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(12) Patent Application Publication (10) Pub. No.: US 2010/0063141 A1 Seed Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0063141 A1 Seed Et Al US 20100063141A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0063141 A1 Seed et al. (43) Pub. Date: Mar. 11, 2010 (54) DEUTERATED BENZYLBENZENE (21) Appl. No.: 12/503,384 DERVATIVES AND METHODS OF USE (22) Filed: Jul. 15, 2009 (75) Inventors: Brian Seed, Boston, MA (US); Binhua LV, Shanghai (CN); Related U.S. Application Data Jacques Y. Roberge, Shanghai (60) Provisional application No. 61/134.968, filed on Jul. (CN); Yuanwei Chen, North 15, 2008. Haven, CT (US); Kun Peng, Shanghai (CN); Jiajia Dong, San Publication Classification Diego, CA (US); Baihua Xu, Shanghai (CN); Jiyan Du, Shanghai (51) Int. Cl. (CN); Lili Zhang, Shanghai (CN); A63L/35 (2006.01) Xinxing Tang, Shanghai (CN); Ge C07D 35/00 (2006.01) Xu, Shanghai (CN); Yan Feng, CD7C 5/6 (2006.01) Ridgefield, NJ (US); Min Xu, (52) U.S. Cl. .......................... 514/460; 549/417:585/400 Shanghai (CN) (57) ABSTRACT Correspondence Address: Provided are compounds having an inhibitory effect on CLARK & ELBNG LLP Sodium-dependent glucose cotransporter SGLT. The inven 101 FEDERAL STREET tion also provides pharmaceutical compositions, methods of BOSTON, MA 02110 (US) preparing the compounds, synthetic intermediates, and meth ods of using the compounds, independently or in combination (73) Assignee: Theracos, Inc., Sunnyvale, CA with other therapeutic agents, for treating diseases and con (US) ditions that are affected by SGLT inhibition. Patent Application Publication Mar. 11, 2010 Sheet 1 of 11 US 2010/0063141 A1 FIG. 1 3: Diode Array Range: 2.963e+1 Area DJJ-1092-UR 2.11 2.50 Tire Height Area Area 6 ANO7016407-1 943.395 1.35 58826 1059.07 0.04 703228 1.37 80940 1581.25 0.05 138 77879 2845.11 O.10 144 61359 823.09 0.03 157 1338459 149976.22 5.04 1.75 2333595. 160565.19 5.40 Major metabolic product 186 1439750 69369,77 2.33 2.25 1.96 320439 9378.24 0.32 2.04 597637 17521,63 0.59 455577 2.11 23.133520 943394,69 31.71 2.15 50.59256 13364181 449 2.25 12853208 455576.63 15.31 2.15 2.34 2.34 8146365 28869103 9.7 133642 288691 2.43 1140041 29960.99 1.01 2.50 23066690 703228. 19 23.63 1.75 2.68 31788 7792.25 0.26 157 1.86 149976 16956, Patent Application Publication Mar. 11, 2010 Sheet 2 of 11 US 2010/0063141 A1 10896Z W Patent Application Publication Mar. 11, 2010 Sheet 3 of 11 US 2010/0063141 A1 Patent Application Publication Mar. 11, 2010 Sheet 4 of 11 US 2010/0063141 A1 |+90°? Patent Application Publication Mar. 11, 2010 Sheet 5 of 11 US 2010/0063141 A1 Patent Application Publication Mar. 11, 2010 Sheet 6 of 11 US 2010/0063141 A1 Patent Application Publication Mar. 11, 2010 Sheet 7 of 11 US 2010/0063141 A1 Patent Application Publication Mar. 11, 2010 Sheet 8 of 11 US 2010/0063141 A1 HO W Patent Application Publication Mar. 11, 2010 Sheet 9 of 11 US 2010/0063141 A1 punoduI0O 9]pdO 6]pdO #GpdO Patent Application Publication Mar. 11, 2010 Sheet 10 of 11 US 2010/0063141 A1 FIG. 6 Based on chromatographic peak area RefA Cpd 16 Ratio MO 1.1OE+06 1.3OE+06 1 : 12 M1 4.26E+05 2.33E-05 18: 1 M2 2.15E+06 3.38E+06 1 : 1.6 M3 8.68E+05 4.43E+05 Ref E Cpd 19 Ratio MO 168E+06 1.67E+06 M1 3.09E+05 2.85E+05 M2 184E+06 1.06E+06 M3 3.17E+05 3.1OE+05 1 : 1 Ref C Cpd 54 Ratio MO 2.24E+05 2.64E+05 1 : 12 M1 100E+06 1.26E+06 1: 13 M2 2.76E+06 1.18E+06 2.3 : 1 M3 9.08E+05 4.54E--05 2 : 1 Based on mass response RefA Cpd 16 Ratio MO 5.29E+05 7.42E+05 1: 14 M1 8.88E+05 3.88E+05 2.3 : 1 M2 3.3OE+05 2.14E+05 15: 1 M3 1.12E+05 3.81E+04. 3.0: 1 Ref E Cpd 19 Ratio MO 2.07E+06 2.06E+06 1: 1 M1 9.91 E+05 3.70E+05 M2 M3 3.2OE+04 194E+04 1.6:1 Ref C Cpd 54 Ratio MO 6.96E+04 1.08E+05 1 : 1.6 M1 6.35E+05 7.13E+05 1 : 1.1 M2 162E+05 7.5OE+04 2.1 : 1 M3 2.33E-04 127E+05 1 : 5.5 Patent Application Publication Mar. 11, 2010 Sheet 11 of 11 US 2010/0063141 A1 US 2010/0063141 A1 Mar. 11, 2010 DEUTERATED BENZYLBENZENE normal serum glucose levels and the absence of general renal DERVATIVES AND METHODS OF USE dysfunction or other disease (Santer et al., JAm Soc Nephrol 14:2873-82, 2003). CROSS-REFERENCE TO RELATED 0006. Therefore, compounds that inhibit SGLT, particu APPLICATIONS larly SGLT2, are promising candidates for use as antidiabetic drugs and new antidiabetic agents providing improved gly 0001. This application claims benefit of U.S. Provisional Application No. 61/134.968, filed Jul. 15, 2008, which is cemic control and lacking these adverse effects are highly hereby incorporated by reference. desired. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0002 The invention provides compositions including 0007. The present invention provides compositions that compounds having an inhibitory effect on Sodium-dependent include compounds having an inhibitory effect on Sodium glucose cotransporter SGLT. The invention also provides dependent glucose cotransporter SGLT. The invention also pharmaceutical compositions and methods of using the com provides pharmaceutical compositions and methods of using pounds, independently or in combination with other thera the compounds, independently or in combination with other peutic agents, for treating diseases and conditions that are therapeutic agents, for treating diseases and conditions which affected by SGLT inhibition. are affected by SGLT inhibition such as: type 1 diabetes 0003. According to the World Health Organization, mellitus, type 2 diabetes mellitus, hyperglycemia, diabetic approximately 150 million people worldwide have diabetes complications, insulin resistance, metabolic syndrome (Syn mellitus. The two principal forms of diabetes are type 1 dia drome X), hyperinsulinemia, hypertension, hyperuricemia, betes, in which the pancreas fails to produce insulin, and type obesity, edema, dyslipidemia, chronic heart failure, and ath 2 diabetes, in which the body fails to respond properly to the erosclerosis. insulin produced (insulin resistance). Accounting for about 0008. In one aspect, the invention features compounds 90% of all diabetes cases, type 2 diabetes is by far the most having the structure: common. In both types of diabetes, the absence of insulin action or proper response to insulin results in elevated levels of serum glucose (hyperglycemia). Serious complications (I) associated with diabetes include retinopathy (leading to visual impairment or blindness), cardiovascular disease, nephropathy, neuropathy, ulcers, and diabetic foot disease. 0004 Individuals with type 1 diabetes currently require insulin therapy. While in many cases type 2 diabetes can be managed with diet and exercise, drug intervention is also frequently required. Besides insulin, which is needed by about one-third of patients with type 2 diabetes, current antidiabetic therapies include biguanides (which decrease glucose production in the liver and increase sensitivity to insulin), Sulfonylureas and meglitinides (which stimulate insulin production), alpha-glucosidase inhibitors (which or any stereoisomer or tautomer thereof, or any pharmaceu slow starch absorption and glucose production), and thiazo tically acceptable prodrug, salt, or Solvate thereof, wherein lidinediones (which increase insulin sensitivity). These medi 0009 each R',R,R,RandR is, independently, H, cines are often used in combination, and even then may not -D, a Substituent that is optionally deuterated, or group provide adequate glycemic control or may produce undesired Q: side effects. Such side effects include lactic acidosis (bigu anides), hypoglycemia (Sulfonylureas), and edema and weight gain (thiazolidinediones). (Q) 0005 One promising target for therapeutic intervention in diabetes and related disorders is the glucose transport system of the kidneys. Cellular glucose transport is conducted by either facilitative (“passive) glucose transporters (GLUTs) or Sodium-dependent ("active) glucose cotransporters (SGLTs). SGLT1 is found predominantly in the intestinal brush border, while SGLT2 is localized in the renal proximal Ril R2 10 tubule and is reportedly responsible for the majority of glu cose reuptake by the kidneys. Recent studies suggest that 0010 each R, R7, R,R,R,R,R,R, and R is, inhibition of renal SGLT may be a useful approach to treating independently, —H, -D, or a Substituent that is option hyperglycemia by increasing the amount of glucose excreted ally deuterated; and in the urine (Arakawa et al., Br J Pharmacol 132:578-86, 2001: Oku et al., Diabetes 48:1794-1800, 1999). The poten 0011 each R', R', R', RandR is, independently, tial of this therapeutic approach is further supported by recent —H, -D, or halogen; findings that mutations in the SGLT2 gene occur in cases of 0012 wherein familial renal glucosuria, an apparently benign syndrome 0013 one of R', R. R. RandR is group Q; characterized by urinary glucose excretion in the presence of (0014) at least one of R'-R' is -D or comprises-D. US 2010/0063141 A1 Mar. 11, 2010 substituted alkyl, haloalkyl, optionally substituted alkoxy alkyl, optionally Substituted alkoxy, haloalkoxy, optionally -continued Substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted alkcy cloalkyl; each R. R. R. R. R', and R' is, independently, —H, -D, halogen, or an optionally deuterated Substituent selected from hydroxyl, optionally substituted carbamoyl, optionally substituted alkyl, haloalkyl, optionally substituted alkoxyalkyl, optionally Substituted alkoxy, haloalkoxy, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, or optionally substituted OCDCD3, alkcycloalkyl; and each R', R', and R' is, independently, —H, -D, optionally substituted alkyl, haloalkyl, optionally Substituted alkoxyalkyl, optionally Substituted alkoxy, haloalkoxy, optionally Substituted alkenyl, optionally Substi tuted alkynyl, optionally substituted cycloalkyl, optionally substituted alkcycloalkyl, -C(O)R', C(O)CR', or —C(O)NR'R'', wherein each R and R is, independently, hydrogen, deuterium, or an optionally deuterated Substituent OCDCD3, selected from optionally substituted alkyl, optionally substi tuted alkenyl, optionally Substituted cycloalkyl, and option ally substituted aryl.
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