CN105250277A - Orally-administered drug composition for resisting diabetes - Google Patents
Orally-administered drug composition for resisting diabetes Download PDFInfo
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- CN105250277A CN105250277A CN201510767496.XA CN201510767496A CN105250277A CN 105250277 A CN105250277 A CN 105250277A CN 201510767496 A CN201510767496 A CN 201510767496A CN 105250277 A CN105250277 A CN 105250277A
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Abstract
The invention discloses an orally-administered drug composition for resisting diabetes. The composition is prepared from 10-20 mg of 5-(3-hydroxy-7-propoxynaphthalene-2-group)-1, 1-dioxo-[1, 2, 5] alkyl thiadiazole-3-ketone sylvite, 20-30 mg of (2S, 3R)-3-((R)-3- (1-(2, 5-bi- (trifluoromethyl) benzyl) -azacyclo-cyclobutane-3-group)-2, 3-dihydrobenzo [b] [1, 4] dioxa cyclohexadiene-6-group)-3-cyclopropyl-2-methyl propionate, 200-300 mg of microcrystalline cellulose, 10-25 mg of crosslinked sodium carboxymethylcellulose and 1-8 mg of magnesium stearate, and the composition is obtained by compounding two different types of active matter. On the premise that the same treatment effect is achieved, usage amount of the drug active matter is lowered by 1/2 at a minimum.
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) (the 2S of 20-30mg, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid
(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, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] Dioxin-6-base) ratio of-3-cyclopropyl-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, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid
(2S, 3R)-3-((R)-3-(1-((R)-1-(2, two (trifluoromethyl) phenyl of 5-) ethyl) azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid
Steps A: divide several parts to 3-vinyl azetidine-1-formic acid esters (1.75g, 9.6mmol) be suspended in the agitating solution in-BuOH (37.00mL) and HO (37.00mL) and add AD-MIX-ALPHA (13.4g, 9.6mmol, SigmaAldrich).Stir this reaction 20h at ambient temperature, then with HO dilution, and extract with EtOAc.With the organic extract that saline (1x) washing merges, dry through MgSO, filter, and concentrate under vacuo.Use the gradient-purified gained residue of 0-100%EtOAc/ hexane to provide (S)-3-(1,2-dihydroxy ethyl) azetidine-1-formic acid esters by silica gel column chromatography (ISCO system, RediSep40g post).
Step B: to (S)-3-(1,2-dihydroxy ethyl) azetidine-1-formic acid esters (1.9g, imidazoles (0.6g is added in solution 8.8mmol) in CHCl (25mL), 8.8mmol) with chlorodiphenyl base silane (2.2mL, 8.8mmol).Stirring at ambient temperature after 20 minutes, filtering gained precipitate and concentrated filtrate under vacuo by crossing.0-65%EtOAC/ hexane is used as the gradient-purified gained residue of eluent to provide (S)-3-(2-((diphenylsilyl group) oxygen base)-1-hydroxyethyl) azetidine-1-t-butyl formate by silica gel column chromatography (ISCO system, RediSep80g post).
Step C: to (S)-3-(2-((diphenylsilyl group) oxygen base)-1-hydroxy-ethyl) azetidine-1-t-butyl formate (0.39g at-50 DEG C, TEA (0.18mL is added in solution 0.9mmol) in CHCl (5mL), 1.3mmol) with MsCl (0.1mL, 1.2mmol).After 20min, adopt this reaction of saturated NHCl aqueous solution cancellation and make it be warmed to room temperature.Then organic layer is separated; dry through MgSO; filter and concentrate to provide (S)-3-(2-((diphenylsilyl group) oxygen base)-1-methylsulfonylethyl) azetidine-1-t-butyl formate, it uses immediately in the next step.
Step D: by (2S; 3R)-3-cyclopropyl-3-(3-hydroxyl-4-iodophenyl)-2 Methylpropionic acid methyl ester (68mg; 0.19mmol); CsCO (122mg; 0.3mmol) be heated to 65 DEG C of lasting 12h with ()-3-(2-((diphenylsilyl group) oxygen base)-1-methylsulfonylethyl) agitating solution of azetidine-1-t-butyl formate (100mg, 0.19mmol) in DMF (2mL).Then wash this reactant mixture with HO, and extract with EtOAc (3x50mL).With the organic layer that salt water washing merges, dry through MgSO, filter, and it is concentrated to provide crude product, it is by ISCO (4g, 0-20%EtOAc/ hexane) purification to be to provide 3-((R)-2-((t-butyldiphenylsilyl) oxygen base)-1-(5-((1R, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2-iodine phenoxy group) ethyl) azetidine-1-formic acid esters.LC/MS：m/e798.92(M+H)
+。
Step e: to 3-((R)-2-((t-butyldiphenylsilyl) oxygen base)-1-(5-((1R, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2-iodine phenoxy group) ethyl) azetidine-1-formic acid esters (45mg, TBAF (0.1mL is dropwise added in solution 0.06mmol) in THF (6mL), 0.1mmol, 1M are in THF).Stir this reaction 30min, then pour in EtOAc and HO with the cancellation of saturated NHCl aqueous solution.Be separated each layer, and with the organic layer that salt water washing merges, dry through MgSO, filter, and be concentrated under vacuo on silica gel.By column chromatography (ISCO system, RediSep24g post) use 0-30-80%EtOAc/ hexane as the gradient-purified crude product of eluent to provide 3-((R)-1-(5-((1R, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2-iodine phenoxy group)-2-hydroxyethyl) azetidine-1-formic acid esters.LC/MS：m/e560.72(M+H)
+。
Step F: purge 3-((R)-1-(5-((1R with N, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2-iodine phenoxy group)-2-hydroxyethyl) azetidine-1-formic acid esters (113mg, 0.2mmol), Pd (OAc) (4.5mg, 0.02mmol), Trixiephos (16mg, 0.02mmol, Strem), with CsCO (132mg, solution 0.4mmol) in toluene (4mL) 10 minutes, is then heated to 50 DEG C of lasting 14h under N.Then, cool this reaction, and dilute with EtOAc.Be separated organic layer, with HO and saline (2x) washing, dry through MgSO, filter, and concentrate under vacuo.By silica gel column chromatography (ISCO system, RediSep24g post) use 0-30%EtOAc/ hexane as the gradient-purified gained residue of eluent to provide 3-((R)-7-((1R, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-2-base) azetidine-1-formic acid esters.LC/MS：m/e432.69(M+H)
+。
Step G: at room temperature to 3-((R)-7-((1R, 2S)-1-cyclopropyl-3-methoxyl group-2-methyl-3-oxopropyl)-2,3-dihydrobenzo [b] [1,4] Dioxin-2-base) azetidine-1-formic acid esters (120mg, TFA (0.2mL, 2.63mmol) is added in solution 0.3mmol) in DCM (5mL).At room temperature stir gained solution 3h, then by being concentrated into dry to provide (2S with methylbenzene azeotropic, 3R)-3-((R)-3-(azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid methyl ester.LC/MS：m/e446.43(M+H)
+。
Step H: at room temperature to (2S, 3R)-3-((R)-3-(azetidine-3-base)-2,3-dihydrobenzo [b] [1,4] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid methyl ester (114mg, (R)-1-(2 is added in solution 0.3mmol) in acetonitrile (3mL), two (trifluoromethyl) phenyl of 5-) ethyl methane sulfonate ester (114mg, 0.4mmol) with CsCO (300mg, 0.9mmol).At 60 DEG C, stir this reaction 12h, then with HO dilution, and extract with EtOAc (3x10mL).With the organic layer that saline (3x10mL) washing merges, dry through MgSO, filter, concentrated.By MPLC (ISCO, 4g, 0-50%EtOAc/ hexane) purification of crude product to be to provide (2S, 3R)-3-((R)-3-(1-((R)-1-(2, two (TRIFLUORO-METHYL) phenyl of 5-) ethyl) azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid methyl ester.LC/MS：m/e572.63(M+H)
+。
Step I: at room temperature to (2S, 3R)-3-((R)-3-(1-((R)-1-(2, two (the trifluoromethyl)-phenyl of 5-) ethyl) azetidine-3-base)-2,3-dihydrobenzo [b] [1,4] Dioxin-6-base) add LiOH in the solution of-3-cyclopropyl-2 Methylpropionic acid methyl ester (84mg, 0.1mmol) in THF (0.75ml)/MeOH (0.75ml)/water (0.5ml).At 55 DEG C, stir this reaction 12h, then with HO dilution, and become pH4-5 with 1NHCl acidify.This reactant mixture is extracted with EtOAc (3x).With the organic layer that salt water washing merges, dry through MgSO, filter, and concentrated to provide crude product, it passes through ISCO (4g, 0-100%EtOAc/ hexane) purification to provide (2S, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid.
1hNMR (500MHz, the third bronze medal): δ (ppm) 0.01 (m, 1H); 0.26 (m, 2H); 0.57 (m, 1H); 0.93 (d, J=6.9Hz, 1.12 (m, 1H); 1.25-1.21 (m, 3H); 1.97 (m, 1H); 2.74 (m, 2H); 3.27-3.18 (m, 2H); 3.50-3.44 (m, 1H); 3.89-3.78 (m, 2H); (4.06 q, J=7.1Hz, 1H); 4.35-4.28 (m, 2H); 6.79-6.70 (m, 3H); (7.82 t, J=7.1Hz, 1H); (7.95 t, J=7.8Hz, 1H); (8.27 s, 1H).
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) (the 2S of 30mg, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid
(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) (the 2S of 20-30mg, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base)-3-cyclopropyl-2 Methylpropionic acid
(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 and (2S, 3R)-3-((R)-3-(1-(2, two (trifluoromethyl) benzyl of 5-)-azetidine-3-base)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] Dioxin-6-base) ratio of-3-cyclopropyl-2 Methylpropionic acid is less than 1.
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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 (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》 * |
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Application publication date: 20160120 |