USOO8222261 B2 (12) United States Patent (10) Patent No.: US 8,222.261 B2 Katamreddy et al. (45) Date of Patent: Jul. 17, 2012 (54) CHEMICAL COMPOUNDS (56) References Cited (75) Inventors: Subba R Katamreddy, Durham, NC U.S. PATENT DOCUMENTS (US); Richard Dama Caldwell, 2004/0176400 A1* 9/2004 Capelli et al. ............ 514,264. 11 Durham, NC (US); Dennis Heyer Durham,s NC (US);s Vincente Samano,s OTHER PUBLICATIONS Durham, NC (US); James Benjamin Fyfe et al GPR119 agonists as potential new oral agents for the Thompson, Durham, NC (US); Andrew treatment of type 2 diabetes and obesity Expert Opin. Drug Discov., J. Carpenter. Durham, NC (US); RaWa A. i.e.ystematic tic ReviewKeview of DrugLJrug Thlnerapy to LelayDelav oof hspp. R E. P. Nc Prevent Type 2 Diabetes’ Diabetes Care, 28(3), p. 736-744, 2005.* (US); ric ugene Soros, Jurnam, Stella et al Prodrugs: Challenges and Rewards, Part 1 Biotechnol (US); Brian D Thompson, Durham, NC ogy: Pharmaceutical Aspects, p. 24, 2007.* (US) Vippagunta et al 'Crystalline Solids' Advanced Drug Delivery Reviews, vol. 48, p. 3-26, 2001.* (73) Assignee: GlaxoSmithKline, LLC, Philadelphia, insulinMayet, SecretionS., et al. inGPR119 insulin-producing activation increasescells and isolatedglucose-dependent rat islets, PA (US) Diabetologia, V48 NSuppl. 2005 p. A166. Fyfe, Matthew, et al., “Discovery of novel, orally active, synthetic (*) Notice: Subject to any disclaimer, the term of this GPR119 agonists as potential agents for treatment of obesity and patent is extended or adjusted under 35 isited metabolic disorders.” Diabetes, V55. NSuppl. Jun. 2006, U.S.C. 154(b) by 652 days. Soga, T, et al., “Lysophosphatidylcholine& 8 enhances glucose-depen dent insulin Secretion via an orphan G-protein-coupled receptor.” (21) Appl. No.: 12/373,524 Biochemical and Biophysical Research Communications, V326, N4. Jan. 28, 2005, pp. 744-751. 1-1. Overton, Hilary, et al., “Deorphanization of a G protein-coupled (22) Filed: Jan. 13, 2009 receptor for eleoylethanoamide and its use in the discovery of Small molecule hypophagic agents.” Cell Metabolism, V3, N3, Mar. 2006, (65) Prior Publication Data pp. 167-175. US 2009/0318477 A1 Dec. 24, 2009 * cited by examiner O O Primary Examiner — Brandon Fetterolf Related U.S. Application Data Assistant Examiner — Christopher R Stone (60) Provisional application No. 60/807.225, filed on Jul. (74) Attorney, Agent, or Firm — Bonnie L. Deppenbrock 13, 2006. (57) ABSTRACT 51) Int. Cl. The present invention relates to novel compounds that are (51) A 6LX3/59 (2006.01) useful in the treatment of metabolic disorders, particularly Type II diabetes mellitus and related disorders, and also to the (52) U.S. Cl. ...................................... 51.4/265.1 methods for the making and use of Such compounds. (58) Field of Classification Search ................ 51.4/265.1 See application file for complete search history. 32 Claims, 22 Drawing Sheets U.S. Patent Jul. 17, 2012 Sheet 1 of 22 US 8,222.261 B2 FIGURE 1 : Vehicle 1. 3 10 30 60 Example 1 (mg/kg) U.S. Patent Jul. 17, 2012 Sheet 2 of 22 US 8,222,261 B2 FIGURE 2 SOO 4OO 300 2OO 100 Vehicle 1 3 O 3O 60 Example 1 (mg/kg) U.S. Patent Jul. 17, 2012 Sheet 3 of 22 US 8,222.261 B2 FIGURE 3 2 O O 1. 5 O 1. O O 5 O Example 1 Example 1 WT U.S. Patent Jul. 17, 2012 Sheet 4 of 22 US 8,222.261 B2 FIGURE 4 SOO 4. O O 23OO OO W U.S. Patent Jul. 17, 2012 Sheet 5 of 22 US 8,222,261 B2 FIGURE 5 200 8 O 1. 5 O 1. 4. O 1. 2 O O O X Ko wt U.S. Patent Jul. 17, 2012 Sheet 6 of 22 US 8,222.261 B2 FIGURE 6 O, 5 O. 4. O, 3 0. 2 0. 1. Example 1 Vehicle Example 1 ko wt U.S. Patent Jul. 17, 2012 Sheet 7 of 22 US 8,222.261 B2 FIGURE 7 Post Pe. Post i Vehicle Example 1 U.S. Patent Jul. 17, 2012 Sheet 8 of 22 US 8,222.261 B2 FIGURE 8 1. sO 1. 4. O 1. pe T. P. U.S. Patent Jul. 17, 2012 Sheet 9 of 22 US 8,222.261 B2 FIGURE 9 | 1. r rost U.S. Patent Jul. 17, 2012 Sheet 10 of 22 US 8,222.261 B2 FIGURE 10 U.S. Patent Jul. 17, 2012 Sheet 11 of 22 US 8,222.261 B2 FIGURE 11 --Vehicle -0-1 mg/kg. Example 1 -0-10mg/kg. Example 1 U.S. Patent Jul. 17, 2012 Sheet 12 of 22 US 8,222,261 B2 FIGURE 12 rose rear u-er u-er u-a-r-rr u-er G S S4 na E --Vehicle w -0-1 g/kg example 1 9. -0-10 g/kg Example 1 2S S. C O Y O K d C C C h 20 a-2S S-1 3 NS 15 --- - ... - - - - - - - ' ' ... t O O 2O 30 40 50 6O 70 8O Time (min) U.S. Patent Jul. 17, 2012 Sheet 13 of 22 US 8,222,261 B2 FIGURE 13 g --Vehicle St 2000 -o-1 mg/kg. Example 1 S -0-10mg/kg. Example 1 1500 3. s is 1000 -- .------ . ...---- O 10 2O 3O 40 50 60 70 80 9 Time (min) U.S. Patent Jul. 17, 2012 Sheet 14 of 22 US 8,222.261 B2 FIGURE 14 3 S O 3 O O -- Vehicle -O-Example 1 2 5 O 2 O O 150 OO U.S. Patent Jul. 17, 2012 Sheet 15 of 22 US 8,222.261 B2 FIGURE 15 -U-Veh -O-Example 1 U.S. Patent Jul. 17, 2012 Sheet 16 of 22 US 8,222.261 B2 FIGURE 16 250 -- Vehide 2OO -O-Example 1 -0- DPPV 150 100 50 Time (minutes) U.S. Patent Jul. 17, 2012 Sheet 17 of 22 US 8,222,261 B2 FIGURE 17 1OOOO 8O O O 6000 2000 DPPIV Example 1 DPPV ko wit U.S. Patent Jul. 17, 2012 Sheet 18 of 22 US 8,222,261 B2 FIGURE 18 -m mmammariner am-Y: * ' a r -a-Vehicle -(-Example 1 U.S. Patent Jul. 17, 2012 Sheet 19 of 22 US 8,222.261 B2 FIGURE 19 Time (min) U.S. Patent Jul. 17, 2012 Sheet 20 of 22 US 8,222.261 B2 FIGURE 20 4N E 5.N " A. t U g O Time (min) U.S. Patent Jul. 17, 2012 Sheet 21 of 22 US 8,222,261 B2 FIGURE 21 SO 110 s70 a. 105 S G 360 5 100 50 s 95 s 30 90 2 O 8 S Vehicle Example Vehicle Example 1 east Treatment U.S. Patent Jul. 17, 2012 Sheet 22 of 22 US 8,222.261 B2 FIGURE 22 6 -- Vehicle e -0- Example 1 E 5 N 94 N 3 N 2 Qu US 8,222,261 B2 1. 2 CHEMICAL COMPOUNDS blood glucose levels. About 49% of individuals with Type II diabetes require oral medication(s), about 40% of individuals This application is filed pursuant to 35 U.S.C. S371 as a require insulin injections or a combination of insulin injec United States National Phase Application of International tions and oral medication(s), and about 10% of individuals Application No. PCT/US2007/073352 filed Jul. 12, 2007, 5 may use diet and exercise alone. which claims priority from U.S. 60/807.225 filed Jul. 13, Current therapies for diabetes mellitus include: insulin; 2006. insulin secretagogues, such as Sulphonylureas, which increase insulin secretion from pancreatic B-cells; glucose FIELD OF THE INVENTION lowering effectors, such as mefformin which reduce glucose 10 production from the liver; activators of the peroxisome pro The present invention relates to novel compounds that are liferator-activated receptor-Y(PPAR-Y), such as the thiazo useful in the treatment and prevention of metabolic disorders, lidinediones, which enhances insulin action; and C-glucosi including diabetes mellitus (Type I and Type II), obesity, and dase inhibitors which interfere with gut glucose production. related disorders, and also includes methods for making, There are, however, deficiencies associated with currently pharmaceutical compositions containing, and therapeutic 15 available treatments, including hypoglycemic episodes, uses for Such compounds. weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema. BACKGROUND OF THE INVENTION There are several areas at which research is being targeted in order to bring new, more effective, therapies to the market Diabetes mellitus is an ever-increasing threat to human place. For example, on-going research includes exploring a health. For example, in the United States current estimates reduction in excessive hepatic glucose production, enhancing maintain that about 16 million people suffer from diabetes the pathway by which insulin transmits its signal to the cells mellitus. Such that they take up glucose, enhancing glucose-stimulated Type I diabetes, also known as insulin-dependent diabetes insulin Secretion from the pancreatic B-cells, and targeting mellitus (IDDM), is caused by the autoimmune destruction of obesity and associated problems with fat metabolism and the insulin producing pancreatic f-cells, and necessitates 25 accumulation. regular administration of exogenous insulin. Without insulin, GIP and GLP-1 are peptides, known as incretins, secreted cells cannot absorb Sugar (glucose), which they need to pro from enteroendocrine K and L cells respectively in response duce energy. Symptoms of Type I diabetes usually start in to ingestion of nutrients, and have a wide variety of physi childhood or young adulthood. People often seek medical ological effects that have been described in numerous publi help because they are seriously ill from Sudden symptoms of 30 cations over the past two decades.