(4H，m)，3.60-3.70(2H，m)，3.80-3.90(2H，m)，4.21(1H，dd，J＝5.2，11.5Hz)，4.36(1H，dd，J＝1.8，11.5Hz)，4.35-4.45(1H，m)，4.45-4.55(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Example 17

4- [ (4-Isopropoxyphenyl) methyl ] -1-isopropyl-5-methyl-3- (6-O-propionyl-. beta. -D-glucopyranosyloxy) pyrazole

Propionyl chloride (0.072g) was added to a solution of 3- (. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole (0.10g) in 2, 4, 6-trimethylpyridine (1mL) at 0 ℃ and the compound was stirred for 5 hours. Citric acid monohydrate (3.3g) and water were added to the reaction mixture, and the resulting mixture was purified by ODS solid-phase extraction (washing solvent: distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) gave 4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methyl-3- (6-O-propionyl-. beta. -D-glucopyranosyloxy) pyrazole (0.074 g).

¹H-NMR(CD₃OD)δppm：

1.05(3H，t，J＝7.5Hz)，1.26(6H，d，J＝5.9Hz)，1.30-1.40(6H，m)，2.07(3H，s)，2.27(2H，q，J＝7.5Hz)，3.25-3.45(4H，m)，3，60-3.70(2H，m)，4.18(1H，dd，J＝5.6，11.8Hz)，4.30(1H，dd，J＝2.2，11.8Hz)，4.35-4.45(1H，m)，4.45-4.55(1H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Example 18

3- (6-O-acetyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole

The title compound was prepared in analogy to the procedure described for example 17 using acetyl chloride instead of propionyl chloride.

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝6.4Hz)，1.30-1.40(6H，m)，1.98(3H，s)，2.08(3H，s)，3.25-3.45(4H，m)，3.60-3.70(2H，m)，4.16(1H，dd，J＝5.6，11.8Hz)，4.29(1H，dd，J＝2.0，11.8Hz)，4.35-4.55(2H，m)，5.00-5.10(1H，m)，6.70-7.80(2H，m)，7.00-7.10(2H，m)

Example 19

3- (6-O-butyryl-beta-D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole

The title compound was prepared in analogy to the procedure described for example 17 using butyryl chloride instead of propionyl chloride.

¹H-NMR(CD₃OD)δppm：

0.88(3H，t，J＝7.4Hz)，1.26(6H，d，J＝6.0Hz)，1.30-1.40(6H，m)，1.50-1.65(2H，m)，2.07(3H，s)，2.15-2.30(2H，m)，3，25-3.50(4H，m)，3.60-3.70(2H，m)，4.17(1H，dd，J＝5.7，11.9Hz)，4.31(1H，dd，J＝2.0，11.9Hz)，4.30-4.55(2H，m)，5.00-5.10(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Example 20

4- [ (4-Isopropoxyphenyl) methyl ] -1-isopropyl-5-methyl-3- (6-O-pivaloyl) -beta-D-glucopyranosyloxy) pyrazole

The title compound was prepared in a similar manner as described in example 17 using pivaloyl chloride instead of propionyl chloride.

¹H-NMR(CD₃OD)δppm：

1.10(9H，s)，1.26(6H，d，J＝6.1Hz)，1.30-1.40(6H，m)，2.06(3H，s)，3.30-3.45(4H，m)，3.60-3.70(2H，m)，4.16(1H，dd，J＝5.8，11.7Hz)，4.30(1H，dd，J＝2.0，11.7Hz)，4.30-4.55(2H，m)，5.05-5.15(1H，m)，6.70-6.80(2H，m)，7.00-7.10(2H，m)

Example 21

1-ethoxycarbonyl-3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-ethiophenyl) methyl ] -5-methylpyrazole

To a solution of 4- [ (4-ethylthiophenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole (0.03g) in 2, 4, 6-trimethylpyridine (0.5mL) was added ethyl chloroformate (0.021mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution, and the resulting compound was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give 1-ethoxycarbonyl-3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-ethinylphenyl) methyl ] -5-methylpyrazole (0.023 g).

¹H-NMR(CD₃OD)δppm：

1.15-1.30(6H，m)，1.39(3H，t，J＝7.1Hz)，2.37(3H，s)，2.87(2H，q，J＝7.3Hz)，3.35-3.50(3H，m)，3.60-3.80(3H，m)，4.12(2H，q，J＝7.1Hz)，4.29(1H，dd，J＝5.3，11.9Hz)，4.35-4.50(3H，m)，5.50-5.60(1H，m)，7.10-7.25(4H，m)

Examples 22 to 43

The compounds listed in table 2 were prepared from the corresponding starting materials in analogy to the procedure described in example 21.

[ Table 2]]

Examples	R	R²	Q
Examples	R	R²	Q	22	Ethoxycarbonyl group	Isopropoxy group	Methyl radical
23	Ethoxycarbonyl group	Propyl radical	Methyl radical	22	Ethoxycarbonyl group	Isopropoxy group	Methyl radical
23	Ethoxycarbonyl group	Propyl radical	Methyl radical	24	Ethoxycarbonyl group	Isobutyl radical	Methyl radical
25	Ethoxycarbonyl group	Propoxy group	Methyl radical	24	Ethoxycarbonyl group	Isobutyl radical	Methyl radical
25	Ethoxycarbonyl group	Propoxy group	Methyl radical	26	Ethoxycarbonyl group	Ethoxy radical	Methyl radical
27	Ethoxycarbonyl group	Trifluoromethyl radical	Methyl radical	26	Ethoxycarbonyl group	Ethoxy radical	Methyl radical
27	Ethoxycarbonyl group	Trifluoromethyl radical	Methyl radical	28	Ethoxycarbonyl group	Tert-butyl radical	Methyl radical
29	Ethoxycarbonyl group	Butoxy radical	Methyl radical	28	Ethoxycarbonyl group	Tert-butyl radical	Methyl radical
29	Ethoxycarbonyl group	Butoxy radical	Methyl radical	30	Ethoxycarbonyl group	Methylthio group	Methyl radical
31	Ethoxycarbonyl group	Methylthio group	Ethyl radical	30	Ethoxycarbonyl group	Methylthio group	Methyl radical
31	Ethoxycarbonyl group	Methylthio group	Ethyl radical	32	Ethoxycarbonyl group	Isopropyl group	Methyl radical
33	Ethoxycarbonyl group	First of allSulfur based radicals	Trifluoromethyl radical	32	Ethoxycarbonyl group	Isopropyl group	Methyl radical
33	Ethoxycarbonyl group	First of allSulfur based radicals	Trifluoromethyl radical	34	Ethoxycarbonyl group	Hydrogen	Trifluoromethyl radical
35	Ethoxycarbonyl group	Methoxy radical	Trifluoromethyl radical	34	Ethoxycarbonyl group	Hydrogen	Trifluoromethyl radical
35	Ethoxycarbonyl group	Methoxy radical	Trifluoromethyl radical	36	Ethoxycarbonyl group	Methoxy radical	Methyl radical
37	Ethoxycarbonyl group	Hydrogen	Methyl radical	36	Ethoxycarbonyl group	Methoxy radical	Methyl radical
37	Ethoxycarbonyl group	Hydrogen	Methyl radical	38	Ethoxycarbonyl group	Methyl radical	Methyl radical
39	Ethoxycarbonyl group	Ethyl radical	Methyl radical	38	Ethoxycarbonyl group	Methyl radical	Methyl radical
39	Ethoxycarbonyl group	Ethyl radical	Methyl radical	40	EthoxycarbonylBase of	Methyl radical	Trifluoromethyl radical
41	Ethoxycarbonyl group	Ethyl radical	Trifluoromethyl radical	40	EthoxycarbonylBase of	Methyl radical	Trifluoromethyl radical
41	Ethoxycarbonyl group	Ethyl radical	Trifluoromethyl radical	42	Ethoxycarbonyl group	Isopropyl group	Trifluoromethyl radical
43	Ethoxycarbonyl group	Chlorine	Trifluoromethyl radical	42	Ethoxycarbonyl group	Isopropyl group	Trifluoromethyl radical

Example 44

3- (6-0-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -1- (ethoxycarbonyloxymethyl) -4- [ (4-methylthiophenyl) methyl ] -5-methyl-pyrazole

To a solution of 3- (. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-methylthiophenyl) methyl ] -1H-pyrazole (0.11g) in water (0.5mL) and ethanol (0.1mL) was added formaldehyde (37% aqueous solution, 0.068mL), and the compound was stirred at 40 ℃ for 3 days. Tetrahydrofuran and anhydrous magnesium sulfate were added to the reaction mixture, and the resulting insoluble matter was removed by filtration. The solvent of the filtrate was removed under reduced pressure. The residue was dissolved in 2, 4, 6-trimethylpyridine (1 mL). To this solution was added ethyl chloroformate (0.099g), and the mixture was stirred at room temperature overnight. Citric acid monohydrate (4g) and water were added to the reaction mixture, and the resulting mixture was purified by ODS solid-phase extraction (washing solvent: 10% citric acid aqueous solution, distilled water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol-15/1) gave 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -1- (ethoxycarbonyloxymethyl) -4- [ (4-methylthiophenyl) methyl ] -5-methylpyrazole (0.058 g).

¹H-NMR(CD₃OD)δppm：

1.23(3H，t，J＝7.1Hz)，1.26(3H，t，J＝7.1Hz)，2.18(3H，s)，2.42(3H，s)，3.30-3.45(3H，m)，3.50-3.60(1H，m)，3.63(1H，d，J＝16.0Hz)，3.70(1H，d，J＝16.0Hz)，4.13(2H，q，J＝7.1Hz)，4.18(2H，q，J＝7.1Hz)，4.28(1H，dd，J＝4.8，11.7Hz)，4.39(1H，dd，J＝2.0，11.7Hz)，5.25-5.35(1H，m)，5.80-5.95(2H，m)，7.10-7.20(4H，m)

Example 45

1-acetyl-4- [ (4-ethinylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methylpyrazole

To a solution of 4- [ (4-ethylthiophenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole (0.41g) in tetrahydrofuran (10mL) were added acetic acid (0.11mL) and acetic anhydride (0.18mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The resulting precipitated crystals were collected by filtration to give 1-acetyl-4- [ (4-ethinylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methylpyrazole (0.36 g).

¹H-NMR(CD₃OD)δppm：

1.24(3H，t，J＝7.3Hz)，2.43(3H，s)，2.54(3H，s)，2.89(2H，q，J＝7.3Hz)，3.30-3.50(4H，m)，3.60-3.75(3H，m)，3.80-3.90(1H，m)，5.45-5.55(1H，m)，7.10-7.30(4H，m)

Example 46

1-acetyl-3- (6-O-ethoxycarbonyl-beta-D-glucopyranosyloxy) -4- [ (4-ethinylphenyl) methyl ] -5-methylpyrazole

To a solution of 1-acetyl-4- [ (4-ethinylphenyl) methyl ] -3- (. beta. -D-glucopyranosyloxy) -5-methylpyrazole (0.03g) in 2, 4, 6-trimethylpyridine (0.5mL) was added ethyl chloroformate (0.012mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution (5mL), and the resulting mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with 10% aqueous citric acid solution and water to give 1-acetyl-3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-ethylthiophenyl) methyl ] -5-methylpyrazole (0.020 g).

¹H-NMR(CD₃OD)δppm：

1.20(3H，t，J＝7.2Hz)，1.24(3H，t，J＝7.4Hz)，2.41(3H，s)，2.55(3H，s)，2.88(2H，q，J＝7.4Hz)，3.30-3.40(1H，m)，3.40-3.50(2H，m)，3.50-3.65(1H，m)，3.65(1H，d，J＝15.8Hz)，3.72(1H，d，J＝15.8Hz)，4.05-4.15(2H，m)，4.27(1H，dd，J＝6.3，11.7Hz)，4.42(1H，dd，J＝2.0，11.7Hz)，5.40-5.55(1H，m)，7.10-7.30(4H，m)

Example 47

3- (6-O-ethoxycarbonyl-beta-D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole

To a solution of 1- (benzyloxycarbonyl) -3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole (0.17g) in tetrahydrofuran (4mL) was added 10% palladium-carbon powder, and the mixture was stirred at room temperature for 3 hours. The resulting insoluble matter was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol ═ 10/1) to give 3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methyl-1H-pyrazole (0.10 g).

¹H-NMR(CD₃OD)δppm：

1.23(3H，t，J＝7.1Hz)，1.26(6H，d，J＝6.0Hz)，2.04(3H，s)，3.30-3.55(4H，m)，3.61(1H，d，J＝15.9Hz)，3.67(1H，d，J＝15.9Hz)，4.12(2H，q，J＝7.1Hz)，4.27(1H，dd，J＝4.9，1 1.7Hz)，4.38(1H，dd，J＝2.0，11.7Hz)，4.45-4.60(1H，m)，5.10-5.20(1H，m)，6.70-6.80(2H，m)，7.00-7.15(2H，m)

Example 48

4- [ (4-Isopropoxyphenyl) methyl ] -3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methyl-1H-pyrazole

The title compound was synthesized in analogy to the procedure described for example 47 using 1- (benzyloxycarbonyl) -4- [ (4-isopropoxyphenyl) methyl ] -3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole instead of 1- (benzyloxycarbonyl) -3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -5-methylpyrazole.

¹H-NMR(CD₃OD)δppm：

1.26(6H，d，J＝5.9Hz)，2.04(3H，s)，3.30-3.55(4H，m)，3.61(1H，d，J＝15.9Hz)，3.67(1H，d，J＝15.9Hz)，3.72(3H，s)，4.28(1H，dd，J＝5.2，11.7Hz)，4.39(1H，dd，J＝1.8，11.7Hz)，4.45-4.55(1H，m)，5.05-5.15(1H，m)，6.70-6.80(2H，m)，7.00-7.15(2H，m)

Test example 1

Determination of the inhibitory Effect on human SGLT2 Activity

1) Construction of a plasmid vector expressing human SGLT2

The cDNA library for PCR amplification was prepared by reverse transcribing total RNA isolated from human kidney (or gene i) 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 the above-mentioned cDNA library of human kidney as a template and the following oligonucleotides 0702F and 0712R represented by SEQ ID Nos. 1 and 2, respectively, as primers. The amplified DNA fragments were ligated into the cloning vector pCR-Blunt (Invitrogen) according to standard methods of the kit. Escherichia coli HB101 was transformed in the conventional manner, and then transformants were selected on LB agar medium containing 50. mu.g/mL of kanamycin. After plasmid DNA was extracted from one of the transformants and purified, a DNA fragment encoding human SGLT2 was amplified by PCR reaction in which the following oligonucleotides 0714F and 0715R represented by SEQ ID 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). This purified DNA fragment was inserted into the corresponding restriction site of the fusion protein expression vector pcDNA3.1(-) Myc/His-B (Invitrogen). Escherichia coli HB101 was transformed in a conventional manner, and then transformants were selected on LB agar medium containing 100. mu.g/mL of ampicillin. After plasmid DNA was extracted from one of the transformants and purified, the base sequence of the DNA fragment inserted into the multicloning site of the vector pcDNA3.1(-) Myc/His-B was analyzed. Wells et al (am. J. Physiol., Vol.263, pp.459-465 (1992)) reported that this clone had a base substitution compared to human SGLT2 (base ATC encoding isoleucine-433 was replaced by GTC). Then, a clone was obtained in which isoleucine-433 was replaced with valine. This plasmid vector expressing human SGLT2, in which a peptide represented by SEQ ID NO. 5 was fused with a carboxy-terminal alanine residue, was named KL 29.

Serial number 1 ATGGAGGAGCACACAGAGGC

Serial number 2 GGCATAGAAGCCCCAGAGGA

Serial number 3 AACCTCGAGATGGAGGAGCACACAGAGGC

Serial number 4 AACAAGCTTGGCATAGAAGCCCCAGAGGA

Serial number 5 KLGPEQKLISEEDLNSAVDHHHHHH

2) Preparation of cells transiently expressing human SGLT2

Plasmid KL29 encoding human SGLT2 was transfected into COS-7 cells (RIKEN CELL BANKRCB0539) by electroporation. Electroporation was carried out using GENE PULSER II (Bio-Rad laboratories) under the following conditions: 0.290kV, 975 muF, 2X 10⁶COS-7 cells, 0.4cm tubes contained 500. mu.L of OPTI-MEM I medium (Gibco-BRL: LIFE TECHNOLOGIES) with 20. mu.g of KL 29. After gene transfer, cells were harvested by centrifugation and resuspended in OPTI-MEM I medium (1 mL/tube). 125. mu.L of this cell suspension was added to each well of a 96-well plate. At 5% CO₂After overnight incubation at 37 ℃ 125. mu.L of DMEM medium containing 10% fetal bovine serum (Sanko Junyaku), 100 units/mL penicillin sodium G (Gibco-BRL: LIFE TECHNOLOGIES), and 100. mu.g/mL streptomycin sulfate (Gibco-BRL: LIFE TECHNOLOGIES) was added to each well. These cells were cultured to the next day, and then used to measure inhibitory activity against the uptake of methyl- α -D-glucopyranoside.

3) Measurement of inhibitory Activity against methyl-alpha-D-glucopyranoside uptake

The test mixture was dissolved in dimethyl sulfoxide and washed with uptake buffer (pH7.4 containing 140mM sodium chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 5mM methyl-. alpha. -D-glucopyranoside, 10mM2- [4- (2-hydroxyethyl) -1-piperazinyl)]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminoethane) were used as test samples to measure inhibitory activity. After removing the medium transiently expressing human SGLT2 from COS-7 cells, 200. mu.L of a pretreatment buffer (pH7.4 containing 140mM choline chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM2- [4- (2-hydroxyethyl) -1-piperazinyl) was added to each well]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminoethane), and the cells were incubated at 37 ℃ for 10 minutes. After removal of the pretreatment buffer, 200. mu.L of the same buffer was added and the cells were incubated at 37 ℃ for 10 minutes. The buffer used for pretreatment was prepared by adding 7. mu.L of methyl-. alpha. -D- (U-14C) glucopyranoside (Amersham Pharmacia Biotech) to 525. mu.L of the prepared test sample. For control, buffers for the assay were prepared without the test compound. To estimate the basal uptake in the absence of test compound and sodium, a buffer for measuring the basal uptake was prepared in a similar manner, this buffer containing 140mM choline chloride instead of sodium chloride. After removal of the pre-treatment buffer, 75 was added to each wellmu.L of each measurement buffer, cells were incubated at 37 ℃ for 2 hours. After removing the measurement buffer, 200. mu.L of a washing buffer (pH7.4 containing 140mM choline chloride, 2mM potassium chloride, 1mM calcium chloride, 1mM magnesium chloride, 10mM methyl-. alpha. -D-glucopyranoside, 10mM2- [4- (2-hydroxyethyl) -1-piperazinyl) was added to each well]Ethanesulfonic acid and 5mM tris (hydroxymethyl) aminoethane) and immediately removed. After washing twice more, 75. mu.L of 0.2mol/L NaOH was added to each well to lyse the cells. After transferring the cell lysate to PicoPlate (Packard) and adding 150. mu.L MicroScint-40(Packard) to each well, the radioactivity was measured using a microplate scintillation counter TopCount (Packard). The difference in uptake is expressed as a percentage, which is calculated by subtracting the radioactivity of the basal uptake from the control and then calculating the concentration at which 50% of the uptake is Inhibited (IC) from the concentration-inhibition curve using the least squares method₅₀). The results are shown in table 3 below.

[ Table 3 ]]

Test compounds	IC₅₀Value (nM)
Test compounds	IC₅₀Value (nM)	Reference example 37	181
Reference example 38	441	Reference example 37	181
Reference example 38	441	Reference example 39	346
Reference example 40	702	Reference example 39	346
Reference example 40	702	Reference example 41	185
Reference example 45	84	Reference example 41	185
Reference example 45	84	Reference example 46	509
Reference example 47	441	Reference example 46	509
Reference example 47	441	Reference example 48	679
Reference example 50	415	Reference example 48	679
Reference example 50	415	Reference example 51	383
Reference example 54	835	Reference example 51	383
Reference example 54	835	Reference example 57	280
Reference example 58	190	Reference example 57	280
Reference example 58	190	Reference example 60	634
Reference example 72	369	Reference example 60	634
Reference example 72	369	WAY-123783	＞100000

Test example 2

Determination of oral absorbability

1) Preparation of samples for measurement of drug concentration after tail vein injection

SD rats (CLEA JAPAN, INC., male, 5 weeks old, 140-170g) fasted overnight were used as test animals. 1.8mL of ethanol, 7.2mL of polyethylene glycol 400, and 9mL of saline were added to dissolve 16mg of test compound, and then a solution of 3.3mg/mL was prepared. The body weight of the rats was measured and a solution of the test compound was intravenously injected at a dose of 3mL/kg (10mg/kg) into the tail vein of the non-anesthetized rats. Intravenous injection into the tail was performed using a 26G needle and a 1mL syringe. The sampling times for blood samples were 2, 5, 10, 20, 30, 60 and 120 minutes after tail vein injection. Blood was centrifuged and plasma was used as a sample to measure drug concentration in plasma.

2) Preparation of samples for measuring drug concentration after oral administration

SD rats (CLEA JAPAN, INC., male, 5 weeks old, 140-170g) fasted overnight were used as test animals. The test compound was suspended or dissolved in 0.5% sodium carboxymethyl cellulose solution to give a concentration of 1mg/mL of active ingredient. When a homogeneous suspension is not obtained at this time, the test compound is dissolved in ethanol to have an active ingredient concentration of 100mg/mL, and then 99-fold volume of a 0.5% sodium carboxymethylcellulose solution is added to this solution to obtain a suspension. After measuring the body weight of the rat, the above-mentioned sample containing the test compound was orally administered at a dose of 10mL/kg (10mg/kg of active ingredient). Rats were orally administered with a gastric tube and 2.5mL syringe. The sampling times for blood samples were 15, 30, 60, 120 and 240 minutes after oral administration. Blood was centrifuged and plasma was used as a sample to measure drug concentration in plasma.

3) Measurement of drug concentration

Method A

An appropriate amount of an appropriate internal standard was added to 0.1mL of the plasma obtained in 1) and 2) above, and then 1mL of methanol was added for deproteinization according to a conventional method. After centrifugation, the methanol phase is evaporated to dryness under nitrogen. The residue was dissolved in 300. mu.L of mobile phase and a 30. mu.L aliquot was added to the HPLC. The drug concentration in plasma was measured by the HPLC method under the following conditions. A standard curve was prepared by adding the appropriate internal standard to 0.1mL of blank plasma and adding sufficient quantities of the corresponding active form at various concentrations according to conventional methods, and performing a similar procedure as described above.

Column: develosil ODS-UG-5 (4.6X 250mm)

Mobile phase: acetonitrile/10 mM phosphate buffer (pH3.0) ═ 22: 78(v/v)

Column temperature: 50 deg.C

Flow rate: 1.0 mL/min

Measuring wavelength: UV 232nm

Method B

An appropriate amount of an appropriate internal standard was added to 50. mu.L of the plasma obtained in the above 1) and 2), and 100. mu.L of distilled water was added, followed by extraction with 1mL of diethyl ether, according to a conventional method. After centrifugation, the diethyl ether phase was evaporated to dryness under nitrogen. The residue was dissolved in 200. mu.L of mobile phase and 10. mu.L aliquots were added to the LC-MS/MS. The drug concentration in plasma was measured by LC-MS/MS method under the following conditions. A standard curve was prepared by adding the appropriate internal standard to 50. mu.L of blank plasma and adding sufficient quantities of the corresponding active forms at different concentrations according to conventional methods, and performing the similar procedure as described above.

LC

Column: symmetry C₈(2.1×20mm)

Mobile phase: acetonitrile/0.1% acetic acid solution 65: 35(v/v)

Column temperature: 40 deg.C

Flow rate: 0.2 mL/min

MS/MS

An ionization method comprises the following steps: ESI (turbo Ion spray), cation detection method

Ion atomization voltage: 5000V

Heater gas temperature: 450 deg.C

Collision energy: 17.5V

Multiplication voltage: 2300V

Flow rate of the turboionic atomizing gas: 7000mL/min

Atomizer gas: 11 BIT

Gas injection: 11 BIT

Collision gas: 4 BIT

The area under the plasma concentration-time curve obtained by intravenous injection of the test compound into the tail vein and oral administration of the test compound was estimated from the plasma concentrations obtained by methods a and B at respective times using WinNonlin standard by Pharsight, and then bioavailability (%) was calculated based on the following formula. The results are shown in table 4 below.

Bioavailability (%) ═ area under the plasma concentration-time curve for oral administration/area under the plasma concentration-time curve for tail vein injection x 100

[ Table 4 ]]

Test compounds	Method	Bioavailability (%)
Test compounds	Method	Bioavailability (%)	Example 1	B	27
Example 15	B	27	Example 1	B	27
Example 15	B	27	Example 16	B	32
Example 47	A	15	Example 16	B	32
Example 47	A	15	Example 48	A	11
Reference example 37	A	0	Example 48	A	11

Test example 3

The facilitation of urine glucose excretion was determined.

SD rats (CLEA JAPAN, INC., male, 7 weeks old, 140-170g) fasted overnight were used as test animals. The test compound was suspended or dissolved in 0.5% sodium carboxymethyl cellulose solution to give a concentration of 2mg/mL of active ingredient. When a homogenous suspension is not obtained at this point, the test compound is dissolved in ethanol to a concentration of 200mg/mL of active ingredient, and then 99 volumes of 0.5% sodium carboxymethylcellulose solution are added to this solution to give a 2mg/mL suspension. Portions of the suspension were diluted with 0.5% sodium carboxymethylcellulose solution to make suspensions of 0.6 and 0.2 mg/mL. After measuring the body weight of the rats, the experimental suspensions were administered orally at a dose of 5mL/kg (1, 3 and 5 mg/kg). For control, a 0.5% sodium carboxymethylcellulose solution was administered orally at a dose of only 5 mL/kg. Immediately after oral administration, 400g/L of glucose solution was orally administered at a dose of 5mL/kg (2 g/kg). Rats were orally administered with a gastric tube and 2.5mL syringe. Each group had three animals. Urine samples were collected in metabolic cages (metabolic cages) after the end of glucose administration. The sampling time for collecting the urine samples was 24 hours after the administration of glucose. After the urine sample was collected, the urine volume was recorded and the glucose concentration in the urine was measured. With the kit for laboratory testing: glucose B-Test WAKO (Wako Pure Chemical Industries, Ltd.) measures glucose concentration. Urine glucose excretion per 200g body weight in 24 hours was calculated using urine volume, urine glucose concentration and body weight. The results are shown in table 5.

[ Table 5 ]]

Test compounds	Dosage (mg/kg)	Excretion amount of urine glucose (mg/24 hours 200g body weight)
Test compounds	Dosage (mg/kg)		Example 1	1	1.6
3	28.3			1	1.6
3	28.3	10		127.5
Example 15	1	10		127.5	1.7
	1	3	36.8		1.7
	10	3	36.8	167.3

Test example 4

Acute toxicity test

Male ICR mice (Japan slc. inc., 20-25g, 5 animals per group) aged 4 weeks were fasted for 4 hours, and then a suspension (200mg/mL) prepared by adding a 0.5% sodium carboxymethylcellulose solution to the test compound was orally administered at a dose of 10mL/kg (2000 mg/kg). Observations were made 24 hours after application. The results are shown in table 6.

[ Table 6 ]]

Test compounds	Number of deaths
Test compounds	Number of deaths	Example 48	0/5

INDUSTRIAL APPLICABILITY

The glucopyranosyloxypyrazole derivative of the invention represented by the above general formula (I) or a pharmaceutically acceptable salt thereof has improved oral absorption. In addition, they can excrete excessive glucose into urine by preventing reabsorption of glucose in the kidney, thereby showing an excellent hypoglycemic effect because they are converted into glucopyranosyloxypyrazole derivatives represented by the above general formula (II) as their active form in vivo, and show a potent inhibitory activity against human SGLT 2. Therefore, the present invention can provide a pharmaceutical composition for preventing or treating diseases associated with hyperglycemia such as diabetes, diabetic complications, obesity and the like, which is also suitable as an oral preparation.

[ sequence Listing text ]

Sequence number 1: synthesis of DNA primers

Sequence number 2: synthesis of DNA primers

Sequence number 3: synthesis of DNA primers

Sequence number 4: synthesis of DNA primers

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

Sequence listing

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

Rattan house elegant era

Vogue beacon

Western village Junyang

Yishi of Zhonglin

Yizuozzhizheng (Yizuozzhi)

<120> glucopyranosyloxypyrazole derivatives and their use in medicine

<130>PCT-A0138

<150>JP 2000/403534

<151>2000-12-28

<160>5

<170> PatentIn version 3.0 and MS Word

<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 the carboxy terminus of alanine residue in 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

1. A glucopyranosyloxypyrazole derivative represented by the following general formula:

wherein R represents a hydrogen atom, a C1-C6 alkyl group, a C2-C7 acyl group, a C2-C7 alkoxycarbonyl group, a C2-C7 acyloxymethyl group, a C1-C6 alkoxycarbonyloxymethyl group; one of Q and T represents a group represented by the following general formula:

wherein P represents a hydrogen atom, a C2-C7 acyl group, a C1-C6 alkoxy C2-C7 acyl group, a C2-C7 alkoxycarbonyl C2-C7 acyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy C2-C7 alkoxycarbonyl group, and the other represents a C1-C6 alkyl group; r²Represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio; provided that P does not represent hydrogen when R represents a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof.

2. The glucopyranosyloxypyrazole derivative according to claim 1, wherein T represents a group represented by the following general formula:

wherein P represents a hydrogen atom, a C1-C6 alkyl group, a C2-C7 acyl group, a C1-C6 alkoxy C2-C7 acyl group, a C2-C7 alkoxycarbonyl C2-C7 acyl group, a C2-C7 alkoxycarbonyl group; q represents C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

3. The glucopyranosyloxypyrazole derivative according to claim 1, which is represented by the following general formula:

wherein R is¹¹Represents a hydrogen atom or a C1-C6 alkyl group; q²And T²One represents a group represented by the following general formula:

wherein P is²Represents C2-C7 acyl, C1-C6 alkoxy C2-C7 acyl, C2-C7 alkoxycarbonyl C2-C7 acyl, C2-C7 alkoxycarbonyl, C1-C6 alkoxy C2-C7 alkoxycarbonyl, and the other represents C1-C6 alkyl; r²¹Represents C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthio, or a pharmaceutically acceptable salt thereof.

4. The glucopyranosyloxypyrazole derivative according to claim 3, wherein T is²Represents a group represented by the following general formula:

wherein P is²Represents C2-C7 acyl, C1-C6 alkoxy C2-C7 acyl, C2-C7 alkoxy carbonyl C2-C7 acyl, C2-C7 alkoxy carbonyl, C1-C6 alkoxy C2-C7 alkoxy carbonyl; q²Represents C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

5. The glucopyranosyloxypyrazole derivative according to claim 3, which is represented by the following general formula:

wherein R11 represents a hydrogen atom or a C1-C6 alkyl group; one of Q3 and T3 represents a group represented by the following general formula:

wherein P is³Represents a C2-C7 acyl group or a C2-C7 alkoxycarbonyl group, and the other represents a C1-C6 alkyl group; r²¹Represents C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthio, or a pharmaceutically acceptable salt thereof.

6. The glucopyranosyloxypyrazole derivative as claimed in claim 5, wherein T is³Represents a group represented by the following general formula:

wherein P is³Represents a C2-C7 acyl group or a C2-C7 alkoxycarbonyl group); q³Represents C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

7. The glucopyranosyloxypyrazole derivative according to claim 3, which is represented by the following general formula:

wherein R is¹²Represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms; q⁴And T⁴One represents a group represented by the following general formula:

wherein P is²Represents C2-C7 acyl, C1-C6 alkoxy C2-C7 acyl, C2-C7 alkoxycarbonyl C2-C7 acyl, C2-C7 alkoxycarbonyl, C1-C6 alkoxy C2-C7 alkoxycarbonyl, while the other represents a linear or branched alkyl group having 1-3 carbon atoms; r²²Represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 3 carbon atoms or a linear or branched alkylthio group having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

8. The glucopyranosyloxypyrazole derivative according to claim 7, wherein T is⁴Represents a group represented by the following general formula:

wherein P is²Represents C2-C7 acyl, C1-C6 alkoxy C2-C7 acyl, C2-C7 alkoxy carbonyl C2-C7 acyl, C2-C7 alkoxy carbonyl, C1-C6 alkoxy C2-C7 alkoxy carbonyl; q⁴Represents a linear or branched alkyl group 3 having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

9. The glucopyranosyloxypyrazole derivative according to claim 7, which is represented by the following general formula:

wherein R is¹²Represents a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms; q⁵And T⁵One represents a group represented by the following general formula:

wherein P is³Represents a C2-C7 acyl group or a C2-C7 alkoxycarbonyl group, the other represents a linear or branched alkyl group having 1-3 carbon atoms; r²²Represents a linear or branched alkyl group having 1 to 4 carbon atoms, a linear or branched alkoxy group having 1 to 3 carbon atoms or a linear or branched alkylthio group having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

10. The glucopyranosyloxypyrazole derivative according to claim 9, wherein T is⁵Represents a group represented by the following general formula:

wherein P is³Represents a C2-C7 acyl group or a C2-C7 alkoxycarbonyl group; q⁵Represents a straight or branched chain alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof.

11. The glucopyranosyloxypyrazole derivative according to claim 10, selected from the group consisting of 4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl- β -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isopropoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, and mixtures thereof, 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-ethylphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethylphenyl) methyl ] -3- (6-O-isobutoxycarbonyl- β -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl- β -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl- β -D-glucopyranosyloxy) -4- [ (4-ethoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 4- [ (4-ethoxyphenyl) methyl ] -3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole, 1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methylpyrazole -4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-4- [ (4-methoxyphenyl) methyl ] -5-methylpyrazole, 1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole, 2-methyl-4-pyridines, 3-isopropyl-4-methyl-4-pyridines, 3-isopropyl-methyl-4-pyridines, 5-methyl-4-pyridines, 2-methyl-4-pyridines, 5-methyl-4-, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole, 3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole and 3- (6-O-isobutoxycarbonyl-. beta. -D-glucopyranosyloxy) -1-isopropyl-5-methyl-4- [ (4-methylthiophenyl) methyl ] pyrazole.

12. The glucopyranosyloxypyrazole derivative according to claim 11, which is selected from the group consisting of 4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-3- (6-O-methoxycarbonyl-. beta. -D-glucopyranosyloxy) -5-methylpyrazole, 3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole, 3- (6-O-isopropoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole and 3- (6-O- isobutoxycarbonyl-beta-D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole.

3- (6-O-ethoxycarbonyl-. beta. -D-glucopyranosyloxy) -4- [ (4-isopropoxyphenyl) methyl ] -1-isopropyl-5-methylpyrazole.

14. A pharmaceutical composition comprising the glucopyranosyloxypyrazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

15. Use of a pharmaceutical composition according to claim 14, for the preparation of a medicament for inhibiting a human SGLT2 inhibitor.

16. The use according to claim 15, wherein the medicament is for the prevention or treatment of a disease associated with hyperglycemia.

17. The use of claim 16, wherein the disease associated with hyperglycemia is selected from the group consisting of diabetes, diabetic complications, obesity, hyperinsulinemia, glucose metabolism disorders, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, and gout.

18. The use of claim 17, wherein the disease associated with hyperglycemia is diabetes.

19. The use of claim 17, wherein the disease associated with hyperglycemia is a diabetic complication.

20. The use of claim 17, wherein the disease associated with hyperglycemia is obesity.

21. The use of claim 15, wherein the medicament is administered orally.

22. Use of a glucopyranosyloxypyrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease associated with hyperglycemia.