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，CDCl3)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，CDCl3)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.