WO2012003811A1

WO2012003811A1 - C-aryl glucoside sglt2 inhibitors and method

Info

Publication number: WO2012003811A1
Application number: PCT/CN2011/077038
Authority: WO
Inventors: Shaojing Hu; Wei LONG; Xiaoyan Shen; Fenlai Tan; Yinxiang Wang
Original assignee: Zhejiang Beta Pharma Inc.
Priority date: 2010-07-09
Filing date: 2011-07-11
Publication date: 2012-01-12

Abstract

C-aryl glucosides which are inhibitors of sodium dependent glucose transporters found in the intestine and kidney (SGLT2), shown as formula I, a pharmaceutical composition and pharmaceutical combination.

Description

THE DESCRIPTION

C-ARYL GLUCOSIDE SGLT2 INHIBITORS AND METHOD

Technical Field

The present invention relates to novel C-aryl glucosides which are inhibitors of sodium dependent glucose transporters found in the intestine and kidney (SGLT2) and to a method for treating diabetes, especially type II diabetes, as well as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis and related diseases, employing such C-aryl glucosides alone or in combination with one, two or more other type antidiabetic agent and/or one, two or more other type therapeutic agents such as hypolipidemic agents.

Background Art

Approximately 100 million people worldwide suffer from type II diabetes (NIDDM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter SGLT2 in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.

The development of novel, safe, and orally active antidiabetic agents is also desired in order to complement existing therapies, including the sulfonylureas, thiazolidinediones, metformin, and insulin, and to avoid the potential side effects associated with the use of these other agents.

Hyperglycemia is a hallmark of type II diabetes (NIDDM); consistent control of plasma glucose levels in diabetes can offset the development of diabetic complications and beta cell failure seen in advanced disease. Plasma glucose is normally filtered in the kidney in the glomerulus and actively reabsorbed in the proximal tubule. SGLT2 appears to be the major transporter responsible for the reuptake of glucose at this site. The SGLT specific inhibitor phlorizin or closely related analogs inhibit this reuptake process in diabetic rodents and dogs resulting in normalization of plasma glucose levels by promoting glucose excretion without hypoglycemic side effects. Long term (6 month) treatment of Zucker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, with no detectable pathology in the kidney and no electrolyte imbalance in plasma. Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications.

Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early SI segment of the renal cortical proximal tubule, and SGLT2 is likely to be the major transporter responsible for this reuptake. SGLT2 is a 672 amino acid protein containing 14 membrane- spanning segments that is predominantly expressed in the early SI segment of the renal proximal tubules. The substrate specificity, sodium dependence, and localization of SGLT2 are consistent with the properties of the high capacity, low affinity, sodium- dependent glucose transporter previously characterized in human cortical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na+/glucose cotransporter in the SI segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in mRNA from rat kidney cortex is inhibited by an antisense oligonucleotide specific to rat SGLT2. SGLT2 is a candidate gene for some forms of familial glucosuria, a genetic abnormality in which renal glucose reabsorption is impaired to varying degrees. None of these syndromes investigated to date map to the SGLT2 locus on chromosome 16. However, the studies of highly homologous rodent SGLTs strongly implicate SGLT2 as the major renal sodium- dependent transporter of glucose and suggest that the glucosuria locus that has been mapped encodes an SGLT2 regulator. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced glucose excretion in diabetic patients.

SGLTl, another Na-dependent glucose cotransporter that is 60% identical to SGLT2 at the amino acid level, is expressed in the small intestine and in the more distal S3 segment of the renal proximal tubule. Despite their sequence similarities, human SGLTl and SGLT2 are biochemically distinguishable. For SGLTl, the molar ratio of Na+ to glucose transported is 2: 1, whereas for SGLT2, the ratio is 1 : 1. The Km for Na+ is 32 and 250- 300 mM for SGLTl and SGLT2, respectively. Km values for uptake of glucose and the nonmetabolizable glucose analog a-methyl- D-glucopyranoside (AMG) are similar for SGLT1 and SGLT2, i. e. 0.8 and 1.6 mM (glucose) and 0.4 and 1.6 mM (AMG) for SGLT1 and SGLT2 transporters, respectively.

However, the two transporters do vary in their substrate specificities for sugars such as galactose, which is a substrate for SGLT1 only.

Administration of phlorizin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting glucose excretion, lowering fasting and fed plasma glucose, and promoting glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one canine diabetes model. No adverse effects on plasma ion balance, renal function or renal morphology have been observed as a consequence of phlorizin treatment for as long as two weeks. In addition, no hypoglycemic or other adverse effects have been observed when phlorizin is administered to normal animals, despite the presence of glycosuria.

Administration of an inhibitor of renal SGLTs for a 6-month period (Tanabe Seiyaku) was reported to improve fasting and fed plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and offset the development of nephropathy and neuropathy in the absence of hypoglycemic or renal side effects.

Phlorizin itself is unattractive as an oral drug since it is a nonspecific SGLT1/SGLT2 inhibitor that is hydrolyzed in the gut to its aglycone phloretin, which is a potent inhibitor of facilitated glucose transport.

Concurrent inhibition of facilitative glucose transporters (GLUTs) is undesirable since such inhibitors would be predicted to exacerbate peripheral insulin resistance as well as promote hypoglycemia in the CNS.

Inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 cotransporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration. The biochemical differences between SGLT2 and SGLT1, as well as the degree of sequence divergence between them, allow for identification of selective SGLT2 inhibitors.

The familial glycosuria syndromes are conditions in which intestinal glucose transport, and renal transport of other ions and amino acids, are normal. Familial glycosuria patients appear to develop normally, have normal plasma glucose levels, and appear to suffer no major health deficits as a consequence of their disorder, despite sometimes quite high (110-114 g/daily) levels of glucose excreted. The major symptoms evident in these patients include polyphagia, polyuria and polydipsia, and the kidneys appear to be normal in structure and function. Thus, from the evidence available thus far, defects in renal reuptake of glucose appear to have minimal long term negative consequences in otherwise normal individuals.

Representative examples of glycosides that have been shown to be useful for the treatment of NIDDM and obesity can be found in the following disclosures: U.S. Patent Nos. 6,515,117;

6,414,126; 7,101 ,856; 7,169,761 ; and 7,202,350; U.S. Publication Nos. US2002/0111315;

US2002/0137903; US2004/0138439; US2005/0233988; US2006/0025349; US2006/0035841 ; and US2006/0632722; and PCT Publication Nos. WO01/027128; WO02/044192; WO02/088157; WO03/099836; WO04/087727; WO05/021566; WO05/085267; WO06/008038; WO06/002912; WO06/062224; WO07/000445; WO07/093610; and WO08/002824. Certain glycosides are genotoxic and impact a cell's genetic material such that they may be potentially mutagenic or carcinogenic. Genotoxic materials may be detected using Standard assays such as the In Vitro Mammalian Cell Micronuleus Test (MNvit), Organization for Economic Co-Operation and Development (OECD) Draft Test Guideline (Draft TG) 487 (2007); In vitro Mammalian

Chromosomal Aberration Test, OECD TG 473 (1997 ); Bacterial Reverse Mutation Test, OECD TG 471 (1997); Mammalian ErythrocyteMicronucleus Test, OECD TG 474 (1997); or the like. Consequently, there still exists a need for a more effective and safe therapeutic treatment and/or prevention of obesity and its associated co-morbidities, in particular, Type 2 diabetes and related disorders.

Summary of Invention The present invention is directed to compounds that are compounds of formula (I) and pharmaceutically acceptable salts thereof, all stereoisomers thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a crystal thereof, all prodrug esters thereof, and mixtures of any of the foregoing:

Wherein Ri is selected from a group consisting of H, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, CI, F, cyano, halo- substituted (Ci-C₂)alkyl, (Ci-C₄)alkyl-S0₂-, (C₃-C₆)cycloalkyl, or substituted(C₃-C₆)cycloalkyl;

R₂ is selected from a group consisting of (Ci-C₆)alkyl, (Ci-C₆)alkoxy, (C₂-C₆)alkynyl, 3- oxetanyloxy, 3-tetrahydrofuranyloxy, CI, F, cyano, halosubstituted (Ci-C₂)alkyl, (Ci-Ce)alkyl-S0₂-, (C₃-C₆)cycloalkyl, or a (C5-C6)heterocycle having lor 2 heteroatoms, the said heteroatom each independently selected from N, O, or S;

R₃ is X-L;

X is selected from a group consisting of (Ci-C₆)alkyl, (Ci-C₆)alkoxyl, (C₂-C₆)alkynyl, (C₂- C₆)alkenyl, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkyl-NH, (Ci-C₆)alkyl-NHC(0), (Ci-C₆)alkyl-NHS(0)_m, wherein m is 1 or 2;

L is selected from a group consisting of H, (Ci-C₆)alkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, halosubstituted (Ci-C₆)alkyl, halosubstituted (C₂-C₆)alkynyl, halosubstituted (C₂-Ce)alkenyl.

It is generally understood by those skilled in the art that various substituents may be added to the compounds of Formula (I) so long as the substituent(s) selected does not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament.

The compound of formula I possesses activity as inhibitors of the sodium dependent glucose transporters (SGLT) found in the intestine and kidney of mammals and is useful in the treatment of diabetes and the micro-and macrovascular complications of diabetes such as retinopathy, neuropathy, nephropathy, and wound healing.

The present invention provides for compound of formula I, pharmaceutical compositions employing such a compound and for methods of using such a compound.

In addition, in accordance with the present invention, a method is provided for treating or delaying the progression or onset of diabetes, especially type I and type II diabetes, including complications of diabetes, including retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance (impaired glucose homeostasis),

hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, atherosclerosis and hypertension, and for increasing high density lipoprotein levels, wherein a therapeutically effective amount of a compound of structure I is administered to a human patient in need of treatment.

In addition, in accordance with the present invention, a method is provided for treating diabetes and related diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of structure I and another type of antidiabetic agent and/or another type of therapeutic agent such as a hypolipidemic agent is administered to a human patient in need of treatment.

The conditions, diseases, and maladies collectively referred to as"Syndrome X" (also known as Metabolic Syndrome) are detailed in Johannsson J. Clin. Endocrinol. Metab. , 82,727-34 (1997).

The flowing compounds of the invention are provided to give the reader an understanding of the compounds encompassed by the invention:

(2S, 3R, AS, 5S, 65^,)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65^,)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol; (2S, 3R, AS, 5S, 65)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65^,)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol; (2R, 3R, AS, 5S, 6S)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 6_lS^,)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol.

The term'Other type of therapeutic agents"as employed herein refers to one or more antidiabetic agents (other than SGLT2 inhibitors of formula I), one or more anti-obesity agents, anti-hypertensive agents, anti- platelet agents, anti-atherosclerotic agents and/or one or more lipid- lowering agents (including anti- atherosclerosis agents).

In the above method of the invention, the compound of structure I of the invention will be employed in a weight ratio to the one, two or more antidiabetic agent and/or one, two or more other type therapeutic agent (depending upon its mode of operation) within the range from about 0.01 : 1 to about 300: 1 , preferably from about 0.1 : 1 to about 10: 1.

The term"Pharmaceutically acceptable excipient" refers to any of a diluent, adjuvant, vehicle, excipient or carrier with which at least one compound of the present disclosure is administered.

Before the present compounds, compositions and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The plural and singular should be treated as interchangeable, other than the indication of number: As used herein, the term "alkyl" refers to a hydrocarbon radical of the general formula C_nH2_n+i . The alkane radical may be straight or branched. For example, the term "(Ci-C6)alkyl" refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, /-propyl, n- butyl, /-butyl, s-butyl, f-butyl, n- pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio group have the same definition as above. When indicated as being "optionally substituted", the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perhaloalkyls) independently selected from the group of substituents listed below in the definition for "substituted." "Halo-substituted alkyl" refers to an alkyl group substituted with one or more halogen atoms (e.g., halomethyl, dihalomethyl, trihalomethyl, perhaloethyl, 1 ,1-dihaloethyl and the like).

The term "cycloalkyl" refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiro ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8-membered ring. For example, cycloalkyl include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornyl, (bicyclo[2.2.1]heptyl),

bicyclo[2.2.2]octyl, and the like.

The term "heterocycle" refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the heterocyclic ring is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Heterocyclic rings include groups such as epoxy, azihdinyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, pipehdinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholino, thiomorpholino, tetrahydrothienyl,

tetrahydrothienyl 1 ,1 -dioxide, and the like.

The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The term "animal" refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species. "Edible animals" refers to food-source animals such as cows, pigs, sheep and poultry.

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. The terms "treating", "treat", or "treatment" embrace both preventative, i.e., prophylactic, and palliative treatment. The terms "modulated" or "modulating", or "modulate(s)", as used herein, unless otherwise indicated, refers to the inhibition of the sodium-glucose transporter (in particular, SGLT2) with compounds of the present invention thereby partially or fully preventing glucose transport across the transporter.

The term "compounds of the present invention" (unless specifically identified otherwise) refer to compounds of Formula (I) and all pure and mixed stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds. Hydrates and solvates of the compounds of the present invention are considered compositions of the present invention, wherein the compound is in association with water or solvent, respectively. The compounds may also exist in one or more crystalline states, i.e. as co-crystals, polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the claims.

Detailed Decription of the Invention

The present invention may be understood even more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.

In one embodiment, Ri is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, F, CI, cyano, - CF₃, cyclopropyl, or cyclobutyl. In another embodiment, Ri is H, methyl, ethyl, isopropyl, methoxy, ethoxy, F, CI, cyano, -CF₃, or cyclopropyl. In a further embodiment, Ri is H, methyl, ethyl, methoxy, ethoxy, F, CI, cyano, -CF₃, or cyclopropyl. In yet a further embodiment, Ri is methyl, ethyl, F, CI, cyano, CF₃, or cyclopropyl;

In one embodiment, R² is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, F, CI, cyano, - CF₃, -CF₂CH₃, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. In another embodiment, R² is methyl, ethyl, isopropyl, methoxy, ethoxy, F, CI, cyano, -CF₃, - CF₂CH₃, ethynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, or cyclopropyl. In a further embodiment, R² is methyl, ethyl, methoxy, ethoxy, F, CI, cyano, -CF₃, -CF₂CH₃, ethynyl, 3- oxetanyloxy, 3- tetrahydrofuranyloxy, or cyclopropyl. In yet a further embodiment, R² is methoxy or ethoxy.

In another embodiment, R₃ is X-L; X is selected from a group consisting of (Ci-C₆)alkyl, , (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (Ci-C₆)alkylcarbonyl, L is selected from a group consisting of H, (Ci-C₆)alkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, halosubstituted (Ci-C₆)alkyl, halosubstituted (C₂- C₆)alkynyl, halosubstituted (C₂-C₆)alkenyl, (Ci-C₆)alkoxyl, (Ci-C₆)alkyl-NH, (Ci-C₆)alkyl- NHC(O), (Ci-C₆)alkyl-NHS(0)_m, wherein m is 1, 2.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art.

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention, protection of remote functionality of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. A "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxyl-protecting groups (O-Pg) include for example, allyl, acetyl (Ac), silyl (like thmethylsily (TMS) or tert-butyldimethylsilyl (TBS)), benzyl (Bn), para-methoxybenzyl (PMB), trityl (Tr), para-bromobenzoyl, para- nitrobenzoyl and the like (benzylidene for protection of 1 ,3- diols). The need for such protection is readily determined by one skilled in the art.

Scheme 1 outlines the general procedures one could use to provide compounds of the present invention.

Scheme 1

Triacetyl protected glycal (1) is commercial available or been prepared by conventional methods known by those skilled in the art. In step a of Scheme 1 , deprotection of acetyl groups can be easily achieve by means of hydrlysis in the presence of an alkali metal hydroxide or alkali alkanoxide (e.g., sodium hydroxide, potassium butoxide).

In step b of Scheme 1 , cyclic silyl protecting groups can be added by treating the intermediate from step a with the appropriate reagents and procedures. For example, (i-Bu)₂Si(OTf)2 (1 equiv) in DMF and -50°C for 12h.

In step c of Scheme 1 , the TBDMS (ieri-butydimethylsilyl) protection group is introduced by treatment with TBDMSC1 (ieri-butydimethylsilylchloride) with the existence of base such as imidazole; other conditions known by those skilled in the art could also be used, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 ).

In step d of Scheme 1, R₃ group is introduced by the treatment of butyl lithium at low temperature, followed by R₃-Y. Y is a good leaving group, such as bromide, iodine or tosylate. R₃ definition is as defined in above.

In step e of Scheme 1 , the intermediates from step d is oxidized by dimethyl dioxirane to form the corresponding epoxides.

In step 6 of Scheme 1, the arylbenzyl group (Ar) is introduced using the desired

organometallic reagent (e.g., organo lithium compound (ArLi) or organomagnesium compound (ArMgX)) in tetrahydrofuran (THF) at a temperature ranging from about -78^°Cto about 20 ^°C followed by hydrolysis (upon standing in protic conditions) to the corresponding silyl protected 5.

The final step in Scheme 1, (A) and (B) can be prepared by removing the protecting groups (Pg²) using the appropriate reagents for the protecting groups employed. For example, the PMB protecting groups may be removed by treatment with trihaloacetic acid in the presence of anisole and dichloromethane (DCM) at about 0^°C to about 23 ^°C(room temperature). The remaining protecting groups (Pg¹) may then be removed using the appropriate chemistry for the particular protecting groups. For example, benzyl protecting groups may be removed by treating with formic acid in the presence of palladium (Pd black) in a protic solvent (e.g., ethanol/THF) at about room temperature to produce the final products (A) and (B). When R¹ is CN, the use of a Lewis acid like boron trichloride at a temperature ranging from about -78 ^°C to about room temperature in a solvent like dichloromethane or 1 ,2-dichloroethane may also be used to remove benzyl protective and/or para- methoxybenzyl protective groups.

The following abbreviations are employed herein: Ph = phenyl, Bn = benzyl, t-Bu = tertiary butyl, Me = methyl, Et = ethyl, TMS = trimethylsilyl, TBS = tert-butyldimethylsilyl, THF = tetrahydrofuran, Et₂0 = diethyl ether, EtOAc = ethyl acetate, DMF = dimethyl formamide, MeOH = methanol, EtOH = ethanol, i-PrOH = isopropanol, HO Ac or AcOH = acetic acid, TFA = trihaloacetic acid, i-Pr₂NEt = diisopropylethylamine, Et₃N = triethylamine, DMAP = 4- dimethylaminopyridine, NaB¾ = sodium borohydride, n-BuLi = n-butyllithium, Pd/C = palladium on carbon, KOH = potassium hydroxide, NaOH = sodium hydroxide, LiOH = lithium hydroxide, K₂C0₃ = potassium carbonate, NaHC0₃ = sodium bicarbonate, Ar = argon N₂ = nitrogen, min = minute (s), h or hr = hour (s), L = liter, mL = milliliter, RL = microliter, g = gram (s), mg = milligram (s), mol = moles, mmol = millimole(s), meq = milliequivalent, RT = room temperature, sat or sat'd = saturated, aq. = aqueous, TLC = thin layer chromatography, HPLC = high

performance liquid chromatography, LC/MS = high performance liquid chromatography/mass spectrometry, MS or Mass Spec = mass spectrometry, NMR = nuclear magnetic resonance, mp = melting point.

Unless otherwise indicated, the term" lower alkyl" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 8 carbons, and the terms"alkyl"and "ahV'as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as halo, for example F, Br, CI or I or CF3, alkyl, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy, optionally substituted amino, hydroxy, hydroxyalkyl, acyl, alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl and/or alkylthio.

Unless otherwise indicated, the term"cycloalkyl"as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl,

alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/or any of the alkyl substituents.

The term"alkanoyl"as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.

The term"halogen"or"halo"as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

The term"metal ion"refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.

Unless otherwise indicated, the term"aryl"or "Aryl"as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, alkoxy, haloalkoxy, alkenyl, trihalomethyl, trihalomethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxy arylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfmylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl and/or any of the alkyl substituents set out herein.

Unless otherwise indicated, the term"lower alkoxy", "alkoxy", "aryloxy"or"aralkoxy"as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.

Unless otherwise indicated, the term"lower alkylthio", alkylthio", "arylthio"or"aralkylthio"as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.

The term"polyhaloalkyl"as used herein refers to an "alkyl"group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or CI, preferably F, such as CF₃CH₂, CF₃ or CF₃CF₂CH₂.

The term"polyhaloalkyloxy"as used herein refers to an"alkoxy"or"alkyloxy" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or CI, preferably F, such as CF₃CH₂0, CF₃0 or CF₃CF₂CH₂0.

The term"prodrug esters"as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like. In addition, prodrug esters which are known in the art for carboxylic and phosphorus acid esters such as methyl, ethyl, benzyl and the like.

Examples of such prodrug esters include Where the compound of structure I are in acid form they may form a pharmaceutically acceptable salt such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, lysine (D or L), ethylenediamine, t- butylamine, t-octylamine, tris- (hydroxymethyl) aminomethane (TRIS), N-methyl glucosamine (NMG), triethanolamine and dehydroabietylamine.

The compounds of the present invention contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless specified otherwise, it is intended that all stereoisomeric forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention. Diastereomehc mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization, distillation, sublimation. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.

Enantiomers can also be separated by use of a chiral HPLC (high pressure liquid

chromatography) column.

It is also possible that the intermediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomehzations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. The equilibrium between closed and opened form of some intermediates (and/or mixtures of intermediates) is reminiscent of the process of mutarotation involving aldoses, known by those skilled in the art.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³1, ¹²⁵I and ³⁶CI, respectively.

Certain isotopically-labeled compounds of the present invention (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon- 14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and

detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission

tomography (PET) studies to examine substrate occupancy, lsotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by the inhibition of the sodium-glucose transporters (in particular SGLT2); therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, carrier or adjuvant.

The compounds of the present invention (including the compositions and processes used therein) may also be used in the manufacture of a medicament for the therapeutic applications described herein.

A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or

pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical compositions also include solvates and hydrates of the compounds of Formula (I). The term "solvate" refers to a molecular complex of a compound represented by Formula (I) (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, ethylene glycol, and the like, The term "hydrate" refers to the complex where the solvent molecule is water. The solvates and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)- propylene glycol, (R)-propylene glycol, 1 ,4-butyne-diol, and the like. The crystalline forms may also exist as complexes with other innocuous small molecules, such as L- phenylalanine, L-proline, L-pyroglutamic acid and the like, as co-crystals or solvates or hydrates of the co- crystalline material. The solvates, hydrates and co-crystalline compounds may be prepared using procedures described in PCT Publication No. WO08/002824, incorporated herein by reference, or other procedures well-known to those of skill in the art.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The present invention further provides a method of treating diseases, conditions and/or disorders modulated by the inhibition of sodium-glucose transporters in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, conditions and/or disorders that benefit from the inhibition of SGLT2. One aspect of the present invention is the treatment of obesity, and obesity-related disorders (e.g., overweight, weight gain, or weight maintenance).

Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m²). Overweight is typically defined as a BMI of 25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m². See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: U.S. Department of Health and Human Services, NIH publication no. 98- 4083 (1998). Another aspect of the present invention is for the treatment or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin- dependent diabetes mellitus, also referred to as "IDDM") and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as "NIDDM") diabetes, impaired glucose tolerance, delayed wound healing, hyperinsulinemia, elevated blood levels of fatty acids, hyperlipidemia, hypertriglyceridemia, Syndrome X, increased high density lipoprotein levels, insulin resistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).

In yet another aspect of the present invention is the treatment of obesity co- morbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes), coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P. Z., et al, "The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth - Where Does the International Diabetes Federation Stand?," Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al, "The Metabolic Syndrome - A New Worldwide Definition," Lancet, 366, 1059-62 (2005).

Preferably, administration of the compounds of the present invention provides a statistically significant (p<0.05) reduction in at least one cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive protein (CRP) and/or cholesterol, as compared to a vehicle control containing no drug. The administration of compounds of the present invention may also provide a statistically significant (p<0.05) reduction in glucose serum levels.

For a normal adult human having a body weight of about 100 kg, a dosage in the range of from about 0.00 lmg to about 10 mg per kilogram body weight is typically sufficient, preferably from about O.Olmg/kg to about 5.0mg/kg, more preferably from about 0.01 mg/kg to about 1 mg/kg. However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular compound being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure. It is also noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in

combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), antidiabetic agents, anti-hyperglycemic agents, lipid lowering agents, anti-inflammatory agents and anti-hypertensive agents.

Suitable anti-obesity agents include cannabinoid-1 (CB-1 ) antagonists (such as rimonabant),

11 β-hydroxy steroid dehydrogenase- 1 (1 Ιβ-HSD type 1 ) inhibitors, stearoyl- CoA desaturase-1 (SCD-1 ) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide -Y antagonists (e.g., NPYY5 antagonists), PYY3-36 (including analogs thereof), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon- like peptide- 1 agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc.,

Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, and the like.

Preferred anti-obesity agents for use in the combination aspects of the present invention include CB-1 antagonists (e.g., rimonabant, taranabant, surinabant, otenabant, SLV319 (CAS No. 464213-10-3) and AVE1625 (CAS No. 358970-97-5)), gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(l H-indol-3-ylmethyl)-5-oxo-l-phenyl-4,5-dihydro-2,3,6,10b- tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO

2005/116034 or US Publication No. 2005-0267100 Al ), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US6,818,658), lipase inhibitor (e.g., Cetilistat), ΡΥΥ₃_₃₆ (as used herein "PYY _ ₆" includes analogs, such as peglated PYY₃_₃₆ e.g., those described in US Publication 2006/0178501 ), opioid antagonists(e.g., naltrexone), oleoyl-estrone (CAS No.180003- 17-2), obinepitide (TM30338), pramlintide (Symlin^®), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta^®), AOD-9604 (CAS No. 221231-10-3) and sibutramine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a phosphodiesterase (PDE)-IO inhibitor, a diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an a-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), an a-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARy agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g., exendin-3 and exendin-4), a protein tyrosine phosphatase-1 B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al, Drug Discovery Today, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., reservatrol), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin), an insulin

secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist and a glucokinase activator. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin).

Suitable anti-inflammatory agents include genital tract/urinary tract infection preventatives and treatments. Exemplary agents include cranberries (i.e. Vaccinium macrocarpon) and cranberry derivatives such as cranberry juice, cranberry extracts or flavonols of cranberries. Cranberry extracts may include one or more flavonols (i.e. anthocyanins and proanthocyanidins) or a purified cranberry flavonol compound, including myricetin-3-P-xylopyranoside, quercetin-3-P-glucoside, quercetin-3-a-arabinopyranoside, 3'-methoxyquercetin-3-a-xylopyranoside, quercetin-3-0-(6"-p- coumaroyl)-P-galactoside, quercetin-3-0-(6"-benzoyl)-P-galactoside, and/or quercetin-3-α- arabinofuranoside.

Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

All temperatures are expressed in degrees Centigrade unless otherwise indicated.

EXAMPLES

Example 1.

(IS, 3R, AS, 5S, 65^,)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol

Step 1. 2-Di-ieri-butyl-6-methyl-8-(iert-butyldimethyl-silanyloxy)-4,4a,8,8a-tetrahydro-l,3,5- trioxa-2-sila-naphthalene To slurry of glycal 2 (Scott W. Roberts and Jon D. Rainier, Org. Lett. 2005, 7, 1141) and THF (0.053 mL) at 0^°Cwas added ί-BuLi (1.36mL of a 1.7 M solution in pentane, 2.3 mmol). After stirring for 0.5 h thereaction mixture was cooled to -78°Cand diluted with THF (0.90ml); CH₃I (0.27mL,4.35mmol) was then slowly added. After warming to rt, the reaction was quenched with aq. NH₄CI (sat., 20 mL). The aqueous phase was extracted with 3: 1 hexanes: ethyl acetate (3 X 10 mL), dried (Na₂S0₄), and concentrated. Flash chromatography (hexanes, then 100: 1 hexanes:ethyl acetate) gave 105 mg (79%) of title compound as a colorless oil. [a]²⁰ _D = -38.1°(c = 1.46, THF); 1H NMR (500 MHz, C₆D₆) δ 4.59 (s, 1 H), 4.51-4.54 (m, 1 H), 4.19 (dd, / = 10.3, 4.9 Hz, 1 H), 4.11 (dd, / = 10.3, 6.8 Hz, 1 H), 3.97 (dd, / = 10.3 Hz, 1 H), 3.79(ddd, / = 10.3, 10.3, 4.9 Hz, 1 H), 1.60 (d, / = 1.0 Hz, 3 H), 1.23-1.21 (m, 21 H), 1.10 (s, 9 H), 1.08 (s, 9 H); ¹³C NMR (125 MHz, C₆D₆) δ 151.3, 101.8, 78.5, 73.4, 72.5, 66.9, 28.0, 27.6, 23.3, 20.4, 19.5, 18.9, 18.8, 13.3; IR (neat) 2866, 1683, 1472, 1109; HRMS (CI) calcd for C₂₁H₄₂O₄S1₂ (M+H)⁺ 415.7268, found 415.7288.

Step 2. la-Methyl-5,5-di-ieri-butyl-7-(iert-butyl-diphenyl-silanyloxy)-hexahydro- l,2,4,6-tetraoxa-5-sila-cyclopropa[b]naphthalene (3a)

To a solution of above title compound (0.012g, 0.019 mmol) and CH₂C1₂ (1 mL) at -78^°Cwas added dimethyl dioxirane (0.29 mL of an ca. 0.1 M solution in acetone, 0.03 mmole) dropwise. Following addition, the reaction was warmed to 0°C and concentrated. While 3a was generally used without purification, an analytical sample of 3a was prepared using flash chromatography (20: 1 hexanes:ethyl acetate) to give 13 mg (100% yield) of 3a as a colorless oil. 1H NMR (500MHz, CD₂CI₂) δ 7.78-7.76 (m, 2 H), 7.74-7.72 (m, 2 H), 7.46-7.24 (m, 11 H), 4.50 (d, / = 11.7Hz, 1 H), 4.46 (d, / = 11.7 Hz, 1 H), 4.13 (d, / = 7.3 Hz, 1 H), 4.05 (dd, / = 10.3, 4.9 Hz, 1 H), 3.92 (dd, / = 10.3, 7.3 Hz, 1 H), 3.85 (dd, / = 10.3, 10.3 Hz, 1 H), 3.68 (d, / = 11.7Hz, 1 H), 3.58 (d, / = 11.7 Hz, 1 H), 3.58 (ddd, / = 10.3, 10.0, 5.2 Hz, 1 H), 2.93 (s, 1 H), 1.12 (s, 9 H), 1.04 (s, 9 H), 0.91 (s, 9 H).

Step 3. 2,2-Di-tert-butyl-8-(tert-butyl-dimethyl-silanyloxy)-6-[4-chloro-3-(4-ethoxy-benzyl)- phenyl]-6-methyl-hexahydro-l,3,5-trioxa-2-sila-naphthalen-7-ol

To a solution of 3a (0.023 mmol) and THF (1.5 mL) at -78^°C was added 4-Chloro-3-(4- ethoxy-benzyl)phenylmagnesium bromide (prepared from4-Chloro-3-(4-ethoxy benzyl)phenyl- bromide, 0.12 mL of a 2.0 M solution in THF, 0.23 mmol) dropwise. After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at rt for 2.5 h. The reaction was quenched with aq. NH₄C1 (sat., 20 ml), extracted with 3: 1 hexanes:ethyl acetate (3 X 10 mL), dried (Na₂SC>4), and concentrated. Flash chromatography (10: 1 hexanes:ethyl acetate) gave 15 mg (91%) of C-ketoside the title compound as a colorless oil. [af D = +3.5 Γ (c = 0.74, THF); 1H NMR (500 MHz,C₆D₆) δ 7.98 (m, 2 H), 7.9 (d, 2 H), 7.26-7.05 (m, 1 1 H), 5.95 (dddd, / = 17.4, 10.2, 7.3,7.3 Hz, 1 H), 5.01 (d, / = 9.3 Hz, 1 H), 4.98 (d, / = 17.1 Hz, 1 H), 4.51 (dd, / = 8.8, 8.8Hz, 1 H), 4.30 (dd, / = 9.8, 4.9 Hz, 1 H), 4.19 (ddd, / = 9.8, 9.8, 4.9 Hz, 1 H), 4.05-3.99(m, 3 H), 3.93 (dd, / = 9.8, 9.8 Hz, 1 H), 3.76 (dd, / = 8.8, 6.3 Hz, 1 H), 3.54 (d, / = 10.7Hz, 1 H), 3.38 (d, / = 10.7 Hz, 1 H), 2.40 (dd, / = 14.2, 6.8 Hz, 1 H), 2.26 (dd, / = 13.7,7.8 Hz, 1 H), 1.75 (d, / = 5.9 Hz,

1 H), 1.29 (s, 9 H), 1.19 (s, 9 H), 1.1 1 (s, 9 H); ¹³C NMR (125 MHz, C₆D₆) δ 138.6, 137.2, 136.4, 136.1 , 134.2, 134.1 , 130.4, 130.3, 129.0, 129.0, 128.5, 128.1 , 128.1 , 1 18.5, 79.9, 79.6, 78.8, 76.9, 74.0, 73.8, 70.8, 68.4, 41.8, 28.2,27.8, 27.8, 23.3, 20.6, 20.5; HRMS (CI) calcd for C₃₆H₅₇0₆Si₂ (M+H)⁺ 643.0052, found 643.0082.

Step 4. (IS, 3R, 4S, 5S, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methyl-tetrahydro-pyran-3,4,5-triol

To a solution of above title compound (0.026g, 0.035 mmol) and THF (1.75 mL) at 0^°C was added HF 'pyridine (0.070 mL of a 1 M solution in THF, 0.07 mmol). After stirring for 6.5 h, the reaction was quenched with aq. NaHC0₃ (sat., 10 mL) at 0^°C . The mixture was extracted with 1 : 1 hexanes:ethyl acetate (3 x 10 ml), dried (Na₂SC>4), and concentrated. Flash chromatography (5 : 1 hexanes:ethyl acetate) gave 14.7mg of 5a as a colorless oil. To a solution of the diol from above (0.0082g, 0.014mmol) and MeOH (lmL) at rt was added p-toluenesulfonic acid monohydrate (0.032 g, 0.168 mmol) over 48h. The reaction was cooled to 0^°C and quenched by the slow addition of aq. NaHC0₃ (sat., 2mL). The resulting mixture was extracted with 1 : 1 hexanes:ethyl acetate (5 x

2 mL), dried (Na₂S0₄), and concentrated. Flash chromatography (3 : 1 hexanes:ethyl acetate tol : l hexanes:ethyl acetate) gave 1.8 mg (27%) of 5a as a colorless oil. [a]²°o = +15.0° (c= 0.0470, THF); 1H NMR (500 MHz, (CD₃)₂CO) δ 7.82-7.79 (m, 4 H), 7.44-7.37 (m, 6H), 3.85 (dd, / = 9.1 , 9.1 Hz,

1 H), 3.74 (d, / = 9.3 Hz, 1 H), 3.63 (dd, / = 1 1.5, 3.2 Hz, 1H), 3.58 (s, 3 H), 3.53 (dd, / = 12.0, 5.2 Hz, 1 H), 3.51 (dd, / = 9.6, 9.6 Hz, 1 H), 3.29 (ddd, / = 8.8, 4.5, 4.5 Hz, 1 H), 2.52 (d, / = 2.0 Hz, 2 H), 1.1 1 (s, 3H), 1.07 (s, 9 H); ¹³C NMR (125 MHz, CDC1₃) δ 171.2, 135.9, 135.9, 133.6, 133.4, 130.4, 130.4, 128.4, 128.3,78.0, 76.6, 75.2, 72.7, 72.0, 62.9, 51.8, 45.1 , 27.3, 19.8, 17.2; HRMS (CI) calcd for C₂₂H₂₇C10₆ (M+H)⁺ 423.8989, found 423.8979.

Example 2. (2S, 3R, 4S, 5S, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol

Step 1. 2-Di-ieri-butyl-6-methoxymethyl-8-(iert-butyldimethyl-silanyloxy)-4,4a,8,8a- tetrahydro-l,3,5-trioxa-2-sila-naphthalene

To slurry of glycal 2 (Scott W. Roberts and Jon D. Rainier, Org. Lett. 2005, 7, 1141) and THF (0.053 mL) at 0^°Cwas added i-BuLi (1.36 mL of a 1.7 M solution in pentane, 2.3 mmol). After stirring for 0.5 h the reaction mixture was cooled to -78^°Cand diluted with THF (0.90 ml);

CH₃OCH₂I (0.27 mL,4.35 mmol) was then slowly added. After warming to rt, the reaction was quenched with aq. NH₄C1 (sat., 20 mL). The aqueous phase was extracted with 3: 1 hexanes:ethyl acetate (3 X 10 mL), dried (Na₂S0₄), and concentrated. Flash chromatography (hexanes, then 100: 1 hexanes:ethyl acetate) gave 105 mg (79%) of title compound as a colorless oil. [a]²°o = -38.1°(c = 1.46, THF); 1H NMR (500 MHz, C₆D₆) δ 4.59 (s, 1 H), 4.51-4.54 (m, 1 H), 4.19 (dd, / = 10.3, 4.9 Hz, 1 H), 4.11 (dd, / = 10.3, 6.8 Hz, 1 H), 3.97 (dd, / = 10.3 Hz, 1 H), 3.79 (ddd, / = 10.3, 10.3, 4.9 Hz, 1 H), 1.60 (d, / = 1.0 Hz, 3 H), 1.23-1.21 (m, 21 H), 1.10 (s, 9 H), 1.08 (s, 9 H); ¹³C NMR (125 MHz, C₆D₆) δ 151.3, 101.8, 78.5, 73.4, 72.5, 66.9, 28.0, 27.6, 23.3, 20.4, 19.5, 18.9, 18.8, 13.3; IR (neat) 2866, 1683, 1472, 1109; HRMS(CI) calcd for C₂₁H₄₂O₄S1₂ (M+H)⁺ 415.7268, found

415.7288.

Step 2. la-Methoxymethyl-5,5-di-iert-butyl-7-(ieri-butyl-diphenyl-silanyloxy)-hexahydro- l,2,4,6-tetraoxa-5-sila-cyclopropa[b]naphthalene (3b)

To a solution of above title compound (0.012g, 0.019 mmol) and CH₂CI₂ (1 mL) at -78^°C was added dimethyl dioxirane (0.29 mL of an ca. 0.1 M solution in acetone, 0.03mmole) dropwise. Following addition, the reaction was warmed to 0^°C and concentrated. While 3b was generally used without purification, an analytical sample of 3b was prepared using flash chromatography

(20: 1 hexanes:ethyl acetate) to give 13 mg (100% yield) of 3b as a colorless oil. 1H NMR (500MHz, CD₂CI₂) δ 7.78-7.76 (m, 2 H), 7.74-7.72 (m, 2 H), 7.46-7.24 (m, 11 H), 4.50 (d, / = 11.7Hz, 1 H), 4.46 (d, / = 11.7 Hz, 1 H), 4.13 (d, / = 7.3 Hz, 1 H), 4.05 (dd, / = 10.3, 4.9 Hz, 1 H), 3.92 (dd, / = 10.3, 7.3 Hz, 1 H), 3.85 (dd, / = 10.3, 10.3 Hz, 1 H), 3.68 (d, / = 11.7 Hz, 1 H), 3.58 (d, / = 11.7 Hz, 1 H), 3.58 (ddd, / = 10.3, 10.0, 5.2 Hz, 1 H), 2.93 (s, 1 H), 1.12 (s, 9 H), 1.04 (s, 9 H), 0.91 (s, 9 H).

Step 3. 2,2-Di-tert-butyl-8-(tert-butyl-dimethyl-silanyloxy)-6-[4-chloro-3-(4-ethoxy-benzyl)- phenyl]-6-methoxymethyl-hexahydro-l,3,5-trioxa-2-sila-naphthalen-7-ol

To a solution of 3b (0.023 mmol) and THF (1.5 mL) at -78^°Cwas added 4-Chloro-3-(4-ethoxy- benzyl)phenylmagnesium bromide (prepared from 4-Chloro-3-(4-ethoxy benzyl)phenyl-bromide, 0.12mL of a 2.0M solution in THF, 0.23 mmol) dropwise. After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at rt for 2.5 h. The reaction was quenched with aq. NH₄C1 (sat., 20 ml), extracted with 3: 1 hexanes:ethyl acetate (3 X 10 mL), dried (Na₂S0₄), and concentrated. Flash chromatography (10: 1 hexanes:ethyl acetate) gave 15 mg (91%) of C-ketoside the title compound as a colorless oil. [a]²⁰ _D = +3.5 F (c = 0.74, THF); 1H NMR (500 MHz,C₆D₆) δ 7.98 (m, 2 H), 7.9 (d, 2 H), 7.26-7.05 (m, 11 H), 5.95 (dddd, / = 17.4, 10.2, 7.3,7.3 Hz, 1 H), 5.01 (d, / = 9.3 Hz, 1 H), 4.98 (d, / = 17.1 Hz, 1 H), 4.51 (dd, / = 8.8, 8.8Hz, 1 H), 4.30 (dd, / = 9.8, 4.9 Hz, 1 H), 4.19 (ddd, / = 9.8, 9.8, 4.9 Hz, 1 H), 4.05-3.99(m, 3 H), 3.93 (dd, / = 9.8, 9.8 Hz, 1 H), 3.76 (dd, / = 8.8, 6.3 Hz, 1 H), 3.54 (d, / = 10.7Hz, 1 H), 3.38 (d, / = 10.7 Hz, 1 H), 2.40 (dd, / = 14.2, 6.8 Hz, 1 H), 2.26 (dd, / = 13.7,7.8 Hz, 1 H), 1.75 (d, / = 5.9 Hz, 1 H), 1.29 (s, 9 H), 1.19 (s, 9 H), 1.11 (s, 9 H); ¹³C NMR (125 MHz, C₆D₆) δ 138.6, 137.2, 136.4, 136.1, 134.2, 134.1, 130.4, 130.3, 129.0,129.0, 128.5, 128.1, 128.1, 118.5, 79.9, 79.6, 78.8, 76.9, 74.0, 73.8, 70.8, 68.4, 41.8, 28.2,27.8, 27.8, 23.3, 20.6, 20.5; HRMS (CI) calcd for

(M+H)⁺ 643.0052, found 643.0082.

Step 4. (25, R, 45, 55, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol

To a solution of above title compound (0.026 g, 0.035 mmol) and THF (1.75 mL) at 0^°C was added HF 'pyridine (0.070 mL of a 1 M solution in THF, 0.07 mmol). After stirring for 6.5 h, the reaction was quenched with aq. NaHC0₃ (sat., 10 mL) at 0^°C . The mixture was extracted with 1 : 1 hexanes:ethyl acetate (3 x 10 ml), dried (Na₂S0₄), and concentrated. Flash chromatography (5: 1 hexanes:ethyl acetate) gave 14.7mg of 5b as a colorless oil. To a solution of the diol from above (0.0082g, 0.014 mmol) and MeOH (1 mL) at rt was added p-toluenesulfonic acid monohydrate (0.032 g, 0.168 mmol) over 48 h. The reaction was cooled to 0^°C and quenched by the slow addition of aq. NaHC0₃ (sat., 2mL). The resulting mixture was extracted with 1 : 1 hexanes:ethyl acetate (5 x 2 mL), dried (Na₂SC>4), and concentrated. Flash chromatography (3 : 1 hexanes:ethyl acetate tol : l hexanes:ethyl acetate) gave 1.8 mg (27%) of 5b as a colorless oil. [a] D ⁼ +15.0° (c= 0.0470, THF); 1H NMR (500 MHz, (CD₃)₂CO) δ 7.82-7.79 (m, 4 H), 7.44-7.37 (m, 6H), 3.85 (dd, / = 9.1 , 9.1 Hz, 1 H), 3.74 (d, / = 9.3 Hz, 1 H), 3.63 (dd, / = 1 1.5, 3.2 Hz, 1H), 3.58 (s, 3 H), 3.53 (dd, / = 12.0, 5.2 Hz, 1 H), 3.51 (dd, / = 9.6, 9.6 Hz, 1 H), 3.29 (ddd, / = 8.8, 4.5, 4.5 Hz, 1 H), 2.52 (d, / = 2.0 Hz, 2 H), 1.1 1 (s, 3H), 1.07 (s, 9 H); ¹³C NMR (125 MHz, CDC1₃) δ 171.2, 135.9, 135.9, 133.6, 133.4, 130.4, 130.4, 128.4, 128.3, 78.0, 76.6, 75.2, 72.7, 72.0, 62.9, 51.8, 45.1 , 27.3, 19.8, 17.2; HRMS (CI) calcd for C₂₃H₂₉C10₇ (M+H)⁺ 453.9252, found 453.9279.

Example 3. (2S, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethylbenzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 4-Chloro-3-(4-ethylbenzyl)phenylbromide used instead of 4-Chloro- 3-(4-ethoxy benzyl)phenyl-bromide. calcd for C₂₂H₂₇C10₅ (M+H)⁺ 407.8998, found 407.9007.

Example 4.

(IS, 3R, AS, 5S, 65^,)-2-[4-Methyl-3-(4-ethoxylbenzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 4-methyl-3-(4-ethoxylbenzyl)phenylbromide used instead of 4-

Chloro-3-(4-ethoxy benzyl)phenyl-bromide. calcd for C₂₃H₃₀O₆ (M+H)⁺ 403.4807, found

403.4819.

Example 5 (2S, 3R, AS, 5S, 65)-2-[4-Methyl-3-(4-ethylbenzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 1 and 4-methyl-3-(4-ethylbenzyl)phenylbromide used instead of 4-Chloro- 3-(4-ethoxy benzyl)phenyl-bromide. calcd for C₂3H₃o0₅ (M+H)⁺ 387.4813, found 387.4831.

Example 6.

(IS, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethylbenzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 2 and 4-chloro-3-(4-ethylbenzyl)phenylbromide used instead of 4-Chloro-3- (4-ethoxy benzyl)phenyl-bromide. calcd for C23H29CIO6 (M+H)⁺ 437.9258, found 437.9269.

Example 7. (2S, 3R, AS, 5S, 65)-2-[4-Methyl-3-(4-ethoxylbenzyl)-phenyl]-6-hydr oxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 2 and 4-methyl-3-(4-ethoxylbenzyl)phenylbromide used instead of 4- Chloro-3-(4-ethoxy benzyl)phenyl-bromide. calcd for C24H32O7 (M+H)⁺ 433.5067, found

433.5056. Example 8.

(2S, 3R, 4S, 5S, 65)-2-[4-Methyl-3-(4-ethylbenzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol

The desired title compound is synthesized by using the same sequence and conditions as described for Example 2 and 4-methyl-3-(4-ethylbenzyl)phenylbromide used instead of 4-Chloro- 3-(4-ethoxy benzyl)phenyl-bromide. calcd for C24H32O6 (M+H)⁺ 417.5073, found 417.5055.

PHARMACOLOGICAL TESTING

The practice of the instant invention for the treatment of diseases modulated by the inhibition of SGLT2 can be evidenced by activity in at least one of the protocols described herein below.

Biological Assays

In- Vitro Assay

The SGLT2 functional assay was designed to detect the inhibition of methyl-alpha-D glucopyranoside (AMG - a non-metabolizable form of glucose) uptake via the SGLT2 transporter. The SGLT2 transporter recovers glucose from the proximal tubules of the kidney; its inhibition results in sugar wasted in the urine. The positive control compound, Phlorizin, is a known inhibitor of glucose uptake for SGLT2 and was used for comparing the high percent effect of SGLT2 inhibition of the test compounds, listed in table 1. Table 1

CHO-FIpIn (Invitrogen, Carlsbad, CA) cells stably expressing human SGLT2

(pcDNA5/FRT) were plated in Iso-TC 96 well plates (Perkin Elmer, Waltham, MA) at a density of 100,000 cells/well in 100 microL of growth media (1 : 1 F-12/DMEM media (Gibco, Carlsbad, CA), 10% FBS (Sigma, St. Louis MO), IX Pen/Strep (Gibco, Carlsbad, CA), 600 microg/mL

Hygromycin (Invitrogen, Carlsbad, CA)). Prior to treating with test compound, confluent cells were serum starved for 2 hours at 37 ^°C in 1 : 1 F-12/DMEM media, replacing with fresh F-12/DMEM media after 1 hour. Test compounds in dimethylsulfoxide (Sigma, St. Louis, MO) were diluted 100 fold in uptake buffer (140mM NaCI (Promega, Madison, Wl), 2mM KCI (Teknova, Hollister, CA), 1 rriM CaCI₂ (Teknova, Hollister, CA), lmM MgCI₂ (Teknova, Hollister, CA), and lOmM HEPES (Gibco, Carlsbad, CA) to cell plates pre-hnsed with uptake buffer. Cells were pre -incubated with test compound for 15 minutes prior to the addition of 50 microL AMG (40 nCi AMG [U-¹⁴C] (Perkin Elmer, Waltham, MA) in unlabelled AMG (Aldrich, St. Louis, MO)) per well yielding a final concentration of 11.33 microM AMG. Cell plates were then incubated for 3 hours at 37°C for AMG uptake. After incubation, cells were washed twice with ice cold wash buffer (uptake buffer containing 200 microM Phlorizin (Sigma), air dried and lysed in 30 microL of 200 mM NaOH and 1% SDS buffer on an orbital shaker. Microscint 40 (Perkin Elmer, Waltham, MA) was added to the lysed cells (giving a final volume of 200 microL) and mixed by orbital shaking for 30 minutes. Plates were stored in the dark overnight and quantitated in the 1540 Microbeta Trilux (Wallac, Waltham, MA) using a normalized protocol for ¹⁴C detection. The percent effect of test compounds to inhibit AMG uptake was calculated using the following calculation:

[% Effect = ((ZPE-Ty(ZPE-HPE)) X 100%]

where "ZPE" is the corrected counts per minute (CCPM) in control wells containing 0.5% DMSO, T is the CCPM in wells containing test compound at various concentrations of the standard curve, and HPE is the high percent effect referring to the CCPM in control wells containing 10 microM Phlorizin. The IC₅₀ values were calculated using a dose response equation and are summarized for the compounds tested. Abbreviations used in the in vitro testing description include:

SGLT2— type 2 sodium/glucose co-transporterll

AMG— methyl-a-D Glucopyranoside

DMEM— Dulbecco's Modified Eagle's Medium

IC50 50%— Inhibition Concentration FBS Fetal Bovine Serum

DMSO— Dimethylsulfoxide

SDS— Sodium Dodecyl Sulfate

CHO-FIpIn— Chinese Hamster Ovary cell containing the FRT site

In- Vivo Assay

Examples 1 and 4 were tested in rats to assess inhibition of glucose transport via urinary glucose excretion. Male Sprague Dawley rats (-300 g) were singly housed in metabolic cages for urine collection. Rats had access to standard laboratory chow and water ad libitum. Rats (n=2 to 5/group) received vehicle or compound by oral gavage. Dosing solutions were 0.03 mg/ml, 0.3mg/ml, 0.9mg/ml, 3mg/ml, 9mg/ml and 18mg/ml for the O. lmg/kg, lmg/kg, 3mg/kg, lOmg/kg, 30mg/kg and 60mg/kg doses respectively. Dosing volume was lmL/300 g of body weight for all doses. One group received a lOmg/kg dose of Example 1A and others received 0.1, 1, 3, 10, 30 or 60 mg/kg dose of Example 4A. The vehicle was 20% v/v PEG400 and 24% v/v hydroxypropyl beta cyclodextrin; HPBCD. Following oral administration, urine was collected for 24 hours. Glucose concentration was measured in urine by UV absorbance spectrophotometry at 340 nm using a Roche Hitachi 917 spectrophotometer (Diamond Diagnostics, Holliston, MA). The total amount of glucose excreted in the urine was calculated as the product of urine concentration and urine volume using the formula below: urinary glucose excreted (mg)/200g body weight = urinary glucose concentration (mg/dL) x urine volume (dl) x 200/rat body weight (g). Amounts of urinary glucose excreted (UGE) were obtained from rats for Example 1 A and Example 4 A by the method described above and are shown in Table 2.

Table 2

Claims

THE CLAIMS What is claimed is:

1. At least one compound of Formula (I) and pharmaceutically acceptable salts thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, a crystal thereof, all stereoisomers thereof, and mixtures of any of the foregoing,

Formula I

Wherein:

Ri is selected from a group consisting of H, (Ci-C₆)alkyl, (Ci-C₆)alkoxy, CI, F, cyano, halo- substituted (Ci-C₂)alkyl, (Ci-C₄)alkyl-S0₂-, (C₃-C₆)cycloalkyl, or substituted(C₃-C₆)cycloalkyl;

R₂ is selected from a group consisting of (Ci-C₆)alkyl, (Ci-C₆)alkoxy, (C₂-C₆)alkynyl, 3- oxetanyloxy, 3-tetrahydrofuranyloxy, CI, F, cyano, halosubstituted (Ci-C₂)alkyl, (Ci-C₆)alkyl-S0₂-, (C₃-C₆)cycloalkyl, or a (C5-C₆)heterocycle having lor 2 heteroatoms, the said heteroatom is each independently selected from N, O, or S;

R₃ is X-L;

X is selected from a group consisting of (Ci-C₆)alkyl, (Ci-C₆)alkoxyl, (C₂-C₆)alkynyl, (C₂-C₆) alkenyl, (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkyl-NH, (Ci-C₆)alkyl-NHC(0), or (Ci-C₆)alkyl-NHS(0)_m, wherein m is 1 or 2;

L is selected from a group consisting of H, (Ci-C₆)alkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, halosubstituted (Ci-C₆)alkyl, halosubstituted (C₂-C₆)alkynyl, or halosubstituted (C₂-C₆)alkenyl.

2. At least one compound according to claim 1, wherein, the said Ri is selected from a group consisting of (Ci-C₄)alkyl, (Ci-C₄)alkoxy, halo-substituted (Ci-C₂)alkyl, (Ci-C₃)alkyl-S0₂-, (C₃-C₅) cycloalkyl, or substituted(C₃-C5)cycloalkyl.

3. At least one compound according to claim 1, wherein, the said Ri is selected from a group consisting of (Ci-C₃)alkyl, (Ci-C₃)alkoxy, (Ci-C₂)alkyl-S0₂-, (C₃-C₄) cycloalkyl, or substituted(C₃- C4)cycloalkyl.

4. At least one compound according to claim 1, wherein, the said Ri is selected from a group consisting of (Ci-C₃)alkyl or (Ci-C₃)alkoxy.

5. At least one compound according to claim 1, wherein, the said Ri is selected from a group consisting of (Ci-C₃)alkyl.

6. At least one compound according to claim 1, wherein, the said Ri is selected from a group consisting of (Ci-C₂)alkyl-S0₂-, (C₃-C₄) cycloalkyl, or substituted(C₃-C₄)cycloalkyl.

7. At least one compound according to claim 1 , wherein, the said Ri is selected from a group consisting of H, CI, F, or cyano.

8. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₃)alkyl, (C₃-C₄) cycloalkyl, or substituted(C₃-C₄)cycloalkyl.

9. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C₅-Ce)heterocycle having lor 2 heteroatoms, the said heteroatom is each independently selected from N, O, or S.

10. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C5-C₆)heterocycle having 1 heteroatom, the said heteroatom is each independently selected from N, or S.

11. At least one compound according to claim 1 , wherein, the said R₂ is selected from a group consisting of a (C₅-C₆)heterocycle having 1 heteroatom, the said heteroatom is each independently selected from N, or O.

12. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C₅-Ce)heterocycle having lor 2 heteroatoms, the said heteroatom is each independently selected from S or O.

13. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C5-C₆)heterocycle having 1 heteroatom, the said heteroatom is N.

14. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C₅-Ce)heterocycle having 1 heteroatom, the said heteroatom is O.

15. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of a (C5-C₆)heterocycle having 1 heteroatom, the said heteroatom is S.

16. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₄)alkyl, (Ci-C₄)alkoxy, (C₂-C₄)alkynyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, (Ci-C₄)alkyl-S0₂-, or (C₃-C₅)cycloalkyl.

17. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₄)alkyl, (Ci-C₄)alkoxy, or (C₂-C₄)alkynyl.

18. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₃)alkyl, or (Ci-C₃)alkoxy.

19. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₄)alkyl, or (C₂-C₃)alkynyl.

20. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₃)alkyl, or halosubstituted (Ci-C₂)alkyl.

21. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of CI, F, or cyano.

22. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of 3-oxetanyloxy, 3-tetrahydrofuranyloxy, (Ci-C₄)alkyl-S0₂-, or (C₃-C₅)cycloalkyl.

23. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of 3-oxetanyloxy, or 3-tetrahydrofuranyloxy.

24. At least one compound according to claim 1, wherein, the said R₂ is 3-oxetanyloxy.

25. At least one compound according to claim 1, wherein, the said R₂ is 3- tetrahydrofuranyloxy.

26. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₄)alkyl-S0₂-, or (C₃-C₅)cycloalkyl.

27. At least one compound according to claim 1, wherein, the said R₂ is selected from a group consisting of (Ci-C₃)alkyl-S0₂-, or (C₃-C₄)cycloalkyl.

28. At least one compound according to claim 1, wherein, the said R₂ is (Ci-C₃)alkyl-S0₂-.

29. At least one compound according to claim 1, wherein, the said R₂ is (C₃-C₄)cycloalkyl.

30. At least one compound according to claim 1, wherein, the said X is selected from a group consisting of (Ci-C₄)alkyl, (Ci-C₄)alkoxyl, (C₂-Cs)alkynyl, (C₂-C₅)alkenyl, (C₁-C₅) alkylcarbonyl, (Ci-C₄)alkyl-NH, (Ci-C₄)alkyl-NHC(0), or (Ci-C₄)alkyl-NHS(0)_m, wherein m is 1 or 2.

31. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (Ci-C₃)alkyl, (Ci-C₃)alkoxyl, (C₂-C₄)alkynyl, or (C₂-C₄)alkenyl.

32. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (Ci-C₃)alkyl, or (Ci-C₃)alkoxyl.

33. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (C₂-C₄)alkynyl, or (C₂-C4)alkenyl.

34. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (C C₄) alkylcarbonyl, (C C₃)alkyl-NH, (C C₃)alkyl-NHC(0), or (C C₃)alkyl- NHS(0)_m, wherein m is 1 or 2.

35. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (Ci-C₃)alkyl-NH, (Ci-C₃)alkyl-NHC(0), or (Ci-C₃)alkyl-NHS(0)_m, wherein m is 1.

36. At least one compound according to claiml , wherein, the said X is selected from a group consisting of (Ci-C₃)alkylcarbonyl, (Ci-C₃)alkyl-NH, or (Ci-C₃)alkyl-NHC(0).

37. At least one compound according to claiml , wherein, the said L is selected from a group consisting of H, (Ci-C₅)alkyl, (C2-C₅)alkynyl, (C₂-C5)alkenyl, halosubstituted (Ci-C₅)alkyl, halosubstituted (C₂-C₅)alkynyl, or halosubstituted (C₂-C₅)alkenyl.

38. At least one compound according to claiml , wherein, the said L is H.

39. At least one compound according to claiml , wherein, the said L is selected from a group consisting of (Ci-C₃)alkyl, (C₂-C₄)alkynyl, or (C₂-C₄)alkenyl.

40. At least one compound according to claiml , wherein, the said L is selected from a group consisting of halosubstituted (Ci-C₃)alkyl, halosubstituted (C₂-C₃)alkynyl, or halosubstituted (C₂- C₄)alkenyl.

41. At least one compound according to claiml , wherein, the said L is selected from a group consisting of (Ci-C₃)alkyl.

42. At least one compound according to claim 1 selected from the group consisting of: (2S, 3R, 4S, 5S, 65^,)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2-methyl- tetrahydro-pyran-3,4,5-triol

(IS, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65^,)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2 -methyl- tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[3-(4-Ethoxy-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2S, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran- -triol;

(2R, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[4-Chloro-3-(4-ethyl-benzyl)-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran-3,4,5-triol;

(2R, 3R, AS, 5S, 65)-2-[3-(4-Ethyl-benzyl)-4-methyl-phenyl]-6-hydroxymethyl-2- methoxymethyl-tetrahydro-pyran- -triol.

43. Use of at least one compound as defined in any one of claims 1 to 42, crystal thereof, or pharmaceutically acceptable salt thereof, for the preparation of a medicament.

44. The use according to claim 43 for the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers.

45. The use according to claim 44 for the preparation of a medicament for delaying or preventing disease progression in type 2 diabetes, impaired glucose tolerance, type 1 diabetes.

46. The use according to claim 45 for the preparation of a medicament for delaying or preventing disease progression in type 2 diabetes.

47. The use according to claim 43 for the preparation of a medicament for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells.

48. A method of modulating glycemia in animals administering to an animal in need of such treatment at least one compound as defined in any one of claims 1 to 42, crystal thereof, or pharmaceutically acceptable salt thereof.

49. A method for treating obesity and obesity-related disorders in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of at least one compound as defined in any one of claims 1 to 42, crystal thereof, or pharmaceutically acceptable salt thereof

50. A method for treating or delaying the progression or onset of Type 2 diabetes and diabetes-related disorders in animals comprising the step of administering to an animal in need of such treatment a therapeutically effective amount of at least one compound as defined in any one of claims 1 to 42, crystal thereof , or pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising (i) a therapeutically effective amount of at least one compound as defined in any one of claims 1 to 42, crystal thereof, or pharmaceutically acceptable salt thereof, and (ii) at least one pharmaceutically acceptable excipient.

52. The pharmaceutical composition according to claim 51, wherein, the said compound, crystal thereof, or pharmaceutically acceptable salt thereof, and the said excipient ratio of 0.1 : 100 to 1 : 10.

53. The pharmaceutical composition according to claim 52, wherein, the said compound, crystal thereof, or pharmaceutically acceptable salt thereof, and the said excipient ratio of 0.1 :50 to 1 :5.

54. The pharmaceutical composition according to any one of claims 51 to 53, wherein, the at least one compound is present in an amount effective for the treatment of at least one disease or disorder selected from hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers.

55. The pharmaceutically composition according to claim 54, wherein, , the at least one compound is present in an amount effective for the treatment of at least one disease or disorder selected from hyperglycemia, type 2 diabetes, impaired glucose tolerance and type 1 diabetes.

56. The pharmaceutically composition according to claim 54, wherein, , the at least one compound is present in an amount effective for the treatment of at least one disease or disorder selected from obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders,

atheroschlerosis and myocardial infarction.

57. Use of the pharmaceutical composition of as defined in any one of claims 51 to 54 for the preparation of a medicament.

58. The use according to claim 57 for the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers.

59. The use according to claim 57 for the preparation of a medicament for delaying or preventing disease progression in type 2 diabetes.

60. The use according to claim 57 for the preparation of a medicament for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells.

61. The use according to claim 57 for the preparation of a medicament for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels.

62. A method for treating obesity and obesity-related disorders in animals comprising the step of administering to an animal in need of such treatment a pharmaceutical composition as defined in claims 51 to 54.

63. A method for treating or delaying the progression or onset of Type 2 diabetes and diabetes-related disorders in animals comprising the step of administering to an animal in need of such treatment a pharmaceutical composition as defined in claims 51 to 54.

64. A method of modulating glycemia in animals administering to an animal in need of such treatment a pharmaceutical composition as defined in claims 51 to 54.

65. A pharmaceutical combination comprising an SGLT2 inhibitor compound as defined in any one of Claims 1 to 42 and an antidiabetic agent other than an SGLT2 inhibitor, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, and/or a lipid-lowering agent.

66. The combination according to claim 65 wherein the antidiabetic agent is 1,2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon- like peptide- 1 (GLP-1), insulin, a meglitinide, a PTPIB inhibitor, a glycogen phosphorylase inhibitor, and/or a glucos-6-phosphatase inhibitor.

67. The combination according to claim 66 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.

68. The combination according to claim 65 wherein the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an AC AT inhibitor.

69. The combination according to 65, therein the said SGLT2 inhibitor compound in a weight ratio to an antidiabetic agent , an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, and/or a lipid- lowering agent within the range from 0.01 : 1 to 300: 1.

70. The combination according to 69, therein the said the rang of weight ratio is 0.1 : 1 to 50:

1.

71. The combination according to 69, therein the said the rang of weight ratio is 0.1 : 1 to 10:

1.