MX2007003467A - C-aryl glucoside sglt2 inhibitors and method for their production - Google Patents

Abstract

A compound of the formula (I) A method is also provided for treating diabetes and related diseases employing the above compound alone or in combination with another therapeutic agent.

Description

INHIBITORS AND METHOD FOR GLUCOSIDES OF C-ARILO SGLT2 FIELD OF THE INVENTION The present invention relates to C-aryl glycosides which are selective inhibitors of glucose-dependent sodium transporters found in the kidney, and to a method for treatment of diabetes or disorders, by use of such glycosides of C- aryl alone or in combination with one or more other type of therapeutic agent. BACKGROUND OF THE INVENTION Approximately 100 million people around the world suffer from type II diabetes (NIDD), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes of which are still unknown . The constant control of plasma glucose levels in diabetes patients can compensate for the development of diabetic complications and beta cell failure seen in advanced disease. Plasma glucose normally seeps into the kidney in the glomerulus and is actively reabsorbed in the proximal tubule. Ninety percent of the glucose reabsorbed in the kidney occurs in the epithelial cells of the early SI segment of the renal cortical proximal tubule. The SGLT2, a No. Ref. : 180379 A protein of 672 amino acids that contains 14 segments of membrane coverage that is predominantly expressed in the early SI segment of the renal proximal tubules, is probably the main transporter responsible for this reabsorption. The specificity of the substrate, sodium dependence, and localization of SGLT2 are consistent with the properties of the low affinity sodium-dependent glucose transporter, high capacity previously characterized in proximal tubules of human cortical kidney. In addition, hybrid suppression studies involve SGLT2 as the predominant Na + / glucose cotransporter in the SI segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in rat kidney cortex mRNA is inhibited by a antisense oligonucleotide specific for rat SGLT2. In humans, mutations in SGLT2 have been associated with familial forms of renal glycosuria, which provides further evidence of the primary role of SGLT2 in renal glucose reabsorption. In such patients, renal morphology and renal function are otherwise normal. Inhibition of SGLT2 could be predicted to reduce plasma glucose levels via improved glucose excretion in diabetic patients. SGLT1, another Na-dependent glucose cotransporter that is 60% identical to SGLT2 at the amino acid level, is expressed in the small intestine and in the S3 segment most distant from the renal proximal tubule. Despite their sequence similarities, human SGLT1 and SGLT2 are distinguishable biochemically. The administration of florizin, a specific inhibitor of SGLT activity, provided an in vivo proof of concept for promotion of glucose excretion, reduction of plasma glucose in fasting and with food, and promotion of glucose utilization without hypoglycemic side effects in several Diabetic rodent models and in a model of canine diabetes. No adverse effects on plasma ion balance, renal function or renal morphology were observed as a consequence of the treatment of florizin over two weeks. In addition, no hypoglycemic effects or other adverse effects were observed when florizin was administered to normal animals, despite the presence of glycosuria. The administration of a renal SGLT inhibitor for a period of 6 months (Tanabe Seiyaku) was reported to improve fasting and feeding plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and compensate the development of nephropathy and neuropathy in the absence of renal hypoglycemic and collateral effects. The general inhibitors of SGLT 1 and 2 activity are not attractive therapeutically because the inhibition of SGLTl can also have serious adverse consequences as illustrated by the hereditary syndrome of glucose / galactose malabsorption (GGM)., in which mutations in the SGLTl cotransporter result in impaired glucose absorption in the intestine, and life-threatening diarrhea and dehydration. Selective inhibition of SGLT2 in diabetic patients could be expected to normalize plasma glucose by improving the excretion of glucose in the urine, thereby improving insulin sensitivity, and slowing the development of diabetic complications, in the absence of effects significant gastrointestinal collaterals. Accordingly, the discovery of compounds that are selective for the SGLT2 transporter may prove useful for the treatment or prevention of diseases or disorders associated with control of plasma glucose levels such as diabetes. BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, a C-aryl glucoside compound is provided having the structure The compound of formula I includes pharmaceutically acceptable salts, complexes, stereoisomers, and prodrug esters thereof. The compound of formula I possesses activity as a selective inhibitor of SGLT2 and therefore may provide utility for the prevention or treatment of diseases or disorders associated with the control of plasma glucose levels. Examples of such diseases or disorders include diabetes and the micro- and macrovascular complications of diabetes. The present invention provides a compound of formula I, pharmaceutical compositions employing such a compound and methods of using such a compound. In particular, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier. In addition, according to the present invention, a method is provided for treatment or retardation of the progress or onset of the diseases or disorders described herein, wherein a therapeutically effective amount of a compound of formula I is administered to a human patient in need of treatment The compound of the invention can be used alone, or in combination with one or more other agent (s) active in the therapeutic areas described herein. In addition, there is provided a method for treating diseases as defined above and hereafter, wherein a therapeutically effective amount of a compound of formula I and another type of antidiabetic agent and / or other type of therapeutic agent, such as As a hypolipidemic agent, it is administered to a human patient in need of treatment. DETAILED DESCRIPTION OF THE INVENTION The following table contains a comparison matrix of the compound of the invention (compound 1, column 4) with compounds of similar structure taking into consideration several characteristics related to the utility of the compound and commercial availability. The structures of the co-sites 1 (the compound of the invention) and 3-5, are illustrated below.

Compound 1 (a compound of formula As shown in the table above, only the compound of formula I demonstrates favorable characteristics in all category tests, that is, only the compound of formula I demonstrates a favorable reduction of plasma glucose in diabetic rats (potency), stability in prototypic formulation (indication of shelf life) and negative results in studies of clastogenic in vitro activity (reduced oncogenic potential) INDIVIDUAL PROTOCOL FOR COMPARATIVE STUDIES I. Protocol for Study A: Determination of Effect of Blood Glucose in Diabetic Rats Treated with Streptozotocin The following analysis was used to reasonably predict the impact on plasma glucose for the compounds analyzed in the previous matrix. The male Sprague Dawley rats (Charles River) weighing 250-275 g were made diabetic by a single intraperitoneal injection of streptozotocin (Sigma) at 65 mg / kg, prepared in fresh cold citrate buffer 0.O1M (4 ° C) . Four days later, the animals were bled in the fed state. The whole blood was collected by the tip of the tail and analyzed for glucose by the glucose oxidation method with an Elite Glucometer (Bayer). Average blood glucose levels ranged from 450-550 mg / dL. On the day of the experiment, the compound was dissolved in the vehicle comprised of 515 m-Pyrol, 20%, PEG 400 and 20 mM SodDiphosphate. The rats were weighed, randomly grouped into 4 groups with 6 rats in each group, and dosed orally with the vehicle or 0.1 mg / kg of the compound. The total volume for oral priming was 1 ml / kg of body weight. After dosing, the feed was removed from the cages and the rats had access to water ad lib during the experiment. Blood samples were obtained from the tip of the tail at 0, 30, 60, 120, 180, 240 and 300 minutes after the administration of the drug. Blood glucose was analyzed by the glucose oxidation method with an Elite Glucometer (Bayer). A. Analysis of statistical data The calculation of average blood glucose values and percentage changes against vehicle at each time point were made using Microsoft Excel. Statistical analyzes (T-tests, or ANOVA followed by Fisher's tests) comparing drug-treated groups against vehicle controls) were performed using Microsoft Excel or the StatView statistical program. A p-value of less than 0.05 was considered to be statistically important.

II. Protocol for Study B: Determination of Stability of Therapeutic Agent Oxidative Labile in the Presence of Solid Excipients Commonly Used under Accelerated Aging Conditions. The following procedure was used to access the chemical stability of compound 3 in the presence of commonly used excipients and common antioxidants. The drug substance was ground in a mortar with the respective antioxidant, and then mixed in the dry state with other excipients listed in the following table. Sodium metabisulfite and butylated hydroxyl anisole (BHA) were used as antioxidants in this study. BHA was used in two levels, 0.01% w / w and 0.05% w / w, and sodium metabisulfite was used at 0.01% w / w. For samples stored at 40 ° C / 73% RH and HIL / uv, the oxygen gas was purged in the jars and sealed. Drug excipient mixtures (A-D) were placed under the different accelerated aging conditions listed within the second table for 1 and 3 weeks before CLAP analysis. Compounds that did not have any apparent oxidative instability (compounds 1, 4 and 5) were found to be chemically stable in the presence of excipients that are commonly used in solid dosage forms.

Table 1: Common Excipients in the Presence and Absence of Antioxidants Used during Stability Evaluations of Prototype Drug Excipient Mixtures.

Table 2 Conditions for Stability Studies of Drug Excipient Mixtures under Accelerated Envelopment Conditions III. Protocol for Study C: Cytogenetic Study in Chinese Hamster Ovarian Cells The early identification of potential therapeutic agents that can be oncogenic in man is highly desirable. In vitro clastogenicity studies provide an early indication of the potential carcinogenicity of a compound. ' The following protocol was used to predict the in vitro clastogenicity activity of compounds of therapeutic interest. The clastogenicity was predicted by determining the potential of compounds of interest to induce structural chromosome damage in Chinese hamster ovary (CHO) cells. If the chromosome damage rises significantly beyond the level of support, this is evidence that the compound has clastogenic potential. The detection of a significantly elevated level of chromosome damage in this arrangement is considered an indicator of genetic damage. to. Test article carrier and control items Vehicle control is dimethyl sulfoxide (DMSO). The positive controls were Mitomycin C for 3 hr and 20 hr exposure without activation of S9 and cyclophosphamide for 3 hr exposure with S9 rat liver enzymes. Both Mitomycin C and cyclophosphamide were diluted with sterile water. B. Administration of the compound of interest Selection of Concentration. Two DMSO reserve solutions of the compound of interest were prepared-one being high concentration, the other low. Aliquots of vehicle control, low and high dosage solutions were collected after treatment of the CHO cells and subsequently analyzed to determine the concentration of the compound of interest. The selected concentrations were based on the results of a cytotoxicity assay (ATP) that found a solubility / miscibility range without GLP with the compound of interest. Once the upper limit of solubility of the compound of interest was determined in DMSO, that DMSO solution was added to the culture medium to determine effects in pH or osmolarity. Eleven concentrations of the compound of interest were evaluated in the cytotoxicity assay which found interval both in the presence (3 hr) and absence (20 hr) of rat liver enzymes (S9). The highest concentration evaluated was 10 mM, 5000 pg / ml, or the solubility limits. Based on the results of the cytotoxicity assay that finds solubility / miscibility interval (ATP), six concentrations were selected for evaluation in the complete cytogenetic study. Test item concentrations The DMSO reserve solution of the compound of interest was 100X concentration of the highest test item concentration to be used in the entire assay. The six concentrations are evaluated. The cytotoxicity dose response observed in the interval-finding study determined the serial dilution factor for the five lower doses. A total dosage volume of 50 μ? (plus DMSO reserve solution) to 5 ml of culture medium for all treatment groups. Experimental design Duplicate cultures will be used for each treatment group. The experimental design was as follows: D. Test System The CHO cell line was derived from an ovarian biopsy of a female Chinese hamster. The cells used in this assay (CHO-WBL) were originally obtained from the laboratory of Dr. S. Wolf, University of California, San Francisco. The cells have been subcloned to maintain karyotypic stability. This cell line has an average cycle time of 12 to 14 hours with a modal chromosome number of 21. Cells are routinely monitored for karyotype stability and potential mycoplasma contamination. E. Identification All matrices and / or culture tubes used in the study were labeled numerically. The centrifugation tubes for harvesting cells, hypotonic treatment, and stabilization were labeled with the identical number according to the corresponding flask. Additionally, the microscope plates prepared from the stabilized cells displayed the same number as the centrifuge tube. The microscope plates were coded by an independent observer for unbiased cytogenetic analysis for chromosome aberrations. The permanent labels were affixed to the encoded plates. F. Experimental methodology The chromosome aberration assay was conducted using standard2"6 procedures by CHO cell exposure cultures at a minimum of four concentrations of the test article in addition to the positive and vehicle controls. , the treatment was for approximately 3 hr and for 20 hr and in the activated test system of S9, the exposure was for 3 hr.7,8 Metabolic Activation S9 The exogenous metabolic activation system (S9) consisted of a fraction (post -mitochondrial) S9 of rat liver induced with Aroclor 1254, in addition to salts and cofactors.The final concentration of S9, salts and cofactors in system (S9) of exogenous metabolic activation was 10 μ? / ml (1 v / v) of fraction (post-mitochondrial) S9 of rat liver induced with Aroclor 1254, 2.5 mM MgCl2 »6H20, 1.25 mM glucose-e-phosphate, 10.3 mM KC1, 1 mM NADP, and 12.8 mM Na2HP04. Addressing L The exponentially growing CHO-WBL cells were seeded in McCoy 5A medium fed 10 fetal bovine serum, L-glutamine (2 mM), penicillin G (100 units / ml), and streptomycin (100 pg / ml) in approximately 0.5 x 106 cells / 25 cm2 vial. The flasks were incubated at approximately 37 ° C in a humidified atmosphere of approximately 5% CO2 in air for 16-24 hr. Treatment of targeting cells On the day after the initiation of the culture, the culture medium was replaced with fresh medium. For the 3 and 20 hr exposures without metabolic activation, the dosage was made in the complete medium described above. For 3 hr exposures, in the presence of S9 metabolic activation, the medium is identical to that as described above, except that it lacks fetal bovine serum and contains S9, salts and cofactors. After the 3 hr treatment with and without metabolic activation, the medium was aspirated, the cells were rinsed with phosphate buffered saline, re-fed with complete medium and returned to the incubator. Collection of metaphase cells A single harvest time of approximately 20 hr was used from the initial treatment. This harvest time corresponds to approximately 1.5 times a cell cycle of approximately 13 hr8. Colcemid® will be added to the cultures in a final concentration of 0.1 g / ml, 2-3 hr before harvesting the cell. The cells were harvested by trypsinization, harvested by centrifugation and an aliquot was removed to determine the cell count and the percentage of viable cells. Cell count and viability percentage were used to determine inhibition of cell growth relative to vehicle control (cytotoxicity). The remnant of the cells were grown with 0.075 M of KC1, were washed with three consecutive changes of fixative (methanol: glacial acetic acid, 3: 1 v / v), covered and stored overnight or more at approximately 2-8 ° C. To prepare the plates, the cells were harvested by centrifugation and resuspended in fresh fixative. The suspension of fixed cells was applied to the glass microscope plates and dried with air. The plates were stained with Giemsa and mounted permanently. G. Analysis of chromosome aberration Based on the observed cytotoxicity, a minimum of three concentrations were selected for chromosome aberration analysis. Generally, concentrations that reduce the cell count or the mitotic index a >; 50% were not evaluated for chromosome aberrations, since there is evidence that excessive cytotoxicity can induce chromosome aberrations that are not related to a direct clastogenic effect of the test article.9"10 A minimum of 500 cells were evaluated for each plate and two plates per flask for the frequency of cells in mitosis (mitotic index) and a minimum of 100 mitotic cells were evaluated for the frequency of numerical aberrations (polyploid and endoreduplication) .From each duplicate flask 50 metaphases were recorded from separate plates for structural chromosome aberrations by two independent evaluations Only metaphases containing 21 ± 2 chromosomes were evaluated.The two independent evaluations were combined to produce 100 metaphases per flask and 200 metaphases per concentration for structural chromosome aberrations. these numbers were not achievable because of the citoto xicity or> 50% of aberrant metaphases observed in the first 25 metaphases / plate. H. Analysis of statistical data The number and types of aberrations found, the percentage of structurally damaged cells (percent of aberrant cells), in the total population of cells examined, and the average aberrations per cell were calculated and reported for each group of cells. treatment. The chromatid and isochromatid spaces were present in the data but were not included in the total percentage of cells with one or more aberrations or in the frequency of structural aberrations per cell. The statistical analysis of the frequency of aberrant cells (structural or numerical) was performed using Fischer's exact test. The Fisher test was used to compare the frequency of aberrant cells in each treatment group with that of the solvent control. In the case of a Fisher exact test positive at any dose level of the test article, the Cochran-Armitage test was used to measure dose sensitivity. As a guide for interpretation of the data, the test article was considered to induce a positive response when the percentage of cells with aberrations was increased in a sensitive dose manner with one or more concentrations that are statistically significant (pO0.05). However, values that were statistically pro significant do not exceed the range of historical negative or vehicle controls can be judged as not biologically significant. The test articles that do not show a statistically significant increase in aberrations were concluded to be negative. I. Criteria for an acceptable trial The complete chromosome aberration trial was considered acceptable if the following criteria were met: 1) Positive control cultures should exhibit an increase in the frequency of chromosome aberration that is statistically significant at the level of 5%. 2) The percentage of damaged metaphases in vehicle control crops should not exceed 6% (as an average). 3) The test article, at least at the highest dose, must exhibit some cytotoxicity (ie, reduced in cell count or mitotic index). If the cytotoxicity at the highest concentration was not observed, but the test article is either at the limit of solubility, or its limit of dosage concentration (ie, 10 mM or 5000 g / ml), or its limit of volume (20%), the trial was considered acceptable.

J. Criteria for a positive response The response to the test article was considered positive if the following criteria were met: 1. A statistically significant increase (p <5%) in the percentage of aberrant cells was demonstrated using Fisher's exact test. . 2. A statistically significant increase (p <5%) in the frequency of chromosome aberration was demonstrated in the Cochran-Armitage test used to measure the sensitivity of the dose. 3. The average percent of damaged metaphases exceeded the upper limit of historical negative control levels (that is, average + 2 standard deviations of the vehicle control groups). REFERENCES FOR THE CYTOGENIC SECTION 1. Snyder D, and Green JW. A review of the genotoxicity of marketed pharmaceuticals, Mutation Research. 2001; 488: 151-169. 2. Evans HJ. Cytological methods for detecting chemical mutagens. In: A. Hollaender editor. Chemical mutagens, principáis and methods for their detection. New York and London, Plenum Press. 1976: vol 4: 1-29. 3. Preston RJ, Au W, Bender MA, Brewen JG, Carrano AV, Heddie JA, McFee AF, Wolff S and Wassom JS. Mammalian in-vivo and in-vitro cytogenetic assays: a report of the U.S. EPA's Gene-Tox Program. Mutation Res. 1981; 87: 143-188. 4. Galloway SM, Bloom AD, Resnick M, Margolin BH, Nakamura F, Archer P, and Zeiger E. Development of a standard protocol for in vitro cytogenetic testing in Chimney hamster ovary cells: Comparison of 22 compounds in two laboratories. Environ Mutagen. 1985; 7: 1-51. 5. Scott, D , Danford, N., Dean, B. , irkiand, D. , and Richardson, C. In-vitro chromosome aberration assays. In B.J. Dean (ed.), Report of the UKEMS Sub-committee on Guidelines for Mutagenicity Testing, The United Kingdom Environmental Mutagen Society. 1983; 41-64. 6. OECD. Guidelines for testing chemicals: No. 473, In vitro mainstream chromosome aberration test: 7. Organization for Economic Cooperation and Development, Paris, Adopted July 21, 1997. 8. Swierenga SHH, Heddle JA, Sigal EA, Gilman JPW, Brillinger RL , Douglas GR and Nestmann ER. Recommended protocols based on a survey of current practice in genotoxicity testing laboratories, IV. Chromosome aberration and sister-chromatid exchange in Chínese hamster ovary, V79 Chínese lung and human lymphocyte cultures. Mutation Research. 1991; 246: 301-322. 9. Galloway SM, Aardema MJ, Ishidate Jr. M, Ivett JL, Kirkiand DJ, Morita T, Mosesso P, and Sofuni T. Report from working group on in vitro test for chromosome aberrations.

Mutation Research. 1994; 312: 241-261. 10. Hillard CA, Amnstrong MJ, Bradt Cl, Hill RB, Greenwood SK, and Galloway SM. Chromosome aberrations in vitro related to cytotoxicity of nonmutagenic chemicals and metabolic poisons. Environ Mol Mutagen. 1998; 31: 316-326. 11. Galloway SM Cytotoxicity and chromosome aberrations in vitro: Experience in industry and the case for an upper limit on toxicity in the aberration assay. Environ Mol Mutagen. 2000; 35: 191-201. The following abbreviations were used in the present: Me - methyl mL = milliliter Et = ethyl 35 g = gram (s) TBS = tert -butyldimethylsilyl mg = milligram (s) THF = tetrahydrofuran mol = moles Et20 = diethyl ether mmol = millimole (s) EtOAc = ethyl acetate meq = milliequivalent DMF = dimethyl fonnamide 40 sat or sat 'd = saturated McOH = methanol aq. = aqueous EtOH = ethanol CCD = thin layer chromatography DMAP = 4-dimethylaminopyridine NMR = nuclear magnetic resonance n-BuLi = n-butyllithium min = minute (s) HPLC = high performance liquid chromatography h or h = hour (s) L = liter CL / EM = high resolution liquid chromatography / mass spectrometry EM or Mass Spec = mass spectrometry The lists below are definitions of various terms used in the description of the present invention.

These definitions apply to the terms that are used throughout the specification (unless otherwise limited in the present specification) either individually or as part of a large group. Any compound that can be converted in vivo to provide the bioactive agent (this is, the compound of the formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrug are also known in the art. A comprehensive description of the prodrugs and prodrugs thereof are described in: The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pp. 113-191 (Harwood Academic Publishers, 1991). The references are incorporated herein by reference. An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent for treating or preventing a treatable condition by administration of a composition of the invention. That amount is enough to exhibit a detectable therapeutic or preventive or relief effect. The effect may include, for example, treatment or prevention of the conditions listed here. The precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutic or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. The compound of the formula I of the invention can be prepared as shown in the following Reaction Scheme 1 and the description thereof, in addition to the relevant published literature procedures that can be readily used by one skilled in the art, without undue experimentation, to prepare the compounds described and claimed herein. The reagents and exemplary methods for these reactions appear hereinafter in the working example.

The compound of formula I can be prepared as shown in reaction scheme 1 by treatment of the compound II with a base such as LiOH or NaOH in a solvent such as a 1: 2: 3 mixture of H20 / THF / MeOH or aqueous McOH or aqueous EtOH. The compound of formula II provides a convenient means for purifying the crude compound of the formula which is obtained as a mixture of alpha and beta anomers. The compound of the formula II can be prepared by treating the compound of the formula la with Ac20 in a solvent such as CH2C12 containing pyridine and a catalyst such as dimethylaminopyridine (DMAP).

The compound of the formula can be prepared by the reduction of a compound of the formula III with a reducing agent such as Et3SiH in a solvent such as 1: 1 CH2Cl2 / MeCN at -10 ° in the presence of a lewis acid catalyst such as BF3 Et20.

The compound of the formula II can alternatively be prepared from the compound of the formula III by first acetylating the compound of the formula III with Ac20 in a solvent such as toluene or CH2C12 containing a base such as a Hunig or Et3N base and a catalyst such as DMAP to generate the compound of formula IV.

The subsequent conversion of the compound of formula IV to the compound of formula II can be obtained by treatment at 20 ° of treatment with a reducing agent such as Et3SiH in a solvent such as MeCN containing 1 equivalent of H20 and a Lewis acid catalyst. such as BF3 Et20. Reaction scheme 2 III The compound of the formula III was prepared, as shown in reaction scheme 2 above, by the addition of a cold THF solution of an aryl lithium of the formula V to a persilylated gluconolactone of the formula VI in a solvent such as toluene at -75 °. Subsequently, a methanol solution of a protic acid such as methanesulfonic acid (MSA) was added after 30 minutes and the solution was stirred at 20 ° until the transformation of the lactol intermediate to III was complete.

The compound of the formula VI can be prepared by treating the commercially available D-gluconolactone with a silylating agent such as trimethylsilyl chloride in a solvent, such as THF, which contains a base such as N-methylmorpholine. The compound of formula V can be prepared by treating the compound of formula VII with an alkyl lithium, such as n-BuLi or t-BuLi, in a solvent such as THF VII The compound of formula VII can be easily prepared by treating the compound of formula VIII with a reducing agent such as Et3SiH in a solvent such as TFA at 60 ° in the presence of a Lewis acid catalyst such as BF3 Et20 or CF3S03H .

VIII The compound of formula VIII can be prepared by Friedel-Craft acylation of commercially available ethylbenzene with 2-chloro-5-bromobenzoyl chloride in a solvent, such as ethylbenzene, containing one equivalent of a Lewis acid, such as A1C13 or AlBr3 . 2-Chloro-5-bromobenzoyl chloride was readily prepared from commercially available 2-chloro-5-bromobenzoic acid by treatment with oxalyl chloride in a solvent, such as CH 2 Cl 2, containing a catalytic amount of DMF. UTILITY AND COMBINATIONS A. UTILITIES The compound of the present invention possesses activity as an inhibitor of the sodium-dependent glucose transporters found in the intestine and kidney of mammals. Preferably, the compound of the invention is a selective inhibitor of renal SGLT2 activity, and therefore can be used in the treatment of diseases or disorders associated with SGLT2 activity. Accordingly, the compound of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treatment or retardation of progress or onset of diabetes (including Type I and Type II, impaired glucose tolerance, insulin resistance, and diabetic complications, such as neuropathy, retinopathy, neuropathy and cataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, healing of wound, tissue ischemia, atherosclerosis and hypertension. The compound of the present invention can also be used to increase the blood levels of high density lipoprotein (HDL).

In addition, the conditions, diseases, and conditions collectively referred to as "Syndrome X" or Etabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol Metab., 82, 727-34 (1997), can be treated using the compound of the present invention. B. COMBINATIONS The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compound of the present invention can be used as an individual treatment, or be used in combination with one or more other therapeutic agents. Other "therapeutic agents" suitable for combination with the compound of the present invention include, but are not limited to, known therapeutic agents useful in the treatment of the above-mentioned disorders including: antidiabetic agents; antihyperglycemic agents; hypolipidemic / lipid lowering agents; anti-obesity agents; antihypertensive agents and appetite suppressants. Examples of antidiabetic agents suitable for use in combination with the compound of the present invention include biguanides (for example, metformin or fenoformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin synthesizers) ), meglitinides (eg, repaglinide), sulfonylureas (eg, glimepiride, glyburide, gliclazide, chloropropamide, and glipizide), combinations of biguanide / glyburide (eg, Glucovance®), thiazolidinediones (eg, troglitazone, rosiglitazone, and pioglitazone) , PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha / dual gamma agonists, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitors, glucagon-like peptide-1 (GLP-1) or other GLP-1 receptor agonists, and dipeptidyl peptidase inhibitors IV (PDD4). It is believed that the use of the compound of formula I in combination with at least one or more other antidiabetic agents provides antihyperglycemic results greater than those possible of each of these drugs alone and greater than the additive antihyperglycemic effects produced by these drugs. Other suitable thiazolidinediones include MCC-55 from Mitsubishi (described in U.S. Patent No. 5,594,016), GL-262570 from Glaxo-Welcome, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT / J &J), JTT-501 (JPNT / P &U), L-895645 (Merck), R-119702 (Sankyo / WL), NN-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi) Examples of PPAR-alpha agonists, PPAR-gamma agonists, and dual PPAR-alpha / gamma agonists include muraglitazar, hazard-killing, AR-H039242 (Astra / Zeneca), GW-409544 (Glaxo-Wellcome), GW-501516 (Glaxo- Wellcome), KRP297 (Kyorin Merck) other than those described by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation - Activated Alpha Receptor (PPAR alpha) and PPAR gamma Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats ", Diabetes 47, 1841-1847 (1998), WO 01/21602 and in U.S. Patent No. 6,653,314, the description of which is incorporated herein by reference, employing dosages as proposed in there, which compounds designated as preferred are preferred for use herein. Suitable aP2 inhibitors include those described in the application of E.U.A. Series No. 09 / 391,053, filed on September 7, 1999, and in the application of E.U.A. series No. 09 / 519,079, filed on March 6, 2000, using doses as proposed herein. Suitable DPP4 inhibitors include those described in WO99 / 38501, W099 / 46272, W099 / 67279 (PROBIODRUG), W099 / 67278 (PROBIODRUG), W099 / 61431 (PROBIODRUG), VP-DPP728A (1- [[[2- [( 5-cyanopyridin-2-yl) amino] ethyl] amino] acetyl] 2-cyano- (S) -pyrrolidine) (Novartis) as described by Hughes et al., Biochemistry, 38 (36), 11597-11603, 1999, TSL-225 (triptofil-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) (described by Yamada et al., Bioorg. & amp;; Med. Chem. Lett. 8 (1998) 1537-1540), 2-cyanopyrrolidides and 4-cyanopyrrolidides, as described by Ashworth et al., Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), the compounds described in U.S. Patent Application No. 10/899641, WO 01/868603 and the Patent No. 6,395,767, using dosages as proposed in the previous references. Other suitable meglitinides include nateglinide (Novartis) or KAD1229 (PF / Kissei). Examples of suitable antihyperglycemic agents for use in combination with the compound of the present invention include glucagon-like peptide I (GLP-I), such as amide GLP-I (I-36), amide GLP-I (7-36), GLP-I (7-37) (as described in U.S. Patent No. 5,614,492), in addition to exenatide (Amylin / Lilly), LY-315902 (Lilly), MK-0431 (Merck), liraglutide (NovoNordisk), ZP-10 (Zealand Pharmaceuticals A / S), CJC-1131 (Conjuchem Inc.), and the compounds described in WO 03/033671. Examples of hypolipidemic / lipid lowering agents suitable for use in combination with the compound of the present invention include one or more MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenase inhibitors. , cholesterol absorption inhibitors, Na + / bilious ileal acid cotransport inhibitors, LDL receptor activity overregulators, bile acid sequestrants, cholesterol ester transfer protein (e.g., CETP inhibitors, such as CP-529414 (Pfizer) and JTT-705 (Akros Pharma)), PPAR agonists (as described above) and nicotinic acid and derivatives thereof. MTP inhibitors that can be employed as described above include those described in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Pat. U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983 and U.S. Patent No. 5,962,440. CoA HMG reductase inhibitors that can be used in combination with one or more compounds of formula I include mevastatin and related compounds, as described in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds, as described in U.S. Patent No. 4,231,938, pravastatin and related compounds, as described in U.S. Patent No. 4,343,227, simvastatin and related compounds, as described in U.S. Patent Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, described in U.S. Patent No. 5,354,772, cerivastatin, as described in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin, as described in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan / Sankyo nisvastatin (NK-104)), as described in U.S. Patent No. 5,011,930, Visastatin (Shionogi-Astra / Zeneca (ZD-4522)), as described in U.S. Patent No. 5,260,440, and related statin compounds described in U.S. Patent No. 5,753,675, pyrazole analogues of mevalonolactone derivatives, as described in the US Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives, as described in the PCT application WO 86/03488, 6- [-2 (substituted pyrrol-1-yl) -alkyl) iran-2-ones and derivatives thereof , as described in U.S. Patent No. 4,647,576, dichloroacetate of SC-45355 (a 3-substituted pentanedioic acid derivative) from Searle, imidazole analogs of mevalonolactone, as described in the PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives , as described in French Patent No. 2,596,393, 2, 3-disubstituted pyrrolo, furan and thiophene derivatives, as described in European Patent Application No. 0221025, analogs of mevalonolactone naphthyl, as described in US Pat. U.S. Patent No. 4,686,237, octahydronaphthalenes, such as are described in U.S. Patent No. 4,499,289, mevinolin keto analogues (lovastatin), as described in European Patent Application No. 0142146 A2, and quinoline derivatives and pyridine, as described in U.S. Patent No. 5, 506, -219 and 5,691,322. Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522. In addition, phosphinic acid compounds useful in inhibition of CoA HMG reductase, such as those described in GB 2205837, are useful for use in combination with the compound of the present invention. The squalene synthetase inhibitors suitable for use herein include, but are not limited to, D-phosphono-sulfonates described in U.S. Patent No. 5,712,396, those described by Biller et al., J. Med. Chem., 1988, Vol. .31, No. 10, pp 1869-1871, including isoprenoid phosphonates (phosphinyl-methyl), in addition to other known squalene synthetase inhibitors, for example, as described in U.S. Patent Nos. 4,871,721 and 4,924,024 and in Biller , SA, Neuenschwander, K., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2, 1-40 (1996). In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates described by P. Ortiz de Montillano et al., J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analogue A and the analogs of pyrocarphosphate presqualene (PSQ-PP) as described by Corey and Volante, J. Am. Chem. Soc. , 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R.W. et al., J.A.C.S., 1987, 109.5544 and cyclopropanes reported by Capson, T.L., doctoral dissertation, June, 1987, Dept. Med. Chem. U of Utah, Summary, Table of Contents, pgs. 16, 17, 40-43, 48-51, Summary. Fibric acid derivatives that can be used in combination with the compound of formula I include fenofibrate, gemfibrozil, clofibrate, benzafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds, as described in US Patent No. 3,674,836, the preferred being probucol and gemfibrozil, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®), in addition to lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanilphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative) , melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives) nicotonic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly (diallylmethylamine) derivatives, such as those described in U.S. Patent No. 4,759,923, poly (diallyldimethylammonium chloride) quaternary amine and ionenes, such as are described in U.S. Patent No. 4,027,009, and other known serum cholesterol lowering agents. The ACAT inhibitor which can be used in combination with the compound of the formula I includes those described in Drug of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters," Nicolosi et al., Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C, et al., Bioorg. Med. Chem. Lett. (1996), 6 (1), 47-50; "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animáis", Krause et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fia .; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al., Curr. Med. Chem. 1994), 1 (3), 204-25; "Inhibitors of acyl-CoA: O-acyl transferase (ACAT) as hypocholesterolemic agents 6. The first water-soluble ACAT inhibitor with lipid-regulating activity Inhibitors of acyl-CoA: acyltransferase (ACAT). a series of substituted N-phenyl- '- [(1-phenylcyclopentyl) methyl] ureas with enhanced hypocholesterolemic activity ", Stout et al., Chemtracts: Org. Chem. (1995), 8 (6), 359-62 or TS-962 (Taisho Pharmaceutical Co., Ltd.). The hypolipidemic agent can be an upregulator of LD2 receptor activity, such as MD-700 (Taisho Pharmaceutical Co. Ltd.) and LY295427 (Eli Lilly). Examples of suitable cholesterol absorption inhibitor for use in combination with the compound of the invention include SCH48461 (Schering-Plow), in addition to those described in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998). Examples of Na + / bilious ileal acid cotransport inhibitors suitable for use in combination with the compound of the invention include compounds as described in Drugs of the Future, 24, 425-430 (1999). The lipoxygenase inhibitors which can be used in combination with the compound of formula I include inhibitors of 15-lipoxygenase (15-LO), such as benzimidazole derivatives, as described in WO 97/12615, 15-LO inhibitors, as are described in WO 97/12613, isothiazolones, as described in WO 96/38144, and 15-LO inhibitors, as described by Sendobry et al., "Attenuation of dietary-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor. lacking significant antioxidant properties, "Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al.," 15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target for Vascular Disease, "Current Pharmaceutical Design, 1999, 5, 11-20. Examples of suitable antihypertensive agents for use in combination with the compound of the present invention include beta adrenergic blockers, calcium channel blockers (type L and type T, eg, diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (eg, example, chlorothiazide, hydrochlorothiazide, flumetiazide, hydroglymetide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benazide, ethacrynic acid tricrinafen, chlorthalidone, furosemide, musolimine, buinetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (eg , captopril, zofenopril, fosinopril, enalapril, caranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg, losartan, irbesartan, valsartan), ET receptor antagonists (eg, sitaxsentan) , back and compounds described in U.S. Patent Nos. 5,612,359 and 6,043,265), Antagonist s of dual ET / AII (e.g., the compounds described in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates . Examples of suitable antiobesity agents for use in combination with the compound of the present invention include a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor (and dopamine), a beta-receptor thyroid drug, 5HT2C agonists, ( such as Arena APD-356); MCHRI antagonists such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor agonists (MC4R), melanin concentration hormone receptor (MCHR) antagonists (such as Sinaptic SNAP-7941 and Takeda T-226926), modulators of galanin receptor, orexin antagonists, CCK agonists, NPY1 or NPY5 antagonists, modulators of NPY2 and NPY4, agonists of corticotropin-releasing factor, modulators of histamine-3 receptor (H3), 11-beta-HSD-inhibitors 1, adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agents, a ciliary neurotrophic factor (CNTF, such as AXO INE0 by Regeneron), BDNF (brain derived neurotrophic factor), leptin modulators and leptin receptor modulators , cannabinoid receptor 1 antagonists (such as SR-141716 (Sanofi) or SLV-319 (Solvay)), and / or an anorectic agent. Beta 3 adrenergic agonists which may optionally be employed in combination with the compound of the present invention include AJ9677 (Takeda / Dainippon), L750355 (Merck), or CP331648 (Pfizer), or other known beta 3 agonists, as described in U.S. Patent Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064. Examples of lipase inhibitors which may be optionally employed in combination with the compound of the present invention include orlistat or ATL-962 (Alizima). The serotonin (and dopoamine) reuptake inhibitor (or serotonin receptor agonists) which may optionally be employed in combination with a compound of the present invention may be BVT-933 (Biovitrum), sibutramine, topiramate (Johnson &Johnson) ) or axokina (Regeneron). Examples of thyroid receptor beta compounds which can be optionally employed in combination with the compound of the present invention include thyroid receptor ligands, such as those described in WO 97/21993 (U. Cal SF), WO 99/00353 ( KaroBio) and GB 98/284425 (KaroBio). The monoamine reabsorption inhibitors which may be optionally employed in combination with the compound of the present invention include fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphenrmine, cloforex, clortermin, picilorex, sibutramine, dexamfetamine, phentermine, phenylpropanolamine or Mazindol The anorectic agent which may optionally be employed in combination with the compound of the present invention includes topiramate (Johnson &Johnson), dexamfetamine, phentermine, phenylpropanolamine or mazindol. The aforementioned patents and patent applications are incorporated herein by reference. The other therapeutic agents above, when used in combination with the compound of the present invention can be used, for example, in those amounts indicated in the Physician's Desk Reference, as in the patents proposed above or as otherwise determined by a ordinary expert in the art. When the compound of the invention is used in combination with one or more other therapeutic agents, either concurrently or sequentially, the following combination ratios and dosage ranges are preferred: When the other antidiabetic agent is a biguanide, the compound of the invention Formula I will be employed in a weight to biguanide ratio within the range of from about 0.01: 1 to about 100: 1, preferably from about 0.1: 1 to about 5: 1. The compound of formula I will be employed in a weight ratio for the glucosidase inhibitor within the range of from about 0.01: 1 to about 100: 1, preferably from about 0.5: 1 to about 50: 1. The compound of the formula I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01: 1 to about 100: 1, preferably from about 0.2: 1 to about 10: 1. The compound of formula I will be employed in a weight ratio to the thiazolidinedione in an amount within the range of from about 0.01: 1 to about 100: 1., preferably from about 0.2: 1 to about 10: 1. Where present, the thiazolidinedione antidiabetic agent can be used in amounts within the range of from about 0.01 to about 200 mg / day which can be administered in single or divided doses one or four times a day. Optionally, the sulfonyl urea and the thiazolidinedione can be incorporated into a single tablet with the compound of the formula I in amounts of less than about 150 mg. Where metformin or salts thereof are present, it can be used in amounts in the range of from about 500 to about 2000 mg per day which can be administered in a single dose or divided one or four times daily. When present the GLP-I peptides can be administered in oral buccal formulations, by nasal or parenteral administration as described in U.S. Patent Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.

The SGLT2 inhibitor of formula I can be used in a weight ratio to meglitinide, PPAR-gamma agonist, PPAR-alpha / gamma dual agonist, aP2 inhibitor or DPP4 inhibitor within the range of from about 0.01: 1 to about 100: 1 , preferably from about 0.1: 1 to about 10: 1. The compound of formula I of the invention will generally be employed in a weight ratio for the hypolipidemic agent (being present), within the range of from about 500: 1 to about 1: 500, preferably from about 100: 1 to about of 1: 100. For oral administration, a satisfactory result can be obtained by employing the MTP inhibitor in an amount within the range of from about 0.01 mg / kg to about 500 mg and preferably from about 0.1 mg to about 100 mg, one or four times daily. A preferred oral dosage form, such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about of 250 mg, once or four times daily. For oral administration, a satisfactory result can be obtained by employing a HMG CoA reductase inhibitor in an amount in the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg. A preferred oral dosage form, such as tablets or capsules, will contain HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 mg. up to about 40 mg.

The squalene synthetase inhibitor can be used in doses in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg. A preferred oral dosage form, such as tablets or capsules, will contain squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg. The compound of the formula I can be administered for any of the uses described herein by any of the appropriate means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, which includes administration to the nasal membranes, such as by inhalation spray; externally, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing pharmaceutically acceptable non-toxic vehicles or diluents. By carrying a preferred method of the invention for treatment of any of the diseases described herein, - Yes ¬ such as diabetes and related disorders, a pharmaceutical composition containing one or more of the compound of the formula I, with or without other antidiabetic agents and / or antihyperlipidemic agents and / or other types of therapeutic agents in association with a vehicle or diluent, will be employed. pharmacist. The pharmaceutical composition can be formulated using solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the desired mode of administration, such as pharmaceutically acceptable carriers, excipients, binders and the like. The compound can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, beads, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, or they can be administered intranasally or in transdermal patches. Common solid formulations will contain from about 10 to about 500 mg of a compound of formula I. The dose for adults is preferably between 10 and 2,000 mg per day, which can be administered in a single dose or in the form of Individual doses of 1-4 times per day. A common injectable preparation can be produced by aseptically placing 250 mg of compound of formula I in a vial, aseptically freezing and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable preparation. It will be understood that the specific dose level and frequency of dosing for any particular subject can be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the time of action of the compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of the drug, and severity of the particular condition. The activity of the SGLT2 inhibitor of the compound of the invention can be determined by use of an assay system as proposed below. Assay for sglt2 activity The mRNA sequence for human SGLT2 (GenBank # M95549) is cloned by reverse transcription and amplification of human kidney mRNA, using standard molecular biological techniques. The cDNA sequence was stably transfected into CHO cells, and the clones were assayed for SGLT2 activity essentially as described in Ryan et al., (1994). The evaluation of inhibition of SGLT2 activity in a clonally selected cell line was performed essentially as described in Ryan et al., With the following modifications. Cells were plated at 10,000 or 20,000 cells per well and cultured in Ham's F-12 medium containing 10% fetal bovine serum and 500 ug / ml geneticin. Cells in approximately 90% confluence were evaluated 2 or 3 days after plating. Cells were washed once with sodium-free buffer, which contains 10 mM Hepes / Tris, 137 mM N-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl2, and 1.2 mM MgSO4 pH 7.4. Inhibitors were evaluated in the presence of 10 pM [14C] AMG (a-methyl-D-glucopyranoside) in 8 concentrations in a 120 minute incubation in protein-free buffer solution containing 10 mM Hepes / Tris, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, and 1.2 M MgSO4, pH 7.4. The response curve was fitted to an empirical four-parameter model to determine the inhibitor concentration in mean maximum response, reported as the IC50. Three replications were made per determination. The assays were quenched by 3-fold washing in ice-cold lx phosphate-buffered saline (PBS) containing 0.5 mM plorizin, and the cells were then lysed in 50 μ? 0.1% NaOH. After the addition of 200 μ? of MicroScint-40 scintillation fluid, cells were left for agitation for 1 hour, and then [14C] AMG was quantified in a TopCount scintillation counter. Control assays in the absence of inhibitor were performed with and without NaCl and a dose response curve for florizin was generated in all assays as a positive control. Ryan MJ, Jonson G, Kira J, Fuerstenberg SM, Zager RA and Torok-Storb B. 1994. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney International 45: 48-57. The following Working Example serves to better illustrate, but not limit, the embodiments of the present invention. Example 1 A. 5-Bromo-2-chloro-4'-ethylbenzophenone To a 2L round bottom flask containing a magnetic stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (410 g, 1.74 mol) in 700 mL of CH2C12 oxalyl chloride (235 g, 1.85 mol) was added followed by 1.5 mL of DMF. To trap the resulting HC1, the flask was coupled with tubing so that the gas was discharged above the surface of a stirred aqueous KOH solution. When the vigorous evolution of the gas ceased after 2 hours, the homogeneous reaction was stirred overnight prior to removal of the volatiles under vacuum using a rotary evaporator. The resulting oil solidified during subsequent evacuation. After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 530 ml of ethylbenzene, the yellow solution was cooled to -3 ° C before adding AiCl3 (257 g, 1.93 mol) in portions of -30 g for 60 minutes as that the temperature did not exceed 10 ° C. The abundant amounts of HCl gas which began to develop after 60% AlCl 3 had been added, were trapped by passing the gas over a stirred concentrated NaOH solution. If the reaction is concentrated more, a magnetic stirrer may not maintain agitation during the term of AlCl3 addition. After stirring for 1 hr when the bath was heated to -15 ° C, the bath was removed. After 4 hr at 20 ° C, the thick syrup was emptied on ice (1.5 kg). Subsequently, once the suspension was cooled, H20 (1L) was added before starting to extract 4x with EtOAc. The combined organic extracts were washed 2x with 1N HCl, 3x with 1M KOH, and 2x are brine prior to drying over Na2SO4.

The volatiles were removed using a rotary evaporator first and then by heating to -60 ° C to 1 Torr. The 1 H NMR analysis of the resulting dark oil revealed that the residue was a 1:14 mixture of ortho / para isomers. Dissolving in hexane and followed by filtration through a pad of silica gel removed more of the color. The concentration of the eluent gave 560 g (99%) of a 14: 1 mixture of 5-bromo-2-chloro-4'-ethylbenzophenone / 5-bromo-2-chloro-2'-ethylbenzophenone. Reaction time HPLC: 4.7 min, YMC S5 C-18 4.6x50mm column, 2.5 mL / min, detection at 220nM; 4 min gradient 0-100% B retained 2 min to 100% B. Solvent A: 10% McOH / H20 + 0.2% H3PO4. Solvent B: 90% McOH / H20 + 0.2% H3PO4. 5-Bromo-2-chloro-'-ethylbenzophenone? NMR (400 MHz, CDCl 3) d 7.73 (d, 2H, JAB = 8.2 Hz), 7. 54 (dd, 1H, J = 2.2 Hz, J = 8.8 Hz), 7.32 (d, 1H, J = 8.8 Hz), 7.295 (d, 2H, JAB = 8.2 Hz), 2.72 (q, 2H, J = 7.7 Hz), 1.27 (t, 3H, J = 7.7 Hz). 13C NMR (100 MHz, CDC13) d 193.13, 151.33, 140.49, 133.8, 133.52, 131.6, 131.44, 130.34, 130.16, 128.28, 120.44, 29.04, 15.02. 5-Bromo-2-chloro-2'-ethylbenzophenone (different signals) H NMR (400 MHz, CDC13) d 2.64 (q, 2H, J = 7.7 Hz), 1.23 (t, 3H, J = 7.7 Hz).

C RM (100 MHz, CDC13) d 28.9, 15.5 B. 5-Bromo-2-chloro-4'-ethylphenylmethane To a stirred solution of Et3SiH (400 g, 3.45 mol and 5-bromo-2-chloro-4'-ethylbenzophenone (534 g, 1.65 mol) containing -7 % of the isomeric ketone in 300 mL of TFA at 30 ° C was added CF3S03H (1.5 g, 0.01 mol) Minutes later the temperature increased causing the solution to reflux violently Caution that this moderate exotherm requires cooling with a bath of external ice.After 1 hr, the HPLC revealed that the reaction was 90% complete.After the addition of an additional Et3SiH (20 g) and heating overnight at 70 ° C, the reaction was> 95% complete During the cooling, the volatiles were removed by bulb-to-bulb distillation at reduced pressure The -1L resulting from the light gray oil was emptied into 1 L of H20.The mixture was extracted 3x with hexane; the organic layers combined were washed 3x with H20, 2x with aqueous Na2C03 and 2x with brine before s NaCl over Na2SO4 After the concentration a rotary evaporator was used, remaining -1L of the transparent light amber oil. This material was also concentrated; (Et3Si) 20 (450 mL) was removed by distillation at 0.6 Torr. Once the temperature of the distillation dome reached 75 ° C, the vessel was allowed to cool. The 1H NMR analysis of the container revealed that it contains an 8: 1 mixture of diarylmethane a (Et3Si) 20. The crystallization of this mixture was achieved by emptying the product under vigorous stirring at 10 ° C, 85% EtOH / H20 (1.2L). After being stirred for several hours, the crystals were collected by filtration, washed with 1: 1. EtOH / H20 cold and dried under vacuum. 5-Bromo-2-chloro-4'-ethyldiphenyl-methane (500 g), was obtained as a low melting solid containing -1% (Et3Si) 20, was used without further purification. HPLC retention time: 5.3 min, YMC S5 C-18 4. 6x50mm column, 2.5 mL / min, 220nM detection; 4 min gradient 0-100% B retained 2 min to 100% B. Solvent A: 10% McOH / H20 + 0.2% H3P04. Solvent B: 90% cOH / H20 + 0.2% H3PO4. * H NMR (125 MHz, CDC13) d 7.27-7.23 (m, 3H), 7.14 (d, 2H, JAB = 7.7 Hz), 7.09 (d, 2H, JAB = 7.7 Hz), 2.63 (q, 2H, J = 7.7 Hz), 1.23 (t, 3H, J = 7.7 Hz). 13 C NMR (100 MHz, CDCl 3) d 142.46, 141.08, 135.68, 133.64, 133.13, 130.85, 130.55, 128.83, 128.1, 120.0, 38.62, 28.43, 15.51.

C. 2,3,4,6-tetra-O-Trimethylsilyl-D-glucolactone To a stirred solution at -5 ° C of gluconolactone (239g, 1.34 mol) and N-me ti lmorfo 1 ina (1180 mL, 10.73 mol ) in 2.4 L of THF under Ar, trimethylsilyl chloride (1022 mL, 8.05 mol) was added via a dropping funnel at a ratio such that the temperature did not exceed 5 ° C. After 1 hr the stirred reaction was heated at 35 ° C for 5 hr whereupon this was allowed to cool to 20 ° C as the reaction stirred overnight. After dilution with 3.6L of toluene, the mixture was cooled to 0-5 ° C prior to carefully adding 7L of H20 at a rate such that the temperature did not exceed 10 ° C. It is observed that a severe exotherm results during the addition of the first portion of H20. After mixing, the phases were allowed to separate and then divided. The organic phase was washed with aqueous NaH2P04 (2L), H20 (1L), and brine (1L). The organic layer was then concentrated under vacuum using a rotary evaporator; The resulting light yellow oil was taken twice to 250 mL of toluene and reconcentrated to provide 616 g.

To a stirred solution at -78 ° of 5-bromo-2-chloro-4'-ethyldiphenylmethane from Part B (88 g, 0.28 mol) in 450 mL of 1: 2 THF / dry toluene under Ar was slowly added 2.5 M of n-BuLi (136 mL, 0.34 mol) in hexane at a ratio that keeps the temperature below -55 °. After stirring for 10 minutes following the addition, this solution was transferred via a cannula to a stirred solution at -78 ° of part C, 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone ( 153 g, 0.33 mol) in toluene (350 mL) at a rate that keeps the reaction below -55 °. The solution was stirred for 30 min at -78 ° before quenching by the addition of 400 mL of McOH containing methanesulfonic acid (28 mL, 0.45 mol). The reaction was stirred overnight for 18 hr at 20 ° C. The reaction was stirred overnight for 18 hr at 20 ° C. The CLAR analysis revealed a new peak which by LC / MS corresponds to the expected mass of the O-methylglucoside. The reaction, once completed, was quenched by the addition of NaHCO3 (42 g, 0.5 mol) in 200 mL of H20. If the pH was not weakly basic, more NaHCO3 would be added prior to dilution 2 times with H20 and 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over a2SO4. After concentration using a rotary evaporator, the oil (140 g, 90%, pure by HPLC analysis) was not further purified but instead was later taken as a diastereomerically impure mixture. XH NMR (400 MHz, CDC13) d 7.37 (m, 1H), 7.23 (m, 2H), 7. 02 (m, 4H), 5.14 (m, 1H), 5.06 (m, 1H), 4.07 (m, 1H), 4. 03 (d, 1H, JAB = 15.4 Hz), 3.97 (d, 1H, JAB = 15.4 Hz), 3.80 - 3.70 (m, 4H), 3.60 (m, 1H), 3.48 (m, 1H), 3.31 (m , 1H), 2.84 (s, 3H), 2.53 (q, 2H, J = 7.5 Hz), 1.14 (t, 3H, J = 7.5 Hz). 13 C NMR (100 MHz, CDCl 3) d 144.4, 140.7, 138.94, 136. 132.51, 131.6, 130.96, 130.6, 130.2, 129.16, 103.36, 77. 74.86, 72.48, 64.27, 51.57, 41.33, 30.75, 17.9. HPLC retention time: 4.28 min, 90% pure, YMC C-18 4.6x50mm column, 2.5 mL / min, 220nM detection; min gradient 0-100% B retained 2 min to 100% B. Solven A: 10% McOH / H20 + 0.2% H3P04. Solvent B: 90% McOH / H20 0.2% H3P04.

A solution of part D of O-methylglucoside (206 g, 0.49 mol) in THF (1 L) containing diisopropylethylamine (465 g, 3.6 mol) and DMAP (0.5 g, 4.1 mmol) was cooled to 0 ° C. Acetic anhydride (326 g, 3.19 mol) was slowly added at a rate such that the temperature did not exceed 5 ° C. After the solution was gradually heated to 20 ° C, this was stirred for 10 hours whereby the tic analysis revealed that the conversion to tetraacetate was completed. The reaction was quenched by the addition of EtOAc (1.5 L) and 10% aqueous H3PO4 (1.5 L). After separation of the layers, the aqueous phase was extracted 2x with EtOAc. The combined organic phases were washed lx with brine before being dried over a2SO4 and concentrated in vacuo. The resulting oil was dissolved twice in 300 mL of toluene and reconcentrated to provide a thick oil (300g, 95% pure HPLC) which was used without further purification of the resulting impure diastereomeric mixture. H NMR (400 MHz, CDC13) d 7.38 (d, 1H, J = 8.3 Hz), 7.28 (dd, 1H, J = 8.3 Hz, J = 2.2 Hz), 7.24 (d, 1H, J = 2.2 Hz), 7.11 (d, 2H, JAB = 8.3 Hz), 7.04 (d, 2H, JAB = 8.3 Hz), 5.56 (t, 1H, J = 9.7 Hz), 5.21 (t, 1H, J = 10.1 Hz), 4.93 ( t, 1H, J = 10.1 Hz), 4.20 (dd, 1H, J = 12 Hz, J = 2 Hz), 4.12 (d, 1H, JAB = 15.4 Hz), 4.02 (m, 1H), 4.018 (d, 1H, JAB = 15.4 Hz), 3.10 (s, 3H), 2,606 (q, 2H, J = 7.7 Hz), 2.097 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H), 1.72sd (s, 3H), 1.21 (t, 3H, J = 7.7 Hz). 13C RM (100 MHz, CDC13) d 170.7, 170.05, 169.47, 168.9, 142.2, 138.74, 136.4, 135.1, 134.7, 129.8, 129.4, 128.6, 128.0, 126.0, 100.02, 73.83, 71.33, 68.87, 68.77, 62.11, 49.43 , 38.75, 28.4, 22.64, 20.68, 20.58, 20.16, 15.5. HPLC retention time: 4.81 min, 90% pure, YMC S5 C- 18 4.6x50mm column, 2.5 mL / min, 220nM detection; 4 min gradient 0-100% B retained 2 minutes at 100% B. Solvent A: 10% McOH / H20 + 0.2% H3PO4. Solvent B: 90% McOH / H20 + 0.2% H3PO4.

A stirred solution of the crude oil from above (301 g, 0.51 mol) in CH2Cl2 (500 mL) containing one equivalent of H20 (9 g, 0.5 mol) and Et3SiH (188 g, 1.62 mol) was cooled to -20 ° C. prior to the addition of BF3 Et20 (145 g, 1.02 mol). During the addition, the temperature was maintained at < 0 ° C. The reaction was subsequently stirred 2hr at 10 ° C and 18 hr at 15-20 ° C before starting to turn off by the addition of CH2C12 (500 mL) and H20 (500 mL). After separation of the layers, the aqueous phase was extracted once with CH2Cl2. The combined organic layers were washed lx with aqueous NaHCO3 and brine before drying over Na2SO4. After removal of Na2SO4 by Ac20 filtration (6.4 g, 65 mmol), diisopropylethylamine (9.5 g, 74 mmol) and DMAP (100 mg, 0.8 mmol) were added. The solution was stirred at 20 ° C for 18 hr to ensure that any hydrolysis of glycoside that is hydrolyzed during the reduction and preparation was re-cemented. The oil, which is obtained after concentration under vacuum, was crystallized during the addition of EtOH. After filtration, the purity of this material by HPLC was 98%; recrystallization of EtOH gave tetraacetylated beta-C-glucoside as a white solid (180 g, 99.8% purity) The general conversion for DF procedures was 61% HPLC retention time: 4.74 min, 100% pure, YMC S5 C -18 4.6x50mm column, 2.5 mL / min, detection at 220nM, 4 min gradient 0-100% B retained 2 min at 100% B. Solvent A: 10% McOH / H20 + 0.2% H3P04 Solvent B: 90% McOH / H20 + 0.2% H3P0. XH NMR (500 MHz, CDC13) d 7.35 (d, 1H, J = 8.2 Hz), 7.19 (dd, 1H, J = 8.2 Hz, J = 2.2 Hz), 7.11 (d, 2H , JAB = 8.5 Hz), 7.086 (d, 1H, J = 2.2 Hz), 7.06 (d, 2H, JAB = 8.5 Hz), 5.28 (t, 1H, J = 9.7 Hz), 5.20 (t, 1H, J = 9.7 Hz), 5.04 (t, 1H, J = 9.7 Hz), 4.31 (d, 1H, J = 9.9 Hz), 4.26 (dd, 1H, J = 12 Hz, J = 5 Hz), 4.135 (dd, 1H, J = 12 Hz, J = 5 Hz), 4.095 (d, 1H, JAB = 7.7 Hz), 3.995 (d, 1H, JAB = 7.7 Hz), 3.79 (m, 1H), 2.605 (q, 2H, J = 7.7 Hz), 2.069 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.67 (s, 3H), 1.21 (t, 3H, J = 7.7 Hz) .13C NMR (125) MHz, CDC13) d 170.64, 170.3, 169.4, 168.7, 142.2, 138.78, 136.4, 135.1, 134.6, 129.9, 129.8, 128.7, 128.0, 125.9, 79.45, 76.1, 74.1, 72.5, 68.45, 62.2, 38.6, 28.4, 20.7, 20.6, 20.59, 20.2, 15.55. LC-MS [M + NH +] at m / z 578.3.

For the white suspension formed by stirring the tetraacetylated beta-C-glucoside from part F (25g, 44.6 mmol) for 5 minutes in 2: 3 THF / MeOH (350 mL) under N2 at 20 ° C was added LiOH-H20 ( 2.0 g, 50 mmol) in H20 (70 mL). After 15 min, the reaction was an opaque solution; after 2.5 hr, by the HPLC analysis the reaction was 98% complete. The conversion increased to 99% after stirring overnight during which the volatiles were removed using a rotary evaporator such that the volume was reduced to 150 mL. The residue, after the addition of 10% aqueous KHS04 (100 mL) was further diluted with 100 mL of H20 prior to beginning to extract 3x with EtOAc. After drying over Na2SO4, the volatiles were removed using a rotary evaporator and the resulting oil in a minimum amount of EtOAc foamed under vacuum. The amount of EtOAc trapped in this material can be reduced by drying under vacuum. This crystalline opaque white solid was collected and further dried at 0.15 Torr at 25 ° C for 24 hr to provide 17.3 g of the desired C-arylglucoside containing 6.7 mol% EtOAc. HPLC retention time: 4.21 min, 98.8% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL / min, 220nM detection; 4 min. gradient 0-100% B retained 2 min to 100% B. Solvent A: 10% McOH / H20 + 0.2% H3PO4. Solvent B: 90% McOH / H20 + 0.2% H3PO4. XH NMR (500 MHz, CD3OD) d 7.34 (d, 1H, J = 8.2 Hz), 7.33 (d, 1H, J = 1.7 Hz), 7.27 (dd, 1H, J = 8.2 Hz, J = 1.7 Hz), 7.08 (partially superimposed AB quartet, 4H), 4.1-4.0 (m, 3H), 3.86 (d, 1H, J = 11.6 Hz), 3.68 (dd, 1H, J = 5.3, 10.6 Hz), 3.46-3.26 (m , 4H) Hz), 2.57 (q, 2H, J = 7 Hz), 1.19 (t, 3H, J = 7 Hz). 13 C NMR (125 MHz, CD 3 OD) d 143.2, 140.0, 139.7, 138.1, 134.5, 131.98, 130.1, 129.8, 128.8, 128.2, 82.8, 82.14, 79.7, 76.4, 71.9, 63.1, 39.7, 29.4, 16.25. MS [M + Na +] at m / z Theoretical 415.1288; Observed 415.1293. Analysis for C2iH25Cl05 »0.07 EtOAc» 0.19 H20 calculated C63.51, H 6.50, Cl 8.80; Found C 63.63, H 6.63, Cl 8.82. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (16)

1. CLAIMS Having described the invention as an antecedent, the content of the following claims is claimed as property: 1. Compound of the formula I characterized in that it is either a pharmaceutically acceptable salt, complex, stereoisomer, or prodrug ester thereof.
2. 2. Pharmaceutical composition characterized in that it comprises a compound of the formula I and a pharmaceutically acceptable carrier thereof.
3. A pharmaceutical combination characterized in that it comprises a compound of the formula I and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent .
4. 4. Pharmaceutical combination according to claim 3, characterized in that it comprises the compound of the formula I and at least one antidiabetic agent.
5. 5. A combination according to claim 4, characterized in that the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonylurea, a glucosidase inhibitor, a PPAR-gamma agonist, a PPAR alpha / gamma dual agonist , an aP2 inhibitor, a PDD4 inhibitor, an insulin sensitizer, a glucagon-like peptide-I (GLP-1), a PTP1B inhibitor, a phosphoryl glycogen inhibitor, a gluco-6-phosphatase inhibitor, insulin and a meglitinide .
6. 6. A combination according to claim 4, characterized in that the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimeiride, glipiride, glipizide, chloropropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, Insulin, isaglitazone, repaglinide, nateglinide, muraglitizar and danger.
7. Combination according to claim 4, characterized in that the compound of the formula I is present in a weight ratio for the antidiabetic agent in the range from about 0.01 to about 300: 1.
8. 8. A combination according to claim 3, characterized in that the anti-obesity agent is at least one agent selected from the group consisting of a beta-3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a beta-receptor drug thyroid, a 5HT2C agonist, an MCHR1 antagonist, a melanocortin receptor agonist, a melanin concentration hormone receptor antagonist, a galanin receptor modulator, an orexin antagonist, CCK agonists, NPY1 or NPY5 antagonists, a modulator of NPY2 and NPY4, a corticotropin releasing factor agonist, a histamine receptor-3 modulator (H3), an 11-beta-HSD-1 inhibitor, an adinopectin receptor modulator, a monoamine reuptake inhibitor, a ciliary neurotrophic factor, brain-derived neurotrophic factor, leptin or leptin receptor modulators, cannabinoid receptor antagonists 1 and an anorectic agent.
9. 9. A combination according to claim 8, characterized in that the anti-obesity agent is at least one agent selected from the group consisting of rimonabant, orlistat, sibutramine, topiramate, dexamfetamine, phentermine, phenylpropanolamine and mazindol.
10. 10. A combination according to claim 3, characterized in that the lipid reducing agent is at least one agent selected from the group consisting of an MTP inhibitor, a CETP inhibitor, a HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor and an ACAT inhibitor.
11. 11. Combination according to claim - Vl - 10, characterized in that the lipid reducing agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate and avasimibe.
12. 12. A combination according to claim 10, characterized in that the compound of the formula I is present in a weight ratio for the lipid reducing agent in the range from about 0.01 to about 300: 1.
13. 13. Use of a compound of formula I for the manufacture of a medicament for treating or slowing the progress or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, high blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis or hypertension, or by an increase in high density lipoprotein levels.
14. 14. Use according to claim 13, which comprises administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, an anti-atherosclerotic agent and a lipid reducing agent.
15. 15. Use of a compound of formula I, alone or in combination with at least one other therapeutic agent selected from the group consisting of an antidiabetic agent, an agent for the treatment of diabetes complications, an anti-obesity agent, an agent antihypertensive, an anti-platelet agent, an anti-atherosclerotic agent and a hypolipidemic agent for the manufacture of a medicament for the treatment of type II diabetes.
16. 16. Compound characterized because it has the structure