CN104892663A - Vanadium coordination compound using aminotriacetic acid derivative as ligand, and preparation method and application thereof - Google Patents
Vanadium coordination compound using aminotriacetic acid derivative as ligand, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a vanadium coordination compound using aminotriacetic acid derivative as a ligand, and a preparation method and application thereof. The preparation method comprises the following steps: 1. reacting aminotriacetic acid in anhydrous pyridine to obtain a compound 1; 2. reacting the compound 1 with aminophenol or hydroxyaniline to obtain a compound A; 3. dissolving vanadyl sulfate in water, and regulating the pH value with NaOH to obtain a compound 2; and 4. dissolving the compound A in water, and reacting with the compound 2 to obtain a compound B. The compound is used in preparing antidiabetic drugs. The animal experiment proves that compared with the vanadyl compound using kojic acid as the ligand, the vanadyl coordination compound using aminotriacetic acid as the ligand has the advantages of lower molecular weight, higher water solubility, higher bioavailability and simpler preparation method.
Description
Technical field
The present invention relates to vanadium class coordination compound and preparation method and its application, the vanadium class coordination compound that to particularly relate to nitrilotriacetic acid derivative be part, its preparation method and its application in antidiabetic medicine.
Background technology
Diabetes are one group of metabolic diseases being feature with glucose-lipid metabolism exception, main be divided into insulin-dependent diabetes mellitus (IDDM) and insulin-dependent diabetes mellitus (IDDM) and type II diabetes and non insulin dependent diabetes (NIDDM), insulin-dependent diabetes mellitus (IDDM) depends on insulinize, and type II diabetes is main treatment means with oral hypoglycemic.According to the recent statistics of International Diabetes Federation in 2013, about have the world population of 8.3% to suffer from diabetes, wherein the diabetic subject of 90% ~ 95% belongs to type II diabetes.At present, diabetic subject's number of China occupies first of various countries, and estimate according to the World Health Organization, will reach 300,000,000 to world diabetic subject in 2025, wherein diabetes mellitus in China patient will reach forty-two million.And diabetes present the trend of rejuvenation.Diabetes have become the fourth-largest cause of the death.Along with the development of science and technology, although treatment diabetes aspect has obtained very large achievement, it is still also very difficult thoroughly to conquer diabetes.
In recent years, large quantity research shows that vanadium compounds all has antidiabetic effect in vivo and in vitro.But vanadium compounds all exists toxicity, show that its toxicity produces mainly owing to easily producing free radical by lot of experiments research, cause oxidative stress.In order to the toxicity overcoming vanadium compounds retains the activity of its hypoglycemic simultaneously, have a direction to be exactly with some natural antioxidantss as flavonoid in the development of vanadium class antidiabetic medicine recently, Polyphenols and tetravalence vanadium oxonium ion form coordination compound.This type of coordination compound has the effect for the treatment of diabetes surely, and toxicity is less.
Summary of the invention
The object of this invention is to provide a kind of new vanadium class coordination compound and preparation method and application, particularly a kind of with the nitrilotriacetic acid derivative vanadium class coordination compound that is part and preparation method and application.Described vanadium class coordination compound Polyphenols antioxidant and nitrilotriacetic acid form the organic micromolecule ligand with good coordination environment and resistance of oxidation, then form new organic vanadium compounds with Vanadyl.This compound has good anti-diabetic effect, and toxicity is less.
The object of the invention is to be achieved through the following technical solutions:
The vanadium class coordination compound being part with nitrilotriacetic acid derivative, is characterized in that, described vanadium class coordination compound general formula is as follows, i.e. compd B:
Wherein, n be more than or equal to 1 integer, further, described n is 1 or 2.
Prepare a method for described compound, its concrete reaction equation is:
Wherein step is:
Step 1, nitrilotriacetic acid is obtained by reacting compound 1 in anhydrous pyridine;
Step 2, is obtained by reacting compd A by described compound 1 with amino phenols or hydroxybenzene amine;
Step 3, is dissolved in the water vanadylic sulfate, uses NaOH to regulate pH, obtains compound 2;
Step 4, is obtained by reacting compd B with described compound 2 after described compd A is dissolved in water.
Further, specifically comprise the following steps:
Step 1, is dissolved in described nitrilotriacetic acid in described anhydrous pyridine, stirs, then adds diacetyl oxide, be obtained by reacting solid matter 3, obtain described compound 1 with ether after washing at 50-70 DEG C;
Step 2, described compound 1 is dissolved in anhydrous N, after in dinethylformamide, add described amino phenols or hydroxybenzene amine or hydroxytryptophan compounds, add anhydrous pyridine again, 12 ~ 24h is reacted at 70 ~ 85 DEG C, solvent evaporated, obtains solid matter 4, is dissolved in the water by described solid matter 4, first pH is regulated to be 8 ~ 10, with an organic solvent extraction obtains solution 5, then the pH of regulator solution 5 is 2.5 ~ 4, adds described anhydrous N, in dinethylformamide, recrystallization obtains described compd A;
Step 3, is dissolved in the water described vanadylic sulfate, uses NaOH to regulate pH to 6 ~ 7, is obtained by reacting described compound 2;
Step 4, is dissolved in described compd A in water and obtains solution 6, then is dissolved in described solution 6 by described compound 2, filters and obtains filtrate, described filtrate drying is obtained compd B after stirring reaction.
Further, described compound 1 is nitrilotriacetic acid acid anhydride.
The application of described compound, described compound is applied in be prepared in antidiabetic medicine.
Beneficial effect of the present invention is:
The new design philosophy of anti-diabetic vanadium compound that the present invention is based on ADME-T is set out, the vanadyl selecting the tetravalence that toxicity is relatively little is the active group of hypoglycemic, have chosen some antioxidants is part (toxicity produced with the strong oxidizing property reduced due to vanadium) simultaneously, and designing, synthesizing a series of take antioxidant as the vanadium complex of part:
Part parent nucleus used in the present invention is nitrilotriacetic acid(NTA) analog derivative, nitrilotriacetic acid(NTA) is a kind of conventional complexone, similar is in amino acid derivative, there is good internal metabolism character, the carboxyl existed in molecule and secondary amino group can form the compound of coordination mode as N-O part and vanadium oxygen, other carboxylic group, by forming amido linkage docking antioxidant groups, is easy to carry out further derivatize.Therefore be the desirable part parent nucleus of synthesizing new vanadium oxide compound.
And hydroxybenzene amine and hydroxyphenethylamine compounds have good oxidation-resistance, anti-inflammatory, suppress the effects such as hypertension, and inflammatory factor causes an inducement of type-II diabetes, so likely not only the toxic reaction that vanadium causes but also the antidiabetic effect strengthening vanadium compound from source can be reduced.
Compound provided by the present invention, solve vanadium compounds and easily produce free radical, cause oxidative stress and the toxicity problem brought, form organic micromolecule ligand by nitrilotriacetic acid and antioxidant, this part forms novel organic vanadium compounds with the Vanadyl of compound 2 again.Prove through experimentation on animals, the vanadium class coordination compound that is part with nitrilotriacetic acid derivative of the present invention has and significantly falls hypoglycemic effect, have remarkable difference, and toxicity is less before administration and after administration.Relative to the vanadium oxide compound taking kojic acid as part, be that the vanadyl complex molecule amount of part is less with nitrilotriacetic acid, water-soluble degree is better, has better bioavailability.Preparation method is simpler and easy.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is described in further detail.But example is not as a limitation of the invention.
Embodiment 1
The preparation of compd B (VOphpada), the chemical structural formula of compd B (VOphpada) is as follows:
A preparation method for the vanadium class coordination compound (VOphpada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 60 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains yellowish brown compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 4.0g compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 2.18g PAP, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 9.18, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution 5pH to 2.85, add DMF (in anhydrous DMF), recrystallization, vacuum-drying obtains compound A-13 .6g, and described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.7 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 2.82g is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by the compound 2 of 2g, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 63.99%.
The chemical feature parameter of compd B (VOphpada) is:
●IR:3342cm
-1(ν
O-H)；1635cm
-1,1399cm
-1,808cm
-1(ringν
C＝C)；1635cm
-1(νas
(COO))；1370cm
-1(νs
(COO))；974cm
-1(ν
V＝O)；
● ESI-MS:m/z 346 (dewatered product), m/z363 (oxidation products), m/z364 [M-1]
● ultimate analysis (%):
◆Anal.Calc.[VO(H
2O)L]:C 39.58N 7.69；
◆Found:C 39.58,N 7.69
Embodiment 2
The preparation of compd B (VOmhpada), the chemical structural formula of compd B (VOmhpada) is as follows:
A preparation method for the vanadium class coordination compound (VOmhpada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 50 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains yellowish brown compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 1mmol compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 1.2mmol3-amino-phenol, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 8.2, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution 5pH to 3, add DMF, recrystallization, vacuum-drying obtains compd A, productive rate 61.49%, described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.3 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 1mmol is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by excessive compound 2, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 72.61%.
The chemical feature parameter of compd B (VOmhpada) is:
●IR:3434cm
-1(ν
O-H)；1617cm
-1,1480cm
-1(ringν
C＝C)；1632cm
-1(νas
(COO))；1410cm
-1(νs
(COO))；974cm
-1(ν
V＝O)
● ESI-MS:m/z 346 (dewatered product), m/z 363 (oxidation products), m/z 364 [M-1]
● ultimate analysis (%)
◆Anal.Calca.C12H12N2O7V(％)：C 39.59；N 7.69
◆found C 39.5N 7.78
Embodiment 3
The preparation of compd B (VOohpada), the chemical structural formula of compd B (VOohpada) is as follows:
A preparation method for the vanadium class coordination compound (VOohpada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 70 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains deep yellow compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 1mmol compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 1.2mmol2-amino-phenol, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 9.6, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution pH to 3.8, add DMF, recrystallization, vacuum-drying obtains compd A, productive rate 64.72%, described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.9 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 1mmol is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by excessive compound 2, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 76.76%.
The chemical feature parameter of compd B (VOohpada) is:
●IR:3434cm
-1(ν
(O-H))；1600cm
-1,1480cm
-1,779cm
-1(ringν
C＝C)；1632cm
-1(νas
(COO))；1453cm
-1(νs
(COO))
● ESI-MS:m/z 346 (dewatered product), m/z363 (oxidation products), m/z364 [M-H]
● ultimate analysis (%)
◆Anal.Calca.C
12H
12N
2O
7V(％)C 39.25N 7.69
◆found C 39.25N 7.93
Embodiment 4
The preparation of compd B (Vodopada), the chemical structural formula of compd B (Vodopada) is as follows:
A preparation method for the vanadium class coordination compound (Vodopada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 60 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains deep yellow compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 1mmol compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 1.2mmol 3,4-dihydroxy-benzene ethamine, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 9.18, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution pH to 2.85, add DMF, recrystallization, vacuum-drying obtains compd A, productive rate 69.7%, described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.7 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 1mmol is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by excessive compound 2, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 75.20%.
The chemical feature parameter of compd B (Vodopada) is:
●IR:3451cm
-1(ν
O-H),1631cm
-1(ringν
C＝C),1625cm
-1(νas
(COO)),1315cm
-1(νs
(COO)),969cm
-1(ν
V＝O)
●ESI:408[M+H2O-1]
● ultimate analysis (%)
◆Anal.Calca.C
14H
18N
2O
9V(％)C 42.67N 6.63
◆found C 42.67N 6.7
Embodiment 5
The preparation of compd B (Votyrada), the chemical structural formula of compd B (Votyrada) is as follows:
A preparation method for the vanadium class coordination compound (Votyrada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 60 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains deep yellow compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 1mmol compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 1.2mmol Uteramin, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 9.18, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution pH to 2.85, add DMF, recrystallization, vacuum-drying obtains compd A, productive rate 70.45%, described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.7 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 1mmol is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by excessive compound 2, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 72.53%.
The chemical feature parameter of compd B (Votyrada) is:
●IR:3434cm
-1(ν
(O-H)),1516cm
-1,1600cmcm
-1,906cm
-1(ringν
C＝C),163 2cm
-1(νas
(COO)),1393cm
-1(νs
(COO)),971cm
-1(ν
V＝O)
●ESI:392[M+H2O-1]
● ultimate analysis (%)
◆Anal.Calca.C
14H
16N
2O
7V(％):C 42.57N 6.63
◆found C 42.63N 7.17
Embodiment 6
The preparation of compd B (VoHTada), the chemical structural formula of compd B (VoHTada) is as follows:
A preparation method for the vanadium class coordination compound (VoHTada) being part with nitrilotriacetic acid derivative, concrete steps are as follows:
Step 1, gets nitrilotriacetic acid 19g, dissolves in the pyridine of 200ml, is warming up to 60 DEG C, after stirring 0.5h, then adds the diacetyl oxide of 20ml, and temperature control 70 ~ 75 DEG C reaction 4h, obtains brown solid matter 3 after concentrating under reduced pressure.In above-mentioned solid matter 3, add anhydrous diethyl ether, grinding, leaches ether, repeated multiple timesly obtains deep yellow compound 1, and its building-up reactions equation is as follows:
The chemical property parameter of compound 1 is: ESI-MS m/z 191[M-1].
Step 2, takes 1mmol compound 1, is dissolved in the anhydrous DMF of 50ml, then adds 1.2mmol5 hydroxytryptophan, utilizes Schlenk system to carry out anaerobic protection, stirs after 10 minutes, adds anhydrous pyridine 6ml, react 24h at 75 DEG C.Solvent evaporated, obtain solid matter 4, be dissolved in by solid matter 4 in 100ml water, use 2MNaOH to adjust pH to be 9.18, extraction into ethyl acetate obtains solution 5, re-use 6MHcl regulator solution pH to 2.85, add DMF, recrystallization, vacuum-drying obtains compd A, productive rate 62.82%, described compd A building-up reactions equation is as follows:
Step 3, takes vanadylic sulfate 10g, is dissolved in the water of 200ml, adjusts pH to 6.7 with NaOH, and after reaction 2h, suction filtration obtains gray solid, and obtain compound 2, described compound 2-in-1 one-tenth reaction equation is as follows:
Step 4, the compd A taking 1mmol is dissolved in the water and obtains solution 2, then is dissolved in described solution 2 by excessive compound 2, stirs 2h, suction filtration, and filtrate recovery is dry obtains compd B, productive rate 70.57%.
The chemical feature parameter of compd B (VoHTada) is:
●IR:3416cm
-1(ν
(O-H)),1600cm
-1,906cm
-1,(ringν
C＝C),1626cm
-1(νas
(COO)),1380cm
-1(νs
(COO)),973cm
-1(ν
V＝O)
●ESI-MS:m/z 461[M-H2O-H]
● ultimate analysis (%)
◆Anal.Calca.C
17H
17N
3O
9V(％)C 42.96N 8.84
◆found C 42.8N 8.4
Embodiment 7
The vanadium class coordination compound prepared by embodiment 1-6 carries out experimentation on animals, and particularly test described vanadium class coordination compound to the impact of blood glucose in diabetic mice, experimental result is as table 1:
Table 1 vanadyl title complex is to diabetic mice hypoglycemic effect
| Compound | Blood glucose value before treatment | Blood glucose value after treatment |
| VOphpada | 26.6 | 7.3 |
| VOmhpada | 26.5 | 6.8 |
| VOohpada | 16.1 | 9.6 |
| Vodopada | 23.9 | 10.9 |
| Votyrada | 18.6 | 12.9 |
| VoHTada | 23.2 | 11.8 |
| Control | 25 | 19.8 |
Wherein, in table 1, Control is diabetic controls group, by table 1, can find out, the present invention's preparation-obtained nitrilotriacetic acid(NTA) vanadyl title complex all has certain hypoglycemic effect.
Embodiment 8
The vanadium class coordination compound VOphpada using embodiment 1 to prepare has carried out the anti-diabetic experimentation on animals of system.
Diabetic mice divides into groups
Db/db diabetic mice is divided into: diabetic controls group (Control group), BMOV positive controls, VOphpada vanadium compound administration group, ligand administration group (Liangd group), often organizes 7.Wherein
(1) diabetic controls group (DM, m=7) normal diet is fed, and continues 7 weeks;
(2) BMOV mixing 0.1mmol/kg/day (actual dose) in BMOV positive controls (DM+BMOV, m=7) normal diet feeds, and continues 7 weeks;
(3) VOphpada mixing 0.1mmol/kg/day (actual dose) in VOphpada vanadium compound administration group (DM+VOphpada, m=7) normal diet feeds, and continues 7 weeks;
(4) ligand administration group (DM+H
2hpada, m=7) mix the H of 0.1mmol/kg/day (actual dose) in normal diet
2hpada feeds, and continues 7 weeks;
Wherein monitoring in an every 6 days blood sugar, mouse fasting 12h before survey blood sugar, morning, 8:00-9:00 measured blood sugar.When surveying blood sugar, first scratch tail vein with sharp blade gently at the tail base of mouse, get 5ul fresh blood with kapillary.The each group of blood sugar effects recorded is in table 2.
Table 2VOphpada and part H thereof
2hpada is on the impact of blood glucose in diabetic mice
| Group | Blood glucose value before treatment | Blood glucose value after treatment |
| Control(n＝7) | 22.3 | 28.2 |
| BMOV(n＝7) | 21.4 | 14.8 |
| Liangd(n＝7) | 22.5 | 19.7 |
| VOphpada(n＝7) | 19.6 | 10.2 |
In order to evaluate the hypoglycemic effect of VOphpada, whole experimental session determines the change of blood sugar (table 2) of each group.VOphpada treatment group blood sugar is slowly reduced to normal level, remains to normal level afterwards until experiment terminates; Positive control BMOV treatment group blood glucose value reduces, but fluctuates to some extent at blood glucose value in whole experimentation; The diabetic groups blood glucose value of part intervention comparatively diabetic groups has reduction a little, but fails lower than 13mmol/l.Illustrate that VOphpada has the hypoglycemic effect being better than BMOV.
Embodiment 9
The VOphpada using embodiment 1 to prepare carries out acute toxicity test (being undertaken by improvement Kou Shi method)
Test method:
Undertaken by improvement Kou Shi method: ICR mouse 60, fasting 12h before experiment, 6 groups are divided at random by body weight, often organize 10, male and female half and half, on the basis of prerun, choosing 1:0.8 is dose ratio, adopt low dosage to be mixed with the drug solution of different concns than dilution method, the medicine giving 6 groups of various dose is fed in oral filling respectively
Administration capacity is 0.2ml/10g.
Test-results:
Mouse is listless after oral administration gavage administration, bradypnoea, and four limbs are weak and limp, few dynamic; , there is diarrhoea in appetite stimulator, dehydration, skin cyanosis subsequently.Animal dead mostly occurs after 12h, and animal is dead because suffering from diarrhoea, dewatering, and dissect animal, visual inspection has no the internal organs such as the heart, liver,spleen,kidney, lung obvious change.If pre-test result shows this product, mouse is not dead after 72 hours, then within several days that observe afterwards, can survive, therefore this experimental period design observation 72 hours.It is 1045mg/kg that the LD50 of administration mouse is fed in the oral filling of this product, 95% be crediblely limited to 963-1185mg/kg (see table 3).
The acute toxicity tests of table 3VOphpada
Above-mentioned experimental result shows, vanadium compounds of the present invention has the effect obviously reducing blood glucose in diabetic mice, and its medium lethal dose is 1045mg/kg, and toxicity is less, is the medicine that a class has DEVELOPMENT PROSPECT very much.
To the above-mentioned explanation of the disclosed embodiments, professional and technical personnel in the field are realized or uses the present invention.To be apparent for those skilled in the art to the multiple amendment of these embodiments, General Principle as defined herein can without departing from the spirit or scope of the present invention, realize in other embodiments.Therefore, the present invention can not be restricted to these embodiments shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (5)
1. with the vanadium class coordination compound that nitrilotriacetic acid derivative is part, it is characterized in that, described vanadium class coordination compound general formula is as follows, i.e. compd B:
Wherein, n be more than or equal to 1 integer.
2. prepare a method for compound as claimed in claim 1, it is characterized in that, its concrete reaction equation is:
Wherein step is:
Step 1, nitrilotriacetic acid is obtained by reacting compound 1 in anhydrous pyridine;
Step 2, is obtained by reacting compd A by described compound 1 with amino phenols or hydroxybenzene amine;
Step 3, is dissolved in the water vanadylic sulfate, uses NaOH to regulate pH, obtains compound 2;
Step 4, is obtained by reacting compd B with described compound 2 after described compd A is dissolved in water.
3. preparation method according to claim 2, is characterized in that, specifically comprises the following steps:
Step 1, is dissolved in described nitrilotriacetic acid in described anhydrous pyridine, stirs, then adds diacetyl oxide, be obtained by reacting solid matter 3, obtain described compound 1 with ether after washing at 50-70 DEG C;
Step 2, is dissolved in described compound 1 after in anhydrous DMF, add described amino phenols or hydroxybenzene amine or hydroxytryptophan compounds, then add anhydrous pyridine, reaction, solvent evaporated, obtains solid matter 4, is dissolved in the water by described solid matter 4, first pH is regulated to be 8 ~ 10, with an organic solvent extraction obtains solution 5, then the pH of regulator solution 5 is 2.5 ~ 4, adds described anhydrous N, in dinethylformamide, recrystallization obtains described compd A;
Step 3, is dissolved in the water described vanadylic sulfate, uses NaOH to regulate pH to 6 ~ 7, is obtained by reacting described compound 2;
Step 4, is dissolved in described compd A in water and obtains solution 6, then is dissolved in described solution 6 by described compound 2, filters and obtains filtrate, described filtrate drying is obtained compd B after stirring reaction.
4. preparation method according to claim 2, is characterized in that, described compound 1 is nitrilotriacetic acid acid anhydride.
5. the application of compound as claimed in claim 1, it is characterized in that, described compound is applied in be prepared in antidiabetic medicine.
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Cited By (4)
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| CN106632455A (en) * | 2016-12-28 | 2017-05-10 | 北京大学 | Vanadium complex with anti-diabetic effect as well as preparation method and application of vanadium complex |
| CN109535026A (en) * | 2017-09-22 | 2019-03-29 | 国立研究开发法人日本原子力研究开发机构 | The method for synthesizing tetraalkyl nitriloacetic acids diacetayl amide compound |
| CN111334300A (en) * | 2020-04-01 | 2020-06-26 | 辽宁石化职业技术学院 | Preparation method of double-effect antioxidant |
| CN113801156A (en) * | 2021-10-13 | 2021-12-17 | 北京大学 | Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632455A (en) * | 2016-12-28 | 2017-05-10 | 北京大学 | Vanadium complex with anti-diabetic effect as well as preparation method and application of vanadium complex |
| CN109535026A (en) * | 2017-09-22 | 2019-03-29 | 国立研究开发法人日本原子力研究开发机构 | The method for synthesizing tetraalkyl nitriloacetic acids diacetayl amide compound |
| CN109535026B (en) * | 2017-09-22 | 2021-10-29 | 国立研究开发法人日本原子力研究开发机构 | Method for synthesizing tetraalkyl nitrilo acetic acid diacetyl amide compound |
| CN111334300A (en) * | 2020-04-01 | 2020-06-26 | 辽宁石化职业技术学院 | Preparation method of double-effect antioxidant |
| CN113801156A (en) * | 2021-10-13 | 2021-12-17 | 北京大学 | Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition |
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