阅读说明：本技术 一种具有胰岛素增敏活性的多钒酸盐烷氧衍生物及其制备方法与应用 (Polyvanadate alkoxy derivative with insulin sensitizing activity and preparation method and application thereof ) 是由 陈坤 殷盼超 刘媛 于 2019-10-25 设计创作，主要内容包括：本发明公开了一种具有胰岛素增敏活性的多钒酸盐烷氧衍生物及其制备方法与应用。所述方法通过酸酐或脂肪酸或苯甲酸与钒酸或钒酸盐进行一步酯化反应制得多钒酸盐烷氧衍生物。本发明所述多钒酸盐烷氧衍生物能够迅速降低糖尿病小鼠的血糖,多钒酸盐烷氧衍生物与胰岛素联合使用比单独使用胰岛素可以更好控制血糖,实现促进胰岛素的葡萄糖响应性和持久活性,从而可以减少了胰岛素的给药次数,并减少了动物同时遭受高血糖和低血糖状态的经历,从而进一步提高了用于胰岛素治疗血糖控制的保真度。(The invention discloses a poly-vanadate alkoxy derivative with insulin sensitizing activity, and a preparation method and application thereof. According to the method, acid anhydride or fatty acid or benzoic acid and vanadate or vanadate are subjected to one-step esterification reaction to prepare the poly-vanadate alkoxy derivative. The polyvanadate alkoxy derivative can quickly reduce the blood sugar of a diabetic mouse, and the combination use of the polyvanadate alkoxy derivative and insulin can better control the blood sugar compared with the single use of the insulin, so that the glucose responsiveness and the lasting activity of the insulin are promoted, the administration frequency of the insulin can be reduced, the experience that animals suffer from hyperglycemia and hypoglycemia states at the same time is reduced, and the fidelity of the blood sugar control in the insulin treatment is further improved.)

1. A poly-vanadate alkoxy derivative with insulin sensitizing activity is characterized in that the molecular formula is A₂[V₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]₃、A₂[V₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]₃、B₂[V₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]Or B₂[V₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]Wherein A is Al or Fe, B is tetrabutylammonium, Na or H, R is phenyl or alkyl containing 1-17 carbon atoms, A or B and [ V ]₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]By ionic bond, A or B with [ V ]₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]Is connected with an ionic bond.

2. The poly-vanadate alkoxy derivative having insulin sensitizing activity according to claim 1, wherein R is CH₃、(CH₂)₄CH₃、(CH₂)₈CH₃、(CH₂)₁₂CH₃、(CH₂)₁₆CH₃And C₆H₅One kind of (1).

3. The preparation method of the poly-vanadate alkoxy derivative with the insulin sensitizing activity according to any one of claims 1 to 2, characterized in that vanadate or vanadate is uniformly mixed with acid anhydride or fatty acid or benzoic acid, then an esterification catalyst and an organic solvent are added, the mixture is reacted for 36 to 60 hours at a temperature of 60 to 100 ℃, cooled and purified, and then cation exchange is carried out, so as to obtain the poly-vanadate alkoxy derivative with the insulin sensitizing activity;

the vanadic acid is hexa-vanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) Or decavanadic acid (Bu)₄N)₂[V₁₀O₁₈{(OCH₂)₃CCH₂OH}₂]The vanadate is hexavanadate or decavanadate;

the molar ratio of the vanadate or vanadate to the anhydride or fatty acid or benzoic acid is 1: 2 to 3.

4. The method for preparing poly vanadate alkoxy derivative having insulin sensitizing activity according to claim 3, wherein the acid anhydride is at least one of acetic anhydride, hexanoic anhydride, decanoic anhydride, myristic anhydride, creatinine, stearic anhydride and benzoic anhydride;

the fatty acid is a fatty acid containing 1-18 carbon atoms; or at least one of acetic acid, caproic acid, capric acid, myristic acid and stearic acid;

the vanadate is at least one of bismuth vanadate, sodium vanadate, copper vanadate, ammonium vanadate, ferric vanadate, calcium vanadate, zinc vanadate and silver vanadate.

5. The method for preparing poly vanadate alkoxy derivative with insulin sensitizing activity according to claim 4, wherein the molar ratio of the esterification catalyst to the acid anhydride or the fatty acid or the benzoic acid is (0.01-2): 1, or (0.4-1.4): 1.

6. the method for preparing poly vanadate alkoxy derivative having insulin sensitizing activity according to claim 4 or 5, wherein the concentration of the acid anhydride or the fatty acid or the benzoic acid in the organic solvent is 0.05-1 mol/L.

7. The method for preparing the poly-vanadate alkoxy derivative with the insulin sensitizing activity according to claim 6, wherein the esterification catalyst is 4-dimethylaminopyridine or N, N' -dicyclohexylcarbodiimide; the organic solvent is at least one of triethylamine, acetonitrile, N' -dimethylformamide and dimethyl sulfoxide; the organic solvent is triethylamine and acetonitrile, and the weight ratio of triethylamine to acetonitrile is 1 mmol: the obtained mixed solvent was mixed in a proportion of 10 mL.

8. The use of the polyvanadate alkoxy derivative having insulin sensitizing activity according to any one of claims 1 to 2 in the biomedical field.

9. The use of the polyvanadate alkoxy derivative having insulin sensitizing activity according to claim 8 in the biomedical field, wherein said use is in the preparation of a medicament for animal medicine.

10. The use of a polyvanadate alkoxy derivative having insulin-sensitizing activity according to claim 9 in the biomedical field, wherein the use is in the preparation of a medicament for modulating insulin-sensitizing activity.

Technical Field

The invention belongs to the field of animal medicine, and particularly relates to a poly-vanadate alkoxy derivative with insulin sensitizing activity, and a preparation method and application thereof.

Background

In recent years, the number of dogs and cats suffering from diabetes in pet hospitals is gradually increased. Canine and feline diabetes belongs to endocrine diseases, is clinically characterized by hyperglycemia, diabetes, polyuria, polydipsia and bulimia, and causes cardiovascular diseases such as cataract, blindness, hair loss, heart failure and the like of pets at the end stage. Insulin resistance plays a crucial role in the pathophysiology of diabetes and vascular disease in dogs and cats. Exogenous insulin is used clinically to treat diabetic dogs and cats for the purpose of controlling blood glucose. However, it is difficult for diabetic dogs and cats to strictly follow the insulin treatment regimen, and serious complications may cause diabetic dogs and cats to experience a hyperglycemic or hypoglycemic state. Long-term instability of blood glucose levels can lead to cardiovascular disease in diabetic dogs, cats and can lead to higher mortality rates. Therefore, there is a need to find effective insulin sensitizers to reduce vascular and metabolic diseases in diabetic dogs and cats.

Vanadium compounds are well known for their anti-diabetic effects in glucose and lipid metabolism. Due to the similarity in size and charge of phosphorus and vanadium, vanadium is an essential element in most organisms and accumulates in the participation of some oxygen-containing organisms in biological processes. Over the last decade, hundreds of vanadium compounds, especially organic derivatives, have been used to treat diabetes. Activation of insulin receptors by vanadate affects the balance of insulin response to glucose. Vanadium complexes, mainly VV and VIV compounds with organic ligands such as maltol (BMOV) and ethyl maltol (BEOV), have been extensively studied to exploit their effects in the treatment of diabetes, given the potential for vanadium complexes to reduce the side effects of inorganic metal drug demetallization and degradation in humans. BMOV and BEOV are currently the only VCs entering clinical trials due to extremely low oral bioavailability (1% on average) and potential long-term toxicity, but were prevented in phase II clinical trials.

Disclosure of Invention

In order to solve the defects and shortcomings of the prior art, the invention aims to provide a poly-vanadate alkoxy derivative with insulin sensitizing activity. The polyvanadate alkoxy derivative is mainly realized by forming the polyvanadate alkoxy derivative through covalent modification of POVs (polyvanadate) and fatty acids such as acetic acid, caproic acid, capric acid, myristic acid, stearic acid and benzoic acid, and can promote the response of diabetic dogs and cats to glucose and enable insulin of the diabetic dogs and cats to have lasting activity.

The invention also aims to provide a preparation method of the polyvanadate alkoxy derivative with insulin sensitizing activity. The poly-vanadate/poly-vanadate and the anhydride/acid/benzoic acid are obtained by esterification reaction under the action of an esterification reaction catalyst, the preparation method is simple, and fatty acids with different chain lengths can be connected to hexavanadate through one-step esterification reaction.

The invention also aims to provide application of the polyvanadate alkoxy derivative with insulin sensitizing activity in the biomedical field. Through regulating and controlling the chain length of fatty acid in the poly-vanadate alkoxy derivative, the sensitization activity of the poly-vanadate alkoxy derivative on insulin is regulated, so that the blood sugar level of an organism is regulated, the blood sugar level of a diabetic dog or a diabetic cat is stabilized, and complications caused by unstable blood sugar are reduced.

The purpose of the invention is realized by the following technical scheme:

a poly vanadate alkoxy derivative with insulin sensitizing activity has a molecular formula of A₂[V₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]₃、A₂[V₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]₃、B₂[V₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]Or B₂[V₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]Wherein A is Al or Fe, B is tetrabutylammonium, Na or H, R is phenyl or alkyl containing 1-17 carbon atoms, A or B and [ V ]₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]By ionic bond, A or B with [ V ]₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]Is connected with an ionic bond.

The R is preferably CH₃、(CH₂)₄CH₃、(CH₂)₈CH₃、(CH₂)₁₂CH₃、(CH₂)₁₆CH₃And C₆H₅One kind of (1).

The poly vanadate alkoxy derivative with insulin sensitizing activity is an ionic compound, wherein the cation of the poly vanadate alkoxy derivative is a cation corresponding to A or B, and the anion of the poly vanadate alkoxy derivative is [ V ]₆O₁₃{(OCH₂)₃CCH₂OCOR}₂]^2-Or [ V ]₁₀O₁₈{(OCH₂)₃CCH₂OCOR}₂]^2-。

The preparation method of the poly-vanadate alkoxy derivative with the insulin sensitizing activity comprises the following steps:

mixing vanadate or vanadate with anhydride or fatty acid or benzoic acid uniformly, adding an esterification reaction catalyst and an organic solvent, reacting at 60-100 ℃ for 36-60 hours, cooling, purifying, and then carrying out cation exchange to obtain a poly-vanadate alkoxy derivative with insulin sensitizing activity;

the vanadic acid is hexa-vanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) Or decavanadic acid (Bu)₄N)₂[V₁₀O₁₈{(OCH₂)₃CCH₂OH}₂]The vanadate is hexavanadate or decavanadate;

the molar ratio of the vanadate or vanadate to the anhydride or fatty acid or benzoic acid is 1: 2 to 3.

The concentration of the acid anhydride or the fatty acid or the benzoic acid in the organic solvent is 0.05-1 mol/L, and preferably 0.1 mol/L.

The organic solvent is at least one of triethylamine, acetonitrile, N' -Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO); preferably triethylamine and acetonitrile in a ratio of 1 mmol: the obtained mixed solvent was mixed in a proportion of 10 mL.

The esterification catalyst is preferably 4-Dimethylaminopyridine (DMAP) or N, N' -Dicyclohexylcarbodiimide (DCC).

The molar ratio of the esterification reaction catalyst to acid anhydride or fatty acid or benzoic acid is (0.01-2): 1; preferably 0.4-1.4: 1.

the acid anhydride is preferably at least one of acetic anhydride, hexanoic anhydride, decanoic anhydride, myristic anhydride, creatinine, stearic anhydride, and benzoic anhydride.

The fatty acid is preferably a fatty acid having 1 to 18 carbon atoms, and more preferably at least one of acetic acid, caproic acid, capric acid, myristic acid, and stearic acid.

The purification method is preferably: and pouring the product mixed solution obtained after cooling into deionized water, and collecting the precipitate.

The cation exchange is carried out by using a cation exchange resin.

The vanadate is preferably at least one of bismuth vanadate, sodium vanadate, copper vanadate, ammonium vanadate, iron vanadate, calcium vanadate, zinc vanadate and silver vanadate.

The poly-vanadate alkoxy derivative with the insulin sensitizing activity is applied to the field of biomedicine.

Preferably in the preparation of animal medicine, more preferably in the preparation of medicine for regulating insulin sensitizing activity.

The technical principle of the invention is as follows: the method for obtaining the long-acting amphiphilic insulin sensitizer POV derivative by covalently modifying hexavanadate/hexavanadate or decavanadate/decavanadate combined with an aliphatic structure domain is adopted by the method for obtaining the long-acting vanadium compound. Vanadium itself has an insulin sensitizing effect. The POV derivative can be reversibly combined with plasma protein to different degrees after entering circulation, and as the volume of the drug molecule is increased after the POV derivative is combined with protein macromolecules, the combined POV derivative is not easy to penetrate out of the blood vessel wall, limits the transmembrane transport of the POV derivative, is not easy to metabolize or excrete, prolongs the action time of the POV derivative in the body, and thus, the long-acting insulin sensitizing effect is generated.

Compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the synthesis process of the poly-vanadate alkoxy derivative with insulin sensitizing activity is simple and easy to implement, alkyl or phenyl with different chain lengths can be modified on vanadate through a simple one-step esterification reaction, the process quality of a product is easy to control, and the industrial production is facilitated.

(2) The poly vanadate alkoxy derivative with the insulin sensitizing activity is mainly realized by forming the poly vanadate alkoxy derivative through covalent modification of POVs and acid anhydride or fatty acid or benzoic acid, and the effective sensitizer can increase the sensitivity of an organism to insulin so as to adjust the blood sugar level of the organism, stabilize the blood sugar level of diabetic animals, reduce complications caused by unstable blood sugar and reduce vascular diseases and metabolic diseases.

(3) According to the invention, fatty acid or acid anhydride containing different carbon chain numbers is adopted to carry out covalent modification on polyvanadate, so that the persistent insulin sensitizing activity is provided for the polyvanadate alkoxy derivative, and the insulin sensitizing effect is shown in a diabetes model mouse. In addition, in healthy mice, the POV derivative has a low hypoglycemic index, and can better avoid unnecessary hypoglycemia symptoms.

(4) The poly-vanadate alkoxy derivative with the insulin sensitizing activity has the advantages of easily available raw materials and simple preparation method; compared with the single use of insulin, the combined use of the poly-vanadate alkoxy derivative and the insulin can better control blood sugar, and simultaneously, the insulin sensitizing activity of the vanadate alkoxy derivative can be regulated and controlled through the length of an alkyl chain, so that a method for maintaining the blood sugar level in an application range during the treatment of the insulin is provided.

(5) The polyvanadate alkoxy derivative with insulin sensitization activity can effectively control the blood sugar level of a diabetic mouse for a long time, so that the blood sugar is stabilized in a certain range and does not fluctuate too much, and the mouse is prevented from being influenced by the state of overhigh blood sugar or overhigh blood sugar.

Drawings

FIG. 1 is a synthesis scheme of poly-vanadate alkoxy derivatives with insulin sensitizing activity prepared by reacting hexavanadate with different acid anhydrides.

FIG. 2 is a graph showing the effect of V6-C10 (in an amount of 5mg/kg) prepared in example 3 on the blood glucose level of STZ-induced diabetic mice.

FIG. 3 is a graph showing the effect of V6-C14 (in an amount of 5mg/kg) prepared in example 4 on the blood glucose level of STZ-induced diabetic mice.

FIG. 4 is a graph showing the effect of V6-C18 (in an amount of 5mg/kg) prepared in example 5 on the blood glucose level of STZ-induced diabetic mice.

FIG. 5 is a graph showing the effect of V6-phen (in an amount of 5mg/kg) prepared in example 6 on blood glucose in STZ-induced diabetic mice.

FIG. 6 is a graph showing the change in blood glucose of diabetic mice after oral administration of 5mg/kg of V6-C10 prepared in example 3, wherein glucose tolerance test IPGTT was performed at 4, 7 and 10 hours after administration of V6-C10, respectively.

FIG. 7 is a graph showing the change in blood glucose of diabetic mice after oral administration of 5mg/kg of V6-C14 prepared in example 4, wherein glucose tolerance test IPGTT was performed at 4, 7 and 10 hours after administration of V6-C14, respectively.

FIG. 8 is a graph showing the change in blood glucose of diabetic mice after oral administration of 5mg/kg of V6-C18 prepared in example 5, wherein glucose tolerance test IPGTT was performed at 4, 7 and 10 hours after administration of V6-C18, respectively.

FIG. 9 is a graph showing the change in blood glucose of diabetic mice after oral administration of 5mg/kg of V6-pen prepared in example 6, wherein glucose tolerance test IPGTT was performed at 4, 7 and 10 hours after the administration of V6-pen, respectively.

FIG. 10 shows the blood glucose changes of diabetic mice after oral administration of 3mg/kg of the alkoxy polyvanadate derivatives V6-C10 and V6-C14 prepared in the examples, respectively, or injection of 1IU/kg of natural insulin or insulin derivative (insulin detemir), respectively.

FIG. 11 shows the change of hypoglycemic index of diabetic mice after oral administration of 3mg/kg of the alkoxy polyvanadate derivatives V6-C10 and V6-C14 prepared in the examples, respectively, or injection of 1IU/kg of natural insulin or insulin derivative (insulin detemir), respectively.

FIG. 12 is a graph showing the response of diabetic mice to IPGTT after oral administration of V6-C10 prepared in example 3 and V6-C14 prepared in example 4 (0.5 mg/kg, 1mg/kg, 2mg/kg, respectively).

FIG. 13 is a graph of STZ-induced changes in blood glucose in diabetic mice orally administered 3mg/kg V6-C14 prepared in example 4 and in healthy mice without any treatment, wherein the mice were subjected to the glucose tolerance test IPGTT at 3 hours after administration of V6-C14.

FIG. 14 is a graph of STZ-induced changes in blood glucose in diabetic mice injected with 3IU/kg of an insulin derivative (insulin detemir) and in healthy mice without any treatment, wherein the mice were subjected to the glucose tolerance test IPGTT at hour 3 after administration of V6-C14.

FIG. 15 is a graph showing the response rate of STZ-induced diabetic mice orally administered with 3mg/kg of V6-C14 prepared in example 4, STZ-induced diabetic mice injected with 3IU/kg of an insulin derivative (insulin detemir), and untreated healthy mice before the glucose tolerance test IPGTT.

FIG. 16 is a graph showing the response rates of STZ-induced diabetic mice orally administered with 3mg/kg of V6-C14 prepared in example 4, STZ-induced diabetic mice injected with 3IU/kg of an insulin derivative (insulin detemir), and healthy mice without any treatment in a glucose tolerance test IPGTT.

FIG. 17 shows the change of blood glucose in healthy mice in example 14 after oral administration of V6-14 and injection of native insulin and an insulin derivative (insulin detemir), respectively.

Detailed Description

The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.

The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.

Method of use of continuous glucose monitor (Dexcom) in the following examples: the sensors of the glucose monitor were implanted subcutaneously in mice, and the mice were injected with native insulin or insulin derivatives (insulin detemir), or the polyvanadate alkoxy derivatives prepared in the examples were orally administered after calibration, according to the manufacturer's instructions.

The insulin derivative (insulin detemir) described in the following examples is named as noro and pencils, the product name is insulin detemir injection, and the manufacturer is danish norand nord company, national drug standard character J20140106.

Example 1

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol acetic anhydride, then 0.1g DMAP, 2mmol triethylamine and 20mL CH are added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. By exchange of H with cation exchange resins⁺Polyvanadate alkoxy derivatives as cations to obtain HV₆O₁₃{(OCH₂)₃CCH₂OCOCH₃}₂]。

Example 2

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol of acetic anhydride, then 0.1g of DMAP, 2mmol of triethylamine and 20mL of CH are added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. By exchange of H with cation exchange resins⁺Polyvanadate alkoxy derivatives as cations, and exchange with Al by ion exchange³⁺Polyvanadate alkoxy derivatives as cations to give Al₂[V₆O₁₃{(OCH₂)₃CCH₂OCOCH₃}₂]₃And is marked as V6-C2.

Example 3

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol decanoic anhydride, then 0.25g DMAP, 2mmol triethylamine and 20mL CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₈CH₃}₂]And is marked as V6-C10.

Example 4

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol myristic anhydride, then 0.3g DMAP, 2mmol triethylamine and 20mL CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₁₂CH₃}₂]And is marked as V6-C14.

Example 5

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol stearic anhydride, then 0.35g DMAP, 2mmol triethylamine and 20mL CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₁₆CH₃}₂]And is marked as V6-C18.

Example 6

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol of benzoic anhydride, then 0.35g of DMAP, 2mmol of triethylamine and 20mL of CH are added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the reaction productThe product mixture was poured into 50mL of deionized water and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCOC₆H₅}₂]And is marked as V6-phen.

Example 7

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol acetic acid, then 0.1g DMAP, 2mmol triethylamine and 20mL CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. By exchange of H with cation exchange resins⁺Polyvanadate alkoxy derivatives as cations to obtain HV₆O₁₃{(OCH₂)₃CCH₂OCOCH₃}₂]。

Example 8

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol acetic acid, then 0.1g DMAP, 2mmol triethylamine and 20mL CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. By exchange of H with cation exchange resins⁺Polyvanadate alkoxy derivatives as cations, and exchange with Al by ion exchange³⁺Polyvanadate alkoxy derivatives as cations to give Al₂[V₆O₁₃{(OCH₂)₃CCH₂OCOCH₃}₂]₃。

Example 9

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol of decanoic acid, then 0.25g of DMAP, 2mmol of triethylamine and 20mL of CH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₈CH₃}₂]。

Example 10

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol myristic acid, then 0.3g DMAP, 2mmol triethylamine and 20mLCH were added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₁₂CH₃}₂]。

Example 11

And (3) synthesis of POV derivatives. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol of stearic acid, then 0.35g of DMAP, 2mmol of triethylamine and 20mL of CH are added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCO(CH₂)₁₆CH₃}₂]。

Example 12

Synthesis of POV derivativesAnd (4) obtaining. 1mmol of hexavanadic acid ((Bu)₄N)₂[V₆O₁₃{(OCH₂)₃CCH₂OH}₂]) And 2mmol of benzoic acid, then 0.35g of DMAP, 2mmol of triethylamine and 20mL of CH are added₃CN, stirring and reacting for 48h at 80 ℃. After cooling to room temperature, the product mixture obtained from the reaction was poured into 50mL of deionized water, and the red precipitate was collected by filtration. Exchanging Na out by cation exchange resin⁺Polyvanadate alkoxy derivatives as cations to obtain Na [ V ]₆O₁₃{(OCH₂)₃CCH₂OCOC₆H₅}₂]。

Example 13

The long-acting insulin sensitizing effect of the poly-vanadate alkoxy derivatives prepared in examples 3-6 is specifically illustrated by taking the examples as examples.

The construction of the diabetes mouse model adopts male d/b mice purchased from Shanghai Jiesi laboratory animals GmbH and the age of the mice is 6-8 weeks. After one week of adaptation, d/b mice were fasted for 4 hours, and then injected intraperitoneally with 150mg of Streptozotocin (STZ) according to the weight of the mice as per 1kg of mice. Next, the mice were allowed to feed ad libitum while blood was taken from the mice peripheral tail vein daily and their blood glucose levels were monitored using a portable blood glucose meter until the fasting mice blood glucose levels were above 400 mg/dL. The control group was: age-matched healthy mice were fed ad libitum under the same conditions while blood was taken from the peripheral tail vein of healthy mice daily and their blood glucose levels were monitored using a portable blood glucose meter.

Glucose tolerance test. The experimental groups were: the polyvanadate alkoxy derivatives prepared in examples 3 to 6 were orally administered to the STZ-induced diabetic mice at a dose of 0.5, 1, 2, 3, 5mg/kg (i.e., 0.5, 1, 2, 3, 5mg/kg) respectively, and fasted overnight. The control group was: the STZ-induced diabetic mice were injected with 1, 3, 5IU/kg (i.e., 1, 3, 5 IU/kg) of native insulin or insulin derivative (insulin detemir) respectively and fasted overnight. And (3) respectively monitoring the blood sugar of vein puncture at the tail ends of the mice of the experimental group and the control group by using a portable glucometer every 6min so as to track the activity of insulin, wherein the test results are shown in figures 2-5 and 10-11. At the same time, the mice (i.e., experimental group and control group mice) which were orally administered with the poly-vanadate alkoxy derivative or injected with the natural insulin or insulin derivative were injected with 1g/kg (i.e., 1 g/kg) of an aqueous glucose solution having a concentration of 10mmol/L after 4h, 7h and 10h or after 3h, and immediately after the injection of the aqueous glucose solution, glucose tolerance IPGTT test was performed, and thereafter, blood glucose was continuously monitored every 6min and a curve of blood glucose concentration versus time was prepared, and the results are shown in FIGS. 6-9 and 13-16, and then insulin responsiveness was quantified by measuring the area under the curve (integration within a 3 hour window from the glucose injection point and after the challenge), and the results are shown in FIG. 12. The results show that the long-acting insulin sensitizer can keep the blood sugar stably within a certain range, and avoid the condition of overhigh or overlow blood sugar and the serious complications.

Example 14

To demonstrate the special potential of the polyvanadate alkoxy derivative (V6-14) prepared in example 4, normoglycemic healthy mice were subjected to a glucose tolerance test. The same amount of the polyoxyvanadic acid alkoxy derivative prepared in example 4 was orally administered to healthy mice as the diabetic mice described above, or insulin derivative (insulin detemir) was injected to healthy mice in the same amount as the diabetic mice described above, and then blood glucose of the mice was monitored. To quantify the rate of induction of hypoglycemia, the hypoglycemic index is calculated by dividing the difference between the initial blood glucose value and the lowest blood glucose value by the time to reach the lowest point. Continuous glucose monitoring was performed by using a continuous glucose monitor (Dexcom). As shown in FIG. 17, the use of polyvanadate alkoxy derivatives having insulin-sensitizing activity can prevent hypoglycemia symptoms such as dizziness, fatigue, etc.

From the figure, it can be known that the covalent modification of poly-vanadate and fatty acid can improve the insulin sensitizing activity and further regulate the blood sugar level, and the combined use effect of poly-vanadate alkoxy derivative and insulin is better than that of the single use of insulin.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.