CN105213382A - A kind of diabetes combination of oral medication - Google Patents
A kind of diabetes combination of oral medication Download PDFInfo
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- CN105213382A CN105213382A CN201510767529.0A CN201510767529A CN105213382A CN 105213382 A CN105213382 A CN 105213382A CN 201510767529 A CN201510767529 A CN 201510767529A CN 105213382 A CN105213382 A CN 105213382A
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Abstract
The invention discloses a kind of diabetes pharmaceutical composition, it comprises following component: the 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1 of (1) 10-20mg, 1-dioxo-[1, 2, 5] thiadiazolidine-3-ketone potassium salt, (2) (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1 of 20-30mg, 1 '-biphenyl]-4-base) chromane-7-base) butanoic acid, (3) 200-300mg microcrystalline Cellulose, (4) 10-25mg cross-linking sodium carboxymethyl cellulose, (5) its composite by two kinds of dissimilar active matters of 1-8mg magnesium stearate, under the prerequisite reaching identical therapeutic effect, the use amount of the active matter of medicine is reduced at least 1/2.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of diabetes combination of oral medication.
Background technology
The metabolic disease of diabetes to be one group with hyperglycemia be feature.Hyperglycemia be then due to defect of insulin secretion or its biological agent impaired, or both have concurrently and cause.Long-standing hyperglycemia during diabetes, causes various tissue, particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction.
The generally acknowledged form of usual existence two kinds of diabetes.In type 1 diabetes or insulin-dependent diabetes (IDDM), patient produces seldom or does not have insulin, regulates the hormone of glucose application.In type 2 diabetes mellitus or noninsulindependent diabetes (NIDDM), still produce insulin in the body.There is in the stimulation glucose of the patient suffering from type 2 diabetes mellitus in main insulin-sensitive tissue (it is muscle, liver and fatty tissue) and lipid metabolism the toleration to insulin action.These patients have the insulin of common level usually, and may have hyperinsulinemia (plasma insulin level of rising), because they compensate by the insulin of secretion rise the insulin effects reduced.Insulin resistance can not be caused by the Insulin receptor INSR reducing quantity but be caused by the rear Insulin receptor INSR binding deficient understood not yet completely substantially.This lacks and to cause in the oxidation of glucose in the activation of the insulin-mediated of inadequate picked-up, muscle and storage and fatty tissue glucose in lipidolysis and liver to produce to the responding ability of insulin and the suppression of insufficient insulin-mediated of secretion.
Current Remedies for diabetes is maintaining treatment effect, many employing 100mg active matter oral doses, and needs daily repeatedly to take.Due to the side effect of active matter, other health hazards are caused to patient, meanwhile, due to the increase of dosage, also make medicine cost increase, cause the raising for the treatment of cost.
Summary of the invention
The object of the invention is to propose a kind of diabetes combination of oral medication, its composite by two kinds of dissimilar active matters, under the prerequisite reaching identical therapeutic effect, the use amount of the active matter of medicine is reduced at least 1/2.
For reaching this object, the present invention by the following technical solutions:
A kind of diabetes combination of oral medication, it comprises following component:
(1) 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 10-20mg
(2) (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid of 20-30mg
(3) 200-300mg microcrystalline Cellulose,
(4) 10-25mg cross-linking sodium carboxymethyl cellulose, and
(5) 1-8mg magnesium stearate.
Described 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt is less than 1 with the ratio of (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid.
Detailed description of the invention
The present invention is described pharmaceutical composition of the present invention by following embodiment.
Embodiment 1
I.5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt
Step 1
3-benzyloxy-7-methoxynaphthalene-2-benzyl formate
5.0g (21.7mmol) 3-hydroxyl-7-methoxynaphthalene-2-formic acid, 9.29g (54.3mmol) benzyl bromide a-bromotoluene and the mixture of 9.01g (65.2mmol) potassium carbonate in 25mLDMF are stirred 24 hours in 60 DEG C.After being cooled to room temperature, by mixture impouring water, be extracted in EtOAc.Organic facies is washed with 3 × water and 1 × saturated NaCl.Use dried over sodium sulfate organic facies, under reduced pressure except desolventizing.Making residual solid crystallization from dichloromethane/ethanol, obtain title compound, is Tan solid, mp96-98 °.
H-NMR (CDCl): δ 8.25 (s, 1H), 7.61 (d, J=8.83Hz, 1H), 7.49 (d, J=7.35Hz, 2H), 7.46-7.30 (m, 7H), 7.24 (d, J=5.88Hz, 2H), 7.18 (dd, J=9.20 and 2.58Hz, 1H), 7.12 (m, 1H), 5.40 (s, 2H), 5.23 (s, 2H), 3.89 (s, 3H). analyze: CHO: value of calculation C, 78.38; H, 5.57. measured value C, 78.28; H, 5.56.
Step 2
3-benzyloxy-7-methoxynaphthalene-2-formic acid
In the suspension of 6.07g (20mmol) 3-benzyloxy-7-methoxynaphthalene-2-benzyl formate in 100mL ethanol, add 24mL1.0NNaOH (1.2 equivalent), mixture is stirred 4 hours in 60 DEG C, in stirring at room temperature 16 hours.Under reduced pressure except desolventizing, residual solid is dissolved in 50mL water.Use washed with diethylether solution, with 2NHCl acidify aqueous phase.Filtration gained precipitates, and washes with water, and dry, obtaining title compound, is faint yellow solid.
Mp177-179 ° of .H-NMR (CDCl): δ 11.01 (s, wide, 1H), 8.70 (s, 1H), 7.67 (d, J=8.82Hz, 1H), 7.53-7.41 (m, 5H), 7.37 (s, 1H), 7.27 (dd, J=8.83 and 2.57Hz, 1H), 7.20 (m, 1H), 5.36 (s, 2H), 3.92 (s, 3H). analyze: CHO: value of calculation C, 74.01; H, 5.23. measured value C, 73.71; H, 5.46.
Step 3
(3-benzyloxy-7-methoxynaphthalene-2-base)-t-butyl carbamate
In the suspension of the anhydrous t-BuOH+40mL dry toluene of 40mL, 2.3g (22mmol) triethylamine is added to 4.6g (14.9mmol) 3-benzyloxy-7-methoxynaphthalene-2-formic acid.In gained solution, add 5.34g (19.4mmol) DPPA, by mixture in stirring at room temperature 5 minutes, then stir 18 hours in 100 DEG C.Mixture is cooled to room temperature, then in impouring water.Mixture extraction is entered in EtOAc, wash organic facies with saturated NaCl.Under reduced pressure except desolventizing, residue uses hexane/ethyl acetate (85: 15) to carry out purification by flash chromatography, elutes title compound, is grease, slowly becomes waxy solid.
H-NMR(CDCl)：δ8.48(s，1H)，7.50(d，J＝8.82Hz，1H)，7.48-7.31(m，7H)，7.10(s，1H)，6.99(dd，J＝8.82and2.57Hz，1H)，5.17(s，2H)，3.84(s，3H)，1.54(s，9H).
Step 4
3-benzyloxy-7-methoxynaphthalene-2-base amine
By 4.99g (13.1mmol) (3-benzyloxy-7-methoxynaphthalene-2-base) solution of-t-butyl carbamate in 50mLTFA/ dichloromethane (1: 1) in stirring at room temperature 30 minutes.Under reduced pressure except desolventizing, 10% sodium bicarbonate aqueous solution is joined in residue.Mixture extraction is entered in EtOAc, use dried over sodium sulfate organic facies.Under reduced pressure except desolventizing, residue uses dichloromethane to carry out purification by flash chromatography, elutes title compound, makes its crystallization from ethanol, obtain white solid,
Mp149-151 ° of .H-NMR (CDCl): δ 7.54-7.32 (m, 6H), 7.09 (s, 1H), 6.92 (d, J=9.20Hz, 2H), 6.89 (dd, J=8.82 and 2.57Hz, 1H), 5.18 (s, 2H), 4.11 (s, wide, 2H), (3.87 s, 3H).
Step 5
(3-benzyloxy-7-methoxynaphthalene-2-base is amino)-methyl acetate
2.26g (14.8mmol) methyl bromoacetate is added in 2.76g (9.88mmol) 3-benzyloxy-7-methoxynaphthalene-2-base amine and the mixture of 2.73g (19.8mmol) potassium carbonate in 20mLDMF.Mixture is stirred 2 hours in 60 DEG C, then in stirring at room temperature 16 hours.By in mixture impouring water, be extracted in EtOAc.Wash organic facies with water (3 ×), saturated NaCl (1 ×), use dried over sodium sulfate.Under reduced pressure except desolventizing, making residue crystallization from ethanol, obtain title compound, is pale solid,
Mp129-131 °.; NMR (CDCl): δ 7.50 (s, wide, 2H), (7.49 d, J=8.46Hz, 1H), 7.45-7.33 (m, 3H), 7.07 (s, 1H), 6.97 (d, J=2.20Hz, 1H), 6.89 (dd, J=8.82 and 2.57Hz, 1H), 6.62 (s, 1H), 5.20 (s, 3H), 4.05 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H) .MS (M+1): 352. analyze: CHNO: value of calculation C, 71.78; H, 6.02; N, 3.99. measured value C, 71.61; H, 5.86; N, 3.91.
Step 6
N-(tertbutyloxycarbonyl sulfamoyl)-N-(3-benzyloxy-7-methoxyl group naphthyl) glycine methyl ester
The solution of 649mg (8.76mmol) tert-butyl alcohol in 3mL dichloromethane is dripped in the solution of 1.24g (8.77mmol) Carbimide. chlorine sulfonyl ester in 25mL dichloromethane.By solution in stirring at room temperature 30 minutes, then drip 2.2g (6.26mmol) (3-benzyloxy-7-methoxynaphthalene-2-base is amino)-methyl acetate and the solution of 1.27g (12.6mmol) triethylamine in 25mL dichloromethane.By mixture in stirring at room temperature 90 minutes, then wash with water.Use dried over sodium sulfate organic facies, under reduced pressure except desolventizing.Residual oil thing uses hexane/ethyl acetate (70: 30) to carry out purification by flash chromatography, elutes title compound, is grease.
H-NMR (CDCl): δ 8.10 (s, 1H), 7.68 (s, wide, 1H), 7.54 (d, J=9.80Hz, 1H), 7.49-7.29 (m, 5H), 7.17 (s, 1H), 7.14-7.08 (m, 2H), 5.23 (s, 2H), 4.63 (s, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 1.41 (s, 9H) .MS (M-1): 529.
Step 7
N-sulfamoyl-N-(3-benzyloxy-7-methoxyl group naphthyl) glycine methyl ester
By 3.1g (5.85mmol) N-(tertbutyloxycarbonyl sulfamoyl)-N-(3-benzyloxy-7-methoxyl group naphthyl) solution of glycine methyl ester in 40mL trifluoroacetic acid/dichloromethane (1: 1) in stirring at room temperature 30 minutes.Under reduced pressure except desolventizing.Joined by dichloromethane in residue, then under reduced pressure (4x) removing, obtaining oily solid, it ground together with ether (16 hours), obtain title compound, is solid,
Mp137-139 °; H-NMR (CDCl): δ 8.01 (s, 1H), 7.58 (d, J=8.83Hz, 1H), 7.51-7.32 (m5H), 7.23-7.05 (m, 3H), 5.17 (s, wide, 2H), 5.15 (s, 2H), 4.39 (s, 2H), 3.85 (s, 3H), 3.67 (s, 3H) .MS (M+1): 431. analyze: CHNOS: value of calculation C, 58.59; H, 5.15; N, 6.51. measured value C, 58.53; H, 5.05; N, 6.62.
Step 8
5-(3-benzyloxy-7-methoxynaphthalene-2-base)-1; 1-dioxo-[1; 2,5] thiadiazolidine-3-ketone potassium salt drips the solution of 4.4mL1.0M potassium tert-butoxide in THF in 1.89g (4.39mmol) N-sulfamoyl-N-(3-benzyloxy-7-methoxyl group naphthyl) solution of glycine methyl ester in 5mLTHF.By mixture in stirring at room temperature 18 hours.Filter the dense thick precipitation of gained, wash with the THF of small size.Drying under reduced pressure solid, obtains title compound, mp182-198 °.
Step 9
5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt
By 1.75g (4.01mmol) 5-(3-benzyloxy-7-methoxynaphthalene-2-base)-1, the 1-dioxo-solution of [1,2,5] thiadiazolidine-3-ketone potassium salt in 150mL water on 500mg10%Pd/C in 50psi hydrogenation 24 hours.Leach catalyst, with ethyl acetate washing containing filter liquor.By aqueous phase lyophilization, obtaining title compound, is light brown amorphous solid.
Mp260-265 ° of H-NMR (DMSO-d:7.90 (s, 1H), 7.54 (d, J=9.04Hz, 1H), 7.14 (s, 1H), 7.12 (d, J=2.64Hz, 1H), 6.98 (dd, J=9.04 and 2.64Hz, 1H), 4.20 (s, 2H), 3.81 (s, 3H) .MS (M-1): 307.
II. (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid
Steps A: (E)-3-(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base) but-2-ene acid methyl ester
At the bromo-2-of N stirred under argon 7-(the fluoro-5'-methoxyl group-[1 of 2'-at 120 DEG C, 1'-biphenyl]-4-base) chromane (1.00g, 2.42mmol, 1.0eq), PdOAc (54.3mg, 0.242mmol), TEA (1.01ml, 7.26mmol, 0.726g/mL, 3.0eq), (Z)-but-2-ene acid methyl ester (727mg, 7.26mmol) and the mixture of tri-o-tolyl phosphine (73.6mg, 0.242mmol) in DMF (15ml) 16 hours.This reactant mixture is cooled to room temperature, then under vacuo except desolventizing.With this reaction of water (15mL) cancellation, and extract twice, this mixture with DCM (15mL).Through the organic layer that anhydrous Na SO drying merges, and concentrated to provide crude product under vacuo.Adopt PE: EtOAc=50: 1 eluting crude product to provide title compound by silica gel chromatography.
1HNMR(400MHz，CDCl
3)δ：7.59(d，J＝7.6，2H)，7.51(d，J＝7.6，2H)，7.11-6.95(m，5H)，6.84-6.82(m，1H)，5.14(d，J＝8.4，1H)，3.82(s，3H)，3.74(s，3H)，3.02-2.82(m2H)，2.55(s，3H)，2.29-2.04(m2H).
Step B:3-(2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) methyl butyrate
At room temperature (E)-3-(2-(2 '-fluoro-5 '-methoxyl group-[1 under H atmosphere, 1 '-biphenyl]-4-base) chromane-7-base) but-2-ene acid methyl ester (2.40g, 5.55mmol) stir 16 hours with the mixture of Rh/AlO (57.0mg, 0.277mmol) in MeOH (20ml).Then, filter this mixture and concentrated filtrate to provide crude product.This crude product is dissolved in DCM (25mL), and washs with water (20mL).Be separated organic layer, dry through anhydrous Na SO, and concentrated to provide the title compound of the form of mixtures of four kinds of diastereomers under vacuo.
Step C:(S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) methyl butyrate
Use Chiralcel post OJH250x4.6mmI.D. by SFC, 5um mobile phase: isopropyl alcohol (0.05%DEA) in CO from 5% to 40%
Flow velocity: 2.5mL/min wavelength: 220nm) non-enantiomer mixture of separating step B to be to provide following eluting order: 3-(2-(2'
Fluoro-5'-methoxyl group-[1,1'-biphenyl]-4-base) chromane-7-base) methyl butyrate (isomer A); 3-(2-(2'
Fluoro-5'-methoxyl group-[1,1'-biphenyl]-4-base) chromane-7-base) methyl butyrate (isomer B); 3-(2-(2'
Fluoro-5'-methoxyl group-[1,1'-biphenyl]-4-base) chromane-7-base) methyl butyrate (isomer C); With 3
(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base) methyl butyrate (isomer D).
Step D:
At room temperature stir Lithium hydrate (21.3mg, 0.892mmo) with 3-(2-(the fluoro-5'-methoxyl group-[1 of 2'-, 1'-biphenyl]-4-base) chromane-7-base) mixture of methyl butyrate (isomer A) (40.0mg, 0.0890mmol) in water (1.0ml), THF (1.0ml) and MeOH (1.0ml) 2 hours.Then use DCM (10mL) to dilute this reactant mixture, and wash with water (20ml).Through the organic layer that anhydrous Na SO drying merges, and concentrated to provide crude product under vacuo.(on the GILSON281 instrument being equipped with PhenomenexSynergiC18100*21.2mm*4um, use water and acetonitrile as eluent by preparation HPLC.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 60-80%B, 0-10min; 100%B, 10.5-12.5min; 5%B, 13-15min) this crude product of purification to be to provide product.
1HNMR(400MHz，CDCl
3)δ：7.56(d，J＝7.6，2H)，7.49(d，J＝7.6，2H)，7.06-6.92(m，3H)，6.78-6.74(m，3H)，5.08(d，J＝9.2，1H)，3.81(s，3H)，3.23-3.20(m，1H)，2.97-2.96(m，1H)，2.80-2.79(m，1H)，2.69-2.56(m，2H)，2.21-2.11(m，2H)，1.30(d，J＝7.2，3H).
By the component I for preparing and II, obtain described diabetes combination of oral medication according to following dosage is composite:
(1) 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 15mg
(2) (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid of 30mg
(3) 268mg microcrystalline Cellulose,
(4) 20mg cross-linking sodium carboxymethyl cellulose, and
(5) 5mg magnesium stearate.
The bull C57BLob/ob mice in 11 week age is housed in reverse smooth circular chamber (from 6:00p.m. to 6:00a.m. illumination) with 6/cage, arbitrarily edible Purina Rodent Meal and drinking-water.At the 1st day, get tail blood sample at 8:00am, measure plasma glucose levels.Animal is randomized into matched group and compound group.The meansigma methods of the plasma glucose levels of each group is mated.Then the Orally administered solvent of animal (there is 0.5% carboxymethyl cellulose of 0.2% tween 80) or the compound (30mg/kg) in solvent is given.Every day, to mice administration, amounts to 3 days.At the 4th day, get basal blood specimens.Adopt the concentration of glucose of YSI2700 dual pathways biochemistry analyzer (YellowSpringsInstrumentCo., YellowSprings, OH) analysed for plasma sample, adopt ELISA algoscopy to measure insulin concentration.Test result shows, its concentration of glucose is 80-120mg/dL, its insulin concentration: 4.4 ~ 8.0mmol/L.
Comparative example 1
Containing the component I of 100mg, not containing component I I, all the other conditions are constant, and its concentration of glucose and insulin concentration are all in the scope of embodiment 1.
Comparative example 2
Containing the component I of 50mg, not containing component I I, all the other conditions are constant, and its concentration of glucose is greater than 150mg/dL.
Comparative example 3
Containing the component I I of 100mg, not containing component I, all the other conditions are constant, and its concentration of glucose and insulin concentration are all in the scope of embodiment 1.
Comparative example 4
Containing the component I I of 50mg, not containing component I, all the other conditions are constant, and its concentration of glucose is greater than 150mg/dL.
Above-described embodiment and comparative example explanation, diabetes combination of oral medication of the present invention, it is composite by two kinds of dissimilar active matters, under the prerequisite reaching identical therapeutic effect, the use amount of the active matter of medicine is reduced at least 1/2, when two kinds of active matters that the present invention adopts are used alone, within the scope of equal volume, glucose in blood cannot be reduced in normal range of the present invention, prove to create cooperative effect between two kinds of active matters that the present invention adopts.
Applicant states, the present invention illustrates diabetes combination of oral medication of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned specific components and formula, does not namely mean that the present invention must rely on above-mentioned detailed component and formula could be implemented.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of auxiliary element, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (2)
1. a diabetes combination of oral medication, it comprises following component:
(1) 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 10-20mg
(2) (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid of 20-30mg
(3) 200-300mg microcrystalline Cellulose,
(4) 10-25mg cross-linking sodium carboxymethyl cellulose, and
(5) 1-8mg magnesium stearate.
2. diabetes combination of oral medication as claimed in claim 1, it is characterized in that, described 5-(3-hydroxyl-7-methoxynaphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt is less than 1 with the ratio of (S or R)-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base) butanoic acid.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687828A (en) * | 2007-06-04 | 2010-03-31 | 诺瓦提斯公司 | Thiadiazole derivatives as antidiabetic agents |
| CN104994848A (en) * | 2013-02-22 | 2015-10-21 | 默沙东公司 | Antidiabetic bicyclic compounds |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101687828A (en) * | 2007-06-04 | 2010-03-31 | 诺瓦提斯公司 | Thiadiazole derivatives as antidiabetic agents |
| CN104994848A (en) * | 2013-02-22 | 2015-10-21 | 默沙东公司 | Antidiabetic bicyclic compounds |
Non-Patent Citations (2)
| Title |
|---|
| 杨玺: "《糖尿病合理用药》", 30 November 2007 * |
| 陈培丰等: "《中西医结合临床内科学》", 31 August 2006 * |
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Application publication date: 20160106 |
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