US 2004O116357A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0116357 A1 Fushimi et al. (43) Pub. Date: Jun. 17, 2004

(54) GLUCOPYRANOSYLOXYPYRAZOLE DERVATIVES AND MEDICINAL USE THEREOF (I) (76) Inventors: Nobuhiko Fushimi, Matsumoto-shi (JP); Hideki Fujikura, Matsumoto-shi (JP); Toshihiro Nishimura, Minamiazumi-gun (JP); Kenji Katsuno, Kamiina-gun (JP); Masayuki Isaji, Shiojiri-shi (JP) Correspondence Address: SUGHRUE MION, PLLC 2100 PENNSYLVANIAAVENUE, N.W. SUTE 800 WASHINGTON, DC 20037 (US) (21) Appl. No.: 10/469,140 (22) PCT Filed: Feb. 26, 2002 (86) PCT No.: PCT/JP02/01708 wherein R', R and R represent a hydrogen atom or a (30) Foreign Application Priority Data halogen atom; R" represents a lower alkyl group or a halo(lower alkyl) group; and R represents a hydrogen atom, Feb. 27, 2001 (JP)...... 2001-053085 a lower alkyl group, a lower alkoxy group, a lower alkylthio group, etc., a pharmaceutically acceptable Salt thereof or a Publication Classification prodrug thereof., which exert an excellent inhibitory activity (51) Int. Cl...... A61K 31/7056 in human SGLT2, and therefore are useful as drugs for the (52) U.S. Cl...... 514/23: 536/17.4 prevention or treatment of a disease associated with hyper glycemia Such as diabetes, diabetic complications or obesity, (57) ABSTRACT pharmaceutically acceptable Salts thereof or prodrugs The present invention provides glucopyranosyloxypyrazole thereof, production intermediates thereof and pharmaceuti derivatives represented by the general formula: cal uses thereof. US 2004/0116357 A1 Jun. 17, 2004

GLUCOPYRANOSYLOXYPYRAZOLE 0005. In recent years, development of new type antidia DERVATIVES AND MEDICINAL USE THEREOF betic agents has been progressing, which promote urinary glucose excretion and lower blood glucose level by prevent TECHNICAL FIELD ing excess glucose reabsorption at the kidney (J. Clin. 0001. The present invention relates to glucopyopyrano Invest., Vol. 79, pp. 1510-1515 (1987)). In addition, it is Syloxypyrazole derivatives, pharmaceutically acceptable reported that SGLT2 (Na"/glucose cotransporter 2) is present in the S1 Segment of the kidney's proximal tubule Salts thereof or prodrugs thereof which are useful as medi and participates mainly in reabsorption of glucose filtrated caments, production intermediates thereof and pharmaceu through glomerular (J. Clin. Invest., Vol.93, pp.397-404 tical uses thereof. (1994)). Accordingly, inhibiting a human SGLT2 activity 0002 More particularly, the present invention relates to prevents reabsorption of excess glucose at the kidney, Sub glucopyranosyloxypyrazole derivatives which have an Sequently promotes excreting excess glucose though the inhibitory activity in human SGLT2, represented by the urine, and normalizes blood glucose level. Therefore, fast general formula: development of antidiabetic agents, which have a potent (I) inhibitory activity in human SGLT2 and have a new mecha nism, has been desired. In addition, Since Such agents promote the excretion of excess glucose though the urine and consequently the glucose accumulation in the body is decreased, they are also expected to have a preventing or alleviating effect on obesity and a urinating effect. Further more, the agents are considered to be useful for various related diseases which occur accompanying the progreSS of diabetes or obesity due to hyperglycemia. 0006 AS compounds having pyrazole moiety, it is described that WAY-123783 increased an amount of excreted glucose in normal mice. However, its effects in human are not described at all (J. Med. Chem., Vol.39, pp. 3920-3928 (1996)). DISCLOSURE OF THE INVENTION 0003 wherein R, R and R may be the same or different 0007 The present inventors have studied earnestly to find and each represents a hydrogen atom or a halogen atom; R' compounds having an inhibitory activity in human SGLT2. represents a lower alkyl group or a halo (lower alkyl) group; AS a result, it was found that compounds represented by the and R represents a hydrogen atom, a lower alkyl group, a above general formula (I) show an excellent inhibitory lower alkoxy group, a lower alkylthio group, a halo(lower activity in human SGLT2, thereby forming the basis of the alkyl) group, a halogen atom, a lower alkenyl group, a cyclic present invention. lower alkyl group, a cyclic lower alkoxy group, a cyclic 0008. The present invention is to provide the following lower alkylidenemethyl group, a 5- or 6-membered aromatic glucopyranosyloxypyrazole derivatives, pharmaceutically heterocyclic group which contains 1-4 the same or different hetero atoms Selected from an oxygen atom, a Sulfur atom acceptable Salts thereof and prodrugs thereof which exert an and a nitrogen atom in the ring, a phenyl group which may inhibitory activity in human SGLT2 and show an excellent have 1-3 the same or different groups Selected from a hypoglycemic effect by excreting excess glucose in the urine halogen atom and a hydroxy group, or a group represented through preventing the reabsorption of glucose at the kidney, by the general formula: HO-A- wherein A represents a production intermediates thereof and pharmaceutical uses lower alkylene group, pharmaceutically acceptable Salts thereof. thereof or prodrugs thereof, which are useful as agents for 0009. This is, the present invention relates to a glucopy the prevention or treatment of a disease Such as diabetes, ranosyloxypyrazole derivative represented by the general diabetic complications or obesity, production intermediates formula: thereof and pharmaceutical uses thereof. (I) BACKGROUND ART R2 0004 Diabetes is one of lifestyle-related diseases with the background of change of eating habit and lack of Aly R' exercise. Hence, diet and exercise therapies are performed in X R4 patients with diabetes. Furthermore, when its sufficient R5 control and continuous performance are difficult, drug treat ment is simultaneously performed. Now, biguanides, Sulfo nylureas and Sensitivity enhancers have been

employed as antidiabetic agents. However, biguanides and Sulfonylureas show occasionally adverse effects Such as lactic acidosis and hypoglycemia, respectively. In a case of using insulin Sensitivity enhancers, adverse effects Such as edema are occasionally observed, and it is also concerned for advancing obesity. Therefore, in order to Solve these problems, it has been desired to develop antidiabetic agents having a new mechanism. US 2004/0116357 A1 Jun. 17, 2004

0010 wherein R', RandR may be the same or different thyroid hormone receptor agonist, a cholesterol absorption and each represents a hydrogen atom or a halogen atom; R' inhibitor, a lipase inhibitor, a microSomal triglyceride trans represents a lower alkyl group or a halo (lower alkyl) group; fer protein inhibitor, a lipoxygenase inhibitor, a carnitine and R represents a hydrogen atom, a lower alkyl group, a palmitoyl-transferase inhibitor, a Squalene Synthase inhibi lower alkoxy group, a lower alkylthio group, a halo (lower tor, a low-density lipoprotein receptor enhancer, a nicotinic alkyl) group, a halogen atom, a lower alkenyl group, a cyclic acid derivative, a bile acid Sequestrant, a Sodium/bile acid lower alkyl group, a cyclic lower alkoxy group, a cyclic cotransporter inhibitor, a cholesterol ester transfer protein lower alkylidenemethyl group, a 5- or 6-membered aromatic inhibitor, an appetite SuppreSSant, an angiotensin-converting heterocyclic group which contains 1-4 the same or different enzyme inhibitor, a neutral , an hetero atoms Selected from an oxygen atom, a Sulfur atom angiotensin II , an -converting and a nitrogen atom in the ring, a phenyl group which may enzyme inhibitor, an antagonist, a have 1-3 the same or different groups Selected from a diuretic agent, a calcium antagonist, a vasodilating antihy halogen atom and a hydroxy group, or a group represented pertensive agent, a Sympathetic blocking agent, a centrally by the general formula: HO-A- wherein A represents a acting antihypertensive agent, an 82-adrenoceptor agonist, lower alkylene group, a pharmaceutically acceptable Salt an antiplatelets agent, a uric acid Synthesis inhibitor, a thereof or a prodrug thereof. uricoSuric agent and a urinary alkalinizer. 0.011) Also, the present invention relates to a pharmaceu 0015 The present invention relates to a method for the tical composition, a human SGLT2 inhibitor and an agent for prevention or treatment of a disease associated with hyper the prevention or treatment of a disease associated with glycemia, which comprises administering an effective hyperglycemia, which comprise as an active ingredient a amount of (A) a glucopyranosyloxypyrazole derivative rep glucopyranosyloxypyrazole derivative represented by the resented by the above general formula (I), a pharmaceuti above general formula (I), a pharmaceutically acceptable cally acceptable Salt thereof or a prodrug thereof, in com Salt thereof or a prodrug thereof. bination with (B) at least one member selected from the group consisting of an insulin Sensitivity enhancer, a glucose 0012. The present invention relates to a method for the absorption inhibitor, a biguanide, an insulin Secretion prevention or treatment of a disease associated with hyper enhancer, an insulin preparation, a receptor glycemia, which comprises administering an effective antagonist, an kinase Stimulant, a tripeptidyl amount of a glucopyranosyloxypyrazole derivative repre peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a Sented by the above general formula (I), a pharmaceutically protein tyrosine phosphatase-1B inhibitor, a glycogen phos acceptable Salt thereof or a prodrug thereof. phorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase 0013 The present invention relates to a use of a glucopy inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsi ranosyloxypyrazole derivative represented by the above tol, a glycogen Synthase kinase-3 inhibitor, glucagon-like general formula (I), a pharmaceutically acceptable Salt -1, a glucagon-like peptide-1 analogue, a glucagon thereof or a prodrug thereof for the manufacture of a like peptide-1 agonist, , an amylin analogue, an pharmaceutical composition for the prevention or treatment amylin agonist, an aldose reductase inhibitor, an advanced of a disease associated with hyperglycemia. glycation endproducts formation inhibitor, a protein kinase 0.014. The present invention relates to a pharmaceutical C inhibitor, a Y-aminobutyric acid receptor antagonist, a combination which comprises (A) a glucopyranosyloxy Sodium channel antagonist, a transcript factor NF-KB inhibi pyrazole derivative represented by the above general for tor, a lipid peroxidase inhibitor, an N-acetylated-O-linked mula (I), a pharmaceutically acceptable Salt thereof or a acid-dipeptidase inhibitor, insulin-like growth factor-I, prodrug thereof, and (B) at least one member Selected from platelet-derived growth factor, a platelet-derived growth the group consisting of an insulin Sensitivity enhancer, a factor analogue, epidermal growth factor, nerve growth glucose absorption inhibitor, a biguanide, an insulin Secre factor, a carnitine derivative, uridine, 5-hydroxy-1-methyl tion enhancer, an insulin preparation, a hidantoin, EGB-761, bimoclomol, Sulodexide, Y-128, a antagonist, an insulin receptor kinase Stimulant, a tripeptidyl hydroxymethyl-glutaryl coenzyme A reductase inhibitor, a peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a fibric acid derivative, a B-adrenoceptor agonist, an acyl protein tyrosine. phosphatase-1B inhibitor, a glycogen phoS coenzyme Acholesterol acyltransferase inhibitor, probcol, a phorylase inhibitor, a glucose-6-phosphatase inhibitor, a thyroid hormone receptor agonist, a cholesterol absorption fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase inhibitor, a lipase inhibitor, a microSomal triglyceride trans inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsi fer protein inhibitor, a lipoxygenase inhibitor, a carnitine tol, a glycogen Synthase kinase-3 inhibitor, glucagon-like palmitoyl-transferase inhibitor, a Squalene Synthase inhibi peptide-1, a glucagon-like peptide-1 analogue, a glucagon tor, a low-density lipoprotein receptor enhancer, a nicotinic like peptide-1 agonist, amylin, an amylin analogue, an acid derivative, a bile acid Sequestrant, a Sodium/bile acid amylin agonist, an aldose reductase inhibitor, an advanced cotransporter inhibitor, a cholesterol ester transfer protein glycation endproducts formation inhibitor, a protein kinase inhibitor, an appetite SuppreSSant, an angiotensin-converting C inhibitor, a Y-aminobutyric acid receptor antagonist, a enzyme inhibitor, a neutral endopeptidase inhibitor, an Sodium channel antagonist, a transcript factor NF-KB inhibi angiotensin II receptor antagonist, an endothelin-converting tor, a lipid peroxidase inhibitor, an N-acetylated-O-linked enzyme inhibitor, an endothelin receptor antagonist, a acid-dipeptidase inhibitor, insulin-like growth factor-I, diuretic agent, a calcium antagonist, a vasodilating antihy platelet-derived growth factor, a platelet-derived growth pertensive agent, a Sympathetic blocking agent, a centrally factor analogue, epidermal growth factor, nerve growth acting antihypertensive agent, an O-2-adrenoceptor agonist, factor, a carnitine derivative, uridine, 5-hydroxy-1-methyl an antiplatelets agent, a uric acid Synthesis inhibitor, a hidantoin, EGAB-761, bimoclomol, Sulodexide, Y-128, a uricoSuric agent and a urinary alkalinizer. hydroxymethyl-glutaryl coenzyme A reductase inhibitor, a 0016. The present invention relates to a use of (A) a fibric acid derivative, a f-adrenoceptor agonist, an acyl glucopyranosyloxypyrazole derivative represented by the coenzyme Acholesterol acyltransferase inhibitor, probcol, a above general formula (I), a pharmaceutically acceptable US 2004/0116357 A1 Jun. 17, 2004

Salt thereof or a prodrug thereof, and (B) at least one member alkyl group, a lower alkoxy group, a lower alkylthio group, Selected from the group consisting of an insulin Sensitivity a halo (lower alkyl) group, a halogen atom, a lower alkenyl enhancer, a glucose absorption inhibitor, a biguanide, an group, a cyclic lower alkyl group, a cyclic lower alkoxy insulin Secretion enhancer, an insulin preparation, a gluca group, a cyclic lower alkylidenemethyl group, a 5- or gon receptor antagonist, an insulin receptor kinase Stimulant, 6-membered aromatic heterocyclic group which contains a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV 1-4 the same or different hetero atoms Selected from an inhibitor, a protein tyrosine phosphatase-1B inhibitor, a glycogen phosphorylase inhibitor, a glucose-6-phosphatase oxygen atom, a Sulfur atom and a nitrogen atom in the ring, inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate a phenyl group which may have 1-3 the same or different dehydrogenase inhibitor, a hepatic gluconeogenesis inhibi groupS Selected from a halogen atom and a hydroxy group, tor, D-chiroinsitol, a glycogen Synthase kinase-3 inhibitor, or a group represented by the general formula: P'-O-A- glucagon-like peptide-1, a glucagon-like peptide-1 ana wherein p' represents a hydrogen atom or a hydroxy logue, a glucagon-like peptide-1 agonist, amylin, an amylin protective group; and A represents a lower alkylene group, analogue, an amylin agonist, an aldose reductase inhibitor, or a Salt thereof, and a glucopyranosyloxypyrazole deriva an advanced glycation endproducts formation inhibitor, a tive represented by the general formula: protein kinase C inhibitor, a Y-aminobutyric acid receptor (IV) antagonist, a Sodium channel antagonist, a transcript factor R2 NF-kB inhibitor, a lipid peroxidase inhibitor, an N-acety lated-O-linked-acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet derived growth factor analogue, epidermal growth factor, XAs R4 nerve growth factor, a carnitine derivative, uridine, 5-hy R droxy-1-methylhidantoin, EGB-761, bimoclomol, Sulodex N ide, Y-128, a hydroxymethyl-glutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a f-adrenoceptor agonist, HN an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol O absorption inhibitor, a lipase inhibitor, a microSomal trig lyceride transfer protein inhibitor, a lipoxygenase inhibitor, 0.019 wherein R', RandR may be the same or different a carnitine palmitoyl-transferase inhibitor, a Squalene Syn and each represents a hydrogen atom or a halogen atom; R' thase inhibitor, a low-density lipoprotein receptor enhancer, represents a lower alkyl group or a halo (lower alkyl) group; a nicotinic acid derivative, a bile acid sequestrant, a Sodium/ and R represents a hydrogen atom, a lower alkyl group, a bile acid cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite SuppreSSant, an angiotensin lower alkoxy group, a lower alkylthio group, a halo(lower converting enzyme inhibitor, a neutral endopeptidase inhibi alkyl) group, a halogen atom, a lower alkenyl group, a cyclic tor, an angiotensin II receptor antagonist, an endothelin lower alkyl group, a cyclic lower alkoxy group, a cyclic converting enzyme inhibitor, an endothelin receptor lower alkylidenemethyl group, a 5- or 6-membered aromatic antagonist, a diuretic agent, a calcium antagonist, a Vasodi heterocyclic group which contains 1-4 the same or different lating antihypertensive agent, a Sympathetic blocking agent, hetero atoms Selected from an oxygen atom, a Sulfur atom a centrally acting antihypertensive agent, an C2-adrenocep and a nitrogen atom in the ring, a phenyl group which may tor agonist, an antiplatelets agent, a uric acid Synthesis have 1-3 the same or different groups Selected from a inhibitor, auricOSuric agent and a urinary alkalinizer, for the halogen atom and a hydroxy group, or a group represented manufacture of a pharmaceutical composition for the pre by the general formula: P'-O-A- wherein p' represents vention or treatment of a disease associated with hypergly a hydrogen atom or a hydroxy-protective group; and A CC. represents a lower alkylene group, or a Salt thereof. 0.017. Furthermore, the present invention relates to a 0020 AS prodrugs of the above mentioned glucopyrano glucopyranosyloxypyrazole derivative represented by the Syloxypyrazole derivatives, a compound represented by the general formula: general formula: (III) R2 (II)

0.018 wherein T represents 2,3,4,6-tetra-O-acetyl-f-D- glucopyranosyloxy group; R', RandR may be the same or different and each represents a hydrogen atom or a halogen atom; R" represents a lower alkyl group or a halo(lower alkyl) group; and R represents a hydrogen atom, a lower US 2004/0116357 A1 Jun. 17, 2004

0021 wherein P represents a hydrogen atom or a group term “cyclic lower alkylidenemethyl group” means a 3- to forming a prodrug; R, R and R may be the same or 6-membered cyclic alkylidenemethyl group Such as a cyclo different and each represents a hydrogen atom or a halogen propylidenemethyl group, a cyclobutylidenemethyl group, a atom; R" represents a lower alkyl group or a halo(lower alkyl) group; R represents a hydrogen atom, a lower alkyl cyclopentylidenemethyl group, a cyclohexylidenemethyl group, a lower alkoxy group, a lower alkylthio group, a group or the like. The term "halogen atom' means a fluorine halo(lower alkyl) group, a halogen atom, a lower alkenyl atom, a chlorine atom, a bromine atom or an iodine atom; group, a cyclic lower alkyl group, a cyclic lower alkoxy and the term “halo(lower alkyl) group” means the above group, a cyclic lower alkylidenemethyl group, a 5- or lower alkyl group Substituted by 1 to 3 the same or different 6-membered aromatic heterocyclic group which contains halogen atoms defined above. The term “lower acyl group' 1-4 the Same or different hetero atoms Selected from an means a Straight-chained, branched or cyclic acyl group oxygen atom, a Sulfur atom and a nitrogen atom in the ring, having 2 to 7 carbon atoms Such as an acetyl group, a a phenyl group which may have 1-3 the same or different propionyl group, a butyryl group, an isobutyryl group, a groupS Selected from a halogen atom and a hydroxy group, pivaloyl group, a hexanoyl group, a cyclohexylcarbonyl or a group represented by the general formula: P'-O-A- group or the like; and the term “lower alkoxy-Substituted wherein p' represents a hydrogen atom or a group forming (lower acyl) group means the above lower acyl group a prodrug, and A represents a lower alkylene group; and with substituted by the above lower alkoxy group. The term the proviso that at least one of P and Rhas a group forming “lower alkoxycarbonyl group” means a Straight-chained, a prodrug can be illustrated. branched or cyclic alkoxycarbonyl group having 2 to 7 0022. In the present invention, the term “prodrug” means carbon atoms Such as a methoxycarbonyl group, an ethoxy a compound which is converted into a glucopyranosyloxy carbonyl group, a propoxycarbonyl group, an isopropoxy pyrazole derivative represented by the above general for carbonyl group, a butoxycarbonyl group, an isobutoxycar mula (I) as an active form thereof in Vivo. AS examples of bonyl group, a Sec-butoxycarbonyl group, a tert groups forming prodrugs, a hydroxy-protective group used butoxycarbonyl group, a pentyloxycarbonyl group, an generally in a prodrug Such as a lower acyl group, a lower isopentyloxycarbonyl group, a neopentyloxycarbonyl alkoxy-Substituted (lower acyl) group, a lower alkoxycar group, a tert-pentyloxycarbonyl group, a hexyloxycarbonyl bonyl-Substituted (lower acyl) group, a lower alkoxycarbo group, a cyclohexyloxycarbonyl group or the like; the term nyl group and a lower alkoxy-Substituted (lower alkoxycar “lower alkoxycarbonyl-Substituted (lower acyl) group bonyl) group can be illustrated. means the above lower acyl group Substituted by the above 0023. In the present invention, the term “lower alkyl lower alkoxycarbonyl group such as a 3-(ethoxycarbonyl)- group” means a Straight-chained or branched alkyl group propionyl group or the like; and the term “lower alkoxy having 1 to 6 carbon atoms Such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an Substituted (loweralkoxycarbonyl) group means the above isobutyl group, a Sec-butyl group, a tert-butyl group, a pentyl lower alkoxycarbonyl group Substituted by the above lower group, an isopentyl group, a neopentyl group, a tert-pentyl alkoxy group Such as a 2-methoxyethoxycarbonyl group or group, a hexyl group or the like; the term “lower alkoxy the like. The term “5- or 6-membered aromatic heterocyclic group” means a Straight-chained or branched alkoxy group group which contains 1 to 4 the same or different hetero having 1 to 6 carbon atoms Such as a methoxy group, an atoms Selected from an oxygen atom, a Sulfur atom and a ethoxy group, a propoxy group, an isopropoxy group, a nitrogen atom in the ring means a univalent group derived butoxy group, an isobutoxy group, a Sec-butoxy group, a from an aromatic heterocycle Such as furan, thiophene, tert-butoxy group, a pentyloxy group, an isopentyloxy pyrrole, Oxazole, isoxazole, thiazole, isothiazole, pyrazole, group, a neopentyloxy group, a tert-pentyloxy group, a imidazole, furazan, tetrazole, pyridine, pyridazine, pyrimi hexyloxy group or the like; and the term “lower alkylthio dine, pyrazine, triazine or the like. The term “hydroxy group” means a Straight-chained or branched alkylthio group protective group” means a hydroxy-protective group used in having 1 to 6 carbon atoms Such as a methylthio group, an general organic Syntheses Such as a benzyl group, a meth ethylthio group, a propylthio group, an isopropylthio group, oxymethyl group, an acetyl group or the like. a butylthio group, an isobutylthio group, a Sec-butylthio group, a tert-butylthio group, a pentylthio group, an isopen 0024. The glucopyranosyloxypyrazole derivatives repre tylthio group, a neopentylthio group, a tert-pentylthio group, Sented by the above general formula (I) of the present a hexylthio group or the like. The term “lower alkylene invention and prodrugs thereof can be prepared according to group” means a Straight-chained or branched alkylene group the following procedure: having 1 to 6 carbon atoms Such as a methylene group, an ethylene group, a trimethylene group, a propylene group or the like; the term “lower alkenyl group” means a Straight Process 1 chained or branched alkenyl group having 3 to 6 carbon atoms Such as an allyl group, a 2-butenyl group, a 2-me thylallyl group or the like; the term “cyclic lower alkyl group” means a 3- to 7-membered cyclic alkyl group Such as l CH HC (VI) R a cyclopropyl group, a cyclobutyl group, a cyclopentyl Her group, a cyclohexyl group, a cycloheptyl group or the like; O s1 the term "cyclic lower alkoxy group” means a 3- to 7-mem bered cyclic alkoxy group Such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclo (V) hexyloxy group, a cycloheptyloxy group or the like, and the US 2004/0116357 A1 Jun. 17, 2004

-continued -continued Process 2 R2 R2 R1 ==v-R M Xyw s’&(), Process 6 e? or its salt R R4 R Acetobromo-C- S O N D-glucose | \ --- O U R4 1(VIII) sin. HN

(VII) O R2 (IV) FFV R1 R2 ();M ==v-Ry Process 7 3& / R4 M 1. Hydrolysis He N Process 3 3& / R4 2. (Occasionally) / POCl3 R removing the Her N protective group N f \ N N O 1 O (III) R2 R1 (IX) (V y R2 R3K / R4 1. Process R5 Process 8 N \ Derivation ();M R N into prodrug 3& / R4 Sa --(For example,

Y N P0-X \ (XI)I (XIII)) N CHO

O

A product of a glucopyranosyl-oxypyrazole derivative represented by the above general formula (I)

(X) 0025) wherein P' represents a group forming a prodrug; R2 X represents a leaving group Such as a bromine atom, a FFV R1 chlorine atom or the like, Y represents MgBr, MgCl or a ();M lithium atom; and R,R,R,R,R, R and Thave the same 3& / R4 R Process 5 meanings as defined above. /N \ 1. hydrogenationCatalytic 0026. Process 1 N ---2. (Occasionally) N acid treatment 0027. A compound represented by the above general formula (VII) can be prepared by condensing a dithiocar O OH bonate ester derivative represented by the above general formula (V) with a ketone derivative represented by the above general formula (VI) in the presence of a base Such as Sodium amide in an inert Solvent. AS the inert Solvent used in the reaction, toluene and the like can be illustrated. The reaction temperature is usually from -20° C. to room temperature, and the reaction time is usually from 30 min (XII) utes to 1 day, varying based on a used Starting material, Solvent and reaction temperature. US 2004/0116357 A1 Jun. 17, 2004

0028) Process 2 be prepared by Subjecting a compound represented by the 0029. An N-phenylpyrazole derivative represented by the above general formula (IV) to glucosidation using aceto above general formula (IX) can be prepared by condensing bromo-O-D-glucose in the presence of abase Such as Sodi a compound represented by the above general formula (VII) umhydroxide, potassium hydroxide, potassium carbonate or with a phenylhydrazine derivative represented by the above the like and a phase transfer catalyst Such as benzyltri(n- general formula (VIII) or a salt thereof in the presence of a butyl)ammonium chloride, benzyltri-(n-butyl)ammonium base Such as triethylamine, diisopropylethylamine or the like bromide, tetra(n-butyl)ammonium hydrogen Sulfate or the in an inert Solvent. AS the inert Solvent used in the reaction, like in water and an inert Solvent. AS the inert Solvent used acetonitrile and the like can be illustrated. The reaction in the glucosidation reaction, dichloromethane, toluene, temperature is usually from O C. to reflux temperature, and benzotrifluoride and the like can be illustrated. The reaction the reaction time is usually from 1 hour to 1 day, varying temperature is usually from O C. to reflux temperature, and the reaction time is usually from 30 minutes to 1 day, based on a used Starting material, Solvent and reaction varying based on a used Starting material, Solvent and temperature. reaction temperature. The obtained compound represented 0030) Process 3 by the above general. formula (III) can be also used in 0031. A corresponding compound represented by the Process 7 after converting into a salt thereof in the usual above general formula (X) can be prepared by Subjecting an way. N-phenylpyrazole derivative to Vilsmeier reaction using 0038. In the compounds represented by the above general phosphorus Oxychloride in an inert Solvent. AS the Solvent formula (IV) of the present invention as starting materials, used in the reaction, N,N-dimethylformamide and the like there can be the following two tautomers, varying based on can be illustrated. The reaction temperature is usually from difference in the reaction conditions. The compounds rep 0 C. to reflux temperature, and the reaction time is usually resented by the above general formula (IV) of the present from 30 minutes to 1 day, varying based on a used Starting invention include both compounds described as the follow material, Solvent and reaction temperature. ing States: 0032) Process 4 0033. A compound represented by the above general formula (XII) can be prepared by condensing a compound R2 represented by the above general formula (X) with a Grig nard reagent or a lithium reagent represented by the above general formula (XI) in an inert solvent. As the solvent used X / R4 in the reaction, tetrahydrofuran, diethyl ether, a mixed R -a-s- s N Solvent thereof and the like can be illustrated. The reaction temperature is usually from -78 C. to room temperature, ( ) and the reaction time is usually from 30 minutes to 1 day, varying based on a used Starting material, Solvent and reaction temperature. O 0034) Process 5 (IV) 0.035 Abenzylpyrazole derivative of the present inven R2 tion represented by the above general formula (IV) can be prepared by Subjecting a compound represented by the above general formula (XII) to catalytic hydrogenation s R1 using a palladium catalyst Such as palladium-carbon powder * / R in the presence or absence of an acid Such as hydrochloric N acid in an inert Solvent, and for a compound having any f \ sulfur atom represented by the above general formula (XII), N Subjecting the resulting compound to acid treatment in an aqueous Solution of trifluoroacetic acid and dimethyl Sulfide OH usually at 0°C. to reflux temperature for 30 minutes to 1 day as occasion demands. AS the Solvent used in the catalytic hydrogenation, methanol, ethanol, tetrahydrofuran, ethyl 0039) Process 7 acetate, acetic acid, iropropanol, a mixed Solvent thereof and 0040. A glucopyranosyloxypyrazole derivative of the the like can be illustrated. The reaction temperature is present invention represented by the above general formula usually from room temperature to reflux temperature, and (I) can be prepared by Subjecting a compound represented the reaction time is usually from 30 minutes to 1 day, by the above general formula (III) to alkaline hydrolysis and varying based on a used Starting material, Solvent and optionally removal of a hydroxy-protective group in the reaction temperature. The obtained compound represented usual way. AS the Solvent used in the hydrolysis reaction, by the above general formula (IV) can be also used in methanol, ethanol, tetrahydrofuran, water, a mixed Solvent ProceSS 6 after converting into a Salt thereof in the usual thereof and the like can be illustrated. AS the base, Sodium way. hydroxide, Sodium methoxide, Sodium ethoxide and the like can be illustrated. The reaction temperature is usually from 0036) Process 6 0 C. to reflux temperature, and the reaction time is usually 0037. A glucopyranosyloxypyrazole derivative of the from 30 minutes to 1 day, varying based on a used Starting present invention represented by the above formula (III) can material, Solvent and reaction temperature. US 2004/0116357 A1 Jun. 17, 2004

0041) Process 8 Syloxypyrazole derivatives of the present invention and 0.042 A prodrug of a glucopyranosyloxypyrazole deriva prodrugs thereof are extremely useful as drugs for the tive represented by the above general formula (I) including prevention or treatment of a disease associated with hyper a prodrug represented by the above general formula (II) can glycemia Such as diabetes, diabetic complications (e.g., be prepared by introducing a hydroxy group generally retinopathy, neuropathy, nephropathy, ulcer, macroangiopa capable for use in a prodrug into a hydroxy group of a thy), obesity, hyperinsulinemia, glucose metabolism disor glucopyranosyloxypyrazole derivative represented by the der, hyperlipidemia, hypercholesterolemia, hypertriglyceri above general formula (I) in the usual way, for example, demia, lipid metabolism disorder, atherosclerosis, using a hydroxy-protecting reagent represented by the above hypertension, congestive heart failure, edema, hyperurice general formula (XIII). mia, gout or the like. 0049 Furthermore, the compounds of the present inven 0043. The glucopyranosyloxypyrazole derivatives repre tion can be Suitably used in combination with at least one Sented by the above general formula (I) of the present member selected from drugs other than SGLT2 inhibitors. invention and the prodrugs thereof obtained by the above Examples of the drugs which can be used in combination production processes can be isolated and purified by con with the compounds of the present invention include an ventional Separation means Such as fractional recrystalliza insulin Sensitivity enhancer, a glucose absorption inhibitor, tion, purification using chromatography, Solvent extraction a biguanide, an insulin Secretion enhancer, an insulin prepa and Solid phase extraction. ration, a glucagon receptor antagonist, an insulin receptor 0044) The glucopyranosyloxypyrazole derivatives repre kinase Stimulant, a tripeptidyl peptidase II inhibitor, a dipep Sented by the above general formula (I) of the present tidyl peptidase IV inhibitor, a protein tyrosine phosphatase invention and prodrugs thereof can be converted into their 1B inhibitor, a glycogen phosphorylase inhibitor, a glucose pharmaceutically acceptable Salts in the usual way. 6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, Examples of Such Salts include acid addition Salts with a pyruvate dehydrogenase inhibitor, ahepatic gluconeogen mineral acids Such as hydrochloric acid, hydrobromic acid, esis inhibitor, D-chiroinsitol, a glycogen Synthase kinase-3 hydroiodic acid, Sulfuric acid, nitric acid, phosphoric acid inhibitor, glucagon-like peptide-1, a glucagon-like peptide-1 and the like, acid addition Salts with organic acids Such as analogue, a glucagon-like peptide-1 agonist, amylin, an formic acid, acetic acid, adipic acid, citric acid, fumaric acid, amylin analogue, an amylin agonist, an aldose reductase maleic acid, oleic acid, lactic acid, Stearic acid, Succinic inhibitor, an advanced glycation endproducts formation acid, tartaric acid, propionic acid, butyric acid, Oxalic acid, inhibitor, a protein kinase C inhibitor, a Y-aminobutyric acid malonic acid, malic acid, carbonic acid, glutamic acid, receptor antagonist, a Sodium channel antagonist, a tran aspartic acid, methaneSulfonic acid, benzeneSulfonic acid, script factor NF-kB inhibitor, a lipid peroxidase inhibitor, an p-tolueneSulfonic acid and the like, Salts with organic N-acetylated-O-linked-acid-dipeptidase inhibitor, insulin amines Such as 2-aminoethanol, piperidine, morpholine, like growth factor-I, platelet-derived growth factor (PDGF), pyrrolidine and the like, and Salts with inorganic baseS Such a platelet-derived growth factor (PDGF) analogue (e.g., as a Sodium Salt, a potassium Salt, a calcium Salt, a magne PDGF-AA, PDGF-BB, PDGF-AB), epidermal growth fac sium Salt and the like. tor (EGF), nerve growth factor, a carnitine derivative, uri dine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclomol, 004.5 The glucopyranosyloxypyrazole derivatives repre Sulodexide, Y-128, a hydroxymethyl-glutaryl coenzyme A Sented by the above general formula (I) of the present reductase inhibitor, a fibric acid derivative, a B3-adrenocep invention and prodrugs thereof include their Solvates with tor agonist, an acyl-coenzyme Acholesterol acyltransferase pharmaceutically acceptable Solvents Such as ethanol, water inhibitor, probcol, a thyroid hormone receptor agonist, a or the like. cholesterol absorption inhibitor, a lipase inhibitor, a 0.046 Among the glucopyranosyloxypyrazole derivatives microSomal triglyceride transfer protein inhibitor, a lipoxy represented by the above general formula (I) of the present genase inhibitor, a carnitine palmitoyltransferase inhibitor, a invention and prodrugs thereof, there are two geometrical Squalene Synthase inhibitor, a low-density lipoprotein recep isomers in each compound having an unsaturated bond. In tor enhancer, a nicotinic acid derivative, a bile acid Seques the present invention, either of cis(Z)-isomer or trans(E)- trant, a Sodium/bile acid cotransporter inhibitor, a choles isomer can be employed. terol ester transfer protein inhibitor, an appetite Suppressant, an angiotensin-converting enzyme inhibitor, a neutral 0047 Among the glucopyranosyloxypyrazole derivatives endopeptidase inhibitor, an angiotensin II receptor antago represented by the above general formula (I) of the present nist, an endothelin-converting enzyme inhibitor, an endot invention and prodrugs thereof, there are two optical iso helin receptor antagonist, a diuretic agent, a calcium antago mers, R-isomer and S-isomer, in each compound having an nist, a vasodilating antihypertensive agent, a Sympathetic asymmetric carbon atom excluding the glucopyranosyloxy blocking agent, a centrally acting antihypertensive agent, an moiety. In the present invention, either of R-isomer or C2-adrenoceptor agonist, an antiplatelets agent, a uric acid S-isomer can be employed, and a mixture of both isomers Synthesis inhibitor, a uricoSuric agent and a urinary alkalin can be also employed. ZC. 0.048. The glucopyranosyloxypyrazole derivatives repre 0050. In case of uses of the compound of the present Sented by the above general formula (I) of the present invention in combination with the above one or more drugs, invention and prodrugs thereof show an excellent inhibitory the present invention includes either dosage forms of Simul activity in human SGLT2. On the other hand, since WAY taneous administration as a single preparation or Separated 123783 has an extremely weak inhibitory activity in human preparations in way of the same or different administration SGLT2, it can not be expected that it exerts an enough effect route, and administration at different dosage intervals as as a human SGLT2 inhibitor. Therefore, the glucopyrano Separated preparations in way of the same or different US 2004/0116357 A1 Jun. 17, 2004

administration route A pharmaceutical combination com glucose metabolism disorder because of lowering blood prising the compound of the present invention and the above glucose level by inhibitory effects on hepatic gluconeogen one or more drugs includes both dosage forms as a Single esis, accelerating effects on anaerobic glycolysis in tissueS or preparation and Separated preparations for combination as improving effects on insulin resistance in peripheral tissues. mentioned above. 0056. As insulin secretion enhancers, tolbutamide, chlo 0051. The compounds of the present invention can obtain rpropamide, tolaZamide, acetohexamide, glyclopyramide, more advantageous effects than additive effects in the pre glyburide (glibenclamide), gliclazide, 1-butyl-3-metanillyl vention or treatment of the above diseases when using urea, carbutamide, glibornuride, glipizide, gliquidone, Suitably in combination with the above drugs. Also, the glisoxapide, glybuthiazol, glybuzole, glyhexamide, Sodium administration dose can be decreased in comparison with glymidine, glypinamide, phenbutamide, tolcyclamide, administration of either drug alone, or adverse effects of glimepiride, nateglinide, mitiglinide calcium hydrate, repa coadministrated drugs other than SGLT2 inhibitors can be glinide and the like are illustrated. Insulin Secretion enhanc avoided or declined. erS are used preferably for diabetes, diabetic complications 0.052 Concrete compounds as the above drugs used for or glucose metabolism disorder, and more preferably for combination and preferable diseases to be treated are exem diabetes or glucose metabolism disorder because of lower plified as follows. However, the present invention is not ing blood glucose level by acting on pancreatic B-cells and limited thereto, and for example, the concrete compounds enhancing the insulin Secretion. include their free compounds, and their or other pharma 0057 AS insulin preparations, human insulin, human ceutically acceptable Salts. insulin analogues, animal-deprived insulin and the like are 0.053 AS insulin sensitivity enhancers, peroxisome pro illustrated. Insulin preparations are used preferably for dia liferator-activated receptor-Y agonists Such as troglitaZone, betes, diabetic complications or glucose metabolism disor pioglitaZone hydrochloride, rosiglitaZone maleate, Sodium der, and more preferably for diabetes or glucose metabolism dargilitazone, GI-262570, isaglitazone, LG-100641, disorder. NC-2100, T-174, DRF-2189, CLX-0921, CS-011, 0058 As glucagon receptor antagonists, BAY-27-9955, GW-1929, ciglitazone, sodium englitazone and NIP-221, NNC-92-1687 and the like are illustrated; as insulin receptor peroxisome proliferator-activated receptor-O. agonistS Such kinase stimulants, TER-17411, L-783281, KRX-613 and the as GW-9578 and BM-170744, peroxisome proliferator-ac like are illustrated; as tripeptidyl peptidase II inhibitors, tivated receptor-C/Yagonists such as GW-409544, KRP-297, UCL-1397 and the like are illustrated; as dipeptidyl pepti NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 and dase IV inhibitors, NVP-DPP728A, TSL-225, P-32/98 and DRF-MDX8, retinoid X receptor agonists such as ALRT the like are illustrated; as protein tyrosine phosphatase 1B 268, AGN-4204, MX-6054, AGN-194204, LG-100754 and inhibitors, PTP-112, OC-86839, PNU-177496 and the like beXaroteine, and other insulin Sensitivity enhancerS Such as are illustrated; as glycogen phosphorylase inhibitors, reglixane, ONO-5816, MBX-102, CRE-1625, FK-614, NN-4201, CP-368296 and the like are illustrated; as fruc CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, tose-bisphosphatase inhibitors, R-132917 and the like are HOL-975, CLX-0900, MBX-668, MBX-675, S-15261, illustrated; as pyruvate dehydrogenase inhibitors, AZD GW-544, AZ-242, LY-510929, AR-HO49020 and 7545 and the like are illustrated; as hepatic gluconeogenesis GW-501516 are illustrated. Insulin sensitivity enhancers are inhibitors, FR-225659 and the like are illustrated; as gluca used preferably for diabetes, diabetic complications, obesity, gon-like peptide-1 analogues, eXendin-4, CJC-1131 and the hyperinsulinemia, glucose metabolism disorder, hyperlipi like are illustrated; as glucagon-like peptide 1 agonists, demia, hypercholesterolemia, hypertriglyceridemia, lipid AZM-134, LY-315902 and the like are illustrated; and as metabolism disorder or atherosclerosis, and more preferably amylin, amylin analogues or amylin agonists, for diabetes, hyperinsulinemia or glucose metabolism dis acetate and the like are illustrated. These drugs, glucose-6- order because of improving the disturbance of insulin Signal phosphatase inhibitors, D-chiroinsitol, glycogen Synthase transduction in peripheral tissues and enhancing glucose kinase-3 inhibitors, glucagon-like peptide-1 are used pref uptake into the tissues from the blood, leading to lowering erably for diabetes, diabetic complications, hyperinsuline blood glucose level. mia or glucose metabolism disorder, and more preferably for 0.054 AS glucose absorption inhibitors, C-glucosidase diabetes or glucose metabolism disorder. inhibitorS Such as acarbose, Voglibose, miglitol, CKD-711, 0059 AS aldose reductase inhibitors, ascorbyl gamo emiglitate, MDL-25,637, camiglibose and MDL-73,945, lenate, tolrestat, epalrestat, ADN-138, BAL-ARI8, and O-amylase inhibitors such as AZM-127 are illustrated. ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat, Sorbi Glucose absorption inhibitors are used preferably for dia nil, ponalrestat, risarestat, Zenarestat, minalrestat, methoSor betes, diabetic complications, obesity, hyperinsulinemia or binil, AL-1567, imirestat, M-16209, TAT, AD-5467, Zopol glucose metabolism disorder, and more preferably for dia restat, AS-3201, NZ-314, SG-210, JTT-811, lindolrestat and betes or glucose metabolism disorder because of inhibiting the like are illustrated. Aldose reductase inhibitors are pref the gastrointestinal enzymatic digestion of carbohydrates erably used for diabetic complications because of inhibiting contained in foods, and inhibiting or delaying the absorption aldose reductase and lowering excessive intracellular accu of glucose into the body. mulation of Sorbitol in accelerated polyol pathway which are in continuous hyperglycemic condition in the tissues in 0.055 As biguanides, phenformin, buformin hydrochlo diabetic complications. ride, metformin hydrochloride and the like are illustrated. Biguanides are used preferably for diabetes, diabetic com 0060 AS advanced glycation endproducts formation plications, hyperinsulinemia or glucose metabolism disor inhibitors, pyridoxamine, OPB-9195, ALT946, ALT711, der, and more preferably for diabetes, hyperinsulinemia or pimagedine hydrochloride and the like are illustrated. US 2004/0116357 A1 Jun. 17, 2004

Advanced glycation endproducts formation inhibitors are hyperlipidemia, hypercholesterolemia, hypertriglyceridemia preferably used for diabetic complications because of inhib or lipid metabolism disorder, and more preferably for obe iting formation of advanced glycation endproducts which sity or hyperinsulinemia because of Stimulating B-adreno are accelerated in continuous hyperglycemic condition in ceptor in adipose tissue and enhancing the fatty acid oxida diabetes and declining cellular damage. tion, leading to induction of energy expenditure. 0061. As protein kinase C inhibitors, LY-333531, midos 0066 AS acyl-coenzyme A cholesterol acyltransferase taurin and the like are illustrated. Protein kinase C inhibitors inhibitors, NTE-122, MCC-147, PD-132301-2, DUP-129, are preferably used for diabetic complications because of U-73482, U-76807, RP-70676, P-06139, CP-113818, inhibiting protein kinase C activity which is accelerated in RP-73163, FR-129169, FY-038, EAB-309, KY-455, continuous hyperglycemic condition in diabetes. LS-3115, FR-145237, T-2591, J-104127, R-755, FCE 0.062 AS Y-aminobutyric acid receptor antagonists, topi 28654, YIC-C8-434, avasimibe, CI-976, RP-64477, F-1394, eldacimibe, CS-505, CL-283546, YM-17E, lecimibide, ramate and the like are illustrated; as Sodium channel 447C88, YM-750, E-5324, KW-3033, HL-004, eflucimibe antagonists, mexiletine hydrochloride, Oxcarbazepine and and the like are illustrated. Acyl-coenzyme A cholesterol the like are illustrated; as transcript factor NF-kB inhibitors, acyltransferase inhibitors are used preferably for hyperlipi dexlipotam and the like are illustrated; as lipid peroxidase demia, hypercholesterolemia, hypertriglyceridemia or lipid inhibitors, tirilaZad meSylate and the like are illustrated; as metabolism disorder, and more preferably for hyperlipi N-acetylated-O-linked-acid-dipeptidase inhibitors, demia or hypercholesterolemia because of lowering blood GPI-5693 and the like are illustrated; and as carnitine cholesterol level by inhibiting acyl-coenzyme Acholesterol derivatives, carnitine, levacecarnine hydrochloride, leVocar acyltransferase. nitine chloride, levocarnitine, ST-261 and the like are illus trated. These drugs, insulin-like growth factor-I, platelet 0067. As thyroid hormone receptor agonists, sodium lio derived growth factor, platelet derived growth factor thyronine, sodium levothyroxine, KB-2611 and the like are analogues, epidermal growth factor, nerve growth factor, illustrated; as cholesterol absorption inhibitors, eZetimibe, uridine, 5-hydroxy-1-methylhidantoin, EGB-761, bimoclo SCH-48461 and the like are illustrated; as lipase inhibitors, mol, Sulodexide and Y-128 are preferably used for diabetic or list at, ATL-962, AZM-131, RED-103004 and the like are complications. illustrated; as carnitine palmitoyltransferase inhibitors, eto 0.063 AS hydroxymethylglutaryl coenzyme A reductase moxir and the like are illustrated; as Squalene Synthase inhibitors, Sodium cerivastatin, Sodium pravastatin, lovasta inhibitors, SDZ-268-198, BMS-188494, A-87049, RPR tin, Simvastatin, Sodium fluvastatin, atorvastatin calcium 101821, ZD-9720, RPR-107393, ER-27856 and the like are hydrate, SC-45355, SQ-33600, CP-83101, BB-476, illustrated; as nicotinic acid derivatives, nicotinic acid, nico L-669262, S-2468, DMP-565, U-20685, BAY-X-2678, BAY tinamide, nicomol, niceritrol, acipimox, nicorandil and the 10-2987, calcium pitavastatin, calcium rosuvastatin, colles like are illustrated; as bile acid Sequestrants, colestyramine, tolone, dalvastatin, acitemate, mevastatin, crilvastatin, colestilan, colesevelam hydrochloride, GT-102-279 and the BMS-180431, BMY-21950, glenvastatin, carvastatin, BMY like are illustrated; as Sodium/bile acid cotransporter inhibi 22089, bervastatin and the like are illustrated. Hydroxym tors, 264W94, S-8921, SD-5613 and the like are illustrated; ethylglutaryl coenzyme A reductase inhibitors are used and as cholesterol ester transfer protein inhibitors, PNU preferably for hyperlipidemia, hypercholesterolemia, hyper 107368E, SC-795, JTT-705, CP-529414 and the like are triglyceridemia, lipid metabolism disorder or atherosclero illustrated. These drugs, probcol, microSomal triglyceride sis, and more preferably for hyperlipidemia, hypercholes transfer protein inhibitors, lipoxygenase inhibitors and low terolemia or atherOSclerosis because of lowering blood density lipoprotein receptor enhancers are preferably used cholesterol level by inhibiting hydroxymethylglutaryl coen for hyperlipidemia, hypercholesterolemia, hypertriglyceri Zyme A reductase. demia or lipidmetabolism disorder. 0068 AS appetite Suppressants, monoamine reuptake 0064. As fibric acid derivatives, bezafibrate, beclobrate, inhibitors, Serotonin reuptake inhibitors, Serotonin releasing binifibrate, ciprofibrate, clinofibrate, clofibrate, aluminum Stimulants, Serotonin agonists (especially 5HT-agonists), clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, noradrenalin reuptake inhibitors, noradrenalin releasing nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate, Stimulants, C.-adrenoceptor agonists, f2-adrenoceptor ago AHL-157 and thelikeare illustrated. Fibric acid derivatives nists, dopamine agonists, cannabinoid receptor antagonists, are used preferably for hyperinsulinemia, hyperlipidemia, y-aminobutyric acid receptor antagonists, H-histamine hypercholesterolemia, hypertriglyceridemia, lipid metabo antagonists, L-histidine, , leptin analogues, leptin lism disorder or atherOSclerosis, and more preferably for receptor agonists, agonists (espe hyperlipidemia, hypertriglyceridemia or atherosclerosis cially, MC3-R agonists, MC4-R agonists), C.-melanocyte because of activating hepatic lipoprotein lipase and enhanc Stimulating hormone, cocaine-and amphetamine-regulated ing fatty acid oxidation, leading to lowering blood triglyc transcript, mahogany protein, enterostatin agonists, calcito eride level. nin, -gene-related peptide, , cholecysto 0065. As B-adrenoceptor agonists, BRL-28410, agonists (especially CCK-A agonists), corticotropin SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL releasing hormone, corticotrophin-releasing hormone 37344, CP-331679, CP-114271, L-750355, BMS-187413, analogues, corticotropin-releasing hormone agonists, uro SR-59062A, BMS-210285, LY-377604, SWR-0342SA, cortin, Somatostatin, Somatostatin analogues, Somatostatin AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, receptor agonists, pituitary adenylate cyclase-activating BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, peptide, brain-derived neurotrophic factor, ciliary neu GW-2696 and the like are illustrated. B-Adrenoceptor ago rotrophic factor, thyrotropin-releasing hormone, neuro nists are used preferably for obesity, hyperinsulinemia, tensin, , Yantagonists, opioid pep US 2004/0116357 A1 Jun. 17, 2004 tide antagonists, antagonists, melanin-concentrating 0072 AS endothelin-converting enzyme inhibitors, CGS hormone antagonists, agouti-related protein inhibitors and 3.1447, CGS-35066, SM-19712 and the like are illustrated; receptor antagonists are illustrated. Concretely, as as endothelin receptor antagonists, L-749805, TBC-3214, monoamine reuptake inhibitors, maZindol and the like are BMS-182874, BO-610, TA-0201, SB-215355, PD-180988, illustrated; as Serotonin reuptake inhibitors, dexfenfluramine Sodium sitaxsentan, BMS-193884, darusentan, TBC-3711, hydrochloride, fenfluramine, sibutramine hydrochloride, , Sodium , J-104132, YM-598, S-0139, fluvoxamine maleate, Sertraline hydrochloride and the like SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT are illustrated; as Serotonin agonists, inotriptan, (+)-norfen 546, enlasentan, BMS-207940 and the like are illustrated. fluramine and the like are illustrated; as noradrenaline These drugs are preferably used for diabetic complications reuptake inhibitors, bupropion, GW-320659 and the like are or hypertension, and more preferably for hypertension. illustrated; as noradrenaline releasing Stimulants, rollipram, 0073. As diuretic agents, chlorthalidone, metolazone, YM-992 and the like are illustrated; as B-adrenoceptor cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, agonists, amphetamine, dextroamphetamine, phentermine, hydroflumethiazide, benzylhydrochlorothiazide, penflutiz benzphetamine, methamphetamine, phendimetrazine, phen ide, methyclothiazide, indapamide, tripamide, mefruside, metrazine, diethylpropion, phenylpropanolamine, cloben aZOSemide, etacrynic acid, torasemide, piretanide, furo Zorex and the like are illustrated; as dopamine agonists, Semide, bumetanide, meticrane, potassium canrenoate, ER-230, doprexin, mesylate and the like are Spironolactone, triamterene, aminophylline, cicletanine illustrated; as cannabinoid receptor antagonists, rimonabant hydrochloride, LLU-C., PNU-80873A, isosorbide, D-man and the like are illustrated; as Y-aminobutyric acid receptor nitol, D-Sorbitol, fructose, glycerin, acetazolamide, meth antagonists, topiramate and the like are illustrated; as azolamide, FR-179544, OPC-31260, lixivaptan, conivaptain H.-histamine antagonists, GT-2394 and the like are illus hydrochloride and the like are illustrated. Diuretic drugs are trated; as leptin, leptin analogues or agonists, preferably used for diabetic complications, hypertension, LY-355 101 and the like are illustrated; as congestive heart failure or edema, and more preferably for agonists (especially CCK-A agonists), SR-146131, SSR hypertension, congestive heart failure or edema because of 125180, BP-3.200, A-71623; FPL-15849, GI-248573, reducing blood pressure or improving edema by increasing GW-7178, GI-181771, GW-7854, A-71378 and the like are urinary excretion. illustrated; and as neuropeptide Yantagonists, SR-120819 0074 AS calcium antagonists, aranidipine, efonidipine A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP hydrochloride, nicardipine hydrochloride, barnidipine 71683, BIBO-3304, CP-671906-01, J-115814 and the like hydrochloride, benidipine hydrochloride, manidipine hydro are illustrated. Appetite Suppressants are used preferably for chloride, cilnidipine, nisoldipine, nitrendipine, nifedipine, diabetes, diabetic complications, obesity, glucose metabo nilvadipine, felodipine, amlodipine besilate, pranidipine, lism disorder, hyperlipidemia, hypercholesterolemia, hyper lercanidipine hydrochloride, isradipine, elgodipine, azelni triglyceridemia, lipid metabolism disorder, atherosclerosis, dipine, lacidipine, Vatanidipine hydrochloride, lemildipine, hypertension, congestive heart failure, edema, hyperurice diltiazem hydrochloride, clentiazem maleate, Verapamil mia or gout, and more preferably for obesity because of hydrochloride, S-Verapamil, fasudil hydrochloride, bepridil Stimulating or inhibiting the activities of intracerebral hydrochloride, gallopamil hydrochloride and the like are monoamines or bioactive in central appetite regu illustrated; as vasodilating antihypertensive agents, indapa latory System and Suppressing the appetite, leading to reduc mide, todralazine hydrochloride, hydralazine hydrochloride, tion of energy intake. cadralazine, budralazine and the like are illustrated; as 0069. As angiotensin-converting enzyme inhibitors, cap Sympathetic blocking agents, amoSulalol hydrochloride, topril, enalapri maleate, alacepril, delapril hydrochloride, teraZOsin hydrochloride, bunaZOsin hydrochloride, praZOsin ramipril, lisinopril, imidaprilhydrochloride, benazepril hydrochloride, doxazosin meSylate, propranolol hydrochlo hydrochloride, ceronapril monohydrate, cilaZapril, Sodium ride, atenolol, metoprolol tartrate, carvedilol, nipradillol, foSinopril, perindopril erbumine, calcium moveltipril, celiprolol hydrochloride, nebivolol, betaxolol hydrochlo quinapril hydrochloride, Spirapril hydrochloride, temocapril ride, pindolol, tertatolol hydrochloride, bevantolol hydro hydrochloride, trandolapril, calcium Zofenopril, moexipril chloride, timolol maleate, carteolol hydrochloride, biso hydrochloride, rentiapril and the like are illustrated. Angio prolol hemifumarate, bopindolol malonate, nipradillol, tensin-converting enzyme inhibitors are preferably used for penbutolol sulfate, acebutolol hydrochloride, tilisolol hydro chloride, nadolol, urapidil, indoramin and the like are illus diabetic complications or hypertension. trated; as centrally acting antihypertensive agents, reSerpine 0070. As neutral endopeptidase inhibitors, omapatrilat, and the like are illustrated; and as C2-adrenoceptor agonists, MDL-100240, fasidotril, sampatrilat, GW-660511X, mixan clonidine hydrochloride, methyldopa, CHF-1035, guana pril, SA-7060, E-4030, SLV-306, ecadotril and the like are benz acetate, guanfacine hydrochloride, moXonidine, lofexi illustrated. Neutral endopeptidase inhibitors are preferably dine, talipexole hydrochloride and the like are illustrated. used for diabetic complications or hypertension. These drugs are preferably used for hypertension. 0071 AS angiotensin II receptor antagonists, candesartan 0075 AS antiplatelets agents, ticlopidine hydrochloride, cileXetil, candesartan cileXetil/hydrochlorothiazide, potas dipyridamole, ciloStaZol, ethyl icosapentate, Sarpogrelate sium loSartan, eprosartan meSylate, Valsartan, telmisartan, hydrochloride, dilazep dihydrochloride, trapidil, beraprost irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, Sodium, aspirin and the like are illustrated. Antiplatelets tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, agents are preferably used for atherosclerosis or congestive BR-9701 and the like are illustrated. Angiotensin II receptor heart failure. antagonists are preferably used for diabetic complications or 0076. As uric acid synthesis inhibitors, allopurinol, oxy hypertension. purinol and the like are illustrated; as uricoSuric agents, US 2004/0116357 A1 Jun. 17, 2004

benzbromarone, probenecid and the like are illustrated; and antagonist and a diuretic agent is preferable; and the com as urinary alkalinizers, Sodium hydrogen carbonate, potas bination with at least one member of the group consisting of sium citrate, Sodium citrate and the like are illustrated. These an aldose reductase inhibitor, an angiotensin-converting drugs are preferably used for hyperuricemia or gout. enzyme inhibitor, a neutral endopeptidase inhibitor and an 0077. In case of use in combination with drugs other than angiotensin II receptor antagonist is more preferable. Fur SGLT2 inhibitors, for example, in the use for diabetes, the thermore, in the use for obesity, the combination with at least combination with at least one member of the group consist one member of the group consisting of an insulin Sensitivity ing of an insulin Sensitivity enhancer, a glucose absorption enhancer, a glucose absorption inhibitor, a biguanide, an inhibitor, a biguanide, an insulin Secretion enhancer, an insulin Secretion enhancer, an insulin preparation, a gluca insulin preparation, a glucagon receptor antagonist, an insu gon receptor antagonist, an insulin receptor kinase Stimulant, lin receptor kinase Stimulant, a tripeptidyl peptidase II a tripeptidyl peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a dipeptidyl peptidase IV inhibitor, a protein inhibitor, a protein tyrosine phosphatase-1B inhibitor, a tyrosine phosphatase-1B inhibitor, a glycogen phosphory glycogen phosphorylase inhibitor, a glucose-6-phosphatase lase inhibitor, a glucose-6-phosphatase inhibitor, a fructose inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate bisphosphatase inhibitor, a pyruvate dehydrogenase inhibi dehydrogenase inhibitor, ahepatic gluconeogenesis inhibi tor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a tor, D-chiroinsitol, a glycogen Synthase kinase-3 inhibitor, glycogen Synthase kinase-3 inhibitor, glucagon-like peptide glucagon-like peptide-1, a glucagon-like peptide-1 ana 1, a glucagon-like peptide-1 analogue, a glucagon-like pep logue, a glucagon-like peptide-1 agonist, amylin, an amylin tide-1 agonist, amylin, an amylin analogue, an amylin ago analogue, an amylin agonist, a f-adrenoceptor agonist and nist and an appetite SuppreSSant is preferable; the an appetite Suppressant is preferable; and the combination combination with at least one member of the group consist with at least one member of the group consisting of a ing of an insulin Sensitivity enhancer, a glucose absorption f-adrenoceptor agonist and an appetite Suppressant is more inhibitor, a biguanide, an insulin Secretion enhancer, an insulin preparation, a glucagon receptor antagonist, an insu preferable. lin receptor kinase Stimulant, a tripeptidyl peptidase II 0078 When the pharmaceutical compositions of the inhibitor, a dipeptidyl peptidase IV inhibitor, a protein present invention are employed in the practical treatment, tyrosine phosphatase-1B inhibitor, a glycogen phosphory various dosage forms are used depending on their uses. AS lase inhibitor, a glucose-6-phosphatase inhibitor, a fructose bisphosphatase inhibitor, a pyruvate dehydrogenase inhibi examples of the dosage forms, powders, granules, fine tor, a hepatic gluconeogenesis inhibitor, D-chiroinsitol, a granules, dry syrups, tablets, capsules, injections, Solutions, glycogen Synthase kinase-3 inhibitor, glucagon-like peptide ointments, Suppositories, poultices and the like are illus 1, a glucagon-like peptide-1 analogue, a glucagon-like pep trated, which are orally or parenterally administered. tide-1 agonist, amylin, an amylin analogue and an amylin 0079 These pharmaceutical compositions can be pre agonist is more preferable; and the combination with at least pared by admixing with or by diluting and dissolving an one member of the group consisting of an insulin Sensitivity appropriate pharmaceutical additive Such as excipients, dis enhancer, a glucose absorption inhibitor, a biguanide, an insulin Secretion enhancer and an insulin preparation is most integrators, binders, lubricants, diluents, buffers, isotonici preferable. Similarly, in the use for diabetic complications, ties, antiseptics, moistening agents, emulsifiers, dispersing the combination with at least one member of the group agents, Stabilizing agents, dissolving aids and the like, and consisting of an insulin Sensitivity enhancer, a glucose formulating the mixture in accordance with pharmaceuti absorption inhibitor, a biguanide, an insulin Secretion cally conventional methods depending on their dosage enhancer, an insulin preparation, a glucagon receptor forms. In case of the use of the compound of the present antagonist, an insulin receptor kinase Stimulant, a tripeptidyl invention in combination with the drugs other than SGLT2 peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a inhibitors, they can be prepared by formulating each active protein tyrosine phosphatase-1B inhibitor, a glycogen phoS ingredient together or individually. phorylase inhibitor, a glucose-6-phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase 0080 When the pharmaceutical compositions of the inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsi present invention are employed in the practical treatment, tol, glycogen Synthase kinase-3 inhibitors, glucagon the dosage of a compound represented by the above general likepeptide-1, a glucagon-likepeptide-1 analogue, a gluca formula (I), a pharmaceutically acceptable Salt thereof or a gon-like peptide-1 agonist, amylin, an amylin analogue, an prodrug thereof as the active ingredient is appropriately amylin agonist, an aldose reductase inhibitor, an advanced decided depending on the age, Sex, body weight and degree glycation endproducts formation inhibitor, a protein kinase of Symptoms and treatment of each patient, which is C inhibitor, a Y-aminobutyric acid antagonist, a Sodium approximately within the range of from 0.1 to 1,000 mg per channel antagonist, a transcript factor NF-KB inhibitor, a day per adult human in the case of oral administration and lipid peroxidase inhibitor, an N-acetylated-O-linked-acid approximately within the range of from 0.01 to 300 mg per dipeptidase inhibitor, insulin-like growth factor-I, platelet day per adult human in the case of parenteral administration, derived growth factor, a platelet derived growth factor and the daily dose can be divided into one to Several doses analogue, epidermal growth factor, nerve growth factor, a per day and administered Suitably. Also, in case of the use of carnitine derivative, uridine, 5-hydroxy-1-methylhidantoin, the compound of the present invention in combination with EGB-761, bimoclomol, Sulodexide, Y-128, an angiotensin the drugs other than SGLT2 inhibitors, the dosage of the converting enzyme inhibitor, a neutral endopeptidase inhibi compound of the present invention can be decreased tor, an angiotensin II receptor antagonist, an endothelin depending on the dosage of the drugs other than SGLT2 converting enzyme inhibitor, an endothelin receptor inhibitors.

US 2004/0116357 A1 Jun. 17, 2004 was added 10% palladium-carbon powder, and the mixture Example 6 was Stirred at room temperature under a hydrogen atmo 0121 4-4-(2-Hydroxyethyl)phenyl)methyl-5-methyl Sphere overnight. Insoluble materials were removed by 1-phenyl-1,2-dihydro-3H-pyrazol-3-one filtration, and the Solvent of the filtrate was removed under reduced pressure. To the residue was added ethanol, and the 0122) To a solution of 4-bromophenethyl alcohol (0.21 g) precipitates was collected by filtration, washed with ethanol in tetrahydrofuran (20 mL) was added tert-butyllithium (1.6 and hexane, and dried under reduced pressure to give the mol/L pentane Solution, 1.5 mL) at -78 C. under an argon title compound (0.78 g). H-NMR (CDC1) 8 ppm. atmosphere, and the mixture was stirred for 30 minutes. To the reaction mixture was added a Solution of 3-benzyloxy 01.04] 2.15 (3H,s), 3.66 (2H,s), 3.77 (3H,s), 6.75-6.85 4-formyl-5-methyl-1-phenyl-1H-pyrazole (0.10 g) in tet (2H, m), 7.10-725 (2H, m), 7.25-7.50 (5H, m) rahydrofuran (3 mL), and the mixture was warmed to 0°C. and stirred for 30 minutes. The reaction mixture was poured Example 2 into a Saturated aqueous ammonium chloride Solution, and 0105 4-(4-Ethylphenyl)methyl-5-methyl-1-phenyl-1, the mixture was extracted with diethyl ether. The organic 2-dihydro-3H-pyrazol-3-one layer was washed with water and dried over anhydrous magnesium Sulfate, and the Solvent was removed under 0106 The title compound was prepared in a similar reduced pressure. The residue was purified by column manner to that described in Example 1 using 1-bromo-4- chromatography on Silica gel (eluent: hexane/ethyl acetate= ethylbenzene instead of 4-bromoanisole. 1/1-1/2) to give an oily substance. The obtained oily Sub stance was dissolved in methanol (4 mL). To the solution 01.07 "H-NMR (CDC1) 8 ppm. was added 10% palladium-carbon powder (0.044 g), and the mixture was stirred at room temperature under a hydrogen 0108) 1.21 (3H, t, J=7.6 Hz), 2.16 (3H, s), 2.60 (2H, q, atmosphere for 17 hours. Insoluble materials were removed J=7.6 Hz), 3.69 (2H, s), 705-715 (2H, m), 7.15-7.25 by filtration, and the solvent of the filtrate was removed (2H, m), 7.25-7.45 (5H, m) under reduced pressure. Diethyl ether was added to the Example 3 residue, and the resulting precipitates were collected by filtration and dried under reduced pressure to give the title 0109) 4-(4-Ethoxyphenyl)methyl-5-methyl-1-phenyl-1, compound (0.032 g). 2-dihydro-3H-pyrazol-3-one 0123) H-NMR (DMSO-d) 8 ppm: 0110. The title compound was prepared in a similar 0.124 2.21 (3H, s), 2.66 (2H, t, J=7.1 Hz), 3.55 (2H, t, manner to that described in Example 1 using 1-bromo-4- J=7.1 Hz), 3.60 (2H, s), 4.58 (1H, brs), 7.00-7.20 (4H, ethoxybenzene instead of 4-bromoanisole. m), 720-7.35 (1H, m), 7.35-7.50 (4H, m), 9.98 (1H, 0111 H-NMR (CDC1) 8 ppm: brs) 0112 1.38 (3H, t, J=7.0 Hz), 2.14 (3H, s), 3.65 (2H, s), Example 7 3.99 (2H, q, J-70 Hz), 6.75-6.85 (2H, m), 7.10-7.20 0125 4-(4-Ethylphenyl)methyl-1-(4-fluorophenyl)-5- (2H, m), 7.25-7.50 (5H, m) methyl-1,2-dihydro-3H-pyrazol-3-one Example 4 0.126 The title compound was prepared in a similar manner to that described in Example 1 using 1-bromo-4- 0113 4-(4-Isopropoxyphenyl)methyl-5-methyl-1-phe ethylbenzene and 3-benzyloxy-1-(4-fluorophenyl)-4- nyl-1,2-dihydro-3H-pyrazol-3-one formyl-5-methyl-1H-pyrazole instead of 4-bromoanisole 0114. The title compound was prepared in a similar and 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole, manner to that described in Example 1 using 1-bromo-4- respectively. isopropoxybenzene instead of 4-bromoanisole. O127 H-NMR (CDC1) 8 ppm: 0115) 'H-NMR (CDC1) 8 ppm: 0128 1.21 (3H, t, J=7.7 Hz), 2.13 (3H, s), 2.61 (2H, q, 0116 1.31 (6H, d, J=6.0 Hz), 2.15 (3H, s), 3.65 (2H,s), J=7.7 Hz), 3.68 (2H, s), 7.05-7.20 (6H, m), 7.25-7.40 440-4.55 (1H, m), 6.70-6.85 (2H, m), 7.10-7.20 (2H, (2H, m) m), 7.25-7.50 (5H, m) Example 8 Example 5 0129. 5-Methyl-4-(4-methylthiophenyl)methyl-1-phe 0117 5-Methyl-4-(4-methylphenyl)methyl-1-phenyl-1, nyl-1,2-dihydro-3H-pyrazol-3-one 2-dihydro-3H-pyrazol-3-one 0.130. To a solution of 1-bromo-4-methylthiobenzene (0.21 g) in tetrahydrofuran (10 mL) was added tert-butyl 0118. The title compound was prepared in a similar lithium (1.6 mol/L pentane solution, 0.67 mL) at -78° C. manner to that described in Example 1 using 4-bromotolu under an argon atmosphere, and the mixture was Stirred for ene instead of 4-bromoanisole. 5 minutes. To the reaction mixture was added a Solution of 0119) H-NMR (CDC1) 8 ppm: 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole (0.20 g) in tetrahydrofuran (3 mL), and the mixture was 0120) 2.14 (3H,s), 2.30 (3H,s), 3.68 (2H,s), 7.00-7.10 warmed to 0° C. and stirred for 30 minutes. The reaction (2H, m), 7.10-7.20 (2H, m), 7.25-7.50 (5H, m) mixture was poured into a Saturated acqueous ammonium US 2004/0116357 A1 Jun. 17, 2004 chloride solution, and the mixture was extracted with diethyl 0140) 1.20 (3H, t, J=7.6 Hz), 1.90 (3H, s), 2.01 (3H, s), ether. The organic layer was washed with water and dried 2.03 (3H, s), 2.03 (3H, s), 2.19 (3H, s), 2.60 (2H, q, over anhydrous magnesium Sulfate, and the Solvent was J=7.6 Hz), 3.61 (1H, d, J=15.4 Hz), 3.71 (1H, d, J=15.4 removed under reduced preSSure. To the residue was added Hz), 3.80-3.90 (1H, m), 4.15 (1H, dd, J=2.3, 12.3 Hz), hexane, and the precipitates were collected by filtration to 4.26 (1H, dd, J=4.5, 12.3 Hz), 5.10-5.35 (3H, m), 5.71 give a white crystals. The obtained crystals were dissolved (1H, d, J=7.7 Hz), 7.00-7.20 (4H, m), 7.25-7.50 (5H, in methanol (5 mL) and tetrahydrofuran (6 mL). To a m) solution was added 10% palladium-carbon powder (0.30g), and the mixture was stirred at room temperature under a Example 11 hydrogen atmosphere for 16 hours. Insoluble materials were removed by filtration, and the solvent of the filtrate were 0141 4-(4-Ethoxyphenyl)methyl-5-methyl-1-phenyl removed under reduced pressure. The residue was purified 3-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranosyloxy)-1H by column chromatography on Silica gel (eluent: hexane/ pyrazole ethyl acetate=6/1-3/1) to give an oily substance. The 0142. The title compound was prepared in a similar obtained oily Substance was dissolved in trifluoroacetic acid manner to that described in Example 9 using 4-(4-ethyOX (1.9 mL) and water (0.1 mL), and to the solution was added yphenyl)methyl-5-methyl-1-phenyl-1,2-dihydro-3H-pyra dimethyl sulfide (0.2 mL), and the mixture was stirred at Zol-3-one instead of 4-(4-methoxyphenyl)methyl-5-me room temperature for 3 hours. The reaction mixture was thyl-1-phenyl-1,2-dihydro-3H-pyrazol-3-one. concentrated under reduced pressure, and the residue was purified by column chromatography on Silica gel (eluent: 0143 H-NMR (CDC1) 8 ppm: hexane/ethyl acetate=2/1) to give the title compound (0.054 0144) 1.39 (3H, t, J=6.9 Hz), 1.92 (3H, s), 2.02 (3H, s), g). 2.03 (3H, s), 2.03 (3H, s), 2.18 (3H, s), 3.58 (1H, d, 0131 H-NMR (CDC1) 8 ppm. J=15.8 Hz), 3.67 (1H, d, J=15.8 Hz), 3.80-3.95 (1H, m), 3.99 (2H, q, J=6.9 Hz), 4.15 (1H, dd, J=2.3, 12.4 Hz), 0132) 2.19 (3H,s), 2.47 (3H,s), 3.73 (2H,s), 7.15-7.25 4.27 (1H, dd, J=44, 12.4 Hz), 5.10-5.35 (3H, m), 5.72 (4H, m), 7.25-7.40 (2H, m), 7.45-7.60 (3H, m) (1H, d, J=7.7 Hz), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m), 7.25-7.50 (5H, m) Example 9 Example 12 0133 4-(4-Methoxyphenyl)methyl-5-methyl-1-phenyl 3-(2,3,4,6-tetra-O-acetyl-B-D-glucopyranosyloxy)-1H 0145 4-(4-Isopropoxyphenyl)methyl-5-methyl-1-phe pyrazole nyl-3-(2,3,4,6-tetra-O-acetyl-B-D-glucopyranosyloxy)-1H pyrazole 0134) To a solution of 4-(4-methoxyphenyl)methyl-5- methyl-1-phenyl-1,2-dihydro-3H-pyrazol-3-one (0.50 g), 0146 The title compound was prepared in a similar acetobromo-f-D-glucose (0.84 g) and benzyltri(n-butyl)am manner to that described in Example 9 using 4-(4-isopro monium chloride (0.53 g) in dichloromethane (16 mL) was poxyphenyl)-methyl-5-methyl-1-phenyl-1,2-dihydro-3H added an aqueous Sodium hydroxide Solution (2 mol/L, 4.3 pyrazol-3-one instead of 4-(4-methoxyphenyl)methyl-5- mL), and the mixture was stirred at room temperature for 1 methyl-1-phenyl-1,2-dihydro-3H-pyrazol-3-one. hour. The reaction mixture was purified by column chroma 0147 'H-NMR (CDC1) 8 ppm: tography on aminopropyl silica gel (eluent: dichlo romethane), and Successively by column chromatography on 0148 1.30 (3H, d, J=6.1 Hz), 1.31 (3H, d, J=6.1 Hz), Silica gel (eluent: hexane/ethyl acetate=1/1) to give the title 1.91 (3H, s), 2.02 (3H, s), 2.02 (3H, s), 2.03 (3H, s), compound (0.38 g). 2.18 (3H, s), 3.58 (1H, d, J=15.6 Hz), 3.67 (1H, d, J=15.6 Hz), 3.80-3.95 (1H, m), 4.10-4.20 (1H, m), 0135 H-NMR (CDC1) 8 ppm. 420-4.35 (1H, m), 4.40-4.55 (1H, m), 5.10-5.35 (3H, 0136) 1.92 (3H,s), 2.01 (3H, s), 2.03 (3H, s), 2.03 (3H, m), 5.71 (1H, d, J=7.4 Hz), 6.70-7.85 (2H, m), 7.05 s), 2.18 (3H, s), 3.59 (1H, d, J=15.6 Hz), 3.67 (1H, d, 7.15 (2H, m), 7.25-7.50 (5H, m) J=15.6 Hz), 3.77 (3H, s), 3.80-395 (1H, m), 4.15 (1H, dd, J=2.2, 12.4 Hz), 4.26 (1H, dd, J=4.9, 12.4 Hz), Example 13 5.15-5.35 (3H, m), 5.65-5.75 (1H, m), 6.75-6.85 (2H, 0149 5-Methyl-4-(4-methylphenyl)methyl-1-phenyl m), 7.05-715 (2H, m), 7.25-7.50 (5H, m) 3-(2,3,4,6-tetra-O-acetyl-3-D-glucopyranosyloxy)-1H pyrazole Example 10 0150. The title compound was prepared in a similar 0137 4-(4-Ethylphenyl)methyl-5-methyl-1-phenyl-3- manner to that described in Example 9 using 5-methyl-4- (2,3,4,6-tetra-O-acetyl-B-D-glucopyranosyloxy)-1H-pyra (4-methylphenyl)-methyl-1-phenyl-1,2-dihydro-3H-pyra Zole Zol-3-one instead of 4-(4-methoxyphenyl)methyl-5-me thyl-1-phenyl-1,2-dihydro-3H-pyrazol-3-one. 0.138. The title compound was prepared in a similar manner to that described in Example 9 using 4-(4-ethylphe 0151 H-NMR (CDC1) 8 ppm: nyl)methyl-5-methyl-1-phenyl-1,2-dihydro-3H-pyrazol-3- one instead of 4-(4-methoxyphenyl)methyl-5-methyl-1- 0152) 1.91 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.03 (3H, phenyl-1,2-dihydro-3H-pyrazol-3-one. s), 2.18 (3H, s), 2.29 (3H, s), 3.60 (1H, d, J=15.3 Hz), 3.70 (1H, d, J=15.3 Hz), 3.80-395 (1H, m), 4.15 (1H, 0139 H-NMR (CDC1) 8 ppm. dd, J-2.4, 12.4 Hz), 4.26 (1H, dd, J-4.4, 12.4 Hz),

US 2004/0116357 A1 Jun. 17, 2004

Test Example 1 formed with EC100 Electroporater (E-C APPARATUS CORPORATION) under the condition: 400 V, 1260 uF, 0205 Assay for Inhibitory Effect on Human SGLT2 3.2x10 cells of COS-7 cell and 20 lug of KL29 in 800 uL of Activity OPTI-MEM I medium (Gibco-BRL: LIFE TECHNOLO 0206 1) Construction of the Plasmid Vector Expressing GIES) in the 0.4 cm type cuvette. After the gene transfer, the Human SGLT2 cells were harvested by centrifugation and resuspended with OPTI-MEM I medium (3.2 mL/cuvette). To each well in 0207 Preparation of the cDNA library for PCR amplifi 96-wells plate, 125 lull of this cell suspension was added. cation was performed by reverse transcription of a total After overnight culture at 37° C. under 5% CO, 125 uL of RNA deprived from human kidney (Origene) with oligo dT DMEM medium which is containing 10% of fetal bovine as the primer, using SUPERSCRIPT Preamplification Sys serum (Sanko Jyunyaku), 100 units/mL sodium penicillin G tem (Gibco-BRL: LIFETECHNOLOGIES). The DNA frag (Gibco-BRL: LIFE TECHNOLOGIES), and 100 lug/mL ment coding for human SGLT2 was amplified by the PCR streptomycin sulfate (Gibco-BRL: LIFE TECHNOLO reaction, in which the human kidney cDNA library GIES) was added to each well. These cells were cultured described above was used as the template and the following until the next day and then they were used for the measure oligo nucleotides 0702F and 0712R, presented as Sequence ment of the inhibitory activity against the uptake of methyl Numbers 1 and 2 respectively, were used as the primers. The C-D-glucopyranoside. amplified DNA fragment was ligated into pCR-Blunt (Invit rogen), a vector for cloning, according to standard method of 0210 3) Measurement of the Inhibitory Activity Against the kit. The Escherichia coli HB101 was transformed the Uptake of methyl-O-D-glucopyranoside according to usual method and then Selection of the trans 0211. After a test compound was dissolved in dimethyl formants was performed on the LB agar medium containing sulfoxide and diluted with the uptake buffer (a pH 7.4 buffer 50 tug/mL of kanamycin. After plasmid DNA was extracted containing 140 mM sodium chloride, 2 mM potassium and purified from the one of the transformants, amplifying chloride, 1 mM calcium chloride, 1 mM magnesium chlo of the DNA fragment coding for human SGLT2 was per ride, 5 mM methyl-O-D-glucopyranoside, 10 mM 2-4-(2- formed by the PCR reaction, in which the following oligo hydroxyethyl)-1-piperazinylethane sulfonic acid and 5 mM nucleotides 0714F and 0715R, presented as Sequence Num tris (hydroxymethyl)aminomethane), each diluent was used bers 3 and 4 respectively, were used as the primers. The as test Sample for measurement of the inhibitory activity. amplified DNA fragment was digested with restriction After removal of the medium of the COS-7 cells expressing enzymes, XhoI and HindIII, and then purified with Wizard transiently human SGLT2, to each well 180 u of the Purification System (Promega). This purified DNA fragment pretreatment buffer (a pH 7.4 buffer containing 140 mM was inserted at the corresponding restriction Sites of choline chloride, 2 mM potassium chloride, 1 mM calcium pcDNA3.1 (-) Myc/His-B (Invitrogen), a vector for chloride, 1 mM magnesium chloride, 10 mM 2-4-(2-hy expressing of fusion protein. The Escherichia coli HB101 droxyethyl)-1-piperazinylethane sulfonic acid and 5 mM was transformed according to usual method and then Selec tris (hydroxymethyl)-aminomethane) was added, and the tion of the transformant was performed on the LB agar cells were incubated at 37 C. for 10 minutes. After the medium containing 100 lug/mL of amplicillin. After plasmid pretreatment buffer was removed, 200 till of the same buffer DNA was extracted and purified from this transformant, the was added again, and the cells were incubated at 37 C. for base Sequence of the DNA fragment inserted at the multi 10 minutes. The buffer for measurement was prepared by cloning sites of the vector pcDNA3. 1 (-) Myc/His-B was adding and mixing 7 till of methyl-O-D-(U-14C)glucopyra analyzed. This clone had a single base substitution (ATC noside (Amersham Pharmacia Biotech) to 525 uL of the which codes for the isoleucine-433 was substituted by GTC) prepared test Sample. For the control, the buffer for mea compared with the human SGLT2 reported by Wells et al Surement without any test compound was prepared. For (Am. J. Physiol, Vol. 263, pp. 459-465 (1992)). Sequen estimate of the basal uptake in the absence of a test com tially, a clone in which Valine is Substituted for isoleucine pound and Sodium, the buffer for measurement of the basal 433 was obtained. This plasmid vector expressing human uptake, which contains 140 mM choline chloride in place of SGLT2 in which the peptide presented as Sequence Number Sodium chloride, was prepared Similarly. After the pretreat 5 is fused to the carboxyl terminal alanine residue was ment buffer was removed, 75 till of the each buffer for designated KL29. measurement was added to each well, and the cells were incubated at 37 C. for 2 hours. After the buffer for mea surement was removed, 180 uL of the washing buffer (a pH Sequence Number 1 ATGGAGGAGCACACAGAGGC 7.4 buffer containing 140 mM choline chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magne Sequence Number 2 GGCATAGAAGCCCCAGAGGA sium chloride, 10 mM methyl-O-D-glucopyranoside, 10 mM Sequence Number 3 AACCTCGAGATGGAGGAGCACACAGAGGC 2-4-(2-hydroxyethyl)-1-piperazinylethane Sulfonic acid and 5 mM tris(hydroxymethyl)aminomethane) was added to Sequence Number 4 AACAAGCTTGGCATAGAAGCCCCAGAGGA each well and immediately removed. After two additional Sequence Number 5 KLGPEQKLISEEDLNSAWDHHHHHH washing, the cells were solubilized by addition of 75 L of 0.2 mol/L Sodium hydroxide to each well. After the cell 0208. 2) Preparation of the Cells Expressing Transiently lysates were transferred to the PicoPlate (Packard) and 150 uL of MicroScint-40 (Packard) was added to each well, the Human SGLT2 radioactivity was measured with microplate Scintillation 0209 KL29, the plasmid coding human SGLT2, was counter Top count (Packard). The difference in uptake was transfected into COS-7 cells (RIKEN CELL BANK obtained as 100% value by Subtracting the radioactivity in RCB0539) by electroporation. Electroporation was per the basal uptake from that in control and then the concen US 2004/0116357 A1 Jun. 17, 2004 trations at which 50% of uptake were inhibited (ICs) were Such as diabetes, diabetic complications, obesity or the like. calculated from the concentration-inhibition curve by least In addition, Since compounds represented by the above square method. The results are shown in the following Table general formula (III) or (IV) and salts thereof are important 1. as intermediates in the production of the compounds repre Sented by the above general formula (I), pharmaceutically TABLE 1. acceptable Salts thereof and prodrugs thereof, the com Test compound ICso value (nM) pounds represented by the above general formula (I), phar Example 18 270 maceutically acceptable Salts thereof and prodrugs thereof of Example 20 2OO the present invention can be readily prepared via Such WAY-123783 >1OOOOO compounds.

Industrial Applicability SEQUENCE LISTING FREETEXT 0212. The glucopyranosyloxyboyrazole derivatives rep Sequence Number 1: Synthetic DNA primer resented by the above general formula (I) of the present Sequence Number 2: Synthetic DNA primer invention, pharmaceutically acceptable Salts thereof and Sequence Number 3: Synthetic DNA primer prodrugs thereof show an excellent hypoglycemic effect by Sequence Number 4: Synthetic DNA primer excreting excess glucose into the urine through preventing Sequence Number 5: Peptide fused to the carboxyl terminal the reabsorption of glucose at the kidney because they alanine residue of human SGLT2 exhibit an excellent inhibitory activity in human SGLT2. The present invention can provide drugs for the prevention or treatment of a disease associated with hyperglycemia 0213)

SEQUENCE LISTING

<160> NUMBER OF SEQ ID NOS: 5 <210> SEQ ID NO 1 &2 11s LENGTH 20 &212> TYPE DNA <213> ORGANISM: Artificial Sequence &22O > FEATURE <223> OTHER INFORMATION: Synthetic DNA primer <400 SEQUENCE: 1 atggaggagc acacagaggc

<210> SEQ ID NO 2 &2 11s LENGTH 20 &212> TYPE DNA <213> ORGANISM: Artificial Sequence &22O > FEATURE <223> OTHER INFORMATION: Synthetic DNA primer <400 SEQUENCE: 2 ggcatagaag ccccagagga

<210> SEQ ID NO 3 &2 11s LENGTH 29 &212> TYPE DNA <213> ORGANISM: Artificial Sequence &22O > FEATURE <223> OTHER INFORMATION: Synthetic DNA primer <400 SEQUENCE: 3

aac citcgaga to gaggagca cacagaggc 29

<210> SEQ ID NO 4 &2 11s LENGTH 29 &212> TYPE DNA <213> ORGANISM: Artificial Sequence US 2004/0116357 A1 Jun. 17, 2004

-continued

&220s FEATURE <223> OTHER INFORMATION: Synthetic DNA primer <400 SEQUENCE: 4 aacaagcttg gcatagaagc cccagagga 29

<210 SEQ ID NO 5 &2 11s LENGTH 25 &212> TYPE PRT <213> ORGANISM: Artificial Sequence &220s FEATURE <223> OTHER INFORMATION: Peptide fused to the carboxyl terminal alanine residue of human SGLT2

<400 SEQUENCE: 5 Lys Lieu Gly Pro Glu Gln Lys Lieu. Ile Ser Glu Glu Asp Lieu. Asn. Ser 1 5 10 15 Ala Val Asp His His His His His His 2O 25

1. A glucopyranosyloxypyrazole derivative represented by the general formula:

wherein P represents a hydrogen atom or a group forming a prodrug; R, R and R may be the same or different and wherein R', RandR may be the same or different and each each represents a hydrogen atom or a halogen atom; R' represents a hydrogen atom or a halogen atom; R' represents represents a lower alkyl group or a halo (lower alkyl) group; a lower alkyl group or a halo (lower alkyl) group; and R' and R'represents a hydrogen atom, a lower alkyl group, a represents a hydrogen atom, a lower alkyl group, a lower lower alkoxy group, a lower alkylthio group, a halo(lower alkoxy group, a lower alkylthio group, a halo(lower alkyl) alkyl) group, a halogen atom, a lower alkenyl group, a cyclic group, a halogen atom, a lower alkenyl group, a cyclic lower lower alkyl group, a cyclic lower alkoxy group, a cyclic alkyl group, a cyclic lower alkoxy group, a cyclic lower lower alkylidenemethyl group, a 5- or 6-membered aromatic alkylidenemethyl group, a 5- or 6-membered aromatic het heterocyclic group which contains 1-4 the same or different erocyclic group which contains 1-4 the same or different hetero atoms Selected from an oxygen atom, a Sulfur atom hetero atoms Selected from an oxygen atom, a Sulfur atom and a nitrogen atom in the ring, a phenyl group which may and a nitrogen atom in the ring, a phenyl group which may have 1-3 the same or different groups Selected from a have 1-3 the same or different groups Selected from a halogen atom and a hydroxy group, or a group represented halogen atom and a hydroxy group, or a group represented by the general formula: P'-O-A- wherein P' represents a by the general formula: HO-A- wherein A represents a hydrogen atom or a group forming a prodrug, and A repre lower alkylene group, a pharmaceutically acceptable Salt Sents a lower alkylene group, a pharmaceutically acceptable thereof or a prodrug thereof. Salt thereof or a prodrug thereof. 2. A glucopyranosyloxypyrazole derivative represented 3. A glucopyranosyloxypyrazole derivative represented by the general formula: by the general formula: US 2004/0116357 A1 Jun. 17, 2004 20

11. A pharmaceutical composition as claimed in claim 9 wherein the disease associated with hyperglycemia is dia betic complications. 12. A pharmaceutical composition as claimed in claim 9 wherein the disease associated with hyperglycemia is obe sity. 13. A method for the prevention or treatment of a disease asSociated with hyperglycemia, which comprises adminis tering an effective amount of a glucopyranosyloxypyrazole derivative as claimed in anyone of claims 1-5, a pharma ceutically acceptable Salt thereof or a prodrug thereof. 14. A use of a glucopyranosyloxypyrazole derivative as claimed in any one of claims 1-5, a pharmaceutically accept able Salt thereof or a prodrug thereof for the manufacture of a pharmaceutical composition for the prevention or treat ment of a disease associated with hyperglycemia. 15. A pharmaceutical combination which comprises (A) a glucopyranosyloxypyrazole derivative claimed in any one of wherein R', RandR may be the same or different and each claims 1-5, a pharmaceutically acceptable Salt thereof or a represents a hydrogen atom or a halogen atom; R" represents prodrug thereof, and (B) at least one member Selected from a lower alkyl group or a halo(lower alkyl) group; and R' the group consisting of an insulin Sensitivity enhancer, a represents a hydrogen atom, a lower alkyl group, a lower glucose absorption inhibitor, a biguanide, an insulin Secre alkoxy group, a lower alkylthio group, a halo(lower alkyl) tion enhancer, an insulin preparation, a glucagon receptor group, a halogen atom, a lower alkenyl group, a cyclic lower antagonist, an insulin receptor kinase Stimulant, a tripeptidyl alkyl group, a cyclic lower alkoxy group, a cyclic lower peptidase II inhibitor, a dipeptidyl peptidase IV inhibitor, a alkylidenemethyl group, a 5- or 6-membered aromatic het protein tyrosine phosphatase-1B inhibitor, a glycogen phos erocyclic group which contains 1-4 the same or different phorylase inhibitor, a glucose-6-phosphatase inhibitor, a hetero atoms Selected from an oxygen atom, a Sulfur atom fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase and a nitrogen atom in the ring, a phenyl group which may inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsi have 1-3 the same or different groups selected from a tol, a glycogen Synthase kinase-3 inhibitor, glucagon-like halogen atom and a hydroxy group, or a group represented peptide-1, a glucagon-like peptide-1 analogue, a glucagon by the general formula: HO-A- wherein A represents a like peptide-1 agonist, amylin, an amylin analogue, an lower alkylene group, or a pharmaceutically acceptable Salt amylin agonist, an aldose reductase inhibitor, an advanced thereof. glycation endproducts formation inhibitor, a protein kinase 4. A glucopyranosyloxypyrazole derivative as claimed in C inhibitor, a Y-aminobutyric acid receptor antagonist, a claim 2 wherein at least one of P and R has a group forming Sodium channel antagonist, a transcript factor NF-KB inhibi a prodrug, or a pharmaceutically acceptable Salt thereof. tor, a lipid peroxidase inhibitor, an N-acetylated-O-linked 5. A glucopyranosyloxypyrazole derivative as claimed in acid-dipeptidase inhibitor, insulin-like growth factor-I, claim 4 wherein each group forming a prodrug in P and P' platelet-derived growth factor, a platelet-derived growth is a lower acyl group, a lower alkoxy-Substituted (lower factor analogue, epidermal growth factor, nerve growth acyl) group, a lower alkoxycarbonyl-Substituted (lower acyl) factor, a carnitine derivative, uridine, 5-hydroxy-1-methyl group, a lower alkoxycarbonyl group or a lower alkoxy hidantoin, EGB-761, bimoclomol, Sulodexide, Y-128, a Substituted (lower alokoxycarbonyl) group, or a pharmaceu hydroxymethylglutaryl coenzyme A reductase inhibitor, a tically acceptable Salt thereof. fibric acid derivative, a B-adrenoceptor agonist, an acyl 6. A pharmaceutical composition comprising as an active coenzyme Acholesterol acyltransferase inhibitor, probcol, a ingredient a glucopyranosyloxypyrazole derivative as thyroid hormone receptor agonist, a cholesterol absorption claimed in any one of claims 1-5, a pharmaceutically accept inhibitor, a lipase inhibitor, a microSomal triglyceride trans able Salt thereof or a prodrug thereof. fer protein inhibitor, a lipoxygenase inhibitor, a carnitine 7. A pharmaceutical composition as claimed in claim 6 palmitoyl-transferase inhibitor, a Squalene Synthase inhibi wherein the composition is a human SGLT2 inhibitor. tor, a low-density lipoprotein receptor enhancer, a nicotinic 8. A pharmaceutical composition as claimed in claim 6 or acid derivative, a bile acid Sequestrant, a Sodium/bile acid 7 wherein the composition is a drug for the prevention or cotransporter inhibitor, a cholesterol ester transfer protein treatment of a disease associated with hyperglycemia. inhibitor, an appetite SuppreSSant, an angiotensin-converting 9. A pharmaceutical composition as claimed in claim 8 enzyme inhibitor, a neutral endopeptidase inhibitor, an wherein the disease associated with hyperglycemia is angiotensin II receptor antagonist, an endothelin-converting Selected from the group consisting of diabetes, diabetic enzyme inhibitor, an endothelin receptor antagonist, a complications, obesity, hyperinsulinemia, glucose metabo diuretic agent, a calcium antagonist, a vasodilating antihy lism disorder, hyperlipidemia, hypercholesterolemia, hyper pertensive agent, a Sympathetic blocking agent, a centrally triglyceridemia, lipid metabolism disorder, atherosclerosis, acting antihypertensive agent, an 82-adrenoceptor agonist, hypertension, congestive heart failure, edema, hyperurice an antiplatelets agent, a uric acid Synthesis inhibitor, a mia and gout. uricoSuric agent and a urinary alkalinizer. 10. A pharmaceutical composition as claimed in claim 9 16. A pharmaceutical combination claimed in claim 15 for wherein the disease associated with hyperglycemia is dia the prevention or treatment of a disease associated with betes. hyperglycemia.

US 2004/0116357 A1 Jun. 17, 2004 22 fructose-bisphosphatase inhibitor, a pyruvate dehydrogenase thase inhibitor, a low-density lipoprotein receptor enhancer, inhibitor, a hepatic gluconeogenesis inhibitor, D-chiroinsi a nicotinic acid derivative, a bile acid Sequestrant, a Sodium/ tol, a glycogen Synthase kinase-3 inhibitor, glucagon-like bile acid cotransporter inhibitor, a cholesterol ester transfer peptide-1, a glucagon-like peptide-1 analogue, a glucagon protein inhibitor, an appetite SuppreSSant, an angiotensin like peptide-1 agonist, amylin, an amylin analogue, an converting enzyme inhibitor, a neutral endopeptidase inhibi amylin agonist, an aldose reductase inhibitor, an advanced tor, an angiotensin II receptor antagonist, an endothelin glycation endproducts formation inhibitor, a protein kinase converting enzyme inhibitor, an endothelin receptor C inhibitor, a Y-aminobutyric acid receptor antagonist, a antagonist, a diuretic agent, a calcium antagonist, a Vasodi Sodium channel antagonist, a transcript factor NF-KB inhibi lating antihypertensive agent, a Sympathetic blocking agent, tor, a lipid peroxidase inhibitor, an N-acetylated-O-linked a centrally acting antihypertensive agent, an C2-adrenocep acid-dipeptidase inhibitor, insulin-like growth factor-I, platelet-derived growth factor, a platelet-derived growth tor agonist, an antiplatelets agent, a uric acid Synthesis factor analogue, epidermal growth factor, nerve growth inhibitor, auricoSuric agent and a urinary alkalinizer, for the factor, a carnitine derivative, uridine, 5-hydroxy-1-methyl manufacture of a pharmaceutical composition for the pre hidantoin, EGB-761, bimoclomol, Sulodexide, Y-128, a vention or treatment of a disease associated with hypergly hydroxymethyl-glutaryl coenzyme A reductase inhibitor, a CC. fibric acid derivative, a B-adrenoceptor agonist, an acyl 27. A glucopyranosyloxypyrazole derivative represented coenzyme Acholesterol acyltransferase inhibitor, probcol, a by the general formula: thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microSomal triglyceride trans fer protein inhibitor, a lipoxygenase inhibitor, a carnitine palmitoyl-transferase inhibitor, a Squalene Synthase inhibi tor, a low-density lipoprotein receptor enhancer, a nicotinic A." acid derivative, a bile acid Sequestrant, a Sodium/bile acid / cotransporter inhibitor, a cholesterol ester transfer protein inhibitor, an appetite SuppreSSant, an angiotensin-converting enzyme inhibitor, a neutral endopeptidase inhibitor, an angiotensin II receptor antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, a diuretic agent, a calcium antagonist, a vasodilating antihy pertensive agent, a Sympathetic blocking agent, a centrally acting antihypertensive agent, an 82-adrenoceptor agonist, wherein T represents 2,3,4,6-tetra-O-acetyl-f-D-glucopyra an antiplatelets agent, a uric acid Synthesis inhibitor, a nosyloxy group; R', R and R may be the same or different uricoSuric agent and a urinary alkalinizer. and each represents a hydrogen atom or a halogen atom; R' 26. A use of (A) a glucopyranosyloxypyrazole derivative represents a lower alkyl group or a halo(lower alkyl) group; claimed in any one of claims 1-5, a pharmaceutically accept and R represents a hydrogen atom, a lower alkyl group, a able Salt thereof or a prodrug thereof, and (B) at least one lower alkoxy group, a lower alkylthio group, a halo(lower member Selected from the group consisting of an insulin alkyl) group, a halogen atom, a lower alkenyl group, a cyclic Sensitivity enhancer, a glucose absorption inhibitor, a bigu lower alkyl group, a cyclic lower alkoxy group, a cyclic anide, an insulin Secretion enhancer, an insulin preparation, lower alkylidenemethyl group, a 5- or 6-membered aromatic a glucagon receptor antagonist, an insulin receptor kinase heterocyclic group which contains 1-4 the same or different Stimulant, a tripeptidyl peptidase II inhibitor, a dipeptidyl hetero atoms Selected from an oxygen atom, a Sulfur atom peptidase IV inhibitor, a protein tyrosine phosphatase-1B and a nitrogen atom in the ring, a phenyl group which may inhibitor, a glycogen phosphorylase inhibitor, a glucose-6- have 1-3 the same or different groups Selected from a phosphatase inhibitor, a fructose-bisphosphatase inhibitor, a halogen atom and a hydroxy group, or a group represented pyruvate dehydrogenase inhibitor, a hepatic gluconeogen by the general formula: P'-O-A- wherein p' represents esis inhibitor, D-chiroinsitol, a glycogen Synthase kinase a hydrogen atom or a hydroxy-protective group; and A 3inhibitor, glucagon-likepeptide-1, a glucagon-like pep represents a lower alkylene group, or a pharmaceutically tide-1 analogue, a glucagon-like peptide-1 agonist, amylin, acceptable Salt thereof. an amylin analogue, an amylin agonist, an aldose reductase 28. A glucopyranosyloxypyrazole derivative represented inhibitor, an advanced glycation endproducts formation by the general formula: inhibitor, a protein kinase C inhibitor, a Y-aminobutyric acid receptor antagonist, a Sodium channel antagonist, a tran script factor NF-kB inhibitor, a lipid peroxidase inhibitor, an N-acetylated-O-linked-acid-dipeptidase inhibitor, insulin like growth factor-I, platelet-derived growth factor, a plate A." let-derived growth factor analogue, epidermal growth factor, x / nerve growth factor, a carnitine derivative, uridine, 5-hy droxy-1-methylhidantoin, EGB-761, bimoclomol, Sulodex ide, Y-128, a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibric acid derivative, a B-adrenoceptor agonist, an acyl-coenzyme A cholesterol acyltransferase inhibitor, probcol, a thyroid hormone receptor agonist, a cholesterol absorption inhibitor, a lipase inhibitor, a microSomal trig wherein R, R and R may be the same or different and each lyceride transfer protein inhibitor, a lipoxygenase inhibitor, represents a hydrogen atom or a halogen atom; R' represents a carnitine palmitoyl-transferase inhibitor, a Squalene Syn a lower alkyl group or a halo(lower alkyl) group; and R US 2004/0116357 A1 Jun. 17, 2004

represents a hydrogen atom, a lower alkyl group, a lower have 1-3 the same or different groups Selected from a alkoxy group, a lower alkylthio group, a halo(lower alkyl) halogen atom and a hydroxy group, or a group represented group, a halogen atom, a lower alkenyl group, a cyclic lower by the general formula: P'-O-A- wherein P' represents alkyl group, a cyclic lower alkoxy group, a cyclic lower a hydrogen atom or a hydroxy-protective group; and A alkylidenemethyl group, a 5- or 6-membered aromatic het represents a lower alkylene group, or a pharmaceutically erocyclic group which contains 1-4 the same or different acceptable Salt thereof. hetero atoms Selected from an oxygen atom, a Sulfur atom and a nitrogen atom in the ring, a phenyl group which may k k k k k