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 insulin 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 endopeptidase inhibitor, an hetero atoms Selected from an oxygen atom, a Sulfur atom angiotensin II receptor antagonist, an endothelin-converting and a nitrogen atom in the ring, a phenyl group which may enzyme inhibitor, an endothelin receptor 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 glucagon receptor glycemia, which comprises administering an effective antagonist, an insulin receptor