WO2010080333A1 - Arylcyclopropylacetamide derivatives useful as glucokinase activators - Google Patents
Arylcyclopropylacetamide derivatives useful as glucokinase activators Download PDFInfo
- Publication number
- WO2010080333A1 WO2010080333A1 PCT/US2009/067603 US2009067603W WO2010080333A1 WO 2010080333 A1 WO2010080333 A1 WO 2010080333A1 US 2009067603 W US2009067603 W US 2009067603W WO 2010080333 A1 WO2010080333 A1 WO 2010080333A1
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- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- compound
- diabetes
- acceptable salt
- solution
- Prior art date
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- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000007410 oral glucose tolerance test Methods 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000012421 spiking Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Diabetes is a progressive disease which adversely affects both longevity and quality of life.
- Existing oral therapies either alone or in combination, do not exhibit 5 adequate or sustained glucose lowering efficacy in patients with diabetes. Consequently, there is an unmet need for improved therapies for patients with diabetes.
- GKAs Glucokinase activators
- GK Glucokinase
- the compounds of the present invention have been found to activate glucokinase 20 both in vitro and in vivo.
- the compounds of the present invention have been found to exhibit improved potency over existing GKAs.
- the compounds of the present invention have been found to exhibit limited blood brain barrier permeability.
- the present invention is directed to compounds which activate glucokinase, pharmaceutical compositions containing them as an active ingredient, methods for the 25 treatment of disorders associated with glucokinase dysfunction, and to their use for the treatment of diabetes, in particular Type II diabetes.
- the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof.
- a compound of the present invention has two stereocenters (*) and thus four possible stereoisomers. It is intended that each stereoisomer and racemic or diastereomeric mixtures, whether pure or partially pure, are included within the scope of the invention.
- a preferred stereoisomer of a compound of the present invention has the structural formula:
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
- the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.
- the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes, in particular type II diabetes.
- a compound of Formula I, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diabetes, in particular Type II diabetes.
- the present invention provides a method for the treatment of diabetes, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.
- the present invention also provides a method for the treatment of Type II diabetes, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.
- the present invention provides a pharmaceutical composition for use in therapy comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- the present invention provides a pharmaceutical composition for use in diabetes, in particular type II diabetes, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- the term "pharmaceutically acceptable salt” refers to salts of a compound of the present invention which are substantially non-toxic to living organisms. Such salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et ah, Handbook of Pharmaceutical Salts: Properties Selection and Use, (VCHA/Wiley-VCH, 2002); and J. Pharm. Sci. 66, 2-19 (1977).
- a preferred pharmaceutically acceptable salt is hydrochloride.
- the compounds of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (A, Gennaro, et ah, eds., 19 th ed., Mack Publishing Co., 1995).
- the present compounds are administered in combination with one or more active substances.
- active substances include for example metformin.
- Administration in combination includes simultaneous, sequential or separate administration.
- the compound names for the following example are generated using AutoNom 2000.
- aqueous phases are back-extracted with ethyl acetate (2 x 500 ml), and the organic layers are combined, dried over magnesium sulfate, and filtered.
- This crude hydrazone solution ( ⁇ 2.1 L, assumed to contain 363 g of hydrozone intermediate) is stirred well while triethylamine (100 mL, 890 mmol) is added slowly. The resulting solution is left to stand overnight, during which time some solid precipitates.
- the mixture is diluted with ethyl acetate to a volume of 3 L, affording a solution, which is washed with 1 L of water, followed by two 500 mL portions of water combined with saturated aqueous sodium chloride solution as necessary to break up any emulsions.
- the resulting slurry is then stirred at 50 0 C for 1 hour, during which time a solution forms.
- Methanol is removed under vacuum, and 1 L of ethylacetate is added.
- the resulting mixture is acidified by the addition of approximately 550 mL of 5% aqueous hydrochloric acid, and the two layers are separated.
- the aqueous layer is then extracted with two 500 mL portions of ethyl acetate.
- the organic phases are combined, washed with 500 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to afford a moist pale yellow solid. This material is then dissolved in 1 L of methanol. Water (1 L) is then added to the stirred solution over the course of 1.5 hours.
- the enantiomeric excess of the acid is determined to be 97.7% by comparison of the integrals for the two peaks corresponding to the enantiomers as separated by chiral chromatography on an AD-H column (150 mm) eluted at 35°C with 10% ethanol in hexanes containing 0.05% trifluoroacetic acid.
- Oxalyl chloride (146.89 mL, 1.69 mol) is added over 15 min to a stirred solution of (lR,2S)-2-cyclohexyl-l-(4-cyclopropanesulfonyl-phenyl)-cyclopropanecarboxylic acid (295.00 g, 0.847 mol) in 10 L of anhydrous dichloromethane under an inert atmosphere.
- Dimethylformamide (654.61 ⁇ L, 8.5 mmol) is then added at once, and the resulting solution is stirred overnight. Volatiles are then removed under vacuum at 40 0 C to afford an oil, which is dissolved in 3 L of anhydrous dichloromethane.
- the resulting mixture is stirred for a few minutes, and then the two layers are separated.
- the aqueous layer is extracted with 1 L dichloromethane, and the dichloromethane solutions are combined, dried over MgSO 4 , filtered, and concentrated under vacuum at 40 0 C.
- the resulting oil (556 g) is applied to silica gel plugs as a dichloromethane solution. Elution of the plugs with 1: 12:7 2M ammonia in methanol/ methyl t-butyl ether /heptane, followed by 1: 19 2M ammonia (in methanol)/ethyl acetate affords a brown foam (351 g).
- the human islet GK isoform is expressed in E.coli as (His)6 -tagged fusion protein and purified with metal chelate affinity chromatography, see e.g. Tiedge et al., Biochem. Biophys. Acta 1337, 175-190, 1997. After purification the enzyme is stored in aliquots at concentration 0.8 mg/ml in 25 mM sodium phosphate, 150 mM sodium chloride, 100 mM imidazole, 1 mM dithiothreitol, 50 % glycerol at -80 0 C. The assay is performed in flat bottom 96-well plates in a final incubation volume of lOO ⁇ L.
- the incubation mixture consists of 25 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES) (pH7.4), 50 mM potassiumchloride, 2.5 mM magnesiumchloride, 2 mM dithiothreitol, 4 U/ml glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides, 5 mM ATP, 1 mM NAD and a set concentration of glucose. Test compounds are dissolved in dimethylsulfoxide and then added to the reaction mixture giving the final dimethylsulfoxide concentration of 10%. The reaction is initiated by addition of 20 ⁇ L GK and run for 20 min at 37°C. The amount of formed NADH is measured as an increase in absorbance at 340 nm using a microplate reader. Absorbance values are used for EC50 calculations.
- HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid
- Rat insulinoma INS-IE cells are maintained at 37 0 C, 5% CO 2 , 95% humidity in 1640 medium supplemented with 11 mM glucose, 5% Fetal Bovine Serum, 50 ⁇ M 2- Mercaptoethanol, 1 mM pyruvate, 10 mM HEPES and antibiotics. Prior to assay, cells are trypsinized, pelleted by centrifugation and seeded into 96-well tissue culture assay plates at the density of 30,000 cells/well. Cells are allowed to attach and incubated for 48 hours at 37 0 C, 5% CO 2 .
- EBSS Earle's Balanced Salt Solution
- BSA Bovine Serum Albumin
- EDTA ethylenediaminetetraacetic acid
- Example 1 decreases plasma glucose in a dose-dependent manner at both fasted and postprandial glucose levels.
- a maximal lowering of glucose AUC versus the untreated control group is observed with the high dose (30 mg/kg) and represents a 42% decrease.
- Interpolation of the data showed that a 20% glucose AUC decrease occurs at an average compound concentration of 99 ng/ml (179 nM) in plasma, corresponding to a 6.9 mg/kg compound dose.
- the compounds of the present invention are shown to activate GK in vivo.
- a stock compound solution is prepared in dimethylsulfoxide at 10 mM.
- a dose solution is then prepared at ImM by diluting 100 ⁇ L of the stock with 900 ⁇ L of propylene glycol.
- the dose is administered as an IV bolus (2.2 mL/kg) via the tail vein into six male CF-I mice (approximately 23 g) for a target dose of 2.17 ⁇ mole/kg.
- Mice are euthanized using both CO 2 and cervical dislocation. Three mice are sacrificed 5 minutes post dose and three 60 minutes post dose. Blood is collected from each animal via cardiac puncture, and plasma is prepared using sodium EDTA, transferred into polypropylene sample tubes and immediately frozen using dry ice.
- Plasma samples are prepared for analysis by precipitation of protein using two parts of extraction sovent (10% tetrahydrofuran in acetonitrile) to one part plasma and mixing with a vortex mixer. For brain tissue, it is assumed that 1 mg brain tissue ⁇ 1 ⁇ L volume and two parts of extraction solvent are added to one part tissue. The samples are immediately homogenized using an ultrasoinc cell dismemberator. Calibration standards are prepared by spiking known concentrations of compound into blank mouse plasma and then treated as plasma samples. All samples are centrifuged at 6000 RCF for 5 minutes. An aliquot of supernatant from each sample is transferred to a polypropylene 96 well plate and sealed for analysis by LC-MS/MS.
- MS/MS is effected using a Sciex API 4000 triple quadrupole mass spectrometer equipped with a turbo ion spray source.
- High Performance Liquid Chromatogaphy is effected using a Phenomenex Hyrdro RP analytical column (10Ox 2.0 mm, 4 ⁇ ) heated to 50 0 C and operated at a constant flow rate of 0.6 mL/minute.
- a mobile phase gradient is utilized consisting of an initial mobile phase of 60:40 5 mM aqueous ammonium formate:5mM ammonium formate in methanol with a hold time of 1 minute followed by a linear 2 minute gradient to 10:90 5 mM aqueous ammonium formate: 5 mM ammonium formate in methanol with a final hold time of 1 minute.
- Column effluent is diverted to waste from 0-2.8 minutes and then directed into the mass spectrometer from 2.8-4.0 minutes MS/MS transitions monitored are 560/84.
- Quantitation of compound in test samples is achieved by comparing peak area values to a quadratic equation weighted 1/x 2 derived from the nominal concentrations of the calibration standards and their respective peak areas.
- Upper and Lower Limits of Quantitation are determined by the back calculated recoveries of calibration standards that exceeded +/- 20% of theory. Brain tissue concentrations are corrected for plasma contribution using a literature factor of 16 ⁇ L of plasma/gm mouse brain.
- Example 1 The in vivo blood brain barrier permeability of Example 1 resulted in a mean brain/plasma ratio of 0.17 five minutes post dose and a mean total brain level of 0.539 nmol/g at that time.
- the compounds of the present invention have been shown to have limited blood brain barrier permeability and so provides limited potential for severe hypoglycaemia.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (21)
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UAA201107562A UA104742C2 (en) | 2008-12-19 | 2009-11-12 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
NZ592930A NZ592930A (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
BRPI0923183-8A BRPI0923183B1 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glycokinase activators, and pharmaceutical composition |
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EA201170845A EA019055B1 (en) | 2008-12-19 | 2009-12-11 | Cyclopropyl derivative, pharmaceutical composition and method for treatment of diabetes |
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MX2011006434A MX2011006434A (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators. |
SG2011044823A SG172256A1 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
CN200980150686XA CN102256952B (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
EP09768316.3A EP2379517B1 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
JP2011542276A JP5497064B2 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
AU2009335931A AU2009335931B2 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
CA2746746A CA2746746C (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
KR1020117014073A KR101290437B1 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
DK09768316.3T DK2379517T3 (en) | 2008-12-19 | 2009-12-11 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
ZA2011/03944A ZA201103944B (en) | 2008-12-19 | 2011-05-27 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
IL213210A IL213210A (en) | 2008-12-19 | 2011-05-30 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
TN2011000294A TN2011000294A1 (en) | 2008-12-19 | 2011-06-09 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
MA33945A MA32902B1 (en) | 2008-12-19 | 2011-06-14 | Arilcyclopropylacetamide derivatives are useful for the activation of glucokinase |
HRP20130983AT HRP20130983T1 (en) | 2008-12-19 | 2013-10-16 | Arylcyclopropylacetamide derivatives useful as glucokinase activators |
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ES2233660T3 (en) | 2000-05-03 | 2005-06-16 | F. Hoffmann-La Roche Ag | GLUCOKINASA ALQUINIL FENIL HETEROAROMATIC ACTIVATORS. |
MXPA02010795A (en) | 2000-05-08 | 2003-03-27 | Hoffmann La Roche | Para amine substituted phenylamide glucokinase activators. |
JP3839723B2 (en) | 2000-05-08 | 2006-11-01 | エフ.ホフマン−ラ ロシュ アーゲー | Substituted phenylacetamide and its use as a glucokinase activator |
MY141521A (en) * | 2002-12-12 | 2010-05-14 | Hoffmann La Roche | 5-substituted-six-membered heteroaromatic glucokinase activators |
PL378117A1 (en) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tri(cyclo) substituted amide compounds |
US7262196B2 (en) | 2003-02-11 | 2007-08-28 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
WO2004076420A1 (en) * | 2003-02-26 | 2004-09-10 | Banyu Pharmaceutical Co., Ltd. | Heteroarylcarbamoylbenzene derivative |
MXPA06012008A (en) | 2004-04-21 | 2007-01-25 | Prosidion Ltd | Tri(cyclo) substituted amide compounds. |
JP2008509898A (en) | 2004-08-12 | 2008-04-03 | プロシディオン・リミテッド | Substituted phenylacetamides and their use as glucokinase activators |
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WO2011123572A1 (en) | 2010-03-31 | 2011-10-06 | The Scripps Research Institute | Reprogramming cells |
EP3199623A1 (en) | 2010-03-31 | 2017-08-02 | The Scripps Research Institute | Reprogramming cells |
EP3936608A1 (en) | 2010-03-31 | 2022-01-12 | The Scripps Research Institute | Reprogramming cells |
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