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13. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels, comprising administering a therapeutically effective amount of a compound of formula I
14. The method of
15. A method for treating type II diabetes comprising administering a therapeutically effective amount of a compound of formula I
alone or in combination with at least one other therapeutic agent selected from the group consisting of antidiabetic agent, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and a hypolipidemic agent.
This application claims the priority benefit of U.S. Provisional Application No. 60/612,599, filed Sep. 23, 2004, the disclosure of which is incorporated herein by reference in its entirety.
The present invention relates to C-aryl glucosides which are selective inhibitors of sodium dependent glucose transporters found in the kidney and to a method for treating diabetes or disorders by employing such C-aryl glucosides alone or in combination with one or more other type of therapeutic agent
Approximately 100 million people worldwide suffer from type II diabetes (NIDDM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes for which are as yet unknown. Consistent control of plasma glucose levels in diabetes patients may offset the development of diabetic complications and beta cell failure seen in advanced disease.
Plasma glucose is normally filtered in the kidney in the glomerulus and actively reabsorbed in the proximal tubule. Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early S1 segment of the renal cortical proximal tubule. SGLT2, a 672 amino acid protein containing 14 membrane-spanning segments that is predominantly expressed in the early S1 segment of the renal proximal tubules, is likely to be the major transporter responsible for this reuptake. The substrate specificity, sodium dependence, and localization of SGLT2 are consistent with the properties of the high capacity, low affinity, sodium-dependent glucose transporter previously characterized in human cortical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na+/glucose cotransporter in the S1 segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in mRNA from rat kidney cortex is inhibited by an antisense oligonucleotide specific to rat SGLT2. In humans, mutations in SGLT2 have been associated with familial forms of renal glucosuria, providing further evidence of the primary role of SGLT2 in renal glucose reabsorption. In such patients, renal morphology and renal function is otherwise normal. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced 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 more distal S3 segment of the renal proximal tubule. Despite their sequence similarities, human SGLT1 and SGLT2 are biochemically distinguishable.
Administration of phlorizin, a specific inhibitor of SGLT activity, provided proof of concept in vivo by promoting glucose excretion, lowering fasting and fed plasma glucose, and promoting glucose utilization without hypoglycemic side effects in several diabetic rodent models and in one canine diabetes model. No adverse effects on plasma ion balance, renal function or renal morphology have been observed as a consequence of phlorizin treatment for as long as two weeks. In addition, no hypoglycemic or other adverse effects have been observed when phlorizin is administered to normal animals, despite the presence of glycosuria. Administration of an inhibitor of renal SGLTs for a 6-month period (Tanabe Seiyaku) was reported to improve fasting and fed plasma glucose, improve insulin secretion and utilization in obese NIDDM rat models, and offset the development of nephropathy and neuropathy in the absence of hypoglycemic or renal side effects.
General inhibitors of SGLT 1 & 2 activity are unattractive therapeutically because inhibition of SGLT1 could also have serious adverse consequences as is illustrated by the hereditary syndrome glucose/galactose malabsorption (GGM), in which mutations in the SGLT1 cotransporter result in impaired glucose uptake in the intestine, and life-threatening diarrhea and dehydration. Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications, in the absence of significant gastrointestinal side effects.
Accordingly, the discovery of compounds that are selective to the SGLT2 transporter may demonstrate a utility for the treatment or prevention of diseases or disorders associated with control of plasma glucose levels, such as diabetes.
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 for a compound of formula I, pharmaceutical compositions employing such a compound and for 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, in accordance with the present invention, a method is provided for treating or delaying the progression 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.
Further, a method is provided for treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I and another type of antidiabetic agent and/or another type of therapeutic agent, such as a hypolipidemic agent, is administered to a human patient in need of treatment.
The following chart contains a matrix comparison of the compound of the invention (compound 1, column 4) to compounds of similar structure taking into consideration several characteristics relating to compound utility and commercial viability. The structures of compounds 1 (the compound of the invention) and 3-5, are illustrated below.
As illustrated in the chart above, only compound of formula I demonstrate favorable characteristics in all of the categories tested. That is, only compound of formula I demonstrate a favorable reduction of plasma glucose in diabetic rats (potency), stability in prototypic formulation (shelflife indication) and negative results in vitro clastogenic activity studies (reduced oncogenic potential).
I. Protocol for Study A: Determination of Blood Glucose Effect in Streptozotocin-Treated Diabetic Rats
The following analysis was utilized to reasonably predict the impact on plasma glucose for the compounds analyzed in the matrix above.
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 (4� C.) 0.01 M citrate buffer. Four days later, animals were bled in the fed state. Whole blood was collected via the tail tip and analyzed for glucose by the glucose oxidation method with a Glucometer Elite (Bayer). Mean blood glucose levels ranged from 450-550 mg/dl.
On the day of the experiment, the compound was dissolved in the vehicle comprised of 5% m-Pyrol, 20% PEG 400 and 20 mM Sodium Diphosphate. Rats were weighed, randomized 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 gavage was 1 ml/kg body weight. After dosing, the food was removed from the cages and the rats had access to water ad lib during the experiment. Blood samples were obtained from the tail tip at 0, 30, 60, 120, 180, 240 and 300 minutes following drug administration. Blood glucose was analyzed by the glucose oxidation method with a Glucometer Elite (Bayer).
A. Statistical Data Analysis
The calculation of mean blood glucose values and percent changes vs. vehicle at each time point were performed using Microsoft Excel. Statistical analyses (T tests, or ANOVA followed by Fisher's test) comparing drug-treated groups vs. vehicle controls) were performed using Microsoft Excel or the statistical program StatView. A p value of less that 0.05 was considered to be statistically significant.
II. Protocol for Study B: Stability Determination of Oxidatively Labile Therapeutic Agent in Presence of Commonly Used Solid Excipients, Under Accelerated Aging Conditions
The following procedure was utilized to access the chemical stability of the compound 3 in the presence of commonly used excipients and typical antioxidants.
The drug substance was triturated in a mortar pestle 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 at two levels, 0.01% w/w and 0.5% w/w, and sodium metabisulfite was used at 0.01% w/w. For samples stored at 40� C./73% RH and HIL/uv, oxygen gas was purged into the vials and they were tightly capped. The drug-excipient blends (A-D) were placed under the different accelerated aging conditions listed within the second table for 1 and 3 weeks prior to HPLC analysis. Compounds that did not have any apparent oxidative instability issues (compounds 1, 4 and 5) were found to be chemically stable in the presence of excipients that are commonly used in solid dosage forms.
Early identification of potential therapeutic agents that could be oncogenic in man is highly desirable. In vitro clastogenicity studies provide one early indication of the potential carcengenicity of a compound1. The following protocol was utilized to predict the in vitro clastogenicity activity of compounds of therapeutic interest.
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 is significantly elevated beyond the background level, this is evidence that compound has clastogenic potential. The detection of a significantly elevated level of chromosome damage in this assay is considered an indicator of genetic damage.
A. Test Article Carrier and Control Articles
The vehicle control is dimethyl sulfoxide (DMSO). The positive controls were Mitomycin C for the 3-hr and 20-hr exposure without S9 activation and cyclophosphamide for the 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 Concentration Selection
Two stock solutions in DMSO of the compound of interest were prepared—one being a high concentration, the other low. Aliquots of the vehicle control, low and high dosing solutions were collected following treatment of the CHO cells and subsequently analyzed to determine the concentration of the compound of interest. The concentrations selected were based on the results of a non-GLP solubility/miscibility/range-finding cytotoxicity (ATP) assay with the compound of interest. Once the upper limit of solubility of the compound of interest was determined in DMSO, that DMSO solution is added to culture medium to determine effects on pH or osmmolality. Eleven concentrations of the compound of interest were tested in the range-finding cytotoxicity assay both in the presence (3 hr) and absence (20 hr) of rat-liver (S9) enzymes. The highest concentration tested was 10 mM, 5000 μg/ml, or the limits of solubility. Based on the solubility/miscibility/range-finding cytotoxicity (ATP) assay results, six concentrations were selected for testing in the full cytogenetics study.
Test Article Concentrations
The DMSO stock solution of the compound of interest was 100� concentration of the highest test-article concentration to be used in the full assay. Six concentrations are tested. The cytotoxicity dose response observed in the range finding study determined the serial dilution factor for the five lower doses. A total dosing volume of 50 μl (stock solution plus DMSO) is added 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. Cells used in this assay (CHO-WBL) were originally obtained from the laboratory of Dr. S. Wolff, University of California, San Francisco. The cells have since 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. The cells are routinely monitored for karyotype stability and potential mycoplasma contamination.
E. Identification
All culture flasks and/or tubes used in the study were labeled numerically. Centrifuge tubes for cell harvest, hypotonic treatment, and fixation were labeled with the identical number as the corresponding flask. Additionally, microscope slides prepared from the fixed cells bared the same number as the centrifuge tube. Microscope slides were coded by an independent observer for an unbiased-cytogenetic analysis for chromosome aberrations. Permanent labels were affixed to the coded slides.
F. Experimental Methodology
The chromosome aberration assay was conducted using standard procedures2-6 by exposing cultures of CHO cells to a minimum of four concentrations of the test article as well as to the positive and vehicle controls. In the non-activated test system, treatment was for approximately 3 hr and for 20 hr and in the S9 activated test system, exposure was for 3 hr.7, 8
S9 Metabolic Activation
The exogenous metabolic-activation (S9) system consisted of an Aroclor 1254-induced rat-liver S9 (post-mitochondrial) fraction, as well as salts and cofactors. The final concentration of S9, salts, and cofactors in exogenous metabolic-activation (S9) system was 10 μl/ml (1% v/v) Aroclor 1254-induced rat-liver S9 (post-mitochondrial) fraction, 2.5 mM MgCl2.6H2O, 1.25 mM glucose-6-phosphate, 10.3 mM KCl, 1 mM NADP, and 12.8 mM Na2HPO4
Preparation of Target Cells
Exponentially growing CHO-WBL cells were seeded in McCoy's 5A medium supplemented with 10% fetal-bovine serum, L-glutamine (2 mM), penicillin G (100 units/ml), and streptomycin (100 g/ml) at approximately 0.5�106 cells/25 cm2 flask. The flasks were incubated at approximately 37� C. in a humidified atmosphere of approximately 5% CO2 in air for 16-24 hr.
Treatment of Target Cells
On the day after culture initiation, the culture medium was replaced with fresh medium. For the 3- and 20-hr exposures without metabolic activation, the dosing is done in the complete medium described above. For the 3-hr exposures, in the presence of S9 metabolic activation, the medium is identical to that as described above, except that it lacks the fetal-bovine serum and contains the S9, salts and cofactors. After the 3-hr treatment with and without metabolic activation, medium was aspirated, the cells rinsed with phosphate buffer saline, refed with complete medium and returned to the incubator.
Collection of Metaphase Cells
A single harvest time of approximately 20 hr from the initial treatment was used. This harvest time corresponds to approximately 1.5 times a cell cycle of approximately 13 hr.8 Colcemid� will be added to the cultures at a final concentration of 0.1 μg/ml, 2-3 hr prior to cell harvest.
Cells were harvested by trypsinization, collected by centrifugation and an aliquot was removed to determine the cell counts and percent viable cells. The cell count and percent viability was used to determine cell growth inhibition relative to the vehicle control (cytotoxicity). The remainder of the cells were swollen with 0.075 M KCl, washed with three consecutive changes of fixative (methanol:glacial acetic acid, 3:1 v/v), capped and stored overnight or longer at approximately 2-8� C. To prepare slides, the cells were collected by centrifugation and resuspended in fresh fixative. The suspension of fixed cells were applied to glass microscope slides and air-dried. The slides were stained with Giemsa and permanently mounted.
G. Chromosome Aberration Analysis
Based on the observed cytotoxicity, a minimum of three concentrations was selected for chromosome aberration analysis. Generally, concentrations that reduce the cell count or mitotic index by >50% were not evaluated for chromosome aberrations, since there is evidence that excessive cytotoxicity can induce chromosome aberrations that are unrelated to a direct clastogenic effect of the test article.9, 10 A minimum of 500 cells from each slide and two slides per flask was evaluated for the frequency of cells in mitosis (mitotic index) and a minimum of 100 mitotic cells were evaluated for the frequency of numerical aberrations (polyploidy and endoreduplication). From each duplicate flask, 50 metaphases from separate slides were scored for structural chromosome aberrations by two independent evaluations. Only metaphases containing 21�2 chromosomes were evaluated. The two independent evaluations were combined to yield 100 metaphases per flask and 200 metaphases per concentration for structural chromosome aberrations. Applicants noted If these numbers were not attainable due to cytotoxicity or ≧50% aberrant metaphases observed in the first 25 metaphases/slide.
H. Statistical Data Analysis
The number and types of aberrations found, the percentage of structurally damaged cells (percent aberrant cells) in the total population of cells examined, and the mean aberrations per cell were calculated and reported for each treatment group. Chromatid and isochromatid gaps were presented in the data but are not included in the total percentage of cells with one or more aberrations or in the frequency of structural aberrations per cell. Statistical analysis of the frequency of aberrant cells (structural or numerical) was performed using the Fisher's exact test. The Fisher's test was used to compare pairwise the frequency of aberrant cells of each treatment group with that of the solvent control. In the event of a positive Fisher's exact test at any test article dose level, the Cochran-Armitage test was used to measure dose-responsiveness. As a guide to 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 dose-responsive manner with one or more concentrations being statistically significant (p≦0.05). However, values that were statistically significant but do not exceed the range of historic negative or vehicle controls may be judged as not biologically significant. Test articles not demonstrating a statistically significant increase in aberrations were concluded to be negative.
I. Criteria for an Acceptable Assay
The full chromosome aberration assay was deemed acceptable if the following criteria were met:
J. Criteria for a Positive Response
The response to the test article was deemed positive if the following criteria are met:
The following abbreviations are employed herein:
Et2O=diethyl ether
EtOAc=ethyl acetate
DMF=dimethyl formamide
h or hr=hour(s)
sat or sat'd=saturated
TLC=thin layer chromatography
NMR=nuclear magnetic resonance
HPLC=high performance liquid chromatography
LC/MS=high performance liquid chromatography/mass spectrometry
MS or Mass Spec=mass spectrometry
Listed below are definitions of various terms used in the description of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
Any compound that can be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives are described in:
a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);
b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and
c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991). Said 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 to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
The compound of formula I of the invention can be prepared as shown in the following reaction Scheme 1 and description thereof, as well as relevant published literature procedures that may readily be used by one skilled in the art, without undue experimentation, to prepare the compounds described and claimed herein. Exemplary reagents and procedures for these reactions appear hereinafter in the working Example.
Compound of formula I can be prepared as shown in Scheme 1 by treatment of compound of formula II
Compound of formula II provides a convenient means to purify crude compound of formula Ia which was obtained as a mixture of alpha and beta anomers. Compound of formula II can be prepared by treatment of compound of formula Ia with Ac2O in a solvent such as CH2Cl2 containing pyridine and a catalyst such as dimethylaminopyridine (DMAP).
Compound of formula Ia can be prepared by reduction of a compound of 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.Et2O.
Compound of formula II can alternatively be prepared from compound of formula III by first acetylating compound of formula III with Ac2O in a solvent such toluene or CH2Cl2 containing a base such as Hunig's base or Et3N and a catalyst such as DMAP to generate compound of formula IV.
Subsequent conversion of compound of formula IV to compound of formula II can be achieved by treatment at 20� treatment with a reducing agent such as Et3SiH in a solvent such as MeCN containing 1 equiv of H2O and a Lewis acid catalyst such as BF3.Et2O.
Compound of formula III can be prepared, as outlined in Scheme 2 above, by addition of a cold THF solution of an aryl lithium of formula V to a persilylated gluconolactone of formula VI in a solvent such as toluene at −75�. Subsequently, a methanol solution of a protic acid such methanesulfonic acid (MSA) was added after 30 min and the solution stirred at 20� until transformation of the intermediary lactol to III was complete.
Compound of formula VI can be prepared by treatment of commercially available D-gluconolactone with a silylating agent such as trimethylsilyl chloride in a solvent, such as THF, containing a base such as N-methylmorpholine.
Compound of formula V can be prepared by treatment of compound of formula VII with an alkyl lithium, such as n-BuLi or t-BuLi, in a solvent such as THF at −75�.
Compound of formula VII can be readily prepared by treatment of 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.Et2O or CF3SO3H.
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 an equivalent of a Lewis Acid, such as AlCl3 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 CH2Cl2, containing a catalytic amount of DMF.
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 may 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, treating or delaying the progression or onset of diabetes (including Type I and Type II, impaired glucose tolerance, insulin resistance, and diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis and hypertension. The compound of the present invention may also be utilized to increase the blood levels of high density lipoprotein (HDL).
In addition, the conditions, diseases, and maladies collectively referenced to as "Syndrome X" or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may be treated employing 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 utilized as an individual treatment, or utilized in combination with one or more other therapeutic agent(s).
Other "therapeutic agent(s)" 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 aforementioned disorders including: anti-diabetic agents; anti-hyperglycemic agents; hypolipidemic/lipid lowering agents; anti-obesity agents; anti-hypertensive agents and appetite suppressants.
Examples of suitable anti-diabetic agents for use in combination with the compound of the present invention include biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance�), thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1) or other agonists of the GLP-1 receptor, and dipeptidyl peptidase IV (DPP4) inhibitors.
It is believed that the use of the compound of formula I in combination with at least one or more other antidiabetic agent(s) provides antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.
Other suitable thiazolidinediones include Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome's GL-262570, 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 PPAR alpha/gamma dual agonists include muraglitizar, peliglitazar, AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), GW-501516 (Glaxo-Wellcome), KRP297 (Kyorin Merck) as well as those disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha (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. Pat. No. 6,653,314, the disclosure of which is incorporated herein by reference, employing dosages as set out therein, which compounds designated as preferred are preferred for use herein.
Suitable aP2 inhibitors include those disclosed in U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S. application Ser. No. 09/519,079, filed Mar. 6, 2000, employing dosages as set out herein.
Suitable DPP4 inhibitors include those disclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine) (Novartis) as disclosed by Hughes et al, Biochemistry, 38(36), 11597-11603, 1999, TSL-225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosed by Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540), 2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth et al, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and 2745-2748 (1996), the compounds disclosed in U.S. application Ser. No. 10/899,641, WO 01/868603 and U.S. Pat. No. 6,395,767, employing dosages as set out in the above references.
Other suitable meglitinides include nateglinide (Novartis) or KAD1229 (PF/Kissei).
Examples of suitable anti-hyperglycemic agents for use in combination with the compound of the present invention include glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492), as well as exenatide (Amylin/Lilly), LY-315902 (Lilly), MK-0431 (Merck), liraglutide (NovoNordisk), ZP-10 (Zealand Pharmaceuticals A/S), CJC-1131 (Conjuchem Inc), and the compounds disclosed in WO 03/033671.
Examples of suitable hypolipidemic/lipid lowering agents 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, ileal Na+/bile acid co-transporter inhibitors, up-regulators of LDL receptor activity, 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/or nicotinic acid and derivatives thereof.
MTP inhibitors which may be employed as described above include those disclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat. No. 5,885,983 and U.S. Pat. No. 5,962,440.
The HMG CoA reductase inhibitors which may be employed in combination with one or more compound of formula I include mevastatin and related compounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds, as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds, such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds, as disclosed in U.S. Pat. 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, disclosed in U.S. Pat. No. 5,354,772, cerivastatin, as disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin, as disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), as disclosed in U.S. Pat. No. 5,011,930, visastatin (Shionogi-Astra/Zeneca (ZD-4522)), as disclosed in U.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives, as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives, as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone, as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No. 0142146 A2, and quinoline and pyridine derivatives, as disclosed in U.S. Pat. Nos. 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 inhibiting HMG CoA reductase, such as those disclosed in GB 2205837, are suitable 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, α-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinyl-methyl)phosphonates, as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
In addition, other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed 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., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
The fibric acid derivatives which may be employed in combination the compound of formula I include fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds, as disclosed in U.S. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex�, Policexide�), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (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), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.
The ACAT inhibitor which may be employed in combination the compound of formula I include those disclosed in Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-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 ApoB100-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 animals", Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; "Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N′-[(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 may be an up-regulator 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-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
Examples of suitable ileal Na+/bile acid co-transporter inhibitors for use in combination with the compound of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999).
The lipoxygenase inhibitors which may be employed in combination the compound of formula I include 15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed by Sendobry et al "Attenuation of diet-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 anti-hypertensive agents for use in combination with the compound of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetamide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
Examples of suitable anti-obesity agents for use in combination with the compound of the present invention include a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta drug, 5HT2C agonists, (such as Arena APD-356); MCHR1 antagonists such as Synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists (such as Synaptic SNAP-7941 and Takeda T-226926), galanin receptor modulators, orexin antagonists, CCK agonists, NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, 11-beta-HSD-1 inhibitors, adinopectin receptor modulators, monoamine reuptake inhibitors or releasing agents, a ciliary neurotrophic factor (CNTF, such as AXOKINE� by Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, cannabinoid-1 receptor antagonists (such as SR-141716 (Sanofi) or SLV-319 (Solvay)), and/or an anorectic agent.
The beta 3 adrenergic agonists which may be optionally employed in combination with compound of the present invention include AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists, as disclosed in U.S. Pat. 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 compound of the present invention include orlistat or ATL-962 (Alizyme).
The serotonin (and dopoamine) reuptake inhibitor (or serotonin receptor agonists) which may be optionally employed in combination with a compound of the present invention may be BVT-933 (Biovitrum), sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron).
Examples of thyroid receptor beta compounds which may be optionally employed in combination with the compound of the present invention include thyroid receptor ligands, such as those disclosed in WO97/21993 (U. Cal SF), WO99/00353 (KaroBio) and GB98/284425 (KaroBio).
The monoamine reuptake inhibitors which may be optionally employed in combination with compound of the present invention include fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol.
The anorectic agent which may be optionally employed in combination with the compound of the present invention include topiramate (Johnson & Johnson), dexamphetamine, phentermine, phenylpropanolamine or mazindol.
The aforementioned patents and patent applications are incorporated herein by reference.
The above other therapeutic agents, when employed in combination with the compound of the present invention may be used, for example, in those amounts indicated in the Physician's Desk Reference, as in the patents set out above or as otherwise determined by one of ordinary skill in the art.
Where the compound of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred:
Where the other antidiabetic agent is a biguanide, the compound of formula I will be employed in a weight ratio to biguanide within the range 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 to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
The compound of 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 from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.
Where present, the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
Optionally, the sulfonyl urea and thiazolidinedione may be incorporated in a single tablet with the compound of formula I in amounts of less than about 150 mg.
Where present, metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.
Where present GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. No. 5,346,701 (TheraTech), U.S. Pat. Nos. 5,614,492 and 5,631,224 which are incorporated herein by reference.
The SGLT2 inhibitor of formula I will be employed in a weight ratio to the meglitinide, PPAR-gamma agonist, PPAR-alpha/gamma dual agonist, aP2 inhibitor or DPP4 inhibitor within 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 of the invention will be generally be employed in a weight ratio to the hypolipidemic agent (were present), within the range from about 500:1 to about 1:500, preferably from about 100:1 to about 1:100.
For oral administration, a satisfactory result may be obtained 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 to 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 250 mg, one to four times daily.
For oral administration, a satisfactory result may be obtained employing an HMG CoA reductase inhibitor in an amount within 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 the 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 to about 40 mg.
The squalene synthetase inhibitor may be employed in dosages 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 the 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 suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; 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, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
In carrying out a preferred method of the invention for treating any of the diseases disclosed herein, such as diabetes and related diseases, a pharmaceutical composition will be employed containing one or more of the compound of formula I, with or without other antidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or other type therapeutic agents in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired 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. Typical 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 from 1-4 times per day.
A typical injectable preparation may be produced by aseptically placing 250 mg of compound of formula I into a vial, aseptically freeze-drying 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 dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
SGLT2 inhibitor activity of the compound of the invention may be determined by use of an assay system as set out below.
Assay for SGLT2 Activity
The mRNA sequence for human SGLT2 (GenBank #M95549) was cloned by reverse-transcription and amplification from human kidney mRNA, using standard molecular biology techniques. The cDNA sequence was stably transfected into CHO cells, and clones were assayed for SGLT2 activity essentially as described in Ryan et al. (1994). 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 were cultured in Ham's F-12 medium containing 10% fetal bovine serum and 500 μg/ml geneticin. Cells at approximately 90% confluence were assayed 2 or 3 days after plating. Cells were washed once with buffer lacking sodium, which contained 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 assayed in the presence of 10 μM [14C] AMG (α-methyl-D-glucopyranoside) at 8 concentrations over a 120-minute incubation in protein-free buffer containing 10 mM Hepes/Tris, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, and 1.2 mM MgSO4, pH 7.4. The response curve was fitted to an empirical four-parameter model to determine the inhibitor concentration at half-maximal response, reported as the IC50. Three replicates were performed per determination. Assays were quenched by washing 3 times in ice cold 1� phosphate buffered saline (PBS) containing 0.5 mM phlorizin, and cells were then lysed in 50 μl 0.1% NaOH. After addition of 200 μl MicroScint-40 scintillation fluid, the cells were allowed to shake for 1 hour, and then [14C]AMG was quantified on a TopCount scintillation counter. Control assays in the absence of inhibitor were performed with and without NaCl and a dose response curve for phlorizin was generated in every assay as a positive control.
Ryan M J, Johnson G, Kirk J, Fuerstenberg S M, Zager R A 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, embodiments of the present invention.
To a 2 L round bottom flask containing a magnetic stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (410 g, 1.74 mol) in 700 mL of CH2Cl2 was added oxalyl chloride (235 g, 1.85 mol) followed by 1.5 mL of DMF. To trap the resultant HCl, the flask was fitted with tubing so that the gas was discharged above the surface of a stirred aq KOH solution. When the vigorous evolution of gas ceased after two hours, the homogeneous reaction was stirred overnight prior to removal of the volatiles under vacuum using a rotary evaporator. The resultant 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. prior to adding AlCl3 (257 g, 1.93 mol) in ˜30 g portions over 60 min to insure that the temperature did not exceed 10� C. The copious amounts of HCl gas which began to evolve after 60% of the AlCl3 had been added were trapped by passing the gas over a stirred conc. NaOH solution. If the reaction were more concentrated, a magnetic stirrer could not have maintained stirring upon completion of the addition of AlCl3. After stirring for 1 hr as the bath warmed to ˜15� C., the bath was removed. After 4 hr at 20� C., the thick syrup was poured over ice (1.5 kg). Subsequently, once the stirred suspension had cooled, H2O (1 L) was added prior to being extracted 4� with EtOAc. The combined organic extracts were washed 2� with 1N HCl, 3� with 1M KOH, and 2� with brine prior to drying over Na2SO4. The volatiles were removed using first a rotary evaporator and then by heating at ˜60� C. at 1 Torr. 1H NMR analysis of the resultant dark oil revealed the residue to be a 1:14 mixture of ortho/para isomers. Dissolution in hexane and followed by filtration through a silica gel pad removed most of the color. Concentration of the eluent yielded 560 g (99%) of a 14:1 mixture of 5-bromo-2-chloro-4′-ethylbenzophenone/5-bromo-2-chloro-2′-ethylbenzophenone.
HPLC retention time: 4.7 min, YMC S5 C-18 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
1H NMR (400 MHz, CDCl3) δ 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, CDCl3) δ 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.
1H NMR (400 MHz, CDCl3) δ 2.64 (q, 2H, J=7.7 Hz), 1.23 (t, 3H, J=7.7 Hz).
13C NMR (100 MHz, CDCl3) δ 28.9, 15.5.
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 CF3SO3H (1.5 g, 0.01 mol). Within minutes the temperature increased causing the solution to reflux violently. Caution this moderate exotherm requires cooling with an external ice bath. After 1 hr, HPLC revealed the reaction to be 90% complete. After addition of an additional Et3SiH (20 g) and heating overnight at 70� C., the reaction was >95% complete by HPLC analysis. Upon cooling, the volatiles were removed by bulb to bulb distillation at reduced pressure. The resultant ˜1 L of light gray oil was poured into 1 L of H2O. The mixture was extracted 3� with hexane; the combined organic layers were washed 3� with H2O, 2� with aq Na2CO3 and 2� with brine before drying over Na2SO4. After concentration using a rotary evaporator, ˜1 L of clear light amber oil remained. This material was further concentrated; the (Et3Si)2O (450 mL) was removed by distillation at 0.6 Torr. Once the temperature at the distillation head reached 75� C., the pot was allowed to cool. 1H NMR analysis of the pot revealed it to contain an ˜8:1 mixture of diarylmethane to (Et3Si)2O. Crystallization of this mixture was achieved by pouring the product into vigorously stirred 10� C. 85% EtOH/H2O (1.2 L), After stirring for several hours, the crystals were collected by filtration, washed with cold 1:1 EtOH/H2O and dried under vacuum. The 5-bromo-2-chloro-4′-ethyldiphenyl-methane (500 g), obtained as a low melting solid containing ˜1% (Et3Si)2O, was used without further purification.
HPLC retention time: 5.3 min, YMC S5 C-18 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
1H NMR (125 MHz, CDCl3) δ 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).
13C NMR (100 MHz, CDCl3) δ 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.
To a stirred −5� C. solution of gluconolactone (239 g, 1.34 mol) and N-methylmorpholine (1180 mL, 10.73 mol) in 2.4 L of THF under Ar was added trimethylsilyl chloride (1022 mL, 8.05 mol) via dropping funnel at a rate such that the temperature did not exceed 5� C. After 1 hr the stirred reaction was heated to 35� C. for 5 hr whereupon it was allowed to cool to 20� C. as the reaction stirred overnight. After dilution with 3.6 L of toluene, the mixture was cooled to 0-5� C. prior to cautiously adding 7 L of H2O at a rate such that the temperature did not exceed 10� C. Note a severe exotherm results upon addition of the first portion of H2O. After mixing, the phases were allowed to separate and then split. The organic phase was washed with aq. NaH2PO4 (2 L), H2O (1 L), and brine (1 L). The organic layer was then concentrated under vacuum using a rotary evaporator; the resultant light yellow oil was twice taken up 250 mL of toluene and reconcentrated to yield 616 g.
To a stirred −780 solution of Part B 5-bromo-2-chloro-4′-ethyldiphenylmethane (88 g, 0.28 mol) in 450 mL of 1:2 dry THF/toluene under Ar was slowly added 2.5 M n-BuLi (136 mL, 0.34 mol) in hexane at a rate that maintained the temperature below −55�. After stirring for 10 minutes following the addition, this solution was transferred by cannula to a stirred −78� solution 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 maintained the reaction below −55�. The solution was stirred for 30 min at −78� prior to quenching by addition of 400 mL of MeOH 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. HPLC analysis revealed a new peak which by LC/MS correspond to the mass of the expected O-methylglucoside. The reaction, once complete, was quenched by the addition of NaHCO3 (42 g, 0.5 mol) in 200 mL of H2O. If the pH was not weakly basic, more NaHCO3 was added prior to dilution 2 fold with H2O and 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over Na2SO4. After concentration using a rotary evaporator, the oil (140 g, 90% pure by HPLC analysis) was not further purified but instead was carried forward as an impure diastereomeric mixture.
1H NMR (400 MHz, CDCl3) δ 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).
13C NMR (100 MHz, CDCl3) δ 144.4, 140.7, 138.94, 136.9, 132.51, 131.6, 130.96, 130.6, 130.2, 129.16, 103.36, 77.0, 74.86, 72.48, 64.27, 51.57, 41.33, 30.75, 17.9.
HPLC retention time: 4.28 min, 90% pure, YMC S5 C-18 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
LC/MS: [M-OMe]+391, 393; [M+Na]+445, 447.
A solution of Part D 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 such a rate that the temperature did not exceed 5� C. After the solution gradually warmed to 20� C., it was stirred for 10 hours whereupon tlc analysis revealed complete conversion to the tetraacetate. The reaction was quenched by addition of EtOAc (1.5 L) and 10% aq. H3PO4 (1.5 L). After separation of the layers, the aq. phase was extracted 2� with EtOAc. The combined organic phases were washed 1� with brine prior to drying over Na2SO4 and concentration under vacuum. The resultant oil was dissolved twice in 300 mL of toluene and reconcentrated to yield a thick oil (300 g, 95% HPLC purity) that was used without further purification of the resulting impure diastereomeric mixture.
1H NMR (400 MHz, CDCl3) δ 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), 1.72 sd (s, 3H), 1.21 (t, 3H, J=7.7 Hz).
13C NMR (100 MHz, CDCl3) δ 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 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
A stirred solution of the above crude oil (301 g, 0.51 mol) in CH2Cl2 (500 mL) containing one equivalent of H2O (9 g, 0.5 mol) and Et3SiH (188 g, 1.62 mol) was cooled to −20� C. prior to addition of BF3.Et2O (145 g, 1.02 mol). During the addition, the temperature was maintained <0� C. The reaction was subsequently stirred 2 hr at 10� C. and 18 hr at 15-20� C. before being quenched by addition of CH2Cl2 (500 mL) and H2O (500 mL). After separation of the layers, the aq phase was extracted once with CH2Cl2. The combined organic layers were washed 1� with aq NaHCO3 and brine prior to drying over Na2SO4. After removal of the Na2SO4 by filtration, Ac2O (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 insure that any glucoside hydroxyls that hydrolyzed during the reduction and work-up were reacetylated. The oil, obtained after concentration under vacuum, crystallized upon addition of EtOH. After filtration the purity of this material by HPLC was 98%; recrystallization from EtOH yielded the tetraacetylated beta-C-glucoside as a white solid (180 g, 99.8% purity. The overall conversion for procedures D-F was 61%.
HPLC retention time: 4.74 min, 100% pure, YMC S5 C-18 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
1H NMR (500 MHz, CDCl3) δ 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, CDCl3) δ 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+NH4 +] at m/z 578.3
To the white suspension formed by stirring the tetraacetylated beta-C-glucoside of Part F (25 g, 44.6 mmol) for 5 min in 2:3 THF/MeOH (350 mL) under N2 at 20� C. was added LiOH.H2O (2.0 g, 50 mmol) in H2O (70 mL). After 15 min, the reaction was an opaque solution; after 2.5 hr, by HPLC analysis the reaction was 98% complete. The conversion increased to 99% after stirring overnight whereupon the volatiles were removed using a rotary evaporator such that the volume was reduced to 150 mL. The residue, after addition of 10% aq KHSO4 (100 mL) was further diluted with 100 mL of H2O prior to being extracted 3� with EtOAc. After drying over Na2SO4, the volatiles were removed using a rotary evaporator and the resultant oil in the minimum amount of EtOAc foamed under vacuum. The amount of EtOAc trapped in this material can be reduced by drying under vacuum. This glassy off white solid was scraped out and further dried at 0.15 Torr at 25� C. for 24 hr to yield 17.3 g of desired C-arylglucoside containing 6.7 mol % of EtOAc.
HPLC retention time: 4.21 min, 98.8% pure, YMC S5 C-18 4.6�50 mm column, 2.5 mL/min, detection at 220 nM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H2O+0.2% H3PO4. Solvent B: 90% MeOH/H2O+0.2% H3PO4.
1H NMR (500 MHz, CD3OD) δ 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).
13C NMR (125 MHz, CD3OD) δ 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
Anal for C21H25ClO5.0.07 EtOAc.0.19H2O Calcd C, 63.51; H, 6.50; Cl, 8.80. Found C, 63.63; H, 6.63; Cl, 8.82.
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text:
Allowing Pop-ups in Mozilla/Firefox
If Firefox blocks a popup for you, you will notice a bar much like this
By clicking on the popup bar in Firefox you will see a drop down box. Here you will have the option to allow popup's from mymtech.
Allowing popup's from Montana Tech webpages will help run Blackboard features.

subset: commoncrawl


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[Guest blog post by Kuo-Yu slayer Chuang from Tawain's Industrial Technology Research Institute, ITRI.]
I'm Kuo-Yu slayer Chuang from ITRI, a government funded research institute in Taiwan. We developed an open standard for exchanging location information via SMS among mobile devices called Open GeoSMS, which has currently been adapted officially by Open Geospatial Consortium (OGC). Several use cases of this standard are shown with the following video:
We introduce Open GeoSMS with a quick and real example. Noritsuna-san is a friend of mine from Japan and a guest researcher in our company. One night, I got an SMS from him saying that he can't get taxi home since it's too late. I had no idea where he was and he could not read the street names in Chinese. I thus asked him to send me an Open GeoSMS with our free application. I then got an Open GeoSMS with the coordinate embedded in URL that points to Google Map service. At the end I totally new where he was and drove my little car to rescue him.
In the previous case, Open GeoSMS sent as a peer to peer message between mobile phones. It can be also used between mobile and server in disaster management. Users who have smart phone with GPS for incident report can attach coordinate in SMS with Open GeoSMS format (usually, with an App such as Ushahidi app on Android that we hacked).
This feature enables users to do incident reporting without a data connection. We know some volunteers bring their own smart phones and work with expensive data roaming fee. This feature also enables the backend server to auto-process the geo-tagged report, and insert this POI to map automatically. Rescuing activity or the resource transportation tasks can be assigned with Open GeoSMS for more specific location information. Especially with the offline map supported such as Open Street Map, POI-based information exchange can be easily achieved through Open GeoSMS.
As for the notification, the server doesn't need to care if the receiver is a smart phone user or not. Open GeoSMS notification is just an SMS and that works for almost every phone. On a smart phone, Open GeoSMS can bring out more information via URL. The latest spec and code are available on Google Code. If the SMS with coordinate is compliant to Open GeoSMS, other applications or services can easily parse it and get the x and y coordinates. Last month during a cyclone simulation of Samoa, PinPointAlerts provided Open GeoSMS as a notification option on http://www.SamoAlert.com so the simulation notification could be sent with this open standard. Our team also shipped five smart phones to Samoa with an Open GeoSMS enabled Ushahidi app installed or this Cyclone Simulation activity. As a result, not only could the general SMS-based incident reports be made, but also the Open GeoSMS style geo-tagged SMS could be sent to server for the possible automation afterwards.
Our team has hacked an Open GeoSMS enabled Ushahidi Android App, now we are working with Ushahidi mobile app team on additional projects to merge our technologies. Our next step is to implement a plug-in for Ushahidi to parse Open GeoSMS in order to gain the automated processing ability. Further objectives include working with offline maps such as Open Street Map (OSM) so users can have a better understanding re incoming Open GeoSMS. For more information and our latest activities, please visit our facebook page.
We really hope this tiny handy open standard can help people in various way :-)


text:
The College of Osteopathic Medicine offers a 36-credit Master of Science in Medical / Health Care Simulation program.
This New York State approved graduate program has been preparing professionals for careers in the growing field of human patient simulation education since 2012. Patient simulation educators use Standardized Patients, mannequin-based simulations, and computer-based simulations to ensure patient safety in clinical settings, teach and assess professional skills at medical and nursing schools, hospitals, and medical licensing boards, and manage patient simulation programs.
Graduates of the program will be prepared to:
- Manage and direct patient simulation centers and patient safety programs
- Develop simulation education courses and curricula
- Develop programs designed to assure quality in clinical settings
- Conduct and collaborate in innovative educational research.
Program highlights include:
- Hybrid online courses offering weekly virtual synchronous contact with faculty
- Self-directed learning projects
- Hands-on course week long residential workshop courses to prepare learners to work with standardized / simulated patients and mannequin-based simulators
- Faculty advisors who are national experts in the human patient simulation field.
Foundation Courses*
MSME 651 Health Care Simulation and Adult Learning
MSME 652 Teaching and Assessing Communication Skills
MSME 653 Standardized Patient Education
MSME 654 Educational Measurement
MSME 655 Patient Simulators and Simulation Education
MSME 656 Methodological Issues and Strategies in Simulation Research
MSME 657 Patient Safety Issues and Patient Simulations
Residential Workshop Courses
MSME 751 Standardized Patient Education Workshop
MSME 757 Mannequin-Based Simulation Workshop
Professional Development Courses*
MSME 752 Leadership and Management
MSME 658 Thesis Advisement
MSME 760 Practicum with Presentation and Defense of Thesis
* Online courses with synchronous contact with faculty
Complete the NYIT on-line application: nyit.edu/application
College of Osteopathic Medicine alumni are invited to apply to the program free of charge by visiting http://nyit.edu/application and using fee waiver code MHSFA14.
For more information about this program, please contact:
Anthony Errichetti, Ph.D.
Chief of Virtual Medicine
Professor, Department of Medical Education Director, Institute For Clinical Competence and MS in Medical / Health Care Simulation Program


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Leadership roles in business and other organizations require carefully developed skills.
As part of Bethany College's Business Department, you will have the opportunity to develop intellectual and practical skills that will serve you well throughout your lifetime and provide a basis for building a successful career.
We believe in active learning. By combining classes, experience, interaction and participation, we help you internalize what you are learning. Our goal is to help you apply your knowledge and skills to business situations and carry these methods and processes into your career.
Bethany's faculty is committed to your success. Our average student-faculty ratio is 13:1, which allows us time to get to know you and become partners with you in your education.
As a Bethany business student, you will have many opportunities to participate in leadership activities such as:
Experienced-Based Education
We help you learn and gain crucial experience while you earn credit through internships. You will gain important skills, make professional contacts and add to you resume.
Business Career Conference
The Business Career Conference is held biennially and gives Bethany students the opportunity to learn from and interact with successful Bethany alumni.
Distinguished Lectureship Series
The Mauney Lecture Series brings distinguished scholars and business leaders who give their perspectives on current topics through public lectures, classroom presentations, discussions and one-on-one conversations with students.
Directed Independent Studies
Students have the opportunity to work with faculty to design interesting and practical courses that give students skills and knowledge in particular areas.
Business Club
An important part of your business studies at Bethany College are the professional and leadership opportunities offered through the Business Club. This group makes annual tours to major business centers and provides presentations to the campus by business professionals.
Business Administration
Business Economics
Business Education Teaching 6-12
Management with International Management Concentration
Marketing with Emphasis in Network Marketing
Operations Management
Sports Management
Computer Applications
Department Chair
Paul Gentine, M.S.Associate Professor of Business
Paul Gentine is Associate Professor of business at Bethany College. He has been a member of the Bethany College faculty since 2000 and has been the Business Department Chair and also serves in the Education Department.
At Bethany College, he teaches classes in business policy, marketing and management. Gentine has more than 37 years of experience in marketing, management and operations, including 22 years with the General Motors Corporation.
After receiving a Bachelors Degree in Social Science from Bethany College, Gentine earned a Masters Degree in Education from Emporia State University, Emporia, Kan.
More recently, Gentine has taken Advanced Graduate Studies at the University of Michigan-Ann Arbor, and received an Honorary Doctor of Automotive Management from the General Motors University of Automotive Management.


text:
Deputy shoots, kills man armed with knife in San Marcos
SAN MARCOS, Calif. - A sheriff's deputy shot and killed a "distraught man armed with a knife," a department spokesman said Sunday.
The incident occurred at 5:44 p.m. Saturday in the 500 block of Charlotte Drive in San Marcos, Lt. Glenn Giannantonio of the Sheriff's Homicide Detail said.
"San Marcos deputies received a call from a relative of an emotionally disturbed person inside a residence who was acting strangely, and had reportedly been taking an excessive amount of medications and drinking alcohol throughout the day," Giannantonio said.
"When deputies arrived, they found the man armed with a knife inside the residence," he said. "One of the three deputies fired his duty pistol at the man, who was struck by the rounds."
Giannantonio said paramedics were called to the scene but lifesaving efforts failed and the man was pronounced dead on arrival.
There were no injuries to deputies or witnesses, Giannantonio said.
Sheriff's Homicide Detail, San Marcos Station detectives and crime laboratory personnel were participating in the investigation.
Giannantonio asked anyone with information on the incident to call the Homicide Detail at (858) 974-2321 or (858) 565-5200 after hours, or call the Crime Stoppers anonymous tip line at (888) 580-8477.


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GRAFTON, Mass.- The Grafton Suburban Credit Union donated $1,000 each to the high school football team and Community Harvest Project.
The football team has an $11,000 goal so the Super Bowl champions, who last won in 1986, can have a banquet celebration, which is scheduled in March.
"The town was so proud of the football team's Super Bowl victory, we knew that we should help them to celebrate," said the credit union's president and CEO, Ed Lopes, in a press release.
The donation did not go unnoticed. "As a team and also an alumnus of Grafton High School, we appreciate the support of the community, and the generous donation from the Grafton Suburban Credit Union," said Grafton High Football Head Coach Mike Ross.
Community Harvest, the North Grafton farm that donates all its crops to the Worcester County Food Bank, also received $1,000.
"Community Harvest Project makes a significant and growing impact on feeding the hungry," Lopes said. "Grafton Suburban is glad to do some small part to help".
Kristin Bafaro, executive director of the charity expressed appreciation for the longstanding relationship with the credit union.
"Grafton Suburban Credit Union has been a wonderful community partner. They have provided financial support, sponsored our Harvest Home event the past six years, and members of the GSCU team have volunteered countless hours to help our organization in a variety of capacities," she said.
Since its inception in 1966, the credit union has contributed to numerous local, regional, civic, and nonprofit organizations and continues to designate special days for member appreciation and community-minded charitable giveback.


text:
See definition in Oxford Advanced Learner's DictionarySaltos de línea: fat fin¦ger
Definición de fat finger en inglés:
Used to refer to clumsy or inaccurate typing, typically resulting from one finger striking two keys at the same time: the programming problem turned out to be a case of fat finger [as modifier]: his texts are full of fat-finger mistakes
Más ejemplos en oraciones
- Due to a fat-finger error on my part, the comments for several posts back were deleted a few minutes ago.
- The company has sued rivals for allegedly stealing calls from toll-free operators through what is called a "fat-finger dialing" scheme.
- The TSE said the so-called "fat finger" mistake had had little impact on the market.
verbo(fat-finger) [with object] Volver al principio
Type (something) inaccurately: you may have fat-fingered your password
Más ejemplos en oraciones
- Ship spectrum data are periodically printed from AESOP and a Sailor must manually key, or "fat-finger," data into the Naval Text Message System.
- It was way too easy to fat-finger some code and not get a compile time error and not get a runtime error either until say a week or two after product goes out.
- Taylor says it was common for mechanics to "fat finger" a part number or shop order, which resulted in poor systems performance.
- 1
fat-fingered adjetivo
- Oraciones de ejemplo
- The official explanation was that it was a fat-fingered trade, caused by someone inputting the wrong data on stock orders.
- Initially, strategists speculated that a fat-fingered trader could be to blame for the early tumble, saying it appeared to have been a blip caused by a mistaken trade, possibly by someone typing in the wrong price.
- Even small, fat-fingered typing mistakes cause regret.
Definición de fat finger en:
- Diccionario Inglés de EE.UU.
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text: A box-shaped hand percussion instrument that has its origins in 18th century Peru, the cajón is played by making contact with the front plate. It's unique in that it's designed for the percussionist to be seated on top of the instrument. The cajón slowly gained popularity throughout South America, and reached a peak in notoriety by the mid-1800s. By the early 20th century, the cajon had undergone considerable technological advancement, and had reached the bass box drum form we see today, with a resonant front plate made from a select tone wood, and open sound board at the rear. Read More>


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'Mud' examines love, relationships through a teen's eyes
Movies and More reviewer John Gillispie thinks "Mud," rated PG-13 and starring Tye Sheridan, Jacob Lofland, Matthew McConaughey and Reese Witherspoon, is an interesting drama.
Matthew McConaughey, the star of "We Are Marshall," plays the title character in the drama "Mud," which is available on DVD.
Set in the South, the character Mud is living alone on an island since he is being sought by the police. He is also being tracked down by a family seeking revenge against him. Joe Don Baker plays the leader of the family trying to find Mud before the police can.
Two teens named Ellis (Tye Sheridan) and Neckbone (Jacob Lofland) meet Mud and decide to help him try to escape. The boys do not have to help Mud, and I wondered why they decide to assist him. It seems that Ellis wants to help Mud because of a story that Mud tells. In his explanation to the teens, Mud places the blame for his situation on his love for a woman named Juniper (played by Reese Witherspoon).
Despite the film's title, Ellis is the main character in the movie. Since he has never had his heart broken, Ellis has an idealistic view of romantic love despite the fact that his parents are struggling with their own relationship. When an older neighbor named Tom (played by Sam Shepard) tries to tell Ellis about the dangers of love, Ellis refuses to listen. This is a lesson that Ellis must learn on his own.
"Mud" is an entertaining drama that takes the time to create interesting characters. But, to me, the way the movie looks at love through the eyes of characters from different generations made the movie even better.
John Gillispie is the public relations director for the Huntington Museum of Art. Contact the writer at email@example.com.


text:
John Heraty
PhD. Texas A&M University, 1990
MSc University of Guelph, 1984
BSc University of Guelph, 1976
Research focuses on the systematics, phylogeny and biogeography of the Chalcidoidea (Hymenoptera). Chalcidoid wasps rank numerically among the largest groups of insects, with estimates of as many as 100,000 species; however, the fauna is poorly known. Most are specialized parasites, and the majority of successful biological control projects have utilized these minute wasps to achieve partial or complete control of insect pests. One area of our research is on the Eucharitidae, a specialized group of ant parasities. The taxonomy of this group is poorly understood, and presently, only a small proportion of the known species can be identified. The larvae of Eucharitidae exhibit several peculiar behaviors associated with gaining access to the ant host, and studies on higher classification using cladistic methodology have led to a greater understanding of the evolution of behavioral patterns within the family, This knowledge has proved useful in studies on other groups of Hymenoptera that parasitize eusocial insects and for postulating a biogeographic hypothesis for the family. A second area of research emphasizes the systematics of the Aphelinidae, which are generally parasites of aphids, whiteflies and scale insects. Most analyses of relationships have been based on internal and external morphological traits, but molecular techniques are now being applied to understanding the higher phylogeny of the Chalcidoidea and the relationships among species of the genus Encarsia (Aphelinidae). Other research interests include studies of the diversity of Hymenoptera on the Galapagos Islands, internal studies of the skeleto-musculature of Hymenoptera and parasitoid interactions with leafmining moths of the family Gracillariidae. All of our studies incorporate morphological, biological or molecular information into analyses that are used to formulate hypotheses of phylogenetic relationships and the evolution of behavioral patterns. The evolution of host associations, an area of paramount importance to biological control programs, is central to all of our studies. This is a fascinating area of research demonstrating the utility and impact of systematics to almost every area of science.


text:
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Sunday, August 02, 2015
Then there's the Seattle General Strike of 1919, which the city's mayor attempted to break up with the help of the army and deputized University of Washington students.
The Seattle General Strike lasted five-days and involved more than 65,000 workers. Seattle Mayor Hanson had federal troops available and stationed 950 sailors and marines across the city by Feb. 7. He added 600 men to the police force and hired 2,400 special deputies -- students from the University of Washington, for the most part.
Strikers called his bluff. But, in the end, workers trickled back to work until finally the General Strike Committee voted to end the general strike on Feb. 11.
Get more information and images from the strike days from the University of Washington page dedicated to it.
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Category Archives: Uncategorized
Half-Square Triangle Blocks
This wonderful block is basic to many quilting patterns. Download instructions Half-square triangle basic
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April Book Lovers Club
We are making progress on our city quilts. My quilt is based on my novella, Christmas in Thirty Minutes. The Eight Hands Around block… representing the quit shop also found in Solomon's Puzzle.
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Another Finished Quilt
Barbara Bourne, friend and colleague, joined my Book Lovers Block of the Month Club at Cottonseed Glory a couple of years ago. She finished her beautiful Solomon's Puzzle Sampler Quilt and our friend and fellow club member, Ann Hazelwood, … Continue reading
This Weekend
Come to see Blessing House Press at Lighthouse Christian Academy's Holiday Showcase Event. I'll bethere to sign books until noon. I'd love it if you stopped by!


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Advice and guidance
Youth centres
Work and practice
Take part
Civic Activity
About us
Contacts and feedback
Helsinki, Vantaa, Espoo and Kauniainen Youth Services have a shared, free membership card. With the card you can participate in the activities organized by all the four cities, no matter if you live in Helsinki, Vantaa, Espoo or Kauniainen.
If you have not got a membership card yet, print out the application form, fill it and let your supervisor sign it (if you are under 18 years old). The application form should be returned to the nearest youth centre. The card itself does not require anything of the card holder.
Why become a member?
With the membership card you can participate in the activities of the Youth Services. Think of all those opportunities that the four Youth Services can offer! The activities of the Youth Services' are various and if you want to set in motion something yourself that is not yet offered, you are free to come with ideas.
With the membership card you can take part in several things: have fun at a youth discos, study photography, practice with your band at our facilities, enroll at courses, participate in dancing, theatre or handicraft activities, discuss about your future, acquire funding for a project, enroll at a summer camp, organize an event…you name it.
The possibilities are endless and most of our activities are free. Ask more about the possibilities from the nearest Youth Center!
If you have questions also check out information about the card.
Print out the Membership card application form!
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En français


text: Mets lefty Jonathon Niese still plans to pitch Sunday against Philadelphia, but may skip his bullpen Thursday and instead do a light session Friday. Niese took a liner off his foot Tuesday and left in the third inning. "I'm going to take it easy on it today," Niese said. "See how it goes tomorrow."


text:
It is now or never for the four remaining sides in
this year's Copa Libertadores de America. This Wednesday and
Thursday, Gremio, Santos, Boca Juniors and Cucuta Deportivo play
their semi-final, second legs in Brazil and Argentina, with a place
in the final of South America's premier club competition up for
grabs.After first leg wins last week, Gremio and Cucuta
appear to have the upper hand, but the experience and Copa
Libertadores pedigree of their esteemed rivals suggest there is
still all to play for this week.
Read on as FIFA.com gives you the rundown on the two ties, as the continental title, not to mention a place at the FIFA Club World Cup Japan 2007, draw ever nearer.
Santos out to rewrite the script
The recently-crowned Paulista state champions came into the semi-finals hoping to extend their unbeaten run in this year's Copa Libertadores. However, that impressive statistic came to an end at the most inopportune moment for Vanderlei Luxemburgo's side when they crashed to a 2-0 first leg defeat away to Gremio.
Now O Peixe will need an equally emphatic victory if they are to stop the resolute Tricolor Gaúcho in theirtracks and give themselves a shot at a third continental crown."They (Gremio) ought to know they will be coming to a packed stadium, where the crowd will be willing us to win. That's not a comfortable situation for any visiting side. We've already shown that we can turn ties around here, like in the final of the Paulistao (Paulista State Championship), and so I'm confident we can do it again," said Luxemburgo.
That said, Gremio will not be lacking in motivation when they arrive at the Vila Belmiro. The 1983 Copa Libertadores winners are desperate to go all the way this year and thus take over the mantle of continental champions from their neighbours and arch-rivals Internacional."We know it will be a difficult fixture and that we haven't qualified yet, but I'd be lying if I said the two-goal lead hadn't helped our preparations," said the Porto Alegre outfit's coach Mano Menezes.
Nor is the visiting side's confidence unfounded. Thanks to their clean sheet in the home leg, a goal from Gremio at the Vila Belmiro would require Ze Roberto and company to score four to go through. A tall order, even if Santos have been the highest scorers in this year's tournament.
Cucuta threaten Boca's ambition
Who could have predicted that Cucuta Deportivo, a club who only two seasons ago were playing in the Colombian second division, would now be just 90 minutes away from the Copa Libertadores final in this their debut appearance? Of course, if they are to achieve that, they will need to preserve their 3-1 first leg lead over Boca Juniors in the fiercely intimidating atmosphere of the Bombonera stadium in Buenos Aires.
Five-time winners of the continental championship, the Xeneizes would love to see their prodigal son Juan Roman Riquelme help them to title number five. If Boca are to go through, then the experience of the veteran playmaker will be vital, as will the crowd at the Bombonera. For his part, coach Miguel Angel Russo is confident, saying: "We'll turn this tie around and go through."
Meanwhile, in the Cucuta camp, all eyes have been on Panamanian striker Blas Perez, the second highest scorer in this year's competition and scorer of two goals in last week's first leg. Sadly for the Colombians, the player is currently with his national team as they prepare for the upcoming CONCACAF Gold Cup and it appears increasingly unlikely that he will be given permission to travel and play in Argentina on Thursday.
"We haven't qualified for anything yet, but we believe that with our type of football we can deny Boca possession and play our game. What we've done is historic, but we want to achieve even more," says coach Jorge Bernal, who has one little bit of history on his side going into the tie. The last time the Xeneizes had to face Colombian opposition in the latter stages of this tournament, they came up short, famously losing the 2004 Copa Libertadores final to Once Caldas.
Fixtures this week
Wednesday 6
Santos (BRA) - Gremio (BRA)
Thursday 7
Boca Juniors (ARG) - Cucuta Deportivo (COL)


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A game for all ages
During her pre-tournament press conference Wednesday, two-time U.S. Women's Open champion and 53-year-old Juli Inkster said if she played her game at the 2014 version at Pinehurst No. 2, she could finish in the top 10 or 15 players even though she barely plays anymore and hasn't earned a top 10 in this tournament since 2006.
Her verdict on Saturday afternoon: "So far."
Inkster shot a near-spotless 66 on Saturday, the best round of the tournament, to move to 2-over for the championship, tied for third four shots behind co-leaders Amy Yang and Michelle Wie, in what she said is her last appearance at a U.S. Women's Open.
It was quite a bounce-back from the 75 she shot on Friday.
"I had a really good round today," she said. "This game is so weird. You never know. It's like, the first day I played great. Yesterday I played horrible. Today I played great. So hopefully
See Inkster/page b4
I'm going to break the pattern and have a good one tomorrow."
Inkster had five birdies on what is traditionally known as "moving day," the day when players differentiate themselves from the rest of the field by playing well enough to move up the leaderboard, stay strong atop it or fall down it.
She went up. Inkster opened with a birdie on the difficult first hole, a hole that had surrendered just 23 birdies in the first two days of the tournament, by draining a 15-foot putt. She had short putts for birdies on holes No. 5 and 7 before three-putting on No. 8 to drop a shot.
But Inkster went right back at it on the back nine, with birdies on 10 and 12. On the tenth hole, a par five, she hit her second shot into the bunker, from where she chipped to 15 feet. Another birdie putt. On hole No. 12, her approach shot fell three feet from the hole for an easy birdie.
All of a sudden, she finds herself in the conversation on Sunday.
"I always think I can be competitive, I just don't play that much anymore," she said. "I still hit the ball relatively good, it's just my concentration. I hit a few loose ones and miss a couple short putts, and you just can't win that way. And that's kind of what I do."
Not on Saturday all that much. She actually made enough short par putts to make just one bogey on a course which was averaging a little over five per round during the first two days. She hit 13 of 14 fairways and 17 of 18 greens in regulation.
This creates some special drama for the final round. If Inkster can keep her play going today, she just might replicate Tom Watson's surprising 2009 Open Championship. Watson, who was 59 at the time and won five Open Championships, the last in 1983, had an eight-foot par putt to win on the 72nd hole on Sunday, but missed it and lost in a playoff to Stewart Cink.
Inkster said she can't be thinking in that vein this week.
"You can think and you can dream all you want, but the bottom line is you've got to come out and make the shots," she said. "So, tomorrow I've got to come out and make the shots. And if I'm tied for the lead coming up 18, then maybe I'll think about it."
Nicole Castrale, a former LPGA Tour winner who missed the cut, is Inkster's roommate for the week.
"She's a mom and obviously a Hall of Famer, but Juli is just Juli," Castrale said. "What you see is what you get. She's very real. She has a huge heart. She's always trying to just give insight about golf and events and just life in general, being a mom."
Well, this 53-year-old mom of two is four shots off the lead at the U.S. Women's Open Championship, 12 years after her last victory in this tournament, her last major.