CN113698384B - Alogliptin gallate and preparation method and application thereof - Google Patents
Alogliptin gallate and preparation method and application thereof Download PDFInfo
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- CN113698384B CN113698384B CN202111244025.2A CN202111244025A CN113698384B CN 113698384 B CN113698384 B CN 113698384B CN 202111244025 A CN202111244025 A CN 202111244025A CN 113698384 B CN113698384 B CN 113698384B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
Abstract
The invention provides alogliptin gallate and a preparation method and application thereof, wherein the structural formula is shown as the following formula I, and the preparation method is as follows: reacting gallic acid and alogliptin in an organic solvent at a molar ratio of 1: 1-5 for 1 min to 6 h, wherein the reaction temperature is 0-50 ℃, and filtering and concentrating under reduced pressure to obtain the alogliptin gallate product. Compared with the prior art, the alogliptin gallate of the invention not only improves the water solubility of alogliptin, but also overcomes the defect of single action mechanism of the existing alogliptin benzoate, improves the activity of the medicament by introducing gallic acid with various pharmacological activities, and increases the prevention and treatment effects of the medicament on complications except for reducing blood sugar
Formula I.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to alogliptin gallate, a preparation method thereof and application thereof in preparation of medicines for treating diabetes.
Background
Oxidative stress is one of the major causes of chronic complications of diabetes. Superoxide and peroxide generated by peroxidation in a diabetic patient can damage vascular endothelial cells, cause dysfunction of the vascular endothelial cells and increase thrombosis. Catalase (CAT) and superoxide dismutase (SOD) are the main components of antioxidant systems and play an important role in the oxidation-antioxidant balance. MDA is an index which reflects the in vivo oxidative stress state reliably and stably and directly reflects the damage degree of cells. The effective intervention on the indexes of the diabetic patients has important significance for preventing and treating diabetic complications.
Gallic acid is also known as gallic acid, chemical name 3,4, 5-trihydroxybenzoic acid (formula A), is an organic acid widely distributed in nature, mainly exists in plants such as tea, Galla chinensis, tara, Galla Turcica, etc., and has effects of anti-tumor, antibacterial, antiinflammatory, antioxidant, cardiovascular protection, etc. (No. 7, No. 10 of 2004 by Chinese pharmacist). In addition, studies show that gallic acid has inhibitory effect on alpha-glucosidase and glucose absorption, and is a competitive alpha-glucosidase inhibitor (2011, 20, 21 st phase of drug research).
Alogliptin (formula B) is a dipeptidyl peptidase 4 (DPP-4) inhibitor (trade name: ninoxin) developed by wutian pharmaceuticals in japan, and is approved for the treatment of type 2 diabetes in japan in 4 months of 2010. The medicine can inhibit the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic secretion polypeptide (GIP) in vivo, and improve the level of endogenous GLP-1 and GIP, so that the glucose-dependent insulin release of islet beta cells is promoted, the glucagon secretion of islet alpha cells is inhibited, and the hyperglycemia is reduced.
Salification is one of effective means for improving the physicochemical property of the drug molecules and improving the pharmaceutical property of the drug molecules, and particularly for fat-soluble drugs, salification can greatly improve the water solubility. In order to reduce side effects, alogliptin is in a benzoate form at present, but benzoic acid does not have an anti-diabetic effect, so that alogliptin has the characteristic of single action mechanism, and is clinically used as a three-line medicament and often combined with other hypoglycemic medicaments.
In addition, the pathogenesis of diabetes is complex, and the index of simple blood sugar reduction is that various drugs with different action mechanisms exist, such as glycosidase inhibition, insulin sensitizer, DPP-4 inhibitor, SGLT-2 inhibitor and the like. While the treatment of diabetes not only lowers blood sugar, but also needs to treat complications, the current alogliptin benzoate form does not have the effect of preventing and treating the complications.
Disclosure of Invention
The invention aims to solve the technical problems and provides a new salt form of alogliptin, namely alogliptin gallate, a preparation method thereof and application thereof in preparing a medicament for treating diabetes.
Aiming at the defects that alogliptin benzoate has a single action mechanism and does not have a complication prevention and treatment effect, the alogliptin gallate is designed, and gallic acid with pharmacological activity replaces benzoic acid, so that the patent drug property of alogliptin is kept, the activity of the drug is improved by introducing gallic acid with various pharmacological activities, and the prevention and treatment effects of the drug on complications except for blood sugar reduction are improved.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention, alogliptin gallate is provided, which has a chemical structural formula shown in formula i:
in a second aspect of the present invention, a process for preparing the compound is provided, which comprises the following reaction scheme:
the preparation process comprises the following steps: reacting gallic acid and alogliptin in an organic solvent at a molar ratio of 1: 1-5 for 1 min to 6 h, wherein the reaction temperature is 0-50 ℃, and filtering and concentrating under reduced pressure to obtain the alogliptin gallate product.
The preferred process conditions are as follows: dissolving gallic acid in an organic solvent, adding alogliptin at the temperature of 0-10 ℃, stirring for 1-2 hours at the temperature of 30-50 ℃ after finishing adding, cooling to room temperature, continuing stirring for 1-2 hours, filtering, and concentrating a filter cake under reduced pressure to constant weight.
Preferably, the organic solvent is selected from any one or more of methanol, ethanol, isopropanol, N-dimethylformamide, tetrahydrofuran, acetonitrile and acetone.
In a third aspect of the invention, the application of alogliptin gallate in preparing a medicament for treating diabetes is provided.
Preferably, the medicament for treating the diabetes mellitus takes the alogliptin gallate as the only active component or a medicinal composition containing the alogliptin gallate.
In a fourth aspect of the invention, a pharmaceutical composition for treating diabetes is provided, which comprises alogliptin gallate and
and pharmaceutically acceptable auxiliary materials.
The pharmaceutically acceptable auxiliary materials refer to conventional pharmaceutical auxiliary materials in the pharmaceutical field. Wherein the diluent and excipient can be selected from water; the binder can be selected from cellulose derivative, gelatin or polyvinylpyrrolidone; the filler is selected from starch; the disintegrating agent can be calcium carbonate or sodium bicarbonate; other adjuvants such as flavoring or sweetening agents may also be added to the composition.
The pharmaceutical composition can be prepared into various dosage forms by adopting the conventional method in the medical field and taking alogliptin gallate as an active ingredient and pharmaceutically acceptable auxiliary materials. When used for oral administration, it can be prepared into conventional solid preparations such as tablets, powders, capsules, etc.; for injection, it can be prepared into injection. In various preparations, the weight percentage of the active ingredients is 0.1-99.9%, preferably 0.5-90%.
The pharmaceutical composition is used for reducing blood sugar. The composition is applied to an individual needing to be treated by oral administration, intraperitoneal injection, subcutaneous injection, intravenous injection, intramuscular injection, lymph node injection, mucosal administration and other ways according to dosage forms, the dosage is generally 1-1000 mg/kg body weight/day, and the composition can be changed according to the age, the illness state and the like of the individual.
The invention has the following beneficial effects:
in the aspect of solubility, compared with alogliptin benzoate with the same dosage, the solubility of alogliptin gallate is improved by more than one time;
in the aspect of drug effect, the alogliptin gallate has DPP-4 and alpha-glycosidase inhibitory activities simultaneously. Animal experiments prove that the alogliptin gallate hypoglycemic effect is superior to alogliptin benzoate, and the difference is obvious.
Therefore, the alogliptin gallate of the invention not only improves the water solubility of alogliptin, but also overcomes the defect of single action mechanism of the existing alogliptin benzoate, improves the activity of the medicament by introducing gallic acid with various pharmacological activities, and increases the prevention and treatment effects of the medicament on complications except for reducing blood sugar.
Drawings
FIG. 1 is a mass spectrum of alogliptin gallate;
FIG. 2 is a hydrogen spectrum of alogliptin gallate;
FIG. 3 is a carbon spectrum of alogliptin gallate;
FIG. 4 is an infrared spectrum of alogliptin gallate.
Detailed Description
The following embodiments are implemented on the premise of the technical scheme of the present invention, and give detailed implementation modes and specific operation procedures, but the protection scope of the present invention is not limited to the following embodiments.
Example 1: preparation of alogliptin gallate
Dissolving gallic acid in an organic solvent, adding alogliptin with the molar ratio of 1-5 times at the temperature of 0-10 ℃, stirring for 1-2 hours at the temperature of 30-50 ℃, cooling to room temperature, continuing stirring for 1-2 hours, filtering, and concentrating a filter cake under reduced pressure to constant weight. The organic solvent is selected from any one or more of methanol, ethanol, isopropanol, N-dimethylformamide, tetrahydrofuran, acetonitrile and acetone. One preferred specific preparation process is as follows:
1.70g of gallic acid (purchased from Yujie Biotech Shanghai Co., Ltd.) was dissolved in 50mL of ethanol, 3.39g of 1 time of alogliptin (synthesized according to literature method: Xixia pharmacy 2011, volume 23, phase 9) was added at 10 ℃, the mixture was stirred at 50 ℃ for 1 hour, cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was concentrated under reduced pressure to constant weight with a yield of 96%.
The test results of alogliptin gallate prepared according to the method are shown in fig. 1 to fig. 4, and the specific results are as follows:
ESI: 340.22 (M + H), 171.0 (M + H) (FIG. 1).
1H NMR (400 MHz, DMSO) δ 7.96 (dd, J = 8.6, 5.5 Hz, 2H), 7.35 (td, J= 8.5, 2.5 Hz, 1H), 7.19 (dd, J = 9.7, 2.2 Hz, 1H), 6.89 (s, 2H), 5.34 (s, 1H), 5.17 (s, 2H), 3.10 (s, 3H), 3.06 (d, J = 11.8 Hz, 1H), 2.91 (d, J = 11.1 Hz, 1H), 2.80 (s, 1H), 2.62 (d, J = 9.4 Hz, 1H), 2.42 (s, 1H), 1.80 (d, J= 9.8 Hz, 1H), 1.74-1.59 (m, 1H), 1.53-1.35 (m, 1H), 1.28-1.10 (m, 1H) (fig. 2).
13C NMR (101 MHz, DMSO) δ 169.00, 166.38, 163.86, 162.73, 159.97, 152.48, 145.93, 145.76, 138.10, 136.56, 117.08, 116.12, 115.40, 109.21, 106.72, 90.01, 58.33, 51.54, 47.41, 46.31, 32.26, 27.86, 23.13 (fig. 3).
IR: 3426.0, 2918.7, 2860.2, 2227.1, 1704.0, 1639.9, 1562.0, 1544.3, 1526.1, 1438.7, 1362.1, 1212.9, 1035.6, 818.3 (fig. 4).
Example 2: comparison of solubility experiments
Putting 10 mL of deionized water into a single-mouth bottle, accurately weighing 500 mg of alogliptin benzoic acid, stirring at the constant temperature of 25 ℃ for 2 hours, stopping stirring and standing for 2 hours, sucking 1 mL of supernatant by a liquid transfer gun, concentrating under reduced pressure, removing a solvent, weighing the mass of the residual medicine, and calculating the room-temperature solubility of the medicine. The alogliptin gallic acid solubility was also performed according to the above method, and the two experiments were repeated 3 times, and the average value was taken. The comparative results are shown in table 1:
according to the experimental results shown in table 1, the solubility of alogliptin gallic acid was improved by more than 1-fold compared with the same dose of alogliptin benzoic acid.
Example 3: alpha-glucosidase activity inhibition assay
1. Experiment article
α -glucosidase: sigma corporation, usa;
dimethyl sulfoxide: shanghai Bo photo-biological technology, Inc.;
gallic acid; yujie Biotech Shanghai Co Ltd
An enzyme-labeling instrument: Bio-Tek, USA;
other reagents used were purchased from the national pharmaceutical group chemical agents limited.
2. Experimental methods
25 mu L of sample solution to be detected with different concentrations, then adding 12.5 mu L of alpha-glucosidase solution (the content is 27.8mg/L, and the preparation is prepared by 25mmol/L of PIPES buffer solution, and the pH value is 6.9), incubating at 37 ℃ for 10min, adding 12.5 mu L of glucose solution with the mass fraction of 0.16% into the system, incubating at 37 ℃, adding 100 mu L of chromogenic reagent into the system when 10min is over, simultaneously stopping the reaction, measuring the absorbance (A) at the wavelength of 630nm, wherein the amount of the residual chromogenic reagent in the reaction reflects the amount of glucose hydrolyzed by enzyme, and directly reflects the activity of the glucosidase. Gallic acid was used as a positive control in this method, and a blank control and an enzyme activity control were set.
The inhibition (%) was calculated as follows:
inhibition (%) = [1- (sample withoutE-sample withE)/(control withoutE-control withE) ] × 100%
3. Results of the experiment
The results of the experiment are shown in table 2:
the experiments show that the medicine has certain inhibition effect on alpha-glucosidase and shows dose-effect dependence. The alogliptin benzoate with the same concentration has no inhibition effect on alpha-glucosidase.
Example 4: therapeutic effect of alogliptin gallate on diabetic rats
1. Establishment of STZ-induced Wistar rat diabetes model:
5-6w healthy male Wistar rats, provided by Shanghai Si Laike laboratory animals, Inc. (quality certification number: 200700566001), were acclimatized for one week, given high-sugar high-fat diet, and given water, and 6 rats in the normal group were given normal diet. Rats are fasted for 12 hours overnight, and are injected with STZ in the abdominal cavity for three days continuously, 25 mg/kg is injected on the first day, 35 mg/kg is injected on the second day, 45 mg/kg is injected on the third day, an equal volume of citric acid/sodium citrate buffer solution is injected on a control group, all rat tail vein random blood sugar is detected by using a Roche glucometer after one week of the last injection, and the random blood sugar is more than or equal to 16.7 mmol/L on three days continuously as a diabetes molding standard. 6 rats without STZ injection served as normal control group.
2. Grouping and administration:
in the control group, 6 normal rats were selected and given a general diet. 29 model rats were selected and randomly divided into 3 groups: the diabetes mellitus model group is used as the model group, the alogliptin gallate treatment group is used as the treatment drug group with the dosage of 50 mg/kg/day, and the alogliptin benzoate treatment group is used as the control drug group with the dosage of 50 mg/kg/day. The model group, the treatment drug group and the control drug group are administered with high-sugar high-fat food, and are administered by intragastric gavage, and the model group and the normal group are administered with equal amount of tap water for intragastric gavage.
3. And (3) biochemical index determination:
the kit is purchased from Biyuntian biotechnology limited company, tail vein blood sampling is adopted in the experimental process, blood sugar, glycosylated hemoglobin GHb and relevant indexes of oxidative stress CAT, SOD and MDA are detected according to the operation of a kit specification, and the experimental result is shown in the following table 3:
as can be seen from the data in Table 3, the blood sugar lowering effect of the treatment drug group and the control drug group is obvious, and the difference p is less than 0.05 compared with the model group; the blood sugar reducing effect of the treatment drug group is better than that of the control drug group, and the difference is significant, and p is less than 0.05; the treatment drug group and the control drug group can reduce CAT and MDA and increase SOD, and the effect of the treatment drug group is better than that of the control drug group.
While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.
Claims (9)
1. Alogliptin gallate is characterized in that the structural formula is as follows:
2. the preparation method of alogliptin gallate according to claim 1, wherein gallic acid and alogliptin are reacted in an organic solvent at a molar ratio of 1: 1-5 for 1 minute to 6 hours at a reaction temperature of 0-50 ℃, and the product alogliptin gallate is produced after filtration and reduced pressure concentration.
3. The method for preparing alogliptin gallate according to claim 2, wherein the preparation method comprises:
wherein the organic solvent is selected from any one or more of methanol, ethanol, isopropanol, N-dimethylformamide, tetrahydrofuran, acetonitrile and acetone.
4. The method for preparing alogliptin gallate according to claim 2, wherein the preparation method comprises:
during preparation, the gallic acid is dissolved in the organic solvent, the alogliptin is added at the temperature of 0-10 ℃, the mixture is stirred for 1-2 hours at the temperature of 30-50 ℃, the mixture is cooled to room temperature, the stirring is continued for 1-2 hours, the filtering is carried out, and the filter cake is decompressed and concentrated to constant weight.
5. The use of alogliptin gallate according to claim 1 in the preparation of a medicament for the treatment of diabetes.
6. Use according to claim 5, characterized in that:
the medicine for treating diabetes takes alogliptin gallate as the only active component or is a medicine composition containing alogliptin gallate.
7. A pharmaceutical composition for treating diabetes, which is characterized by consisting of alogliptin gallate defined in claim 1 and pharmaceutically acceptable auxiliary materials.
8. The pharmaceutical composition for the treatment of diabetes according to claim 7, characterized in that:
wherein, the pharmaceutical composition is an oral solid preparation or an injection preparation.
9. The pharmaceutical composition for the treatment of diabetes according to claim 7, characterized in that:
wherein, in the pharmaceutical composition, the alogliptin gallate accounts for 0.5-90% by mass.
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