CN104248633B - Dulcitol potassium sulfate ester or dulcitol sodium sulfate ester and preparation method and application thereof - Google Patents
Dulcitol potassium sulfate ester or dulcitol sodium sulfate ester and preparation method and application thereof Download PDFInfo
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- CN104248633B CN104248633B CN201410488368.7A CN201410488368A CN104248633B CN 104248633 B CN104248633 B CN 104248633B CN 201410488368 A CN201410488368 A CN 201410488368A CN 104248633 B CN104248633 B CN 104248633B
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- dulcitol
- sodium
- sulfuric ester
- winged euonymus
- potassium
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Abstract
The invention discloses dulcitol potassium sulfate ester or dulcitol sodium sulfate ester. The dulcitol potassium sulfate ester or dulcitol sodium sulfate ester is prepared according to the steps of firstly generating dulcitol sulfate ester by reacting dulcitol as the raw material and formamide and chlorosulfonic acid which are added inside, and then carrying out neutralization by adding potassium hydroxide or a potassium hydroxide solution to generate dulcitol potassium sulfate ester or dulcitol sodium sulfate ester. The dulcitol potassium sulfate ester or dulcitol sodium sulfate ester has the function of treating chronic renal failure.
Description
【Technical field】
The present invention relates to a kind of preparation method, in particular to a kind of winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate
Preparation method.
【Background technology】
Dulcitol (Dulcitol), also known as sweet and pure, galactitol, hexanhexol.Structural formula is HOCH2(CHOH)4CH2OH,Molecular weight：182.18, it is colourless monocline column crystallization.Taste is micro- sweet.It is slightly soluble in alcohol and ether；It is dissolved in
PH is 4-7 during water, is particularly soluble in boiling water.Colorless crystalline powder.Taste is micro- sweet.1g is dissolved in 2ml boiling water, 30ml cold water, micro-
It is dissolved in ethanol.Relative density (d20) 1.47.188～189 DEG C of fusing point.275～280 DEG C of boiling point (0.13kPa).Dulcitol was once
It is used clinically for treating rheumatoid for many years, there is certain effect.But there is spreading out for biological activity by Material synthesis of dulcitol
Biological research is not a lot, it is therefore desirable to provide a kind of derivant as Material synthesis with dulcitol with biological activity
Method.
【The content of the invention】
The invention provides a kind of derivant winged euonymus alcohol sulfuric ester potassium of dulcitol or dulcitol sodium sulfovinate and its preparation
Method, present invention also offers winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate are sick as treatment chronic renal failure is prepared
The application of medicine.
For achieving the above object, the present invention is employed the following technical solutions：
A kind of winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate, with dulcitol as raw material, add Methanamide, at 1-5 DEG C
Temperature range under, Deca chlorosulfonic acid at a temperature of 60-60 DEG C, is reacted, after the completion of reaction, add ethanol make life
Into winged euonymus alcohol sulfuric ester precipitation, after being precipitated with washing with alcohol winged euonymus alcohol sulfuric ester, potassium hydroxide or potassium hydroxide solution are added, it is raw
Into winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate.
A kind of preparation method of winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate, the method is comprised the following steps：
With dulcitol as raw material, Methanamide, Deca chlorosulfonic acid at 1-5 DEG C is added after reacting at 60-65 DEG C, to add second
Alcohol obtains winged euonymus alcohol sulfuric ester precipitation, after being precipitated with washing with alcohol, adds potassium hydroxide or sodium hydroxide molten in gained precipitation
Liquid, generates winged euonymus alcohol sulfuric ester potassium or sodium solution.
Preferably, the preparation method of a kind of winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate, the dulcitol sulfur that will be formed
Acid esters potassium or sodium solution, respectively by anions and canons exchange column, then with the potassium hydroxide or hydroxide of 5-15% percentage by weights
Sodium solution adjusts pH to 7.5-8.5, and Jing after ethanol is precipitated, centrifugation is dried, and obtains winged euonymus alcohol sulfuric ester potassium or dulcitol sulfur
Acid esters sodium.
Another preferred, the ratio of the amount of dulcitol and Methanamide is 1000 grams：30～50 liters.
Another preferred, the ratio of the amount of dulcitol and chlorosulfonic acid is 1000 grams：2～5 liters.
Another preferred, the concentration of the ethanol is 75-85% percetages by weight.
Another preferred, the washing with alcohol is precipitated as with the washing with alcohol winged euonymus of 75-85% weight percent concentrations
Alcohol sulfuric ester is precipitated 2-4 time.
Another preferred, the concentration of potassium hydroxide or sodium hydroxide solution is 5-15% mass percents.
Winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate are obtained by said method.
The compound of winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate treats chronic renal failure disease medicine as preparing
The application of thing.
From the chemical structure analysis of dulcitol, with reference to dulcitol clinically using when the side effect analysis that finds, winged euonymus
Alcohol sulfuric ester sodium can be used to improve the auxiliary treatment of microcirculation and chronic renal failure.Can with heavy dose of adenine raising rat
Cause tubular degeneration, necrosis, come off, glomerule destruction and quantity are reduced.Performance metabolism disorder, azotemia, uremic toxinses
It is detained in vivo, it is similar to human body chronic kidney hypofunction.
1st, test of pesticide effectiveness preliminary observation effect of the dulcitol sodium sulfovinate to adenine inducing chronic renal failure.
A. materials and methods
Material：Lewis is sheerly rat, and male, body weight about 200g, adenine is the subpackage import of Shanghai biochemical research institute
Reagent, dulcitol sodium sulfovinate sodium is self-control sample.
B. experimental technique
B.1 packet divides at random 4 groups with male rat 32 is raised, 8 per group, i.e. blank control group (A groups), adenine group
(B groups), adenine add low dose of dulcitol sodium sulfovinate group (C groups), adenine escalated dose dulcitol sodium sulfovinate group (D
Group).Continued with former forage feed with A groups after commercial solid forage feed 3 days, other groups plus adenine or/and add dulcitol sulfur
Acid esters sodium.Adenine consumption is 0.75% (300mg/kg/d), and dulcitol sodium sulfovinate consumption is shown in Table 1.
Table 1
Raise and anaesthetized with 3% pentobarbital sodium after 21d, heart extracting blood is cut open the belly and takes kidney.
B.2 conclusion：Adenine escalated dose dulcitol sodium sulfovinate group (D groups) can cause tubular degeneration, bad without discovery
Extremely, come off, glomerule destruction, the phenomenon that quantity is reduced.Show dulcitol sodium sulfovinate to rat chronic renal failure caused by adenine
There is protective effect.
2nd, the mitigation effect that dulcitol is damaged to Renal of Diabetic Rats function and structure.
A methods：Diabetes rat male rat 16 divides at random 2 groups, 8 per group, i.e. blank control group (A groups), winged euonymus
Alcohol sulfuric ester sodium group (B groups).After processing 14 weeks using dulcitol sodium sulfovinate (1% drinking-water), renal function and structure are checked
The extent of damage.
B results：Compared with control rats, blood glucose in diabetic rats, serum creatinine (Scr), blood urea nitrogen (BUN) level and
Urinary albumin excretion is significantly raised.Using dulcitol sodium sulfovinate process blood sugar level is substantially reduced, but Scr, BUN and
Urinary albumin excretion is decreased obviously.After giving dulcitol sodium sulfovinate, the elevated glomerular volume/body of diabetes rat is made
Anharmonic ratio is substantially reduced.Diabetic glomeruli basement membrane is thickened in segmental, epithelium podocytic process partial fusion and filtration intermembrane space
Increase.These ultrastructural changes are obviously improved after the process of dulcitol sodium sulfovinate.
Conclusion：Dulcitol sodium sulfovinate has obvious mitigation to act on the infringement of Renal of Diabetic Rats function and structure.
3rd, dulcitol sodium sulfovinate causes the therapeutical effect of Nephrotic Syndrome in Rats to injecting Cationic bovine serum albumin
A. method：Male SD rat 30 is chosen, 6 is randomly selected for matched group, remaining rat enters modeling.Modeling is big
Mus give subcutaneous multi-point injection Cationic bovine serum albumin (C-BSA) totally 4 weeks to make nephropathy model.Model is set up after 4 weeks
Success, survival rats are randomly divided into 3 groups, respectively model group, Low molecular heparin group and winged euonymus alcohol sulfuric ester group.Low molecular heparin
Group is treated 4 weeks with Low molecular heparin lumbar injection 4 weeks, dulcitol sodium sulfovinate tail vein injection, and matched group and model group give
Physiological saline solution tail vein injection.Detect respectively before each group rat experiment and the 24h at the 4th weekend and the 8th weekend urinates after experiment
Protein quantification (U-TP), serum urea nitrogen (BUN), creatinine (Cr), albumin (ALB), triglyceride (TG), cholesterol (TC).
B. result：1. the 4th week each group urine protein is significantly raised after testing, and the twenty-four-hour urine albumen at the weekend of each treatment group 8 is determined
Measure to compare with 4 weekends and significantly reduce (P ＜ 0.01), and substantially less than model group (P ＜ 0.05), without substantially poor between each treatment group
It is different；2. no significant difference between 3 groups of change of serum C r, BUN level.Model group TG, TC substantially rises (P ＜ 0.0.5) compared with normal group,
Model group ALB level is decreased obviously (P ＜ 0.05) compared with normal group.Cr, BUN level after each treatment group's treatment is significantly lower than model
Group (P ＜ 0.05).There was no significant difference compared with model group for TG levels after each group treatment.TC levels after each group treatment are obvious
It is substantially back to normal less than model group (P ＜ 0.01).The hypoproteinemia for the treatment of group is significantly improved after the treatment (P ＜
0.01)。
Conclusion：Dulcitol sodium sulfovinate can reduce urine protein, improve hyperlipemia, reduce blood urea nitrogen, reduce creatinine；
Reduce urine protein and improve hyperlipemia and hypoproteinemia aspect, dulcitol sodium sulfovinate and Low molecular heparin have no obvious area
Not.
4th, dulcitol sodium sulfovinate improves microcirculation
The hemorheology test of dulcitol sodium sulfovinate
A. method：The whole blood thixotroping ginseng of 30 patients with chronic renal failure is determined using Low shear-30 rheometry instrument
Number, after having taken dulcitol sodium sulfovinate, determines each patient whole blood's thixotroping parameter and packed cell volume (HCT) and blood plasma is glutinous
Each blood drawing 5ml, uses EDTA anticoagulants before and after degree (η p) medication, using miniature erythrocyte pressure year product instrument (Damon/Iecdvision,
Needham height, Massachusetts) packed cell volume of each standard is determined, yield stress (CO) is calculated respectively,
The non newtonian component (η s- μ) of apparent viscosities (η s) and viscosity of the newton component μ of viscosity in 2.37S-1, structural parameters balance
Speed constant (ARC) result of value (A) and folded even depolymerization reaction is as follows：
| Inspection project | Detected value | After taking |
| HCT packed cell volumes | 0.45 | 0.43 |
| Η p (Plasma Viscosity) | 1.71 | 1.57 |
| τ (yield stress) | 12.36 | 8.78 |
| μ (the newton component of viscosity) | 9.72 | 9.12 |
| η s (apparent plasma viscosity) | 18.43 | 13.25 |
| η s- μ (viscosity non newtonian component) | 5.32 | 4.12 |
| A (Equilibrium value of structure parameter) | 0.24 | 0.16 |
| ARC (folded even depolymerization reaction speed constant) | 0.39 | 0.42 |
Conclusion：After having taken dulcitol sodium sulfovinate, hemorheology index is improved.
Dulcitol sulfuric ester sodium salt 0.2g/kg and 0.1g/kg intravenous injection can respectively suppress ADP and collagen-induced rat
Platelet aggregation.With ↑ 3H-5HT labelling platelet, in observing the relation of platelet aggregation and release reaction, its sodium salt 1-2mg/
Ml has substantially suppression to the platelet aggregation of thrombin induction, at the same also suppression ↑ 3H-5HT discharge from platelet ↑.In ischemia
Property curing apoplexy in, blood viscosity can be reduced to increase brain microcirculation by inhibition thrombosis.Experimental result table is made with rat
Bright dulcitol sodium sulfovinate can strengthen antiplatelet effects with low-dose aspirin combination.Platelet aggregation and release reaction with
Platelet produces endoperoxide PGG2, PGH2 and thromboxane A2 (TXA2) of prostaglandin by arachidonic acid (AA) metabolism
It is relevant.TXA2 can be directly translated into TXB2, and PGH2 not only synthesizes TXA2, also be partially converted into malonaldehyde (MDA).The generation of MDA
Amount can reflect that TXA2 is generated.MDA contents when colorimetry and fluorescence spectrometry platelet aggregation.As a result show that winged euonymus sodium alkoxide suppresses
Platelet aggregation and release reaction effect may suppress TXA2 to generate relevant with suppression platelet prostaglandin metabolism.Winged euonymus
Alcohol sulfuric ester sodium can increase renal blood flow, and with renal medulla the effect of vascular prostaglandin-like is expanded.
With immediate prior art ratio, the beneficial effect of technical scheme that the present invention is provided is：Sulfur is carried out to dulcitol
Acidifying modification, the dulcitol sodium sulfovinate or potassium of gained have good effect in terms for the treatment of chronic renal failure disease is prepared.
Dulcitol sodium sulfovinate or potassium have obvious mitigation to act on the infringement of Renal of Diabetic Rats function and structure, dulcitol sodium sulfovinate
Or potassium can reduce urine protein, improve hyperlipemia, reduce blood urea nitrogen, reduce creatinine；Reduce urine protein and improve hyperlipemia
Disease and hypoproteinemia aspect, dulcitol sodium sulfovinate or potassium and Low molecular heparin have no significant difference.Dulcitol sodium sulfovinate
Or potassium can increase renal blood flow, with renal medulla the effect of vascular prostaglandin-like is expanded.
【Specific embodiment】
Embodiment 1
1000 grams of dry dulcitol is taken, in being placed in sulphonation kettle, 35 liters of Methanamide is added, is stirred, outside sulphonation kettle,
Brine ice cooling is passed through, while stirring 4 liters of Deca chlorosulfonic acid, keeps the temperature in sulphonation kettle to exist during Deca chlorosulfonic acid
1-5 DEG C, after Deca chlorosulfonic acid is finished, reactant is warming up to into 65 DEG C and is reacted；After completion of the reaction, ethanol is added, makes ethanol
Concentration be 75% percetage by weight so as to generate winged euonymus alcohol sulfuric ester precipitation；Washed with the ethanol of 75% weight percent concentrations
Wash winged euonymus alcohol sulfuric ester to precipitate 3 times；With the sodium hydroxide solution of 10% weight percent concentrations, pH to 7.5 is adjusted, generate winged euonymus
Alcohol sulfuric ester sodium solution；The dulcitol sodium sulfovinate solution that will be formed, respectively Jing anions and canons exchange columns, refine, then with 10%
The potassium hydroxide of percentage by weight or sodium hydroxide solution adjust the ethanol of the weight percent concentrations of pH to 7.5, Jing 75% and carry out
After precipitation, centrifugation is dried, and obtains dulcitol sodium sulfovinate.
The clinical trial of embodiment 2
30 experimenters, oral dulcitol sodium sulfovinate, each 0.15g three times a day, has no adverse reaction after medication, right
Patients of chronic renal failure has different degrees of curative effect.
Example 1 is male, 70 years old age, with uremia.Long-term inpatients take dulcitol sodium sulfovinate one month, plasma urea nitrogen
By 11.3mmol/L, 6.8mmol/L is reduced to, plasma cholesterol is down to 4.8mmol/L by 5.5mmol/L, and creatinine is by 600 μ
Mol/L is reduced to 220 μm of ol/L.
Example 2 is male, 57 years old age, containing uremia.Take dulcitol sodium sulfovinate two months, plasma urea nitrogen by
10.2mmol/L, is reduced to 6.6mmol/L, and plasma cholesterol is down to 4.8mmol/L by 5.4mmol/L, and creatinine is by 1000 μm of ol/
L is reduced to 220 μm of ol/L, and triglyceride 1.35mmol/L is down to 0.75mmol/L.
The female of example 3,66 years old age, with uremia.Take dulcitol sodium sulfovinate two months, plasma urea nitrogen by
8.4mmol/L, is reduced to 4.8mmol/L, and plasma cholesterol is down to 4.8mmol/L by 7.3mmol/L, and creatinine is by 800 μm of ol/L
It is reduced to 200 μm of ol/L.
It is only above the detailed description that presently preferred embodiments of the present invention is carried out, but the present invention is not limited to above reality
Apply example.It should be understood that in the case of the spirit and scope without departing from claims hereof, those skilled in the art
The various modifications made, still fall within the scope of the present invention.
Claims (4)
1. the preparation method of a kind of winged euonymus alcohol sulfuric ester potassium or sodium, it is characterised in that：Methods described comprises the steps：
With dulcitol as raw material, addition Methanamide, Deca chlorosulfonic acid at 1-5 DEG C, after reacting at 60-65 DEG C, addition concentration is 75-
The ethanol of 85% percetage by weight obtains winged euonymus alcohol sulfuric ester precipitation, with the washing with alcohol that concentration is 75-85% percetages by weight
After precipitation, potassium hydroxide or sodium hydroxide solution are added in gained precipitation, generate winged euonymus alcohol sulfuric ester potassium or sodium solution；
By the winged euonymus alcohol sulfuric ester potassium for being formed or sodium solution, respectively by anions and canons exchange column, then 5-15% weight percents are used
The potassium hydroxide of ratio or sodium hydroxide solution adjust pH to 7.5-8.5, and Jing concentration is carried out for the ethanol of 75-85% percetages by weight
After precipitation, centrifugation is dried, and obtains winged euonymus alcohol sulfuric ester potassium or dulcitol sodium sulfovinate；
The ratio of the amount of dulcitol and Methanamide is 1000 grams：30～50 liters；
The compound of winged euonymus alcohol sulfuric ester potassium or sodium according to obtained in methods described is for preparing treatment chronic renal failure
The winged euonymus alcohol sulfuric ester potassium or the compound of sodium of medicine.
2. the preparation method of winged euonymus alcohol sulfuric ester potassium according to claim 1 or sodium, it is characterised in that：Dulcitol and chlorine sulphur
The ratio of the amount of acid is 1000 grams：2～5 liters.
3. the preparation method of winged euonymus alcohol sulfuric ester potassium according to claim 1 or sodium, it is characterised in that：It is 75- with concentration
The washing with alcohol winged euonymus alcohol sulfuric ester of 85% percetage by weight is precipitated 2-4 time.
4. the preparation method of winged euonymus alcohol sulfuric ester potassium according to claim 1 or sodium, it is characterised in that：Potassium hydroxide or hydrogen
The concentration of sodium hydroxide solution is 5-15% mass percents.
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