RS20060322A - Substituted benzimidazole-, benztriazole-, and benzimidazolone-o-glucosides - Google Patents

Abstract

This invention relates to to substituted benzimidazole-O-glucosides, benztriazole-O-glucosides, and benzimidazolone-O-glucosides, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of diabetes and Syndrome X.

Description

SUBSTITUTED BENZIMIDAZOLE-, BENZTRIAZOLE-,

IBENZYMIDAZOLONE-O-GLUCOSIDES

This invention relates to substituted benzimidazole-O-glucosides, benztriazole-O-glucosides, and bezimidazolone-O-glucosides, to compositions containing them, and to methods of using them, for example, for the treatment or prophylaxis of diabetes and syndrome X.

Diabetes is a chronic disorder that affects the metabolism of carbohydrates, fats and proteins in animals.

Type I diabetes mellitus, which accounts for about 10% of all diabetes cases, was previously classified as insulin-dependent diabetes mellitus ("IDDM") or juvenile-onset diabetes. This disease is characterized by a progressive loss of function of the beta cells of the pancreas to secrete insulin. Non-idiopathic, or "secondary" diabetes originating from pancreatic disease also has this characteristic. Type I diabetes mellitus is associated with the following clinical signs or symptoms: persistent elevation of plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or hyperphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension that can lead to blindness, end-stage renal disease, limb amputation, and myocardial infarction.

Type II diabetes mellitus [non-insulin-dependent diabetes mellitus ("NIDDM")] is a metabolic disorder that includes impaired glucose metabolism and reduced insulin sensitivity. Type II diabetes mellitus usually develops in adulthood and is associated with the body's inability to use or produce enough insulin. In addition to the insulin resistance observed in target tissues, patients suffering from type II diabetes mellitus have a relative lack of insulin—i.e. patients have insulin levels lower than predicted for a given plasma glucose concentration. Type II diabetes mellitus is characterized by the following clinical signs or symptoms: persistent increase in plasma glucose concentration or hyperglycemia; polyuria; polydipsia and/or hyperphagia; chronic microvascular complications such as retinopathy, nephropathy and neuropathy; and macrovascular complications such as hyperlipidemia and hypertension that can lead to blindness, end-stage renal disease, limb amputation, and myocardial infarction.

Syndrome X, also called Insulin Resistance Syndrome (IRS), Metabolic Syndrome, or Metabolic Syndrome X, is seen in 2% of diagnostic coronary catheterizations. In addition to frequent disturbances, it causes symptoms or risk factors for the development of type II diabetes mellitus and cardiovascular disease, including impaired glucose tolerance (IGT

- impaired glucose tolerance), reduced fasting glucose (IFG - impaired fasting glucose), hyperinsulinemia, insulin resistance, dyslipidemia (for example, high triglyceride level, low HDL level), hypertension and obesity

Therapy in IDDM patients has consistently focused on the administration of exogenous insulin, which can be obtained from a variety of sources (eg, human, bovine, porcine insulin). The use of materials from heterogeneous species leads to an increase in the formation of anti-insulin antibodies that have the effect of limiting activity and lead to a progressive need for higher doses to achieve the desired hypoglycemic effects.

Typical treatment for type II diabetes mellitus is aimed at keeping blood glucose levels as close to normal as possible, with lifestyle adjustments related to diet and exercise, and when necessary, treatment with antidiabetic agents, insulin, or a combination of both. NIDDM that cannot be controlled by adjusting the diet is treated with oral antidiabetic agents.

Although insulin resistance is not always treated in all patients with Syndrome X, in those who show a pre-diabetic condition (eg (IGT, IFG), where fasting glucose levels may be higher than normal but not meet the diagnostic criteria for diabetes), it is treated in some countries (eg, Germany) with metformin to prevent diabetes. Anti-diabetic agents can be combined with pharmacological agents to treat concomitant disease states (eg, antihypertensive agents for hypertension, lipid-lowering agents for lipidemia).

Primary therapies typically include metformin and sulfonylureas as well as thiazolidinediones. Metformin monotherapy is the first choice, especially for the treatment of patients with type II diabetes who are both obese and dyslipidemic. After the absence of an adequate response to metformin, treatment with metformin in combination with sulfonylureas, thiazolidinediones, or insulin often follows. Sulfonylurea monotherapy (including all drug generations) is also a common primary treatment option. Another choice of primary therapy could be thiazolidinediones. Alpha glucosidase inhibitors are also used as primary and secondary therapy. Patients who do not respond adequately to oral anti-diabetic monotherapy are given combinations of the above agents. When glycemic control cannot be maintained with oral anti-diabetics alone, insulin therapy is used either as monotherapy or in combination with oral anti-diabetics.

One recent procedure in the treatment of hyperglycemia is aimed at excreting excess glucose directly into the urine. Specific SGLT inhibitors have been shown to increase urinary glucose excretion and lower blood glucose levels in rodent models of IDDM and NIDDM.

BRIEF OVERVIEW OF THE INVENTION

One aspect of the present invention relates to methods and compositions for the treatment or prophylaxis of diabetes. Syndrome X, or related symptoms or complications. More particularly, the present invention contemplates a novel method of treating diabetes or Syndrome X, or associated symptoms or complications, in a subject suffering from such condition, said method comprising administering one or more glucose reabsorption inhibitors and administering one or more antidiabetic agents for the treatment of diabetes or Syndrome X, or associated symptoms or complications Another aspect of the invention provides compounds of formula (III):

where:

X is CH, N, or C=O;

R 1 is H or absent;

R 2 is H, F, Cl, OCH 3 , O CH 2 CH 3 , C 1-6 alkyl, CF 3 , SCH 3 , substituted or unsubstituted phenyl and NR 3 R 4 ;

R 31 R 4 are H, C 1-6 alkyl, or form together with the nitrogen atom to which both are attached a 5-6 membered heterocyclic ring with optionally 1-2 additional heteroatoms independently selected from O, S and N Q is -(CH 2 )n- where n is 1 or 2;

P is H, C 2-7 acyl, or (C 1-6 alkoxy)carbonyl; and

Z is substituted or unsubstituted, and is selected from C3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl with 1 or 2 heteroatoms independently selected from N, O and S, one biaryl, one 9- or 10-membered fused bicyclyl or fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O and S; or a pharmaceutically acceptable salt thereof.

One aspect of the invention provides a pharmaceutical composition comprising a glucose reabsorption inhibitor, at least one additional anti-diabetic agent, and a pharmaceutically acceptable carrier. The invention also provides a method of formulating a pharmaceutical composition, which together comprises the formulation of a glucose reabsorption inhibitor, one or more antidiabetic agents, and a pharmaceutically acceptable carrier.

One embodiment of the invention is a method of treating diabetes or Syndrome X, or associated symptoms or complications, in a subject, wherein said method comprises administering to said subject a collectively effective amount of a glucose reabsorption inhibitor and administering to said subject a collectively effective amount of an anti-diabetic agent, the combined administration of which provides the desired therapeutic effect.

Another embodiment of the invention is a method of inhibiting the onset of diabetes or Syndrome X, or associated symptoms or complications in a subject, with said method comprising administering to said subject a jointly effective dose of a glucose reabsorption inhibitor and administering to said subject a jointly effective amount of one or more antidiabetic agents, the combined administration of which provides the desired prophylactic effect.

In the methods described, diabetes or Syndrome X, or associated symptoms or complications, is selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy; retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, inflammatory bowel disease, inflammation and cataracts.

The invention also includes the use of one or more glucose reabsorption inhibitors in combination with one or more antidiabetic agents for the preparation of a medicament for treating conditions selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy; retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, inflammatory bowel disease, inflammation and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

All diabetics, regardless of genetic or social background, have in common an apparent lack of insulin or inadequate insulin function. Because the transfer of glucose from the blood to the muscles and adipose tissue depends on insulin, diabetics do not have the ability to use glucose adequately, which leads to an unwanted accumulation of glucose in the blood (hyperglycemia). Chronic hyperglycemia leads to a decrease in insulin secretion and contributes to increased insulin resistance, and the concentration of glucose in the blood, so that diabetes itself worsens

( Diabetologia, 1985, " Hyperglycaemia as an inducer as well as a conseauence of impaired isle

cell function and insulin resistance: implications for the management of diabetes", Vol. 28, p.

119; Diabetes Cares, 1990, Vol. 13, No. 6, "Glucose Toxicity", p. 610-630).Therefore, by treating hyperglycemia, the self-exacerbating cycle mentioned above is interrupted, thus allowing the prophylaxis or treatment of diabetes.

US Patent No. 6,153,632 (R. Rievelev) describes a method and composition claimed to be administered for the treatment of diabetes mellitus (type I, impaired glucose tolerance ["IGT"] and type II), comprising a therapeutic amount of one or more insulin sensitizing agents in addition to one or more orally administered insulin, injected insulin, sulfonylurea, biguanide, or alpha-glucosidase inhibitor for the treatment of diabetes mellitus.

According to one aspect, the invention features a combination of a PPAR modulator, preferably a PPAR 8 agonist, and an SGLT inhibitor, preferably an SGLT 2 inhibitor, or a selective SGLT 2 inhibitor.

A. Dates

Some terms are defined below and according to their use throughout this description.

Unless otherwise specified, "alkyl" and "alkoxy" as used herein, whether used alone or as part of a substituent group, includes linear, cyclic and branched chain alkyl having 1 to 8 carbon atoms, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 2-butenyl, 2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from previously described linear or branched chain alkyl groups. Alkyl and alkoxy groups can be independently substituted by one to five, preferably one to three groups selected from halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and alkoxy. Alkyl and alkoxy groups can be independently attached to one or more PEG radicals (polyethylene glycol).

The term "acyl" as used herein, whether used alone or as part of a substituent group, means an organic radical having a carbonyl group attached to a hydrocarbyl group having 1 to 7 carbon atoms (branched or linear chain or cyclic) derived from an organic acid by removal of a hydroxyl group. For example, C4acyl may include (CO)CH2CH2CH2CH3 and (CO)(CH2(CH)(CH3)2; similarly, C6acyl includes both (CO)(C6H,3) and (CO)(C6H5). The term "Ac" as used herein, whether used alone or as part of a substituent group, means acetyl.

"Aryl" is a carbocyclic aromatic radical including, but not limited to, phenyl, 1-or 2-naphthyl and the like. A carbocyclic aromatic radical may be substituted by replacing 1 to 3 hydrogen atoms on it with halogen, OH, CN, mercapto, nitro, amino, cyano, optionally substituted C1-C8-alkyl, optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino, di(Ci-C8-alkyl)amino, formyl, carboxyl, alkoxycarbonyl, Alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-lower alkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy, benzoyloxy, alkyl-CO-O-, alkyl-O-CO-,

-CONH2, alkyl-O-CO-O-, or alkyl-CO-NH-. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl indene ( 1, indane (

), fluorophenyl, difluorophenyl, benzyl,

benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamyl-phenyl and the like. "Ph" or "PH" stands for phenyl.

The term "heteroaryl" as used herein refers to a stable five- or six-membered monocyclic or bicyclic aromatic ring system consisting of carbon atoms and one to three heteroatoms selected from N, O, and S. The heteroaryl group may be attached to any heteroatom or carbon atom, resulting in a stable structure. Examples of heteroaryl groups include, but are not limited to, benzofuranyl, benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl. Preferred heteroaryl groups include pyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents independently selected from halogen, OH, CN, mercapto, nitro, amino, cyano, optionally substituted C1-C8-alkyl, optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino, di(Ci-C8-alkylamino, formyl, carboxyl, alkoxycarbonyl, Alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-lower alkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy, benzoyloxy, alkyl-CO-O-, alkyl-O-CO-,

-CONH2, alkyl-O-CO-O-, or alkyl-CO-NH-.

The terms heterocycle", "heterocyclic", and "heterocyclyl" refer to an optionally substituted, fully or partially saturated, aromatic or non-aromatic, cyclic group which is, for example, a system of 4- to 7-membered monocyclic, 7- to 11-membered (or 9- to 10-membered) bicyclic (or heterobicyclyl), or 10- to 15-membered tricyclic ring, which has at least one heteroatom at least one ring-containing carbon atom. Each heterocyclic group can have 1, 2, or 3 heteroatoms selected from nitrogen atoms, and sulfur atoms, where the nitrogen and sulfur atoms can optionally be quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl; oxetanil; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanil; thiethanil; thiiranil; and the like. Examples of bicyclic heterocyclic groups (or heterobicyclyls) include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanil; isoindolinyl; benzimidazolyl; benzthiazolyl; piperonyl; tetrahydroquinolinyl; and the like. When the heteroaryl group is substituted, the heterocyclyl may be independently substituted with one to five, preferably one to three groups selected from halogen, OH, CN, mercapto, nitro, amino, cyano, optionally substituted C1-C8-alkyl, optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino, di(Ci-C8-alkyl)amino, formyl, carboxyl, alkoxycarbonyl, Alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-lower alkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy, benzoyloxy, alkyl-CO-O-, alkyl-O-CO-,

-CONH2, alkyl-O-CO-O-, or alkyl-CO-NH-.

The term "biaryl" includes any heteroaryl attached to a phenyl, any phenyl attached to a heteroaryl (such as thiophene, pyridine, and pyrazole), and any phenyl attached to a phenyl. Examples of phenyl-phenyl, heteroaryl-phenyl, heteroaryl-phenyl, and phenyl-heteroaryl, respectively, include:

The term "composition" is intended to include any product containing specific ingredients in specific amounts, as well as any product that results, directly or indirectly, from combinations of those specific ingredients, in specific amounts.

The term "combined giving" includes comparative giving where: 1) two or more funds are given to an entity at substantially similar times; and 2) two or more agents are administered to a subject at different times, at independent intervals that may or may not overlap or coincide.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, which is the subject of treatment, observation or experiment.

The term "RXR modulator" as used herein refers to Retinoid-X receptor agonists, partial agonists, or antagonists. The modulator preferably enhances insulin sensitivity. In one embodiment, this modulator is an RXR agonist.

Diabetes, Syndrome X, and associated symptoms or complications, include such conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy; retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, inflammatory bowel disease, inflammation, and cataracts. Examples of pre-diabetic conditions include

IGT and IFG.

In the existing state of the art, procedures are known for determining effective doses for therapeutic and prophylactic purposes for the described pharmaceutical compositions or described drug combinations, whether they are formulated in the same composition or not. For therapeutic purposes, the term "combined effective amount" as used herein, means that amount of any active compound or pharmaceutical agent, alone or in combination, which produces a biological or medical response in a tissue system, animal or human sought by an investigator, veterinarian, medical doctor or other clinician, which includes attenuation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term "combined effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder sought by an investigator, veterinarian, medical doctor, or other clinician, which delay is mediated by modulation of glucose reabsorption activity or the activity of another anti-diabetic agent, or both. Thus, the present invention provides a combination of two or more drugs where, for example, (a) each drug is administered in an independently therapeutically and prophylactically effective amount; (b) at least one drug in that combination is administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with those other or additional drugs according to this invention; or (c) both drugs are administered in an amount that is sub-therapeutic or sub-prophylactic if administered alone, but is therapeutic or prophylactic when administered together.

The term "protecting groups" refers to those moieties known in the prior art that are used to mask functional groups; protecting groups may be removed during subsequent synthetic transformations or states of metabolism or other administration in vivo. During any procedures for obtaining the compounds of this invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any participating molecules. This can be achieved using conventional protecting groups, such as those described in Protective Groups in Organic

Chemistry, ed. J:F:W. McOrnie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective

Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Protecting groups can be removed at a convenient subsequent stage using procedures known in the art. Examples of hydroxyl and diol protecting groups are given below.

Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, and silyl ethers.

Substituted methyl ethers

Examples of substituted methyl ethers include methoxymethyl, methylthiomethyl, /-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, /?-methoxybenzyloxymethyl. (4-Methoxy-phenoxy)methyl, /-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-Methoxytctrahydro-pyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxo, l-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, l,4-dioxan-2-yl, tetrahydrofuranyl, and tetrahydrothiopyranyl. 233a,4,5,6,7α-octahydro-7,8,8-trimethyl-4β-methanobenzofuran-2-yl.

Substituted ethyl ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzoxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, allyl, /?-methoxyphenyl ethers. 2,4-dinitrophenyl, benzyl, and polyethylene glycol.

Substituted benzyl ethers

Examples of substituted benzyl ethers include /?-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl,/7-nitrobenzyl,/?-halobenzyl, 2,6-dichlorobenzyl,/?-cyanobenzyl,/»-phenylbenzyl, 2-i4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,/</->dinitrobenzhydryl. 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, ^-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3 -(imidazol-1 -ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1,1 -bis/4-methoxyphenyl-1 '-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxo.

Ether force

Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyltexylsilyl, /-butyldimethylsilyl, /-butyldiphenylsilyl, tribenzylsilyl, tri- /7-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and /-butylmethoxyphenylsilyl.

Esther

In addition to ethers, some hydroxyl groups can be protected as esters. Examples of esters include esters of formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, /?-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, of 4-methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), and polyethylene glycol.

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(tri methy 1 si 1 i I )ethy 1, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl,/»-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyl dithiocarbonate, and polyethylene glycol carbonate.

Assisted cleavage

Examples of assisted cleavages include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Various esters

Examples of various esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(l,l,3,3-tetramethylbutyl)phenoxyacetate,'2,4-bis(l,l-dimethyl-propyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, (E)-2-butenoate. o-(Methoxycarbonyl)benzoate, /?-P-benzoate, a-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.

Sulfonates

Examples of sulfonates include sulfates, methanesulfonate (mesylate), benzylsulfonate, and tosylate.

PROTECTION FOR 1, 2- 1 1, 3- DIOLE

Cyclic acetals and ketals

Examples of cyclic acetals and ketals include methylene, ethylidene, l-/-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, /?-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.

Cyclic ortho esters

Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,.2-dimethoxyethylidene, α-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl derivatives

Examples of silyl derivatives include a di-/-butylsilylene group, and a 1,3-(1,1,3,3-tetraisopropyldisiloxanilidene) derivative.

Glucose reabsorption inhibitors

One procedure for treating hyperglycemia is to excrete excess glucose directly into the urine so that the blood glucose concentration is normalized. For example, sodium-glucose co-transporters (SGLTs

- sodium-glucose cotransporters), which are primarily found in the chorionic membrane of the intestines and kidneys, are a family of proteins that are actively involved in the normal process of glucose absorption. Among them, SGLT1 is present in intestinal and renal epithelial cells (Lee et al., 1994), while SGLT2 is found in renal epithelium (You et al., 1995, MacKenzie et al., 1994). Intestinal glucose absorption is primarily mediated by SGLT1, a low-capacity, high-affinity transporter with a 2:1 ratio of Na<+>:glucose transport. SGLT2, also known as SAAT1, transports Na<+>i glucose in the ratio of l.T a functions as a transporter of high capacity and low affinity. The characteristics of these SGLTs are shown in Table 1:

Renal reabsorption of glucose is mediated by SGLT1 and SGLT2 (Silverman et al., 1992; Deetjen et al., 1995). Glucose in the plasma is filtered in the glomerulus and transepithelially reabsorbed in Malpighian tubules. SGLT1 and SGLT2 are located in the plasma of the apical membranes of the epithelium and get their energy from the internal sodium gradient created by the Na<+>/K<+>ATPase pumps located on the basolateral membrane. When it is reabsorbed, the elevated cytosolic glucose is transported into the interstitial space by assisted glucose transporters (GLUT1 and GLUT2). Therefore, SGLT inhibition lowers plasma glucose by suppressing glucose reabsorption in the kidney. A therapeutically or prophylactically effective amount of an SGLT inhibitor, which would be sufficient to enhance urinary glucose excretion, or to lower plasma glucose, in a subject by a desirable daily amount, can be readily determined by methods used in the prior art. Recently, it was found that phlorizin, a natural glycoside present in the bark and stems of Rosaceae (for example, apple, pear, etc.). inhibits co-transporters of Na<+->glucose located in the chorionic membrane of the intestines and kidneys. By inhibiting the activity of the Na<+->glucose co-transporter, phlorizin inhibits the reabsorption of glucose in the renal tubules and promotes the excretion of glucose so that the plasma glucose level is regulated at a normal level for a long time through the daily

subcutaneous administration (Journal of Clinical Investigation, 1987, Vol. 79, p. 1510)

Other SGLT inhibitors include alkyl- and phenyl-glucosides, 1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via protein kinase C), p-chloromercuribenzoate (PCMB), N,N'-dicyclohexylcarbodiimide (DCCD), copper and cadmium ions, and trivalent lanthanides.

B. JEDIN JENJA

The present invention provides compounds of Formula (III):

where:

X is CH, N, or C=O;

R 1 is H or absent;

R 2 is H, F, Cl, OCH 3 , O CH 2 CH 3 , C 1-6 alkyl, CF 3 , SCH 3 , substituted or unsubstituted phenyl and NR 3 R 4 ;

R 3 and R 4 are H, C 1-6 alkyl, or form together with the nitrogen atom to which they are both attached a 5-6 membered heterocyclic ring with optionally 1-2 additional heteroatoms independently selected from O, S and N; Q is -(CH2)n- where n is 1 or 2;

P is H, C 2-7 acyl, or (C 1-6 alkoxy)carbonyl; and

Z is substituted or unsubstituted, and is selected from C3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl with 1 or 2 heteroatoms independently selected from N, O and S, one biaryl, one 9- or 10-membered fused bicyclyl or fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O and S; or a pharmaceutically acceptable salt thereof.

Examples of compounds of Formula (III) include those wherein: (a) H is or is absent; (b) R 2 is H, methyl, or ethyl; (c) Q is -(CH2)n- and it is 1; (d) Z is independently substituted with between 1 and 3 substituents independently selected from C 1-4 alkoxy, phenoxy, C 1-4 alkyl, C 3-6 cycloalkyl, halo, hydroxy, cyano, amino, C 1-4 alkylthio, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, C 1-4 aminoalkyl, mono- and di(C 1-4 alkyl)amino, phenyl, C 1-4 alkylaminosulfonyl (SO2NHR), amino-(alkylsulfonyl) (-NHSO2R-), C1-4dialkylaminosulfinyl (SONHRR), C1-4alkylamido (NHCOR), C1-4alkylcarbamido (CONHR), a 5- to 6-membered heterocyclyl containing between 1 and 3 heteroatoms independently selected from N, S, and O; and wherein the substituent(s) on Z may be further independently substituted with between 1 and 3 substituents independently selected from C 1-4 alkoxy, C 1-4 alkyl, halo, hydroxy, cyano, amino, mono or di C 1-4 alkylamino and C 1-4 alkylthio; (e) Z is 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indenyl, indanyl, naphthyl, or 2,3-dihydrobenzo[l,4]dioxanyl; (f) Z is unsubstituted or substituted with between 1 and 3 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl; (g) Z is biphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-imidazol-1-yl)-phenyl, 4-(1H-pyrazol-yl)-phenyl, (4-propyl)phenyl, (4-ethyl)phenyl, (4-methoxyphenyl), dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl; (h) Rije absent, X is CH; and R 2 is H, methyl, ethyl, or methoxy; (i) Q is -(CH2)n-; her 1 or 2; and R 2 is H, methyl, or ethyl; (j) restriction (i) and Rije absent; (k) Rije absent; Q is -(CH 2 ) n -; her 1 or 2; and R 2 is H, methyl, or ethyl; a Z is 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indenyl, indanyl, naphthyl, or 2,3-dihydrobenzo[l,4]dioxanyl; (1) Z is biphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-imidazol-1-yl)-phenyl, 4-(1H-pyrazol-yl)-phenyl, (4-ethyl)phenyl, (4-methoxyphenyl), dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl; and Z is unsubstituted or substituted with between 1 and 3 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl; (m) and combinations of the above.

Examples of the most preferred compounds include those selected from 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-(3-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside.

Additional examples of preferred compounds include those selected from 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(4-mctoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-{3-[2-(4-methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D glucopyranoside; 2-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-β-D glucopyranoside.

Further examples of compounds of the present invention include those selected from 2-[3-(2-naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-P-D glucopyranoside and 2-{3-[2-(4-methoxyphenyl)-ethyl]-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-P-D glucopyranoside.

Additional preferred compounds include those selected from 2-[3-(5-ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-|3-D glucopyranoside; 2-[3-(4-thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyrazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyridin-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-imidazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-(3-biphenyl-4-ylmethyl-3H-benzoimidazol-4-yloxy])-P-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-6-methoxy-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-6-trifluoromethyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzotriazol-4-yloxy}-P-D glucopyranoside; 2- {3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzotriazol-4-yloxy]-β-D glucopyranoside.

More preferred compounds of the invention include those selected from 2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-P-D glucopyranoside,2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-P-D glucopyranoside; 2-{3-[2-(4-methoxy-phenyl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D glucopyranoside; 2-[3-(5-ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-berisofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-[3-(4-thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-β-D glucopyranoside; 2-{3-[2-(2,3-dicyclo-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzotriazol-4-yloxy}-P-D glucopyranoside; 2-{3-[2-(23-dihydro-benzofuran-5-yl)-ethyl]-3H-benzotriazol-4-yloxy}-β-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzotriazol-4-yloxy]-β-D glucopyranoside.

C. Synthesis procedures

One aspect of the present invention provides a compound of formula (III). These compounds can be obtained according to traditional organic synthesis methods or combinatorial or matrix synthesis methods. The following schematic and chemical examples 1-10 provide general guidelines.

Compounds of the present invention where n is 1 or 2; and R 1 , R 2 , X and Z are as defined in Formula (III) can be prepared as shown in Scheme 1. Compounds of Formula 1 where R 2 H is can be obtained by Curtius rearrangement of commercially available 3-methoxy-2-nitrobenzoic acid followed by treatment with t-butanol at reflux temperatures as described by Orjales et al (J. Med. Chem. 1997, 40, 586) and by palladium-catalyzed hydrogenation to reduce the nitro group. By subsequent acylation of the resulting diamine intermediate with substituted acyl chlorides in the presence of a base such as triethylamine in a chlorinated solvent or by treatment with a substituted carboxylic acid, EDCI and HOBt in a suitable solvent such as DMF followed by reduction of the resulting amide with a borane complex of tetrahydrofuran or lithium aluminum hydride in a solvent such as tetrahydrofuran (THF) at temperatures of 20°C to reflux, compounds of Formula 2 where n is 1 or 2 can be obtained. Compounds of Formula 2 can be formed directly by treating intermediate diamines with substituted benzaldehydes in the presence of acetic acid and sodium cyanoborohydride. Removal of the t-butoxycarbonyl (BOC) protecting group in the presence of an acid such as hydrochloric or trifluoroacetic acid affords compounds of Formula 4 wherein R 2 is H and P is methyl.

Alternatively, commercially available 2-amino-3-nitrophenol can be acylated with substituted acyl chlorides or carboxylic acids as described above and then treated with TBDMSCI or MOMBr to give compounds of Formula 3 where n is 1 or 2. The nitro group can then be reduced using palladium-catalyzed hydrogenation conditions followed by reduction of the amide with borane to give compounds of Formula 4 where R is H and PL is TBDMS or

MOM.

Compounds of Formula 4 wherein R2 groups are as defined above and not H can be obtained by acylating commercially available 2-amino-3-nitrophenols with substituted acyl chlorides or carboxylic acids as described above followed by protection of the phenolic hydroxyl groups with a methyl or pivaloyl group using procedures known in the art. Starting substituted phenols that are not readily available commercially can be prepared by starting with appropriately substituted phenols, protecting the hydroxyl group, then applying standard techniques known in the art (Ogawa, M. et al., EP 579204; Widdowson, et al. US 5780483) to modify or extend the functionality at the R2 position to give compounds of Formula 5 where R2 is as defined in Formula (III).

Compounds of Formula 5 can be converted to compounds of Formula 6 by direct nitration or an initial bromination step using bromine or N-bromosuccinamide (NBS) in solvents such as carbon tetrachloride or chloroform, followed by nitration. Suitable nitration reagents include nitronium tetrafluoroborate which can be added to a solution of the intermediate in a solvent such as acetonitrile at temperatures between 0°C and 20°C or ammonium nitrite in the presence of trifluoroacetic anhydride in a chlorinated solvent. Palladium-catalyzed hydrogenation in a polar solvent such as methanol, ethanol, or 2-propanol can simultaneously reduce the nitro group and remove the bromine of compounds of Formula 6. Reduction of the amide using a borane tetrahydrofuran complex as described earlier can provide compounds of Formula 4 wherein R 2 includes the groups defined in Formula (III).

Compounds of Formula 2 can be dissolved in DMF and heated in the presence of a base such as potassium carbonate in an oil bath at 130°C for one to two hours to provide compounds of Formula 7 where P is methyl.

Alternatively, compounds of Formula 4 can be converted to compounds of Formula 7, wherein PiTBDMS, MOM OR Pivaloyl, by treatment with triphosgene, urea or carbonyldiimidazole using known methods.

Additionally, compounds of Formula 4 can be heated with triethylorthoformate in the presence of a catalytic amount of p-toluenesulfonic acid at 120°C for three to five hours to give compounds of Formula 8 or treated with sodium nitrite at 0°C to give compounds of Formula 9.

Deprotection of P1 to give compounds of Formula 10 can be accomplished using the known procedures described by Green and Wuts (Protecting Groups in Organic

Chemistry, 3rd edition; Wiley Interscience).

Compounds of Formula 11 can be obtained from compounds of Formula 10 by glycosidation of the phenyl group with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in a suitable solvent such as acetone, acetonitrile or DMF under alkaline conditions such as potassium carbonate, lithium carbonate or lithium hydroxide, followed by deprotection of the acetyl group in an alcoholic solvent such as methanol using slightly alkaline conditions such as potassium carbonate or sodium methoxide at room temperature.

Compounds of Formula 12 can be prepared by adding mixed imidazole carbonates to a mixture of compounds of Formula 11 such as NaH. A mixed imidazolyl can be prepared by reacting equimolar amounts of an alcohol with carbonyldiimidazole at 0°C and may be preferred over space-demanding reagents such as alkyl chloroformate to regioselectively acylate 6-OH

glucose group (Bertolini, et al. JOC 1998, 63, 6031)

D. Additional anti-diabetic agents

Anti-diabetic agents that can be used according to this invention, as a second, third, or subsequent anti-diabetic agent, in a composition, formulation, or combined treatment method (dosing regimen) include, but are not limited to the classes and compounds given as examples in Table 2.

E. Combinations

The invention provides a combination therapy comprising the administration of a glucose reabsorption inhibitor, such as an SGLT inhibitor, one or more anti-diabetic agents for the treatment of diabetes or Syndrome X, or associated symptoms or complications. The efficacy of SGLT inhibitors demonstrated in numerous models of NIDDM confirms the utility of this drug alone for the treatment of NIDDM in humans. Since glucose reabsorption inhibitors have a mechanism of action that differs from the action of other anti-diabetic agents, such as RXR modulators, the described combination may have the advantage of reducing the amount of both drugs required to achieve combined therapeutic or pharmaceutical efficacy compared to the individual intake of one of these drugs, thereby reducing one or more side effects, which often occur in the form of weight gain, edema, cardiac hypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or any combination thereof.

The present invention provides a method of treating diabetes or Syndrome X, or complications thereof, in a subject, said method comprising administering to said subject a collectively effective amount of a glucose reabsorption inhibitor in combination with a collectively effective amount of an anti-diabetic agent, such as an RXR modulator. In one aspect of the invention, the anti-diabetic agent is an RXR agonist or RXR antagonist that increases insulin sensitivity in a subject. For example, an insulin sensitizer can increase glucose tolerance in a subject in an oral glucose tolerance test.

Preferably, diabetes or Syndrome X, or associated symptoms or complications are selected from IDDM, NIDDM, IGT, and IFG.

The present invention provides a pharmaceutical composition comprising one or more glucose reabsorption inhibitors (alone or in combination with one or more anti-diabetic agents), and a pharmaceutically acceptable carrier. In one aspect of the invention, the anti-diabetic agent is an RXR agonist or RXR antagonist that increases insulin sensitivity in the subject.

The glucose reabsorption inhibitor is in particular an SGLT1 and/or SGLT2 inhibitor.

For use in medicine, a salt or salts of a compound of Formula (V) refers to a non-toxic "pharmaceutically acceptable salt or salts". Other salts, however, may be useful in preparing the compounds of the present invention or pharmaceutically acceptable salts thereof. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, tartaric, citric, benzoic, mandelic, methanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamino, salicylic, sakhalin or trifluoroacetic acid. Representative alkaline/cationic salts include, but are not limited to, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc. Compounds of Formula (V) or pharmaceutically acceptable salts thereof, may include an intramolecular salt thereof, or a solvate or hydrate thereof.

F. Administration, Formulations, and Dosage

The utility of the described compounds, compositions, and combinations for the treatment of disorders of glucose and lipid metabolism can be determined according to procedures well known in the art (see the list of references below), as well as any procedures described in US Pat. 5424406, 5731292, 5767094, 5830873, WO01/16122 and WO0116123 which are incorporated herein by reference. The compound can be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal, and parenteral.

The present invention also provides pharmaceutical compositions comprising one or more glucose reabsorption inhibitors and one or more modulators, together with a pharmaceutically acceptable carrier.

The daily dose can vary widely from 1 to 1000 mg per adult per day. For oral administration, it is preferable to provide the compositions in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 10, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 250 or 500 milligrams of the active component for symptomatic dosage adjustment according to the patient to be treated. The compounds can be administered in a 1 or 2 times daily regimen. Dosage, however, may vary depending on the needs of the patient, the severity of the condition being treated, and the compounds used. Either daily administration can be used or post-periodic dosing can be used. Preferably, these compositions are in unit dose form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosols or liquid metered sprays, drops, ampoules, self-injection devices, or suppositories; for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or inhalation. Alternatively, the composition may be administered in a form suitable for weekly or weekly administration; for example, some insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a long-acting formulation for intramuscular administration. To obtain solid compositions such as tablets, the main active component or components are mixed with a pharmaceutical carrier, for example conventional tableting components such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or resin, and other pharmaceutical solvents, for example water, to obtain a solid preformulation composition containing a homogeneous mixture of one or more glucose reabsorption inhibitors and one or more anti-diabetic agents, or some of their pharmaceutically acceptable salts. When these preformulation compositions are said to be homogeneous, it is meant that the active component or components are uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is further divided into unit dosage forms of the type previously described and containing from 0.1 to about 500 mg of the active component or components of the present invention. Tablets or pills of this novel composition may be coated or otherwise shaped to provide a dosage form that provides the advantage of prolonged action. For example, a tablet or pill may comprise an internal dosage component or an external dosage component, with the latter component being in the form of a coating over the former. These two components may be separated by some layer suitable for abdominal conditions that serves to resist decomposition in the stomach and allow the internal component to pass intact into the duodenum or to delay its release. There are various materials that can be used for such belly layers or shells and such materials include a variety of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the novel compositions of the present invention may be mixed for oral or injection administration include aqueous solutions, flavored syrups, aqueous or oily suspensions, and flavor-enhanced emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable suspending and dispersing agents for aqueous suspensions include synthetic and natural resins such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Liquid forms in taste-adjusted suspensions and sprays may include both synthetic and natural resins, for example, tragacanth, acacia, methylcellulose, and the like. For parenteral administration, sterile suspensions and solutions are preferred. Isotonic preparations generally containing suitable preservatives are used when intravenous administration is desired.

Conveniently, combinations of one or more glucose reabsorption inhibitors, alone or in combination with one or more additional anti-diabetic agents, can be administered in a single daily dose, or the total daily dosage can be administered in divided doses for two, three or four daily administrations. In addition, one or more glucose reabsorption inhibitors and/or one or more anti-diabetic agents according to the invention can be administered in intranasal form by using a topical application of a suitable intranasal carriers, or via transdermal patches well known to those of ordinary skill in the art. For administration in the form of a transdermal delivery system, the dosage of administration will certainly be continuous throughout the administration regimen, rather than intermittent administration.

For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with some oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerin, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may be added to the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic resins such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Dissolving agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When a drug according to the present invention is to be administered in combination, the compounds may be co-administered simultaneously, one after the other, or in a single pharmaceutical composition. When the compounds are administered separately, the number of doses of individual compounds administered per day does not have to be the same, for example, where one compound has a longer duration of action, it will therefore be administered sequentially.

The optimal dosage can be readily determined by those skilled in the art, and will vary according to the compound used, the strength of the preparation, the route of administration, and the course of the disease state. In addition, factors related to the patient being treated, including the patient's age, weight, diet and timing of administration, lead to the need for dosage adjustments.

The novel compositions of the present invention can also be administered in the form of liposome delivery systems, such as small uni-lamellar sachets, large uni-lamellar sachets, and multi-lamellar sachets. Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, phosphatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylnositols, diacyl trimethylammonium propane, diacyl dimethylammonium propane, and stearylamines, neutral lipids such as triglycerides, and combinations thereof. They can either contain cholesterol or be free of cholesterol.

From Formula (III) and other described formulas, it is obvious that some compounds in the compositions may have one n or more asymmetric carbon atoms in their structure. Stereochemically pure isomeric forms of the compounds as well as their racemates are intended to be included within the scope of this invention. Stereochemically pure isomeric forms can be obtained by applying principles known in the art. Diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers can be separated from each other by selective crystallization of diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers can also be obtained synthetically from a suitable stereochemically pure starting material, or by using stereospecific reactions.

Some compounds in the compositions of this invention may have various individual isomers, such as trans and cis, and various alpha and beta linkages (below and above the plane of the drawing). In addition, where the methods of preparing the compounds of the invention give rise to mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be obtained as a single isomer or in racemic form as a mixture of some possible stereoisomers. Non-racemic forms can be obtained either by synthesis or resolution. Compounds, for example, can be resolved into their constituent enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. Compounds may also be resolved by covalent attachment to a chiral excipient, followed by chromatographic and/or crystallographic separation, and removal of the chiral excipient. Alternatively, compounds can be resolved using chiral chromatography. Unless otherwise indicated, this invention is intended to cover all such isomers or stereoisomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and also racemic mixtures of enantiomers (optical isomers).

The therapeutic effects of administering a glucose reabsorption inhibitor in combination with one or more anti-diabetic agents in the treatment of diabetes, Syndrome X, or related symptoms or complications can be demonstrated by methods known in the art. The following examples of treatment in combination with SGLT inhibitors and other agents such as RXR modulators are provided to illustrate, but not to limit, the invention.

D. Examples of chemical synthesis

One aspect of the present invention provides compounds of formula (III) as described earlier in the Summary of the Invention section, the description and the appended claims. These described compounds can be obtained according to traditional methods of synthesis in organic hernia or according to matrix or combinatorial chemical methods. Schemes and Examples 1-9 below provide general guidance and detailed examples of how the described compounds can be prepared.

HNMR spectra were measured on a Brucker AC-300 spectrometer (300 MHz) using tetramethylsilane (TMS) as an internal standard.

Example 1

2-[3-(2-Naphthalin-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-p-D-glucopyranoside

A. tert-butyl ester (2-amino-3-methoxy-phenyl)-carbamic acid la: Thionyl chloride (2,3

ml, 32 mmol) was added to a suspension of commercially available 3-methoxy-2-nitrobenzoic acid (4.2 g, 21.3 mmol) in toluene (20 ml). The mixture was stirred under reflux for 30 minutes, cooled to room temperature (RT) and concentrated to dryness. The acid chloride was then dissolved in acetone (HPLC grade, 20 mL) and added dropwise through an addition funnel to a cold (0 °C) solution of sodium azide (2.2 g, 33.8 mmol) in water (30 mL) with stirring. The resulting suspension was stirred for 10 minutes at 0°C, then for 50 minutes at RT. Water (150 mL) was added and the white solid was collected by filtration. The solid was diluted with t-butanol (25 ml) and heated to reflux in an oil bath. After 20 minutes under reflux, excess t-butanol was removed under reduced pressure and the residue

was purified by silica gel chromatography (EtOAcHexane; 5:100) to give the desired product as a yellow solid (4.59 g, 80%). This product (2.84 g, 9.2 mmol) was then dissolved in ethanol (40 mL), hydrogenated over 10% Pd/C (250 mg) under 40 psi H2 for 3 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound as a solid

(2.2g, 100%)

B. [3-Methoxy-2-(2-naphthalen-2-yl-acetylamino)-phenyl]-carbamic acid tert-butyl ester lb: a mixture of compound la (0.413 g, 1.74 mmol), obtained in Part A above, 2-naphthylacetic acid (0.32 g, 1.74 mmol), l-hydroxybenyotriol hydrate (0.53 g, 3.5 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.83 g, 4.3 mmol) in dry DMF (4 mL) was stirred overnight at RT, poured into H 2 O (40 mL) and extracted with EtOAc (x 60 mL). The combined EtOAc extract was washed with brine, dried over MgSO 4 , filtered and concentrated to give a crude oil. Column chromatography gave the title compound as a solid (0.5 g, 70%)-C. [3-Methoxy-2-(2-naphthalen-2-yl-ethylamino)-phenyl]-carbamic acid tert-butyl ester lc and 3-methoxy-(2-naphthalen-2-yl-ethyl)-benzene-1,2-diamine ld: To a cold (0°C) solution of compound lb (0.423 g, 1.04 mmol), obtained in Part B, in tetrahydrofuran (30 mL) was slowly added the complex. borane tetrahydrofuran (IM solution, 2 ml). The reaction mixture was stirred for 2 hours at reflux, cooled to 0°C, and 1N NaOH solution was slowly added to it. Water (5 mL) was added and the mixture was stirred overnight at RT. The mixture was diluted with water (50 ml) and the diluted mixture was extracted with ethyl acetate (2 x 60 ml). The combined organic extracts were washed with brine, dried over MgSC, concentrated and chromatographed (silica gel, EtOAc/hexane; 1:4 ratio) to give the title compound, [3-methoxy-2-(2-naphthalen-2-yl-ethylamino)-phenyl]-carbamic acid tert-butyl ester lc (0.26 g, 64%) as a clear oil and 3-Methoxy-(2-naphthalen-2-yl-ethyl)-benzene-1,2-diamine ld (80 mg 20%) as a white solid

substances.

D. 7-Methoxy-1-(2-naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one: A mixture of carbamate 1c (0.48 g, 1.2 mmol), obtained in Part C, and K2CO3 (0.24 g, 1.5 mmol), in DMF (10 mL) was heated in an oil bath at 150°C for 1.5 h, cooled to RT, poured into H2O (30ml), stirred for 20 min at RT and filtered to give the crude solid. The solids were washed with Et 2 O and dried to give the title compound in the form

whitish solids.

E. 7-Hydroxy-1-(2-naphthalen-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-one 1f: A mixture of compound 1e (0.28 g, 0.88 mmol), obtained in Part D, in dichloromethane (50 mL) was cooled to -78°C and boron tribromide (1M solution in CH 2 Cl 2 ; 4.4 mL) was slowly added. The reaction mixture was stirred. 30 minutes at -78°C then slowly heated to RT and stirred for 24 hours at RT. IM solution of HC1 (5 ml) added dropwise followed by ice-cold H20 (50 ml). The methylene chloride was removed under reduced pressure and the diluted mixture was extracted with EtOAc (2 x 60 mL). The combined EtOAc extract was washed with brine, dried over MgSO 4 and concentrated to afford the title compound as a yellow solid (0.267 g, 100%).

F. 2-[3-(2-Naphthalin-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-P-D glucopyranoside 1: To a solution of 1f (0.26 g, 0.87 mmol), obtained in Part E, in DMF (5 mL) was added potassium carbonate (0.30 g, 2.2 mmol), and then 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.54 g, 1.3 mmol). The reaction mixture was stirred for 24 hours at room temperature. The solids were filtered and washed with ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over MgSO 4 and concentrated in vacuo. The rest is

chromatographed (silica gel, EtOAc/hexane; 3:2) to give the pure product (24% - relative to recovered starting material) as a solid. The solid was diluted with methanol (3 ml) and sodium methoxide (1M solution in MeOHm 0.2 ml) was added. The resulting solution was stirred for 1 h at RT, diluted with water (20ml) and evaporated to remove MeOH. The diluted mixture was extracted with EtOAc (2 x 60 mL). The combined EtOAc extract was washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel: eluting with 5% methanol in chloroform gave the title compound (0.023, 57%) as a solid. 'HNMR (300MHz, CD3OD) 5 7.82 - 7.78 (m, 3H), 7.72 (s, IH), 7.47 - 7.42 (m, 3H), 7.04 (m, 2H), 6.82 - 6.79 (dd, J = 6.25 HZ, J = 2.31 Hz, 1H), 5.18 (d, J = 7.73 Hz, IH), 4.47-4.41 (m2), 2.92 (d, J = 10.9 Hz, IH), 3.74-3.63 (m, 2H), 3.54 - 3.46 (m, 3H), 3.28 - 3.23 (m, 2H), MS:m/z (MH<+>) 467.

Example 2

2-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]"P-D glucopyranoside

A. 7-Methoxy-1-(2-naphthalen-2-yl-ethyl)-1H-benzoimidazole 2a: Uniting ld (0.66 g, 2.26

mmol), obtained in Part C of Example 1, and triethyl orthoformate (0.45 mL, 2.71 mmol) added

is the catalytic amount of /?-toluenesulfonic acid. The mixture was heated for 5 hours in an oil bath at 120°C, then cooled to RT. The residue was purified by chromatography (silica gel, 10% EtAOc in hexane) to give the title compound (0.513 g, 75%).

B. 2-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-P-D glucopyranoside 2: Compound 2 obtained in the previous step was demethylated and then glycosylated in the same way

as described in Parts E through F to obtain the title compound. 'HNMR (400MHz, CD3OD) 8 7.79 - 7.68 (m, 3H), 7.58 (s, IH), 7.47 (s, IH), 7.42 - 7.39 (m, 2H), 7.13 - 7.15 (m, 4H), 5.24 (d, J = 7.91 Hz, IH), 4.93 (m, 1H), 4.74 (m, 1H), 3.96 - 3.92 (d, J = 11.9 Hz, J = 1.8 Hz, 1H), 3.77 - 3.65 (m, 2H), 3.57 - 3.33 (m, 5H). MS: m/z (MH<+>)451.

Example 3

2-[3-(4-ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-one-4-yloxy]-O-D glucopyranoside.

A. [2-(4-Ethyl-benzoylamino)-3-methoxy-phenyl]-carbamic acid tert-butyl ester 3a: To a solution of compound la (1.5 g, 6.3 mmol), obtained in Part A of Example 1, and triethylamine (1.3 ml, 9.45 mmol) in methylene chloride (40 ml) was added dropwise 4-ethyl benzoyl chloride (1.06 ml, 6.3 mmol). The resulting mixture was stirred for 6.25 hours at RT, poured into water (50 ml) and the layers were separated. The organic layer was dried over MgSO 4 , filtered and concentrated to give the crude mixture of the title compound in quantitative yields.

B. [2-(4-Ethyl-benzylamino)-3-methoxy-phenyl]-carbamic acid tert-butyl ester 3b and N2-(4-ethyl-benzyl)-3-methoxy-benzene-1,2-diamine 3c: Workup of compound 3a obtained in

of the previous step with the borane tetrahydrofuran complex using the same procedure as described in Part C of Example 1 gave the title compound in quantitative yields. C. 2-[3-(4-Ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-β-D glucopyranoside (3): The title compound was obtained in the same manner as described in Parts D - F of Example 1 except that compound 1a was replaced by 3b obtained in the previous step. 'HNMR (300MHZ, CD3OD) § 7.24 (d, J = 7.90 Hz, 2H), 7.12 (d, J = 8.14 Hz, 2H), 7.02 - 6.93 (m, 2H), 6.80 (d, J = 7.69 Hz, IH), 5.44 (d, 15.51 Hz, IH), 5.27 (d, J = 15.61 Hz, IH), 5.00 (d, J = 7.33 Hz, IH), 3.90 - 3.86 (dd, J = 1.93, J = 12.05, IH), 3.69 - 3.66 (dd, .1 = 5.53, J = 12.00, IH), 3.51 - 3.36 (m, 4H), 2.59 (q, 2H). 1.19 (t, 3H) MS: m/z (MH<+>) 431.

Example 4

2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-(3-D glucopyranoside

2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside 4: Compound 3c obtained in Part B of Example 3 was worked up as described in Example 2 with compound 1d replaced by 3c to give the title compound. 'HNMR (300MHz, CD3OD) 5 8.09 (s, IH), 7.34 (d, J = 8.00 IH), 7.20 - 7.13 (m, 5H), 7.09 (d, J = 7.95, IH), 5.86 (d, J = 15.29, IH), 5.61 (d, J = 15.27, IH), 5.09 (d, J = 7.28, IH), 3.89 (d, J = 11.91, IH), 3.71 - 3.67 (dd, J = 5.48, J = 11.86, IH), 3.55 - 3.36 (m, 4H), 2.59 (q, J = 7.7 Hz, 2H). 1.18 (t, J = 7.4 Hz, 3H), MS:m/z (MH<+>) 415. Example 5 2- {3-[2-(4-methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-fi-D glucopyranoside A. N-(2-hydroxy-6-nitro-phenyl)-2-(4-methoxy-phenyl)-acetamide 5a: In a mixture of commercially available To 2-amino-3-nitrophenol (5 g, 32.4 mmol) and triethylamine (9 mL, 64.9 mmol) in methylene chloride (20 mL) was slowly added /?-methoxyphenylacetyl chloride (5 mL, 32.4 mmol). The resulting mixture was stirred overnight at RT, poured into ice water (30 ml) and 0.5M HCl solution (20 ml) was added. Another 30 ml of methylene chloride was added and the layers were separated. The methylene chloride layer was washed with water, brine and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure to give the title compound as a dark solid (9.45 g, 96%). B. N-[2-(tert-butyl-dimethyl-silanyloxy)-6-nitro-phenyl]-2-(4-methoxy-phenyl)-acetamide 5b: To a cold (0°C) solution of compound 5a (3.1 g, 10.3 mmol), obtained in Part A, itert-butyldimethylsilyl chloride (1.86 g, 12.3 mmol) in dry DMF (10 mL) was slowly added imidazole (1.7 g, 25.7 mmol). Stirring was continued for 30 minutes at 0°C then 3 hours at RT. The resulting mixture was poured into cold water (80 mL) and extracted with Et 2 O (2 x 80 mL). The combined ether extracts were dried over MgSO 4 and concentrated to give the product as an oil in quantitative yield. C. N-[2-amino-6-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-(4-methoxy-phenyl)-acetamide 5c: A solution of compound 5b (1.4 g, 3.36 mmol), obtained in Part B, in ethanol was hydrogenated over 10% Pd/C at 40 psi of hydrogen pressure for 4 h. The catalyst was filtered off through Celite and the filtrate concentrated in vacuo. The title compound was isolated as an off-white solid (0.693 g, 53%) by recrystallization from Et2O.

D. 3-(tert-butyl-dimethyl-silanyloxy)-N2-[2-(4-methoxy-phenyl)-ethyl]-benzene-1,2-diamine 5d and 3-amino-2-[2-(4-methoxy-phenyl)-ethylamino]-phenol 5e: To a cold (0°C) solution of compound 5c (0.693 g, 1.8 mmol) obtained in Part C, in dry tetrahydrofuran (20 mL) was added. borane complex (IM solution, 2.7 ml) was added slowly at reflux and NaOH solution (1.5 ml) was added and the mixture was stirred overnight at RT and the diluted mixture was extracted with ethyl acetate (2 x 30 ml). solution, dried over

MgSCU, concentrated and chromatographed (silica gel, EtOAc/Hexane; 1:4 ratio) to give the title compound 5d (0.4 g, 60%) as a white solid and

title compound 5e (0.7 g, 35%).

E. 7-(tert-butyl-dimethyl-silanyloxy)-1-[2-(4-methoxy-phenyl)-ethyl]-1H-benzoimidazole 5f: To a mixture of compound 5d (0.38 g, 1.02 mmol), obtained in Part D, and triethyl orthoformate (0.23 mL, 1.23 mmol) was added a catalytic amount of p-toluenesulfonic acid. The mixture was heated for 5 hours in an oil bath at 120°C, then cooled to room temperature. The residue was purified by chromatography (silica gel, EtOAc/Hexane; 1:4) to give the title

compound (0.33 g, 84%).

F. 3-[2-(4-Methoxy-phenyl)-ethyl]3Hbenzoimidazol-4-ol 5g: To a cold (0°C) solution of compound 5f (0.30 g, 0.78 mmol) obtained in Part E in dry tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (2 mL, 1.96 mmol). The resulting mixture was heated to RT, stirred for 1 hour and water (15 ml) was added. The solid precipitate was collected by filtration and dried under reduced pressure to give the title compound (0.206

g, 99%) in the form of a yellow-brown solid.

G. 2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside 5: The title compound was obtained by treating compound 5g with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as described in Part F of Example 1. 'HNMR (400MHz, CD3OD) 5 7.59 (s, IH), 7.31 (d, J = 8.1 Hz, IH), 7.20 (t, J = 7.9 Hz, IH), 7.13 (d, 7.8 Hz, IH), 6.95 (d, J - 8.4, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.21 (d, H = 7.8 Hz, IH), 4.62 - 4.58 (m, IH), 3.95 - 3.91 (m, 1H), 3.76 - 3.72 (m, 4H), 3.65 - 3.45 (m, 5H), 3.27-3.12 (m, 2H), MS: m/z (MH<+>) 431. Example 6 2-[3-(2-(4-methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside

A 7-(tert-butyl-dimethyl-silanyloxy)-1-[2-(4-methoxy-phenyl)-ethyl]-1,3-dihydro-benzoimidazol-2-one 6a: Triphosgene (0.40 g, 1.35 mmol) was added to a cold (0 °C) solution of compound 5d (=.50 g, 1.35 mmol), obtained in Part D of Example 5, in dry THF (20 mL). Stirring was continued for 30 minutes at 0°C and then for 2 hours at RT. Saturated NaHCO 3 solution (60 mL) was slowly added and the mixture extracted with EtOAc (2 x 60 mL). The combined EtOAc extracts were washed with brine and dried over MgSO 4 . The mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a solid (0.53 g, 98%).

B 2-[3-(2-(4-Methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D-glucopyranoside 6: The title compound was prepared in the same manner as described in Part F of Example 5 except that compound 5f was replaced by compound 6a followed by treatment with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide as described in Part F of Example 1. 'HNMR (400MHz, CD3OD) δ 7.17 (d, J = 8.38 Hz, 2H), 7.03 - 6.98 (m, 2H), 6.84 - 6.78 (m, 3H), 5.14 (d, J = 7.7 Hz, IH), 4.37 - 4.26 (m, 2H), 3.90 (d, J = 12.1 Hz, 1H), 3.76 (s, 3H), 3.73 - 3.69 (m, 1H), 3.62 - 3.43 (m, 4H), 3.14 - 2.96 (m, 2H). MS:m/z (MH<+>) 447. Example 7 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D glucopyranoside

A. 2-[2-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-3-nitro-phenol 7a: A mixture of 2-amino-3-nitrophenol (1.0 g, 6.6 mmol), (2,3-dihydro-benzofuran-5-yl)-acetic acid (1.07 g, 6.5 mmol; Dunn et al., J. Med. Chem. 1986, 29 2326),1-hydroxybenzotriazole hydrate (3.0 g, 19.5 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.73 g, 19.5 mmol) in dry DMF 810 mL) were stirred overnight at RT, poured into H2O (80 mL) and extracted with EtOAc (2 x 80 mL). The combined EtOAc extract was washed with brine, dried over MgSO 4 and concentrated to give a crude oil. Column chromatography gave the title compound as a white solid

substance (0.3 g, 15%).

B. 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D

glucopyranoside 7: The title compound was obtained in the same manner as described in Parts B to G of Example 5, with compound 5a being replaced by compound 7a obtained in the previous step. 'HNMR (300MHz, Acetone-d6) 5 7.71 (s, IH), 7.32 - 7.29 (m, IH), 7.09 - 7.04 (m, 3H), 6.87 (d, J = 7.98 Hz, IH), 6.58 (d, J = 8.14 Hz, IH), 5.24 (d, J = 7.5 Hz, IH). 4.79 - 4.75 (m, 2H), 4.59 - 4.45 (m, 5H), 3.89 (d, J = 11.95 Hz, IH), 3.77 - 3.54 (m, 5H), 3.16 - 3.08 (m, 4H) MS:m/z (MH<+>) 443.

Example 8

2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-(3-D glucopyranoside

A. 4-Ethyl-N-(2-hydroxy-4-methyl-phenyl)-benzamide 8a: To a solution of commercially available 2-amino-5-methylphenol (6 g, 48.7 mmol) and triethylamine (7 ml, 97.4 mmol) in methylene chloride (80 ml) was added dropwise 4-ethyl benzoyl chloride (7.2 ml, 48.7 mmol). The resulting mixture was stirred for 2 hours at RT, poured into water (100ml) and the layers were separated. The methylene chloride layer was washed with dilute HCl then again with H 2 O and dried over MgSO 4 . The mixture was filtered and concentrated dry to give a semi-solid substance. Recrystallization from hexane gave the title compound in quantitative yield in spec

solid substances.

B. 4-Ethyl-N-(2-methoxy-4-methyl-phenyl)-benzamide 8b: Methyl iodide (1.2 mL, 19.2 mmol) was added dropwise to a mixture of compound 8a (4.0 g, 15.7 mmol), obtained in Part A, and potassium carbonate (5 g, 36.2 mmol) in DMF (20 mL). The resulting mixture was stirred for 6 hours at RT and water (60 ml) was added. The diluted mixture was extracted with Et 2 O (2 x 60 mL). The combined EtOAc extracts were dried over MgSO 4 , concentrated in vacuo and chromatographed (silica gel; EtOAc in Hexane) to give the title

compound (3.58 g, 85%).

C. N-(5-Bromo-methoxy-4-methyl-phenyl)-4-ethyl-benzamide 8c: To a solution of compound 8b (3.58 g, 13.3 mmol) obtained in Part B and iodine (3 crystals) in carbon tetrachloride (100 mL) was slowly added bromine (0.75 mL, 14.6 mmol). Another quantity of 100 ml of carbon tetrachloride was added and the resulting suspension was stirred for 6 hours at RT. The mixture was poured into a 10% sodium sulfite solution (400 ml), dichloromethane (200 ml) was added and the layers were separated. The organic layer was washed with saturated NaHCO 3 (1 v), dried over MgSO 4 , filtered and concentrated under reduced pressure. The product as a white solid was precipitated with hexane and isolated by filtration to give the title compound (3.1 g,

67%).

D. N-(3-Bromo-6-methoxy-4-methyl-2-nitro-phenyl)-4-ethyl-benzamide 8d: Nitronium tetrafluoroborate (0.434 g, 3.3 mmol) was added in one portion to a cold (0°C) solution of compound 8c (1.13 g, 3.2 mmol), obtained in Part C, in acetonitrile. The resulting mixture was stirred for 11 min at 0°C then for 15 min at RT and H2O (30 mL) was added. The solid precipitate was collected by filtration and dried under reduced pressure to give the title

compound (0.93 g, 73%) as an off-white solid.

E. N-(2-amino-6-methoxy-4-methyl-phenyl)-4-ethyl-benzamide 8e: A solution of compound 8d (1.2 g,

3.1 mmol), obtained in Part D, and K 2 CO 3 (0.5 g, 3.6 mmol) in ethanol was hydrogenated for 6 h over 10% Pd/C at 40 psi hydrogen pressure. The catalyst was filtered through celite and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc 830 mL), WASHED with H 2 O (1x30 mL), and dried over MgSO 4 . It is mixed filtered and concentrated

gave the title compound (0.728 g, 83%) as a solid.

F. N-2-(4-ethyl-benzyl)-3-methoxy-5-methyl-benzene-1,2-diamine 8f: To a cold (0°C) solution of compound 8e (0.69g, 2.4 mmol), obtained in Part E, in dry tetrahydrofuran (25 mL) was slowly added borane tetrahydrofuran complex (1M solution, 4.8 mL). The reaction mixture was stirred for 6 hours at RT, cooled to 0°C and 1N NaOH solution (1.5 ml) was slowly added. Water (5 mL) was added and the mixture was stirred overnight at RT. The mixture was diluted with water (25 ml) and the diluted mixture was extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine, dried over MgSO 4 , concentrated and chromatographed (silica gel, EtOAc/Hexane;

ratio 1:4) to give the title compound (0.31 g, 46%) as a white solid

substances.

G. 1-(4-Ethyl-benzyl)-7-methoxy-5-methyl-1H-benzamide 8g: To Compound 8f (0.275 g, 1.0

mmol), obtained in Part F, and triethylorthoformate (0.20 mL, 1.2 mmol) was added with a catalytic amount of p-toluenesulfonic acid. The mixture is heated for 3 hours in an oil bath, then cooled to RT. The residue was purified by chromatography (silica gel,

EtOAc/Hexane, 1:4) to give the title compound (0.253 g, 88%).

H. 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside 8: The title compound was obtained in the same manner as described in Parts E to F

Example 1 with the compound le replaced by 8g. 'HNMR (400MHz, CD3OD) 8 8.03 (s, IH), 7.21 -7.14 (m, 5H), 6.95 (s,3H), 5.81 (d, J = 15.4 Hz, IH), 5.58 (d, J = 15.2 Hz, IH), 5.07 (d, J = 7.37 Hz, IH), 3.88 - 3.92 (dd, J = 12.1 Hz, J= 2.2 Hz, IH), 3.66 - 3.71 (dd, J = 12.0 Hz, J = 5.8 Hz, IH), 3.52 - 3.37 (m, 4H), 2.63 - 2.58 (q, J = 7.45 Hz, 2H), 2.43 (s, 3H), 1.19 (t, J = 7.62 HZ, 3H). MS: m/z (MH<+>) 429.

Example 9

2-{3-[2-(4-methoxy-phenyl)-ethyl]-3H-benzotriazol-4-yloxy}-(3-D glucopyranoside

A 3-[2-(4-Methoxy-phenyl)-ethyl]-3H-benzotriazol-4-ol (9a): To a cold 80°C9 mixture of compound 5e (0.49 g, 1.9 mmol), obtained in Part D of Example 6, in 3N HCl (20 mL) was rapidly added sodium nitrite (0.152 g, 2.0 mmol). The resulting mixture was mixed l? hour at 0°C, neutralized to pH 6 with 3N NaOH and diluted with H2O (40 ml). The diluted mixture was extracted with EtOAc (2 x 60 mL). The combined EtOAc extracts were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10% EtOAc/Hexane) to give the title compound

compound (0.25 g, 49%).

B 2-{3-[2-(4-Methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}-P-D glucopyranoside (9): The title compound was obtained by treating compound 9a with 2,3,4,6-tetra-O-glucopyranosyl bromide as described in Part F of Example 1. 'HNMR (400MHz, CD3OD) 5 7.59 (d, J = 8.12 Hz IH), 7.35 (t, J = 8.1 Hz, IH), 7.27 (d, J = 7.67 Hz, IH), 7.08 (d, J = 8.51 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.24 (d, J = 7.95 Hz, IH), 5.17 (m, 1 Hz), 5.06 (m,lH), 3.93 (d, J = 12.02 Hz, 1H), 3.74 (s, 3H), 3.73 - 3.64 (m, 2H), 3.57 - 3.46 (m, 3H) 3.28 - 3.26 (m, 2H). MS: m/z (MH<+>) 432. Example 10 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-P-D glucopyranoside

A l-(4-ethyl-benzyl)-7-methoxy-lH-benzotriazole 10a: To a cold mixture of compound 3c,

obtained in Part B of Example 3 (1.3 g, 5.1 mmol) in 3N HCl (40 mL) was rapidly added sodium nitrite (0.39 g, 5.6 mmol). The resulting mixture was stirred for 2 hours at 0°C, neutralized to pH 6 with 3N NaOH and diluted with H2O (100 ml). The diluted mixture was extracted with EtOAc (3 x 60 mL). The combined EtOAc extracts were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 10% EtOAc/Hexane) to give the title compound (0.69

g, 51%).

B 3-(4-Ethyl-benzyl)-3H-benzotriazol-4-ol 10b: A mixture of compound 10a obtained in Part A (0.68 g, 2.58 mmol) in dichloromethane (20 ml) was cooled to -78°C and boron tribromide (1M solution in CH2Cl2; 10 ml) was added slowly. The reaction mixture was stirred for 30 minutes at -78°C then slowly warmed to RT and stirred for 24 hours at RT. IM HCl solution (20 mL) was added dropwise followed by ice-cold H2O (20 mL). The dichlorometal was removed under reduced pressure and the diluted mixture was extracted with EtOAc (3x30 mL).

The combined EtOAc extracts were washed with brine, dried over MgSO 4 , and concentrated to afford the title compound as a yellow solid (0.5 g,

77%).

C 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-|3-D glucopyranoside 10c: To a solution of compound 10b (0.4 g, 1.58 mmol) obtained in Part B in MeOH (10 mL) was added lithium hydroxide (0.42 g, 1.74 mmol) and the solution was stirred at RT. After 5 minutes, the solution was evaporated to dryness. 2,3,4,6-tetra-O-acetyl α-D-glucopyranosyl bromide (3.25 g, 7.91 mmol) was added after the residue was diluted in DMF (12 mL). After stirring the reaction mixture overnight at RT, potassium carbonate (2.2 g, 1.58 mmol) and MeOH (5 mL) were added and stirred overnight at RT. The resulting solution was poured into water (50 ml) and the product was extracted with EtOAc (3 x 50 ml), ether was added and the organic extract was washed with water (4 x 50 ml) and brine. The combined extracts were dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, dichloromethane, 97:3) to give the title compound (0.1 g, 15%) as a white solid. 'HNMR (300MHz, CD3OD) 8 7.60 (d, J = 7.78 IH), 7.29 (m, 4H), 7.14 (d, J = 8.09, 2H), 6.17 (d, J = 15.04, IH), 6.01 (d, J = 15.06, IH), 5.16 (d, J = 15.06, IH). 7.70, IH), 3.90 (dd, J = 1.95, J = 12.13, IH), 3.68 (m, 2H), 3.51 (m, 3H), 2.59 (q, J = 7.64, J =

15.19, 2H), 1.17 (t, J = 7.59, 3H), MS: m/z (MH<+>) 416.

H. Biological examples

EXAMPLE 1

Materials and methods

Human SGLT1 and human SGLT2 cDNA cloning and mammalian expression vector construction: Human SGLT1 cDNA (Genbank M24847) was cloned from human small intestine. Human SGLT2 cDNA (Genbank M95549) was cloned from human kidney. Both full-length cDNAs were sub-cloned into pcDNA and sequenced to confirm the integrity of the construct.

Generations of CHO-K1 cells stably expressing human SGLT1 and human SGLT2: Transfection of CHO-K1 cells was performed using DMPJE-C reagent (Life Technologies, Gaithersburg, MD). Transfectants were then selected in the presence of antibiotic G418 (Gibco-BRL, Grand Island, NY) at 400 ug/ml. Then, the characterization of individual clones was carried out using functional tests, which are described below.

Cell-based sodium-dependent glucose transport assay: Next, cell lines stably expressing human SGLT1 or SGLT2 were used for functional assays of Na + -dependent glucose uptake. Briefly, cells were plated at a density of 65,000 cells per well in a 96-well plate and allowed to grow for 48 hours. Cells were then washed once with assay buffer (50 mM HEPES pH 7.4, 20 mM Tris, 5 mM KCl, 1 mM MgCl 2 , 1 mM CaCl 2 , and 137 mM NaCl) and treated for 15 min in the absence or presence of NaCl. Cells were then labeled with <14>C-α-methylglucopyranoside (AMG, Sigma, St. Louis, MO), a glucose analog that is not metabolized by the specific sodium-dependent glucose transporter as described previously.

( Peng, H. And LeverJ. E. Post/ transcriptional regulation of Na +/ glucose cotransporter (SGLT1)

gene expression in LLC-PL1 cells. JBiol Chem 1995; 270:20536-20542). After 2 hours, the labeled cells were washed three times with ice-cold PBS. After aspiration, cells were solubilized using Microsoft 20 (Packard, Meriden, CT) and the amount of Na-dependent <14>C-AMG uptake was determined by measuring radioactivity. Plates were counted in TopCount (Packard, Meriden, CT). Results are given as % inhibition or IC 50 value from a representative experiment. For functional tests, variation was typically within 20%.

EXAMPLE 2

In vivo efficacy test

Male Zucker Diabetic Fatty rats (7–8 weeks) were obtained from Charles River. Animals were maintained on a 12-hour light/dark cycle in a temperature-controlled room. Animals had ad libitum access to food (Purina 5008 standard rodent diet) and water. The animals were deprived of food for 12 hours before the start of the experiment. On the morning of the experiment, animals were given vehicle (0.5% methylcellulose) or compound orally by gavage (1 ml/kg). After one hour, animals were challenged by receiving oral glucose (4 ml/kg 50% solution) and immediately placed in metabolic cages. Animals were given free access to vision and urine was collected for 4 hours. The amount of glucose in the urine was determined using the Trinder reagent (Sigma).

EXAMPLE 3

Effects on plasma glucose, plasma insulin, plasma triglycerides

free fatty acids in plasma, liver weight, and body weight

To examine the effect of an SGLT inhibitor in combination with an RXR agonist, female db/db mice (6-7 weeks of age/Jacfao Labs, ME) were given vehicle (0.5% methylcellulose), an RXR agonist (0.1-10 mpk (mg/kg)) daily for 11 days. Some SGLT inhibitor (100 mpk), or some RXR agonist plus SGLT inhibitor. Mice (n=8 animals per group) received test compounds or vehicle orally via gastric tube in an amount of 10 ml/kg body weight. Body weight is recorded on day 1, before dosing, and on days 4, 8 and 11. Eighteen hours after the last dose, mice are weighed and anesthetized with CO 2 / 0 2 (70:30). Mice are then bled via retro-orbital sinus puncture into 2 ml heparinized polypropylene tubes on ice. Plasma samples are tested for glucose, insulin, triglycerides, and free fatty acids. Livers are removed, weighed and frozen.

SGLT inhibitors and RXR agonists have distinct mechanisms of action. Improved glycemic control, measured as reductions in plasma glucose, plasma insulin, plasma free fatty acids, or plasma triglycerides, or combinations thereof, may be observed at lower concentrations of an RXR agonist when given in combination with an SGLT inhibitor. Therefore, for the effects of an RXR agonist on the above parameters, a shift to the left in the dose-response curve can be observed. In addition, the weight gain observed after treatment with RXR agonists is less pronounced when they are given with an SGLT inhibitor, since the SGLT inhibitor causes glucose to be excreted in the urine and calories to be lost from the body as demonstrated by weight loss or weight gain. Also, because SGLT inhibitors cause mild diuresis, the swelling (and edematous weight gain) commonly seen after treatment with RXR agonists may be less pronounced or absent. Reducing the amount of RXR agonist required to achieve efficacy in turn improves the side effect profile. Reduced side effects may include such conditions as fatty liver, increased liver weight, weight gain, heart weight gain, edema, cardiac hypertrophy, hepatic hypertrophy, hypoglycemia, and hepatotoxicity, or any combination thereof.

EXAMPLE 4

Effects on plasma glucose, HbAlc, hematocrit, plasma insulin, triglycerides in

plasma, free fatty acids in plasma, total cholesterol, HDL, levels

of drugs in plasma, liver weight, heart weight, fat content and body weight

To examine the effect of an SGLT inhibitor in combination with an RXR agonist, male ZDF rats (age 6 weeks/GMI) were administered vehicle (0.5% methylcellulose), an RXR agonist (0.1 mpk - 10 mpk), an SGLT inhibitor (3-100 mpk), or an RXR agonist plus an SGLT inhibitor daily for 28 days. Rats (n=8 animals per group) received test compounds or vehicle orally via gavage in an amount of 2 ml/kg body weight. Body weight was recorded on day 1, before dosing, and twice a week during the study. One hour after the last dose, rats are weighed and anesthetized with C02/02 (70:30). Rats are then bled via retro-orbital sinus puncture into 2 ml heparinized polypropylene tubes on ice. Rats were then challenged with oral glucose (2 ml/kg p.o.) and placed in metabolic cages for urine collection (4 hours). The animals were then sacrificed, the fat pads of the epididymis, liver, and heart were removed, weighed and frozen for histological examination. Plasma samples are then tested for glucose, HbAlC, insulin, hematocrit, plasma drug levels, total cholesterol, HDL, free fatty acids, and triglycerides. Urine volume, glucose, protein, osmolarity, electrolytes (Na, K, Cl), BUN and creatinine are measured.

SGLT inhibitors and RXR agonists have distinct mechanisms of action. It can be noticed

improved glycemic control, measured as reductions in plasma glucose, plasma insulin, or plasma triglycerides, or combinations thereof, at lower concentrations of RXR agonist when given in combination with an SGLT inhibitor. Therefore, for the effects of an RXR agonist on the above parameters, a shift to the left in the dose-response curve can be observed. In addition, the weight gain observed after treatment with RXR agonists is less pronounced when they are given with an SGLT inhibitor, since the effect of SGLT inhibitors to excrete glucose through the urine and lose calories from the body is demonstrated by weight reduction or weight gain. Also, because SGLT inhibitors cause mild diuresis, the swelling (and edematous weight gain) commonly seen after treatment with RXR agonists may be less pronounced or absent. This can be demonstrated by slowing the increase in heart weight induced by RXR agonists. Reducing the amount of RXR agonist required to achieve efficacy in turn improves the side effect profile. Reduced side effects may include such conditions as fatty liver, increased liver weight, weight gain, heart weight gain, edema, cardiac hypertrophy, hepatic hypertrophy, hypoglycemia, and hepatotoxicity, or any combination thereof.

The above examples may also show that oral administration of an SGLT inhibitor in combination with an anti-diabetic agent such as an RXR modulator improves the status of other markers of diabetes mellitus including the level of glycosylated hemoglobin (Hgb A1C). In particular, oral administration of an SGLT inhibitor in combination with one or more RXR modulators can reduce body weight or weight gain, as well as liver weight or liver weight gain, compared to administration of one or more RXR modulators alone.

Accordingly, for the treatment of diabetes, particularly type II diabetes mellitus, or Syndrome X, a compound of Formula (III) can be used in combination with one or more anti-diabetic agents, such as an RXR agonist that increases insulin sensitivity, comprising the administration of repeated oral doses of the compound of Formula (III) in the range of about 25 to 1000 mg once or twice daily and repeated doses of the anti-diabetic agent in jointly effective doses. A commonly effective dose for the anti-diabetic agents described herein can be readily determined by those skilled in the art based on standard dosing guidelines. Such combined administration may be particularly effective in achieving a reduction in body weight, weight gain, liver weight, or liver weight gain in a subject.

Additionally, a method comprising (a) administering to a subject a commonly effective amount of a glucose reabsorption inhibitor; and (b) administering to a subject a collectively effective amount of an anti-diabetic agent such as an RXR modulator can be used to reduce body weight, weight gain, or liver weight in a subject in need thereof, wherein the combined administration can be in any order and the combined collectively effective amounts provide the desired therapeutic effect.

Also, a method comprising (a) administering to a subject a commonly effective amount of a glucose reabsorption inhibitor; and (b) administering to the subject a collectively effective amount of an anti-diabetic agent can be used to control body weight, weight gain, liver weight, or liver weight gain in a subject having diabetes, Syndrome X, or symptoms or complications associated therewith, wherein the combined administration can be in any order and the combined collectively effective amounts provide the desired therapeutic effect.

The optimal doses to be administered can be readily determined by those skilled in the art, and will vary with the particular compound used, the route of administration, the strength of the preparation, and the stage of the disease state. In addition, factors associated with the particular patient being treated, including the patient's sex, age, weight, diet, timing of administration, and other co-morbidities, will result in the need for dosage adjustments.

Although the above description shows the principles of this invention, with examples given for the purpose of illustrating it, it is understood that in practice this invention includes all common variations, adaptations and/or modifications as they occur, within the scope of the following patent claims and their equivalents.

Claims (54)

1. Compound of formula (III): where: X is CH, N, or OO; R 1 is H or absent; R 2 is H, F, Cl, OCH 3 , O CH 2 CH 3 , or C 1-6 alkyl, CF 3 , SCH 3 , substituted or unsubstituted phenyl and NR 3 R 4 ; R 3 and R 4 are H, C 1-6 alkyl, or form together with the nitrogen atom to which they are both attached a 5-6 membered heterocyclyl with optionally 1-2 additional heteroatoms independently selected from O, S and N; Q is -<CH2)n- where n is 1 or 2; P is H, C 1-7 acyl, or (C 1-6 alkoxy)carbonyl; and Z is substituted or unsubstituted, and selected from Cy7cycloalkyl, phenyl, 5- or 6-membered heteroaryl with 1 or 2 heteroatoms independently selected from N, O and S, one biaryl, one 9- or 10-membered fused bicyclyl or fused heterobicyclyl, wherein said fused heterobicyclyl has between 1 and 4 heteroatoms independently selected from N, O and S; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, where H is present or absent. 3. A compound according to claim 1, where H, methyl, or ethyl. 4. A compound according to claim 1, wherein Q is -(CH2)n- and n is 1 5. A compound according to claim 1, wherein Z is independently substituted with 1 and 3 substituents independently selected from C 1-4 alkoxy, phenoxy, C 1-4 alkyl, C 3-cycloalkyl, halo, hydroxy, cyano, amino, C 1-4 alkylt.io, C 1-4 alkylsulfonyl, C 1-4 alkylsulfinyl, C 1-4 alkyl, mono- and di(C 1-4 alkyl)amino, phenyl, C 1-4 alkylaminosulfonyl (SO 2 NHR), amino(alkylsulfonyl)(-NHS02R-), C1-4dialkylamino-sulfinyl (SONHRR), C1-4 alkylamido (CONHR), 5-6 membered heterocyclyl containing between 1 and 3 heteroatoms independently selected from N, S and O; and wherein the substituents on Z may be further independently substituted with between 1 and 3 substituents independently selected from C 1-4 alkoxy, C 1-4 alkyl, halo, hydroxy, cyano, amino, mono or di C 1-4 alkylamino and C 1-4 alkylthio. 6. A compound according to claim 1, wherein Z is 4-substituted phenyl, 3,.4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophenes, biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indenyl, indanyl, naphthyl, or 2,3-dihydro-benzo[1,4]dioxanyl. 7. A compound according to claim 4, wherein Z is unsubstituted or substituted with between 1 and 2 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl, and isopropyl. 8. A compound according to claim 1, wherein Z is biphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-imidazole, 1 yl)-phenyl, 4-(1H-pyrazol-1-yl)-phenyl, (4-ethyl)phenyl, (4-propyl)phenyl, (4-methoxyphenyl, dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl). 9. A compound according to claim 1, wherein R is absent; X is CH and Ri is H, methyl, ethyl, or methoxy. 10. A compound according to claim 1, where Q is -(CH2)n-, nj 1 or 2; and R 2 is H, methyl, or ethyl. 11. A compound according to claim 10, wherein Rije is absent. 12. Compound according to claim 1, where Rije is absent; Q is -(CH 2 ) n -; her 1 or 2; and R 2 is H, methyl, or ethyl; and Z is 4-substituted phenyl, 3,4-disubstituted phenyl, benzhydryl, substituted or unsubstituted thiophene, biaryl, benzofuranyl, hydrobenzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl, indenyl, indanyl, naphthyl, or 2,3-dihydro-benzo[1,4]dioxanyl. 13. A compound according to claim 1, where Z is biphenyl, 4-(3-pyridyl)phenyl, 4-(2-thienyl)phenyl, 4-(1H-imidazol-1-yl)-phenyl, 4-(1H-pyrazol-1-yl)-phenyl, (4-ethyl)phenyl, (4-propyl)phenyl, (4-methoxyphenyl), dihydrobenzofuran-5-yl, or dihydrobenzofuran-6-yl; and Z is unsubstituted or substituted with between 1 and 2 substituents independently selected from methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, butyl and isopropyl. 14. A compound according to claim 1, selected from 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-β-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-(3-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-β-D glucopyranoside. 15. A compound according to claim 1, selected from 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(4-methoxyphenyl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-{3-[2-(4-methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}-R-D glucopyranoside; 2-[3-(2-naphthalen-2-yl-ethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-β-D glucopyranoside. 16. A compound according to claim 1, selected from 2-[3-(2-naphthalin-2-yl-ethyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-P-D glucopyranoside and 2-[3-(2-(4-methoxyphenyl)-ethyl)-1,3-dihydro-benzoimidazol-2-on-4-yloxy]-P-D glucopyranoside. 17. A compound according to claim 1, selected from 2-[3-(5-ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-ethoxy-benzyl)-3H-benzoimidazol-4-yloxy]-P-D glucopyranoside; 2-[3-(4-ethoxy-benzyl)-3H-benzotriazol-4-yloxy]-P-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-β-D glucopyranoside; 2-[3-(4-thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-P-D glucopyranoside: 2-[3-(4-pyrazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-P-D glucopyranoside; 2-[3-(4-pyridin-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-imidazol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-(3-biphenyl-4-ylmethyl-3H-benzoimidazol-4-yloxy)-β-D glucopyranoside; 2-[3-(4- ethyl-benzyl)-6-methoxy-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-6-trifluoromethyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-6-O-ethoxycarbonyl-β-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-6-0-ethoxycarbonyl-β-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside. 18. A compound according to claim 1, selected from 2-[3-(4-ethyl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-[3-(4-ethyl-benzyl)-3H-benzotriazol-4-yloxy]-β-D glucopyranoside, 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(4-methoxyphenyl)-ethyl]-3H-benzotriazol-4-yloxy}-P-D glucopyranoside; 2-[3-(5-ethyl-thiophen-2-ylmethyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2- {3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-[3-(4-thiophen-3-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-[3-(4-pyrrol-1-yl-benzyl)-3H-benzoimidazol-4-yloxy]-β-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzoimidazol-4-yloxy}-P-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-6-methyl-3H-benzotriazol-4-yloxy}-P-D glucopyranoside; 2-{3-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-3H-benzotriazol-4-yloxy}-P-D glucopyranoside; and 2-[3-(4-ethyl-benzyl)-6-methyl-3H-benzotriazol-4-yloxy]-β-D glucopyranoside. 19. A pharmaceutical composition comprising a compound from claim 1, 5, 6, 11, 12, 14, 15, 16, 17 or 18 and a pharmaceutically acceptable carrier. 20. Pharmaceutical composition according to claim 19, which includes a compound from claim 14 and a pharmaceutically acceptable carrier. 21. A method for treating diabetes in mammals, which method comprises administering to a mammal in need of said treatment an effective amount of the pharmaceutical composition of claim 19. 22. The method of claim 21, wherein said diabetes is type II diabetes. 23. A method of lowering serum glucose in a mammal, which method comprises administering to a mammal in need of treatment an effective amount of the pharmaceutical composition of claim 19. 24. A method of treating impaired glucose tolerance in a mammal, which method comprises administering to the mammal in need of treatment an effective amount of the pharmaceutical composition of claim 19. 25. A method of treating or inhibiting impaired glucose tolerance, which method comprises administering to a mammal in need of treatment an effective amount of the pharmaceutical composition of claim 19. 26. A method of lowering body mass index, body weight, or body fat percentage, which method comprises administering to a mammal in need of treatment an effective amount of the pharmaceutical composition of claim 19. 27. The method according to claim 26, wherein said lowering of the body mass index is a method for treating obesity or overweight conditions. 28. A method of inhibiting the sodium glucose transporter in a cell by exposing said cell to the compound of claim 1 or its metabolite. 29. A method of treating diabetes or Syndrome X, or symptoms or complications associated therewith in a subject, comprising (a) administering to said subject a collectively effective amount of a glucose reabsorption inhibitor of formula (III); (b) administering to said subject a collectively effective amount of another anti- diabetic agent, with said combined administration in any order and the combined jointly effective amounts providing the desired therapeutic effect. 30. The method of claim 29, wherein the second anti-diabetic agent is an RXR agonist. 31. The method of claim 29, wherein diabetes or Syndrome X, or symptoms or complications associated therewith are selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy; retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, inflammatory bowel disease, inflammation and cataracts. 32. The method of claim 29, wherein the diabetes or Syndrome X, or symptoms or complications associated therewith, is IDDM. 33. The method of claim 29, wherein the diabetes or Syndrome X, or the symptoms or complications associated therewith, is NIDDM. 34. The method of claim 29, wherein the diabetes or Syndrome X, or the symptoms or complications associated therewith, is IGT or IFG. 35. The method of claim 29, further comprising administering to said subject a collectively effective amount of a third anti-diabetic agent. 36. The method of claim 35, wherein the third anti-diabetic agent is selected from (aa) insulin, (bb) insulin analogs, (cc) insulin secretion modulators, and (dd) insulin secretagogues. 37. The method of claim 29, wherein the glucose reabsorption inhibitor is an SGLT inhibitor. 38. The method of claim 29, wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor. 39. The method of claim 29, wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor. 40. The method according to claim 29, where the glucose reabsorption inhibitor is a compound of Formula (III) or an optical isomer, enantiomer, diastereomer, racemate or a racemic mixture thereof, an ester, a prodrug form, or a pharmaceutically acceptable salt thereof. 41. The method of claim 29, wherein the collectively effective amount of an SGLT inhibitor is from about 10 to 1000 mg. 42. The method of claim 29, wherein the collectively effective amount of an SGLT inhibitor is an amount sufficient to lower the postprandial spike in plasma glucose. 31. A method of inhibiting the onset of diabetes or Syndrome X, or symptoms or complications associated therewith in a subject, comprising (a) administering to said subject a collectively effective amount of a glucose reabsorption inhibitor of formula (III); (b) administering to said subject a collectively effective amount of another anti- diabetic agent, with said combined administration in any order and the combined jointly effective amounts providing the desired therapeutic effect. 44. The method according to claim 43, wherein said development is from a pre-diabetic state to NIDDM. 45. A pharmaceutical composition comprising a glucose reabsorption inhibitor of formula (III), another anti-diabetic agent and a pharmaceutically acceptable carrier. 46. A pharmaceutical composition according to claim 43, 44 or 45, wherein the glucose reabsorption inhibitor is an SGLT inhibitor. 47. The pharmaceutical composition according to claim 43, wherein the glucose reabsorption inhibitor is an SGLT1 inhibitor. 48. The pharmaceutical composition according to claim 43, wherein the glucose reabsorption inhibitor is an SGLT2 inhibitor. 49. A method of formulating a pharmaceutical composition comprising the formulation together with a glucose reabsorption inhibitor, another anti-diabetic agent, and a pharmaceutically acceptable carrier. 50. A process for obtaining a pharmaceutical composition that includes mixing one or more glucose reabsorption inhibitors in combination with another anti-diabetic agent for the preparation of a drug for the treatment of a condition selected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy; retinopathy, atherosclerosis, polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, inflammatory bowel disease, inflammation and cataracts. 51. A method of inhibiting the progression of a pre-diabetic state in a subject to a diabetic state comprising (a) administering to said subject a collectively effective amount of a glucose reabsorption inhibitor of formula (III); and (b) administering to said subject a collectively effective amount of another anti- diabetic agent, provided that said combined administration is in any order and the combined jointly effective amounts provide the desired therapeutic effect. 52. The method according to claim 51, wherein said condition is IGT or IFG. 53. The method according to claim 51, wherein said inhibition of the progression of the pre-diabetic state is prevention of the progression of the pre-diabetic state to the diabetic state. 54. The method according to claim 51, where the glucose reabsorption inhibitor is some compound of formula (III), which optionally has one or more hydroxyl or diol protecting groups, or some optical isomer, enantiomer, diastereomer, racemate or racemic mixture, ester, some form of prodrug, or their pharmaceutically acceptable salt.