CN110668947A - O-hydroxybenzoic acid polyglycol ester compound and synthesis preparation method and medical application thereof - Google Patents
O-hydroxybenzoic acid polyglycol ester compound and synthesis preparation method and medical application thereof Download PDFInfo
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Abstract
The invention discloses an o-hydroxybenzoic acid polyglycol ester compound, a synthesis preparation method and medical application thereof, wherein the o-hydroxybenzoic acid polyglycol ester compound has a structure shown in a formula I or a formula II; the compound has obvious effect of prolonging the blood coagulation time, is suitable for preventing and treating the thrombotic diseases, has the advantages of good safety, simple and convenient medication, low and easily obtained raw materials, convenient transportation and storage,
wherein n is 1-20, and R is selected from: h, -C1‑20Alkyl and 2-acetoxyA benzoyl group.
Description
Technical Field
The invention relates to an o-hydroxybenzoic acid polyglycol ester compound and a preparation method thereof, and also relates to application of the compound in anticoagulation, belonging to the field of medicine synthesis and medical health.
Background
Cardiovascular and cerebrovascular diseases become the first killer of human health, and the number of dead people worldwide is 1200 thousands of people every year due to cerebral apoplexy, myocardial infarction, coronary heart disease, atherosclerosis and the like. Thrombotic diseases mainly comprise myocardial infarction, pulmonary embolism, atrial fibrillation, cerebral infarction and the like, and especially the myocardial infarction and cerebral apoplexy which take the embolism as the main cause are still the main death causes of cardiovascular and cerebrovascular diseases. The number of people who die from cardiovascular and cerebrovascular diseases in China each year reaches more than 260 million, 75 percent of the surviving patients cause disability, and more than 40 percent of the patients have serious disability. Along with the continuous increase of the prevalence rate of cardiovascular diseases of residents in China in recent years, the market demand of antithrombotic medicaments is continuously increased. According to statistics, the market scale of antithrombotic drugs in 2016 in China reaches 275.1 hundred million yuan, which is 7.76% higher than that in 2015.
Aspirin is marketed in 1898 years, has been applied for hundreds of years, has strong antipyretic and analgesic effects, and is widely used for anti-inflammatory and antirheumatic treatment; the aspirin with small dosage can be used for preventing cardiovascular and cerebrovascular diseases and transient ischemic diseases, inhibiting platelet aggregation, and preventing intravascular thrombosis. Therefore, patients with cardiovascular and cerebrovascular diseases are clinically recommended to take small dose of aspirin to prevent thrombosis so as to prevent cardiovascular and cerebrovascular events. However, with the continuous and deep clinical application research of aspirin, a large number of clinical researches and long-term follow-up findings, after long-term oral aspirin therapy, a part of patients with cardiovascular and cerebrovascular diseases still have thromboembolic events, and the therapeutic dose is increased, so that the treatment and prevention purposes cannot be achieved, adverse reactions are increased, and the phenomenon of aspirin resistance occurs. Therefore, the application of the aspirin as an antithrombotic therapeutic drug in clinic still has defects, so that the aspirin is modified through design and screening, and the aspirin derivative-o-hydroxybenzoic acid polyglycol ester compound is successfully prepared.
Current patents on aspirin include: a compound snakegourd fruit-aspirin stomach enteric-coated pellet capsule, a preparation method and application thereof (2017); an arginine aspirin tablet and its preparation method (2017); a method for monitoring drug resistance of aspirin; the method for combined medication of prednisone and aspirin and the application thereof in preparing the combined medicine for treating the positive infertility of antinuclear antibodies, etc., but the related derivatives are different from the application, and the compound is a novel compound.
Disclosure of Invention
The invention aims to provide an o-hydroxybenzoic acid polyglycol ester compound, which has obvious anticoagulation effect and dose dependence, and the effect is superior to the anticoagulation effect of aspirin with the same dose. The method has the advantages of simple synthetic route, effective saving of synthetic time, cost reduction, simple operation, easy implementation and suitability for industrial production.
Therefore, the invention provides an o-hydroxybenzoic acid polyglycol ester compound with the structure shown in formula I or formula II,
wherein n is 1-20, R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
The compound of the invention is preferably a compound with a structure shown in formula I
Wherein n is 1-20, R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
The compound of the present invention is more preferably a compound having the following structure
Wherein R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
The most preferred compound of the present invention is a compound of the structure
Chemical name: 1, 2-dihydroxy ethyl 2-acetoxybenzoate, molecular formula: c13H16O5Molecular weight: 252.
the present invention further provides a process for the preparation of preferred compounds according to the invention, which comprises the following synthetic route:
the preparation method comprises the following steps:
(1) synthesis of aspirin chloride: sequentially adding acetylsalicylic acid, thionyl chloride and pyridine into a dry round-bottom flask for reaction, then evaporating excessive thionyl chloride, adding dichloromethane, and sealing for later use;
(2) synthesis of poly glycol ortho-hydroxybenzoate: adding glycol ether, triethylamine and a reaction product into a round-bottom flask in sequence;
(3) and (3) separation of a product: mixing with dichloromethane: separating by silica gel column chromatography with ethyl acetate 15:1 as mobile phase;
wherein the reaction time in step (1) is 1 to 4 hours, preferably 1.5 hours. The excess of thionyl chloride is 1-10 times (molar weight). Pyridine is used as a catalyst. Wherein, aspirin acyl chloride in the step (2): ethylene glycol diethyl ether (v: v) ═ 10:1 to 1:1, preferably 5: 1. Wherein, dichloromethane in step (3): ethyl acetate 100: 1-100: 50 (v: v), preferably 15: 1.
the invention further provides the use of a compound according to the invention for the preparation of a medicament having a prolonged blood clotting effect, the so-called anticoagulant effect.
The invention further provides pharmaceutical compositions containing the compounds of the invention. The pharmaceutical composition is selected from any pharmaceutically acceptable preparation form. Such as tablet, capsule, granule, powder, oral liquid, and injection. The preparation of the formulation is carried out in a manner conventional in the art.
The invention aims to develop a preparation method of an o-hydroxybenzoic acid polyglycol ester compound. The research results can be effective in developing new compound types. And the method has wide social benefits, foresees huge economic benefits and has wide application prospect.
The experimental route of the invention is feasible and reasonable. The total yield of the obtained poly (glycol) o-hydroxybenzoate compounds can reach 42% at most, and the purity can reach more than 99% at most. Compared with aspirin, the aspirin-based blood brain barrier has the following main advantages that the aspirin-based blood brain barrier has better lipid solubility, can better penetrate through the blood brain barrier, reduces the dosage of a medicine, and has better tolerance; the compound is neutral, has no irritation to gastric mucosa, and reduces potential gastrointestinal reaction; the acid and the alkali are more stable, and the stability of the medicine is facilitated, and the transportation is facilitated. In addition, the method has reasonable process design, is feasible, has lower cost, uses less toxic and harmful reagents, does not pollute the environment, and is suitable for mass industrial production.
Drawings
FIG. 1 is a synthetic route of poly glycol esters of ortho-hydroxybenzoic acid;
FIG. 2 is a hydrogen spectrum diagram for identifying the structure of poly (glycol) esters of ortho-hydroxybenzoic acid;
FIG. 3 is a carbon spectrum diagram for identifying the structure of poly (glycol) esters of ortho-hydroxybenzoic acid;
FIG. 4 shows the effect of the compounds of the poly (glycol) esters of ortho-hydroxybenzoic acid on the clotting time of mice;
the data are expressed as mean ± standard deviation,*P<0.05vs. normal control group,**P<0.01vs. normal control group.
FIG. 5 Effect of poly (glycol) ortho-hydroxybenzoate on mouse serum TXA2/PGI2 levels;
the data are expressed as mean ± standard deviation,*P<0.05vs. normal control group,**P<0.01vs. normal control group.
Detailed description of the invention
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
EXAMPLE 1 Synthesis of polyalkylene glycol ortho-hydroxybenzoate Compounds
In a dry 50mL round bottom flask, 1.2g of acetylsalicylic acid, 2mL of thionyl chloride and one drop of pyridine are sequentially added, the mixture is reacted at 70 ℃ for 1.5h, excessive thionyl chloride is evaporated, 10mL of dichloromethane is added, and the mixture is sealed for standby. Wherein 2% sodium hydroxide is used as tail gas receiving liquid. Adding 200 mu L of ethylene glycol ethyl ether, 300 mu L of triethylamine and 5mL of dichloromethane into a 50mL round-bottom flask in sequence, dripping 10mL of dichloromethane aspirin acyl chloride solution, reacting at room temperature for 1h, and reacting with dichloromethane: separating by silica gel column chromatography with ethyl acetate 15:1 as mobile phase. This gave 0.27g of a pale yellow oil in 51.9% yield. The product is 2-acetoxybenzoic acid 1, 2-dihydroxy ethyl ester.
EXAMPLE 2 Synthesis of polyalkylene glycol esters of o-hydroxybenzoic acid
In a dry 500mL round bottom flask, 20g of acetylsalicylic acid, 34mL of thionyl chloride and one drop of pyridine are sequentially added, and after 1.5h of reaction at 70 ℃ and excessive thionyl chloride is evaporated, 40mL of dichloromethane is added and the mixture is sealed for standby. Wherein 2% sodium hydroxide is used as tail gas receiving liquid. Adding 3.4mL of ethylene glycol ethyl ether, 5mL of triethylamine and 80mL of dichloromethane into a 250mL round-bottom flask in sequence, dripping 40mL of dichloromethane aspirin acyl chloride solution, reacting at room temperature for 1h, and adding dichloromethane: separating by silica gel column chromatography with ethyl acetate 15:1 as mobile phase. 5.2037 g of a pale yellow oil were obtained in 59.9% yield. The product is 2-acetoxybenzoic acid 1, 2-dihydroxy ethyl ester.
Example 3 Synthesis of Aspirin propylene glycol monoethyl ester
In a dry 50mL round bottom flask, 1g of acetylsalicylic acid, 2mL of thionyl chloride and one drop of pyridine are sequentially added, the mixture is reacted at 70 ℃ for 1.5h, excessive thionyl chloride is evaporated, 10mL of dichloromethane is added, and the mixture is sealed for standby. Wherein 2% sodium hydroxide is used as tail gas receiving liquid. In a 50mL round bottom flask, 230 mu L of propylene glycol ethyl ether, 300 mu L of triethylamine and 5mL of dichloromethane are sequentially added, 10mL of dichloromethane aspirin acyl chloride solution is added dropwise, and after reaction is carried out for 1h at room temperature, the mixture is reacted with dichloromethane: separating by silica gel column chromatography with ethyl acetate 15:1 as mobile phase. 0.3g of a pale yellow oil was obtained in 53% yield. The product is 2-acetoxybenzoic acid 1, 2-dihydroxy ethyl ester.
Example 4 identification of the Structure of polyalkylene glycol esters of o-hydroxybenzoic acid
The o-hydroxybenzoic acid polyglycol ester compound is light yellow oily matter,1H-NMR(600MHz,DMSO-d6) δ 8.06(1H, dd, J ═ 7.8,1.8Hz), 7.56(1H, t, J ═ 7.8,1.8Hz), 7.32(1H, td, J ═ 7.6, 1.3Hz), 7.10(1H, dd, J ═ 8.1,1.3Hz) are ortho-and meta-coupled proton signals on the benzene ring, 4.42(2H, t), 3.73(2H, t), 3.56(2H, q, J ═ 7.0Hz) are three methylene proton signals, 2.37(3H, s), 1.23(3H, t, J ═ 7.0Hz) are methyl proton signals. The carbon spectrum gives 13 carbon signals, where δ 169.8, 164.6 are the ester carbonyl carbon signals, δ 150.7, 133.9, 132.0, 126.0, 123.8, 123.2 are the carbon signals on the phenyl ring, δ 68.3, 66.7, 64.4 are the oxygen continuous carbon signals, δ 21.0, 15.1 are the carbon signals.
The above information was combined to determine the structure of the compound as shown below.
Example 5 efficacy test 1 for the products of the invention
1. Experimental Material
Experimental animals: SPF grade Male Kunming mice (20-25g) 90.
The tested drugs are: polyalkylene glycol o-hydroxybenzoate (i.e., the compound prepared in example 1 of the present invention), aspirin (Bayer pharmaceuticals Co., Ltd.)
2. Principle of experiment
The administration is carried out by intragastric administration to mice, the intragastric volume is 0.1ml/10g, the intragastric administration is carried out once a day, and the administration is continued for 7 days. All animals were free to eat and drink water, and weights were weighed every three days. After the gavage is finished on the seventh day, blood is taken from the inner canthus of the eye of the mouse, and the blood coagulation time is measured; serum is separated, and the levels of thromboxane A2(TXA2) and prostacyclin (PGI2) in the serum are measured by using an ELISA kit, so that the anticoagulant effect of the poly (glycol) ortho-hydroxybenzoate compounds is further evaluated.
3. Experimental methods
3.1 animal grouping
90 male Kunming mice of SPF grade were purchased, quarantined for all animals, and observed for an adaptation period of 3 days, with one weight measurement each during the animal receiving and quarantine periods. Qualified animals enter formal experiments according to the conditions of weight increase, general physical signs, activities and the like of the animals in the adaptation period. After adaptive feeding, Kunming male mice of SPF grade were weighed and randomly divided into 6 groups, namely a normal control group (same volume of olive oil is given by intragastric administration), an aspirin low dose group (7mg/kg/d), an aspirin high dose group (40mg/kg/d), an o-hydroxybenzoic acid polyglycol ester compound low dose group, a medium dose group and a high dose group (7mg/kg/d, 16mg/kg/d, 40mg/kg/d), and 15 mice in each group.
3.2 Experimental procedures
The gavage volume of the mice is 100ml/kg, and the gavage is performed once a day for 7 days. The aspirin group uses normal saline as a solvent, and the test substance group uses olive oil as a solvent. All mice were fed freely, water. After 30 minutes from the completion of the gavage on the seventh day, venous blood is taken from the canthus in the eye, and the blood coagulation time is measured; serum was isolated, and the levels of TXA2 and PGI2 in the serum were determined to calculate TXA2/PGI 2. General clinical observations were made once daily during the course of the experiment. The appearance, spirit and movement of the mice after administration were observed. If the animals die or are dying, the cause of death is known in time, the number of death is recorded and the animal is supplemented. (see Table 1)
TABLE 1 administration and diet of the animals of each group
3.3 Main test indexes
(1) The body weight was weighed every three days.
(2) And (3) blood coagulation time determination: 30 minutes after administration on day seven, each group of mice was anesthetized with 200mg/kg avermectin, blood was taken from the canthus at the eyes, the first two drops were discarded, two drops were dropped onto a clean glass slide, and the slide was examined once every 15 seconds with a clean fine needle, based on the criterion that the blood drop on the glass slide could be pulled up to silk, i.e., the process of changing soluble fibrinogen in the blood to insoluble fibrin, the process of changing the blood from a fluid state to a non-fluid gelatinous clot was recorded, and the average clotting time of the two drops was recorded.
(3) Measurement of blood levels of TXA2, PGI 2: after 30 minutes of administration on the seventh day of the animals, blood was collected from the inner canthus of the eyes, and the blood levels of TXA2 and PGI2 were measured by ELISA kit to calculate TXA2/PGI 2.
4. Experimental data and results
4.1 data processing
The measurement data is tested by a paired t test method, the counting data is tested by a nonparametric test method, the grade data is tested by NPar TestsMann-Whitney, each administration group data and the same period control group data are respectively tested for significance, and P <0.05 and P <0.01 respectively indicate significant difference and very significant difference; p >0.05 indicates no significant difference.
4.2 results of the experiment
4.2.1 clotting time statistics
After each group of mice was anesthetized with 200mg/kg of avertin, venous blood was collected from the canthus at the eyes and dropped on a glass slide, and the clotting time was determined based on the fibrin appearance time. The blood coagulation time is prolonged and is positively correlated with the anticoagulation effect strength of the medicine. The results are shown in table 2 and fig. 4, the aspirin low-dose group significantly prolongs the blood coagulation time (P <0.05) of mice compared with the normal control group, and is consistent with the clinical anticoagulant treatment effect of aspirin, which indicates that the experimental anticoagulant pharmacodynamics evaluation system has better stability. Compared with the normal control group, the low-dose, medium-dose and high-dose groups of the o-hydroxybenzoic acid polyglycol ester compound can obviously prolong the blood coagulation time of mice (P is less than 0.01), and compared with the aspirin group with the same dose, the blood coagulation time is obviously prolonged. The result shows that the o-hydroxybenzoic acid polyglycol ester compound has obvious anticoagulation effect.
TABLE 2 evaluation of blood coagulation time measurement function
Note: data are expressed as mean ± standard deviation, # P <0.05vs. normal control group, # P <0.01vs. normal control group.
4.2.2 Thrombin A2/prostacyclin (TXA2/PGI2) levels
Centrifuging the taken blood sample, reserving plasma, detecting the levels of the thromboxane A2 and the prostacyclin in the plasma by using a thromboxane A2 enzyme-linked immunosorbent assay kit and a prostacyclin enzyme-linked immunosorbent assay kit, calculating the ratio of the thromboxane A3578 enzyme-linked immunosorbent assay kit and the prostacyclin enzyme-linked immunosorbent assay kit, and evaluating the anticoagulation function of the drug, wherein the lower the ratio is, the stronger the anticoagulation function of the drug is. The results are shown in table 3 and fig. 5, and the aspirin low-dose group has no significant change in TXA2/PGI2 levels (P >0.05) compared with the normal control group, indicating that the aspirin low-dose group has no platelet aggregation-promoting effect; the level of TXA2/PGI2 in the aspirin high-dose group is remarkably increased compared with that in the normal control group (P <0.01), which indicates that the aspirin high-dose group has remarkable platelet aggregation promoting effect; the water average of TXA2/PGI2 in the low dose, medium dose and high dose groups of the o-hydroxybenzoic acid polyglycol ester compounds has no significant effect compared with the normal control group (P > 0.05). The result shows that the o-hydroxybenzoic acid polyglycol ester compound has no obvious function of promoting the platelet aggregation. Experiments show that the aspirin with high dosage can promote the formation of blood platelets and is not beneficial to the antithrombotic effect, but the aspirin with high dosage has no defect.
TABLE 3 evaluation of anti-platelet aggregation function
Note: the data are expressed as mean ± standard deviation,*P<0.05vs. normal control group,**P<0.01vs. normal control group.
Claims (10)
1. The o-hydroxybenzoic acid polyglycol ester compound with the structure shown in formula I or formula II,
wherein n is 1-20, R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
2. The compound of claim 1, which is a compound of the structure of formula I
Wherein n is 1-20, R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
3. The compound of claim 2, of the structure
Wherein R is H, -C1-20Alkyl and 2-acetoxybenzoyl.
4. The compound of claim 3, of the structure
5. A process for the preparation of the compound of claim 3, wherein the synthetic route is as follows:
6. the preparation method according to claim 5, comprising the steps of:
(1) synthesis of aspirin chloride: sequentially adding acetylsalicylic acid, thionyl chloride and pyridine into a dry round-bottom flask for reaction, then evaporating excessive thionyl chloride, adding dichloromethane, and sealing for later use;
(2) synthesis of poly glycol ortho-hydroxybenzoate: adding glycol ether, triethylamine and a reaction product into a round-bottom flask in sequence;
(3) and (3) separation of a product: mixing with dichloromethane: separating by silica gel column chromatography with ethyl acetate 15:1 as mobile phase;
wherein the reaction time in the step (1) is 1-4 hours, and the addition amount of the thionyl chloride is 1-10 times of that of the acetylsalicylic acid; pyridine is used as a catalyst; wherein, the aspirin acyl chloride in the step (2): ethylene glycol diethyl ether (v: v) ═ 10:1 to 1: 1.
7. Use of a compound according to claim 1 for the preparation of a medicament having a blood clotting prolonging effect.
8. A pharmaceutical composition comprising a compound of claim 1.
9. The pharmaceutical composition of claim 8, selected from any one of pharmaceutically acceptable formulation forms.
10. The pharmaceutical composition of claim 9, selected from the group consisting of tablets, capsules, granules, powders, oral liquids, and injections.
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| WO2021073038A1 (en) * | 2019-10-14 | 2021-04-22 | 新乡海盈生物科技有限责任公司 | O-hydroxybenzoic acid polyglycol ester compound, and synthetic preparation method and pharmaceutical use thereof |
| CN113893242A (en) * | 2021-10-12 | 2022-01-07 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
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| EP0576868A1 (en) * | 1992-07-02 | 1994-01-05 | REHAU AG + Co | Medical articles |
| WO1996015809A2 (en) * | 1994-11-22 | 1996-05-30 | Laboratori Alchemia S.R.L. | Process for the preparation of a pharmacologically active chemical combination |
| CN1616404A (en) * | 2004-09-02 | 2005-05-18 | 中国海洋大学 | Anti-oxidizing derivative of aspirin and its synthetic method and use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0576868A1 (en) * | 1992-07-02 | 1994-01-05 | REHAU AG + Co | Medical articles |
| WO1996015809A2 (en) * | 1994-11-22 | 1996-05-30 | Laboratori Alchemia S.R.L. | Process for the preparation of a pharmacologically active chemical combination |
| CN1616404A (en) * | 2004-09-02 | 2005-05-18 | 中国海洋大学 | Anti-oxidizing derivative of aspirin and its synthetic method and use |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021073038A1 (en) * | 2019-10-14 | 2021-04-22 | 新乡海盈生物科技有限责任公司 | O-hydroxybenzoic acid polyglycol ester compound, and synthetic preparation method and pharmaceutical use thereof |
| CN113893242A (en) * | 2021-10-12 | 2022-01-07 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
| CN113893242B (en) * | 2021-10-12 | 2023-10-13 | 广东宝康生物医药有限公司 | Use of ASH in myocardial protection |
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