CN105232545A - Antidiabetic oral drug composition - Google Patents
Antidiabetic oral drug composition Download PDFInfo
- Publication number
- CN105232545A CN105232545A CN201510767527.1A CN201510767527A CN105232545A CN 105232545 A CN105232545 A CN 105232545A CN 201510767527 A CN201510767527 A CN 201510767527A CN 105232545 A CN105232545 A CN 105232545A
- Authority
- CN
- China
- Prior art keywords
- base
- drug composition
- biphenyl
- dimethyl
- oral drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses an antidiabetic oral drug composition. The antidiabetic oral drug composition is prepared from 10-20 mg of 5-(3-hydroxyl-7-methoxynaphthalene-2-yl)-1,1-dioxo-[1,2,5]thiadiazolidine-3-keto-kali salt, 20-30 mg of 3-(2-(2',6'-dimethyl-[1,1'-biphenyl]-3-yl)benzodihydropyran-6-yl)propionic acid, 200-300 mg of microcrystalline cellulose, 10-25 mg of croscarmellose sodium and 1-8 mg of magnesium stearate. According to the antidiabetic oral drug composition, through compounding of two different types of active matter, on the premise of achieving the same treatment effect, the usage amount of the active matter of the drug is decreased by at least one half.
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) 3-(2-(2', 6'-dimethyl-[1,1'-the biphenyl]-3-base) chromane-6-base) propanoic 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 3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) ratio of propanoic acid is less than in 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.3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) propanoic acid
Steps A: (E)-3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) acrylic acid methyl ester..
To containing the bromo-2-(2' of 6-, 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane (165mg, 0.420mmol), Pd (dba) (7.68mg, 8.39 μm of ol), and add dioxane in the bottle of the nitrogen purging with Teflon nuts sealing of tri-butyl phosphine (3.39mg, 0.017mmol).Then, by syringe interpolation-cyclohexyl--methyl cyclohexylamine (90mg, 0.461mmol) and acrylic acid methyl ester. (0.076ml, 0.839mmol).At room temperature stir this mixture 12h.Then, this reactant mixture is poured in water (10mL), then use ether (2x10mL) to extract.The organic layer drying (MgSO4) that merges is concentrated.By HPLC (ISCO24g cylinder, 0 to 50%EA/Hex) purification gained residue to provide title compound.
1HNMR(500MHz，CDCl3)δ7.65(d，1H)，7.51-7.10(m，9H)，6.94(d，1H)，6.34(d，1H)，5.19(d，1H)，3.81(s，3H)，3.02(m，1H)，2.82(m，1H)，2.31(m，1H)，2.13(m，1H)，2.04(d，6H).
Step B:3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) methyl propionate.
To (E)-3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) acrylic acid methyl ester. (135mg, Pd (OH) (20%wt is added in EtOAc (2mL) solution 0.339mmol), 13mg, 0.019mmol).Purge this mixture and use hydrogen balloon (1atm) backfill.This mixture of strong agitation 1h in a hydrogen atmosphere.Then filter this reactant mixture by Celite and concentrate under vacuo.By HPLC (0 to 50%EA/Hex) purification gained residue to provide product.
1HNMR(500MHz，CDCl
3)δ7.52-7.41(m，2H)，7.24-7.12(m，5H)，7.00(d，1H)，6.98(s，1H)，6.87(d，1H)，5.12(d，1H)，3.72(s，3H)，3.00(m，1H)，2.91(t，2H)，2.80(dt，1H)，2.62(t，2H)2.25(m，1H)，2.12(m，1H)2.08(d，6H).
Step C:3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) propanoic acid.
To 3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) the THF/MeOH/ water (1:1:1 of methyl propionate (120mg, 0.30mmol), 1.5mL) add LiOH (72mg, 3.0mmol) in solution.Then on heat block, this reaction is heated to 60 DEG C.After 12h, this reaction poured into 1NHCl (10mL) and extract with EtOAc (2x10mL).The organic layer drying (MgSO) that merges is concentrated.By HPLC (ISCO, 24g, 0 to 50%MeOH/DCM) purification gained residue to provide product.
1HNMR(500MHz，CDCl
3)δ7.47(m，2H)，7.24-7.12(m，5H)，7.00(m，2H)，6.90(d，1H)，5.14(d，1H)，3.01(m，1H)，2.95(t，2H)，2.80(dt，1H)，2.70(t，2H)，2.24(m，1H)，2.15(m，1H)，2.04(d，6H).
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) 3-(2-(2', 6'-dimethyl-[1,1'-the biphenyl]-3-base) chromane-6-base) propanoic 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) 3-(2-(2', 6'-dimethyl-[1,1'-the biphenyl]-3-base) chromane-6-base) propanoic 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] ratio of thiadiazolidine-3-ketone potassium salt and 3-(2-(2', 6'-dimethyl-[1,1'-biphenyl]-3-base) chromane-6-base) propanoic acid is less than in 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510767527.1A CN105232545A (en) | 2015-11-11 | 2015-11-11 | Antidiabetic oral drug composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510767527.1A CN105232545A (en) | 2015-11-11 | 2015-11-11 | Antidiabetic oral drug composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105232545A true CN105232545A (en) | 2016-01-13 |
Family
ID=55030545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510767527.1A Pending CN105232545A (en) | 2015-11-11 | 2015-11-11 | Antidiabetic oral drug composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105232545A (en) |
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 |
-
2015
- 2015-11-11 CN CN201510767527.1A patent/CN105232545A/en active Pending
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 (1)
| Title |
|---|
| 万祺 等: "治疗2型糖尿病新靶标及新先导化合物的研究进展", 《中国新药杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5002077B2 (en) | Novel 3-hydroxy-5-arylisothiazole derivatives | |
| MX2013012520A (en) | Novel 3-hydroxyisothiazole 1-oxide derivative. | |
| US9193756B2 (en) | Adrenomedullin production enhancer | |
| CN104557944B (en) | A kind of hypoglycemic medicine and preparation method thereof | |
| CN105232545A (en) | Antidiabetic oral drug composition | |
| CN102030709B (en) | Benzazepines compounds serving as vasopressin receptor antagonism | |
| CN105412095A (en) | Anti-diabetes oral drug composition | |
| CN105287532A (en) | Anti-diabetic orally-administered pharmaceutical composition | |
| CN105232543A (en) | Anti-diabetic oral drug composition | |
| CN105287531A (en) | Anti-diabetic orally-administered pharmaceutical composition | |
| CN105193801A (en) | Diabetes mellitus resistant oral medicine composition | |
| CN105232544A (en) | Anti-diabetic oral drug composition | |
| CN105287533A (en) | Anti-diabetes oral pharmaceutical composition | |
| CN105213386A (en) | A kind of diabetes combination of oral medication | |
| CN105193821A (en) | Diabetes mellitus resistant oral medicine composition | |
| CN105287534A (en) | Anti-diabetes oral pharmaceutical composition | |
| CN105250276A (en) | Orally-administered drug composition for resisting to diabetes | |
| CN105287535A (en) | Anti-diabetes oral pharmaceutical composition | |
| CN105232547A (en) | Anti-diabetic oral drug composition | |
| CN105250277A (en) | Orally-administered drug composition for resisting diabetes | |
| CN105213380A (en) | A kind of diabetes combination of oral medication | |
| CN105213382A (en) | A kind of diabetes combination of oral medication | |
| CN105232552A (en) | Anti-diabetic oral drug composition | |
| CN105213379A (en) | A kind of diabetes combination of oral medication | |
| CN105476990A (en) | Oral anti-diabetic pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160113 |
|
| WD01 | Invention patent application deemed withdrawn after publication |