CN105232544A - Anti-diabetic oral drug composition - Google Patents
Anti-diabetic oral drug composition Download PDFInfo
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- CN105232544A CN105232544A CN201510767479.6A CN201510767479A CN105232544A CN 105232544 A CN105232544 A CN 105232544A CN 201510767479 A CN201510767479 A CN 201510767479A CN 105232544 A CN105232544 A CN 105232544A
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Abstract
The invention discloses an anti-diabetic oral drug composition which comprises 10-20 mg of 5-(3-hydroxyl-7-propoxynaphthalene-2-yl)-1,1-dioxo-[1,2,5] thiadiazole alkane-3-dipotassium salt, 20-30 mg of (2S,3S)-3-cryclobutyl-3-((R or S)-2-(2'-fluorine-5'-methoxy-[1,1'-biphenyl]-4-yl)chroman-7-yl)-2-methyl propionic acid, 200-300 mg of microcrystalline cellulose, 10-25 mg of cross-linked sodium carboxymethylcellulose and 1-8 mg of magnesium stearate. By compounding two different types of actives, on the premise that the identical treatment effect is achieved, the use amount of the actives of the drug is decreased by a half at least.
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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 10-20mg
(2) (2S, 3S)-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-the base)-2 Methylpropionic 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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt and (2S, 3S) ratio of-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid is less than 1.
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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt
Step 1
3-hydroxyl-7-propoxyl group naphthalene-2-propyl formate
3.0g (14.7mmol) 3,7-dihydroxy naphthlene-2-formic acid is added in the suspension of 1.6g (29.6mmol) Feldalat NM in DMA (30mL).By mixture in stirring at room temperature 1 hour, then add 5.05g (29.7mmol) propyl iodide, continue stirring 48 hours.By in mixture impouring water, use 2NHCl acidify.Be extracted with ethyl acetate mixture, by (3 ×) water and saline (1 ×) washing organic facies.Use dried over sodium sulfate solution, under reduced pressure except desolventizing.Residual oil thing carries out purification by flash chromatography dichloromethane, elutes title compound, isolates as yellow oil.MS(M-1)：287。
Step 2
3-benzyloxy-7-propoxyl group naphthalene-2-propyl formate
0.98g (5.73mmol) benzyl bromide a-bromotoluene is added in 1.5g (5.21mmol) 3-hydroxyl-7-propoxyl group naphthalene-2-propyl formate and the mixture of 1.08g (7.81mmol) potassium carbonate in DMF (15mL).By mixture in stirring at room temperature 48 hours, then in impouring water.Be extracted with ethyl acetate mixture, wash organic facies with water (3x) and saline (1x).Use dried over sodium sulfate solution, under reduced pressure except desolventizing.Residual oil thing uses dichloromethane to carry out purification by flash chromatography, elutes title compound, is separated into yellow oil.
Step 3
3-benzyloxy-7-propoxyl group naphthalene-2-formic acid
In the solution of 680mg (1.8mmol) 3-benzyloxy-7-propoxyl group naphthalene-2-propyl formate in EtOH (15mL), add 2.0mL1.0NNaOH, then mixture is stirred 3 hours in 60 DEG C.Under reduced pressure except desolventizing, residual solid is soluble in water.Use MTBE wash solution, with 1NHCl acidify aqueous phase.Filtration gained precipitates, and washing with water, drying under reduced pressure, obtain title compound, is white solid, mp125-128 ° of .MS (M-1): 335.
5-(3-hydroxyl-7-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt
In accordance with known methods, title compound is obtained, mp250-255 ° by 3-benzyloxy-7-propoxyl group naphthalene-2-formic acid.
1h-NMR (DMSO-d6: δ 7.88 (s, 1H), 7.54 (d, J=9.04Hz, 1H), 7.13 (s, 1H), 7.12 (d, J=2.64Hz, 1H), 6.98 (dd, J=9.04 and 2.64Hz, 1H), 4.19 (s, 2H), 3.98 (t, 2H), 1.75 (m, 2H), 1.00 (t, 3H) .MS (M-1): 335.
II. (2S, 3S)-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid
Steps A: (2R or 2S, 3S)-3-cyclobutyl-3-((R or S)-((S)-2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester
Under a nitrogen to 3-cyclobutyl-3-(2-(the fluoro-5'-methoxyl group-[1 of 2'-under-78C, 1'-biphenyl]-4-base) chromane-7-base) methyl propionate (isomer A) (200mg, LDA (0.632mL, 1.26mmol) is dropwise added in solution 0.421mmol) in anhydrous THF (4.0mL).Under-78C, stir this mixture 30min, then dropwise add iodomethane (179mg, 1.26mmol) in this mixture.Under-78C, stir this reactant mixture 1h, then use water (5.0mL) cancellation.Water phase separated also extracts with EtOAc (5mL × 3).With the organic layer that water (5.0mL) and saline (5.0mL) washing merge, dry and filter through anhydrous MgSO.Under reduced pressure concentrated filtrate.By preparative TLC (PE:EtOAc=5:1, v/v) purification gained residue is to provide 3-cyclobutyl-3-(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-the base)-2 Methylpropionic acid methyl ester of two kinds of enantiomeric mixture forms.
Step B:(2S, 3S)-3-cyclobutyl-3-((R or S)-(2-(fluoro-5'-methoxyl group-[1 of 2'-, 1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester and (2R, 3S)-3-cyclobutyl-3-((R or S)-(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester
Post is used: ChiralpakAD-3150 × 4.6mmI.D. by SFC, 3um mobile phase: 40% methanol (0.05%DEA) flow velocity in CO: 2.5mL/min wavelength: 254nm is separated the product (165mg from steps A, 0.338mmol) to provide 3-cyclobutyl-3-(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester (isomer AA); With 3-cyclobutyl-3-(2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester (isomer AB).
Step C:(2S, 3S)-3-cyclobutyl-3-((R or S)-2-(the fluoro-5'-methoxyl group of 2'--[1,1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid
To 3-cyclobutyl-3-(2-(the fluoro-5'-methoxyl group-[1 of 2'-, 1'-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid methyl ester (isomer AA) (83.0mg, LiOH (143mg, 3.40mmol) is added in solution 0.170mmol) in THF (1.0mL), MeOH (1.0mL) and HO (1.0mL).This reactant mixture 12h is stirred at 50 DEG C.Then HCl aqueous solution (1.0M) is added in this solution to regulate pH to 5.EtOAc (5mL × 3) is adopted to extract this solution.The under reduced pressure concentrated organic layer merged.By preparation HPLC (assembling PhenomenexSynergiC18100*21.2mm*4um GILSON281 instrument on use water and acetonitrile as eluent. mobile phase A: water is (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile. gradient: 72-92%B, 0-10min; 100%B, 10.5-12.5min; 5%B, 13-15min) purification gained residue.
1HNMR(400MHz，CDCl
3)δ7.58(d，J＝7.6Hz，2H)，7.50(d，J＝8.4Hz，2H)，7.08(t，J＝9.6Hz，1H)，6.99～6.95(m，2H)，6.86～6.83(m，1H)，6.71～6.66(m，2H)，5.08(d，J＝8.4Hz，1H)，3.84(s，3H)，3.02～2.70(m，5H)，2.25～2.09(m，3H)，1.85～1.68(m，4H)，1.53～1.52(m，1H)，1.13(d，J＝7.2Hz，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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 15mg
(2) (2S, 3S)-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-the base)-2 Methylpropionic 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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt of 10-20mg
(2) (2S, 3S)-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-the base)-2 Methylpropionic 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-propoxyl group naphthalene-2-base)-1,1-dioxo-[1,2,5] thiadiazolidine-3-ketone potassium salt is less than 1 with the ratio of (2S, 3S)-3-cyclobutyl-3-((R or S)-2-(2 '-fluoro-5 '-methoxyl group-[1,1 '-biphenyl]-4-base) chromane-7-base)-2 Methylpropionic acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101365441A (en) * | 2005-12-19 | 2009-02-11 | 詹森药业有限公司 | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
| 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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- 2015-11-11 CN CN201510767479.6A patent/CN105232544A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101365441A (en) * | 2005-12-19 | 2009-02-11 | 詹森药业有限公司 | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
| 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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Application publication date: 20160113 |