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WO 2016/066666 Al 6 May 2016 (06.05.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/066666 Al 6 May 2016 (06.05.2016) P O P C T (51) International Patent Classification: (74) Agent: SEVINC, Erkan; Istanbul Patent A.S., Plaza-33, Λ 61Κ 45/06 (2006.01) A61K 31/4985 (2006.01) Buyukdere cad. 33/16, Sisli, 3438 1 Istanbul (TR). A61K 9/14 (2006.01) A61K 31/538 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/40 (2006.01) A61P 3/10 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/42 (2006.01) A61P 5/50 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/422 (2006.01) A61P 43/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP20 15/074930 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 28 October 2015 (28.10.201 5) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 2014/12671 30 October 2014 (30. 10.2014) TR GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: SANOVEL ILAC SANAYI VE TICARET TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, A.S. [TR/TR]; Balabandere Cad. Ilac, Sanayi Yolu No: 14 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Istinye, Sariyer, 34460 Istanbul (TR). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: TURKYILMAZ, Ali; Sanovel Ilac Sanayi VE SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Ticaret A.S., Balabandere Cad. Ilac, Sanayi Yolu No: 14 GW, KM, ML, MR, NE, SN, TD, TG). Istinye, 34460 Istanbul (TR). YELKEN, Giilay; Sanovel Ilac Sanayi VE Ticaret A.S., Balabandere Cad. Ilac, Sanayi Published: Yolu No: 14 Istinye, 34460 Istanbul (TR). GOKCEK, — with international search report (Art. 21(3)) Sevgi; Sanovel Ilac Sanayi VE Ticaret A.S., Balabandere Cad. Ilac, Sanayi Yolu No: 14 Istinye, 34460 Istanbul (TR). © v o (54) Title: PHARMACEUTICAL COMBINATIONS OF SITAGLIPTIN AND PPAR AGONISTS (57) Abstract: A pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt thereof in combination with a PPAR dual agonist or a pharmaceutically acceptable salt. PHARMACEUTICAL COMBINATIONS OF SITAGLIPTIN AND PPAR AGONISTS Field of Invention The present invention relates to a pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt thereof in combination with a PPAR dual agonist or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Background of Invention Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin. There are two types of incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. Sitagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar. Formula I - Sitagliptin It is named as (3R)-3-amino-1 -[3-(trifluoromethyl)-6,8-dihydro-5H-[1 ,2,4]triazolo[4,3- a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1 -one or (2R)-4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1 -(2,4,5- trifluorophenyl)butan-2-amine) and its chemical structure is shown in the Formula I. Sitagliptin is licensed as its phosphate monohydrate salt in the US and EU under the name of JANUVIA in the strength of 100 mg, 50 mg, and 25 mg. The recommended dose is 100 mg once daily. Formula II - Sitagliptin phosphate monohydrate Fixed dose combinations (FDC) of sitagliptin are also available in the market. JANUMET® (sitagliptin and metformin combination) is a dipeptidyl peptidase-4 (DPP- 4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. JUVISYNC® (sitagliptin and simvastatin combination) is a dipeptidyl peptidase-4 (DPP-4) inhibitor and HMG-CoA reductase inhibitor combination indicated in patients for whom treatment of hypercholesterolemia and type 2 diabetes mellitus. In contrast to these examples, there is no combination of sitagliptin and PPAR dual agonists in prior art or in the market for the treatment of cardiovascular disease in patients with type-2 diabetes mellitus. Sitagliptin increases plasma GLP-1 concentration and elevate cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas PPAR agonists regulate lipid homeostasis, cellular differentiation, proliferation and the immune response. Therefore, it is anticipated that a combination therapy of sitagliptin and PPAR agonists may synergistically represents a novel approach to modifying metabolic risk factors associated with adverse cardiovascular outcomes in patients with type 2 diabetes. PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subclass have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with type-2 diabetes mellitus. PPAR (peroxisome proliferator-activated receptor) agonists are divided into five classes PPARa (alpha), PPARy (gamma), PPAR5 (delta), dual acting PPARa/γ (alpha/gamma) and PPAR pan (alpha/delta/gamma) agonists. PPAR alpha agonists (glitazones) are used for dyslipidemia to increase HDL (High Density Lipoprotein), decrease TG (Triglycerides) without effect on LDL (Low Density Lipoprotein). PPAR gamma agonists (fibrates) are insulin sensitizers for type 2 diabetes. PPAR delta agonists are developed to deal with glucose resulting in insulin resistance and diabetes. PPAR dual (alpha and gamma) agonists (glitazars) are for combined treatment of type 2 diabetes and dyslipidemia. PPAR pan (alpha/delta/gamma) agonists are for combined treatment of type 2 diabetes and dyslipidemia. PPAR alpha agonists are also known as glitazones or thiazolidinediones (TZDs). They comprise pioglitazone, rosiglitazone, ciglitazone, darglitazone, englitazone, lobeglitazone, mitaglitazone, netoglitazone and troglitazone. PPAR gamma agonists (also known as fibrates) comprise bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, simfibrate, lifibrate, pirifibrate, theofibrate, tiafibrate, timofibrate, tocofibrate. PPAR delta agonists comprise endurobol. PPAR dual (alpha and gamma) agonists (also known as glitazars) comprise saroglitazar, aloglitazar, chiglitazar, farglitazar (faraglitazar), imiglitazar, muraglitazar, naveglitazar, ragaglitazar, reglitazar, peliglitazar, pemoglitazar, sodelglitazar, tesaglitazar, oxeglitazar, imiglitazar and sipoglitazar. PPAR dual agonists are the glitazars that combine increased insulin sensitization with lipid control. They bind and activate both the alpha and gamma PPAR isoforms and improvement is achieved both in lipid profiles and insulin sensitization while avoiding dyslipidemia and weight gain. Glitazars are ideally suitable drugs in treatment of type 2 diabetic patients who have cardiovascular risk secondary to elevated triglyceride concentration. These molecules do not only target the dyslipidemia but also contribute to improved glycemic control. Saroglitazar is marketed under the trade name Lipaglyn recommended in strength of 4 mg, developed by the Zydus Cadila. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in 201 3. Lipaglyn is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, Lipaglyn has demonstrated reduction of triglycerides (TG), low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, non - high density lipoprotein (non- HDL) cholesterol and an increase in HDL cholesterol. It has also shown favorable glycemic indices by reducing the fasting plasma glucose and glycosylated hemoglobin in diabetic patients. The chemical name of saroglitazar is (2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4- methylsulfanylphenyl)pyrrol-1 -yl]ethoxy]phenyl] propanoic acid and the chemical structure is shown in Formula III. Formula III - Saroglitazar Ragaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and ameliorate diabetic dyslipidemia.
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