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(12) United States Patent (10) Patent No.: US 9,492.422 B2 Takahashi Et Al

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(12) United States Patent (10) Patent No.: US 9,492.422 B2 Takahashi Et Al USOO9492422B2 (12) United States Patent (10) Patent No.: US 9,492.422 B2 Takahashi et al. (45) Date of Patent: Nov. 15, 2016 (54) THERAPEUTIC OR PROPHYLACTIC JP 52-136161 A 11/1977 AGENT FOR DIABETES JP 54-095552 A 7/1979 JP 54-130543. A 10, 1979 JP 55-000313 A 1, 1980 (75) Inventors: Takehiro Takahashi, Kamakura (JP); JP 55-022636 A 2, 1980 Hiroki Kumagai, Kamakura (JP); JP 55-057559 A 4f1980 JP 58-219 162 A 12/1983 Takashi Kadowaki, Tokyo (JP): Naoto JP 59-137445. A 8, 1984 Kubota, Tokyo (JP); Tetsuya Kubota, JP 59-141536 A 8, 1984 Tokyo (JP) JP 59-157050 A 9, 1984 JP 61-030519 A 2, 1986 (73) Assignees: Toray Industries, Inc. (JP); The JP 61-267580 A 11, 1986 JP 62-286924 A 12/1987 University of Tokyo (JP) JP 105.3672 B 11, 1989 JP 2-167227 A 6, 1990 (*) Notice: Subject to any disclaimer, the term of this JP 3-005457 A 1, 1991 patent is extended or adjusted under 35 JP 3-246252 A 11, 1991 U.S.C. 154(b) by 36 days. JP 10-251.146 A 9, 1998 JP 2001-512478 A 8, 2001 JP 2006-199694 A 8, 2006 (21) Appl. No.: 13/509,483 JP 2006-523668 A 10, 2006 JP 2007-191494. A 8, 2007 (22) PCT Filed: Nov. 12, 2010 JP 2007-536229 A 12/2007 JP 2008-530097 A 8, 2008 (86). PCT No.: PCT/UP2010/070185 WO 99.1388.0 A1 3, 1999 WO OOO7992 A1 2, 2000 S 371 (c)(1), WO 02/088084 A1 11, 2002 (2), (4) Date: Jun. 18, 2012 WO 2006/034510 A2 3, 2006 (87) PCT Pub. No.: WO2011/059053 OTHER PUBLICATIONS PCT Pub. Date: May 19, 2011 Asano et al. (Journal of the Japan Diabetes Society, 1994, vol. 37 (65) Prior Publication Data No. 5, pp. 379-382, abstract only).* Nakagawa et al. (Journal of the Japan Diabetes Society, 1998, vol. US 2012/O258988 A1 Oct. 11, 2012 41 No. 11, pp. 989-994, abstract only).* Nishimura et al. (Journal of Diabetes and its Complications, 1995, (30) Foreign Application Priority Data vol. 9 No. 4, pp. 330-333, abstract only).* Miyazaki et al. (Diabetes Care, vol. 25. No. 3, Mar. 2002).* Nov. 13, 2009 (JP) ................................. 2009-259544 Raef. H. et al., “Adding Rosiglitazone to Metformin in Patients with Type 2 Diabetes: Effect on Diabetes Control and Metabolic Param (51) Int. Cl. eters.” International Journal of Diabetes Mellitus, Apr. 2009, vol. 1, A 6LX 3/5585 (2006.01) No. 1, pp. 2-6. A6IP3I/O (2006.01) A6 IK3I/343 (2006.01) (Continued) A6 IK 3/4439 (2006.01) A 6LX 3/55.75 (2006.01) (52) U.S. Cl. Primary Examiner — Kortney L. Klinkel CPC ......... A6 IK3I/343 (2013.01); A61 K3I/4439 Assistant Examiner — William Lee (2013.01); A61 K3I/5575 (2013.01) (74) Attorney, Agent, or Firm — DLA Piper LLP (US) (58) Field of Classification Search None See application file for complete search history. (57) ABSTRACT (56) References Cited A therapeutic or prophylactic agent for diabetes includes a thiazolidine derivative as a PPAR-Yagonist as an effective U.S. PATENT DOCUMENTS component which exhibits a reduced side effect of the 3,963,716 A 6, 1976 Inoue et al. PPAR-Y agonist. The therapeutic or prophylactic agent for 4,306,075 A 12/1981 Aristoff diabetes includes a particular IP agonist Such as beraprost 4,687,777 A 8/1987 Meguro et al. sodium (BPS), and a thiazolidine derivative such as piogli 5,981,594 A * 11/1999 Okamoto et al. ............. 514/573 taZone or a pharmaceutically acceptable salt thereof. Since 2009/0176848 A1* 7/2009 Kurumatani et al. ........ 514,381 the therapeutic or prophylactic agent exhibits a sufficiently FOREIGN PATENT DOCUMENTS effective hypoglycemic action without being accompanied by side effects characteristic to PPAR-Yagonists, the agent DE 3 504 677 A1 8, 1986 is useful as a highly safe and effective therapeutic or EP 1894 567 A1 5, 2008 GB 1583 961 A 2, 1981 prophylactic agent for diabetes. JP 48-097898 A 12/1973 JP 50-70380 A 6, 1975 JP 50-070380 A 6, 1975 4 Claims, No Drawings US 9,492.422 B2 Page 2 (56) References Cited Hidetoshi Hashida et al., “Beneficial Hemodynamic Effects of Oral Prostacyclin (PG12) Analogue, Beraprost Sodium, on a Patient with Primary Pulmonary Hypertension: A Case Report.' Angiology, vol. OTHER PUBLICATIONS 49, 1998, pp. 161-164. Hisanori Wakita et al., “Total Synthesis of Optically Active Giuseppe Paolisso et al., Low-Dose Iloprost Infusion Improves m-Phenylene PGI Derivative: Beraprost.” Heterocycles, vol. 53, No. 5, 2000, pp. 1085-1110. Insulin Action in Aged Healthy Subjects and NIDDM Patients.: Ezequiel Balmori Melian et al., “Beraprost: A Review of its Phar Diabetes Care, vol. 18, No. 2, Feb. 1, 1995, pp. 200-205. macology and Therapeutic Efficacy in the Treatment of Peripheral Masayuki Miyata et al., “Protective Effect of Beraprost Sodium, a Arterial Disease and Pulmonary Arterial Hypertension.” Drugs, vol. Stable Prostacyclin Analogue, in Development of Monocrotaline 62, 2002, pp. 107-133. Induced Pulmonary Hypertension.” Journal of Cardiovascular Phar macology, vol. 27. Issue 1, Jan. 1996, pp. 20-26. * cited by examiner US 9,492,422 B2 1. 2 THERAPEUTIC OR PROPHYLACTIC exhibited by using a PPAR-Y agonist in combination with AGENT FOR DABETES another therapeutic agent or prophylactic agent for diabetes having a different action mechanism (e.g., C.-glycosidase RELATED APPLICATIONS inhibitor, Sulfonylurea agent, biguanide, aldose reductase inhibitor, statin compound, squalene synthesis inhibitor, This is a S371 of International Application No. PCT/ fibrate compound, LDL catabolism promoter orangiotensin JP2010/070185, with an international filing date of Nov. 12, converting enzyme inhibitor) (JP 2007-191494 A). 2010 (WO 2011/059053 A1, published May 19, 2011), It has been disclosed that an IP agonist Such as a prosta glandin I derivative has the actions of vasodilation, platelet which is based on Japanese Patent Application No. 2009 10 259544, filed Nov. 13, 2009, the subject matter of which is aggregation inhibition, Smooth-muscle proliferation inhibi incorporated by reference. tion, vascular endothelium protection and inflammatory cytokine inhibition and is effective as a therapeutic agent for diabetes in cases where it is used alone (JP 2-167227 A. Paolisso et al., Diabetes Care, 18, 200-205, 1995), and that TECHNICAL FIELD 15 an IP agonist is effective for therapy or prophylaxis of diabetes when combined with a PPAR-Yagonist (JP 2006 1996.94 A). However, in JP 694, the PPAR-Y agonist is This disclosure relates to a therapeutic or prophylactic merely listed as one of many arbitrary components and there agent for diabetes, with a reduced side effect. is no particular description Suggesting or Supporting a com bined effect with an IP agonist. Further, the fact that cicle tanine, which is known as an endogenous prostacyclin BACKGROUND inducer, exerts a synergistic therapeutic effect for diabetes when used in combination with a PPAR-Yagonist (Japanese 25 Translated PCT Patent Application Laid-open No. 2006 Diabetes is a group of diseases whose main symptom is 523668), and expected matters on lipid metabolism, control chronic hyperglycemia accompanied by insufficiency of the of edema and reduction of hepatotoxicity of PPAR-Yago action of insulin, and involves various characteristic meta nists are described (WO 2006/034510). However, these bolic disorders. The number of patients suffering from reports do not describe that an IP agonist Suppresses body diabetes is increasing and, due to changes in lifestyle Such 30 weight gain due to a PPAR-Yagonist. as consumption of high-fat diets and lack of exercise, patients suffering from type 2 diabetes, which is a diseased An IP agonist beraprost sodium has been widely state associated with risk factors such as obesity, hypertri employed as an orally-available stable prostaglandin I glyceridemia, low HDL cholesteremia, glucose metabolism derivative for basic research and clinical applications, to be disorder and/or hypertension and occurs with the metabolic 35 used as a therapeutic agent for chronic artery obstruction syndrome, are especially increasing. Since it is known that (Melian et al., Drugs, 62. 107-133, 2002) or primary pull insulin resistance (insufficiency of the action of insulin) is monary hypertension (Hashida et al., Angiology, 49, 161 strongly involved in the increase in the number of patients, 164, 1998 and Miyata et al., J. Cardiovasc. Pharmacol., 27. development of a therapeutic agent for type 2 diabetes 20-26, 1996). Since beraprost sodium and its derivatives having an action that improves insulin resistance has been 40 have a platelet aggregation inhibition action, they are Sug especially strongly demanded. gested as having possibilities to be useful as antithrombotic Peroxisome proliferator-activated receptor gamma agents, and also reported to have an anti-hyperlipemic action (PPAR-Y) agonists, which are nuclear receptors, are recently (JP 1-53672 B and JP 62-286924 A). Further, it has been developed therapeutic agents for type 2 diabetes, and known discovered that beraprost sodium is effective for diabetic to improve insulin resistance and thereby exert a hypogly 45 complications such as arterial Sclerosis, diabetic nephropa cemic action, which is effective for prophylaxis and therapy thy, diabetic microangiopathy, diabetic neuropathy, diabetic of diabetes. retinopathy and diabetic macroangiopathy (WO 99/13880), As PPAR-Yagonists, only pioglitazone hydrochloride and and that the combination of beraprost sodium and an antidi rosiglitaZone maleate are currently commercially available, abetic drug enables amelioration of decrease in the functions but agents such as IsaglitaZone, RivoglitaZone, Bardox 50 of the motor nerve and the sensory nerve, which have not olone, Aleglitazar, Lobeglitazone, ZYH-1, AVE-0897, been able to be sufficiently treated with conventional antidi Chiglitazar, THR-0921, GFT-505, Indeglitazar, GSK abetic drugs, by improvement of the nerve conduction 376501 and Inoglitazone are now being developed and velocity.
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