CN111574435A - 4,4' -bipyridine methylpyrazine derivative eutectic - Google Patents
4,4' -bipyridine methylpyrazine derivative eutectic Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly provides a 4,4' -dipyridyl methylpyrazine derivative eutectic, a preparation method thereof and application thereof in preparation of a blood fat reducing medicine. The 4,4 '-bipyridine methylpyrazine derivative eutectic prepared by the invention is formed by combining a methylpyrazine derivative and 4,4' -bipyridine according to a molar ratio of 2:1, Cu-Ka radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta is as follows: characteristic peaks are at 9.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.1 +/-0.2 degrees and 27.1 +/-0.2 degrees. The 4,4' -dipyridyl methylpyrazine derivative eutectic prepared by the invention is high in product purity and good in stability after being placed in a solid state, and animal experiments prove that the eutectic has good drug effect. The invention has simple preparation process and better industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic drug co-crystals, and particularly relates to a 4,4' -dipyridyl methylpyrazine derivative co-crystal.
Background
Pharmaceutical co-crystals are based on the supramolecular chemistry principle, i.e. molecular recognition and supramolecular self-assembly by intermolecular interactions. The pharmaceutical active ingredient (API) is self-assembled with a suitable co-crystal former (CCF) through hydrogen bonds, or non-covalent bonds with saturation and directionality (such as Van der Waals force of aromatic hydrocarbon or benzene ring, pi-pi conjugation and halogen bonds), to form a novel structure, namely, the pharmaceutical co-crystal. The method is based on hydrogen bonds, does not need to form new covalent bonds or destroy existing covalent bonds, can modify the physicochemical properties of the medicament while retaining the pharmacological action of the medicament, such as improving the stability of the medicament, reducing the hygroscopicity of the medicament, improving the solubility, improving the bioavailability and the like, and provides a wide development prospect for the application of pharmaceutical co-crystals in the aspect of pharmaceutical industry. In recent years, pharmaceutical co-crystal research has received increasing attention. At the present stage, the research on pharmaceutical co-crystals in foreign countries is gradually increased and deepened; and domestic research on the method is relatively less. For the imitation drugs, the research on the pharmaceutical co-crystal can also break the patent protection of the original research pharmaceutical company on the pharmaceutical crystal form, and is beneficial to the market of the imitation drugs. Therefore, it is of great practical significance to obtain more novel, practical and inventive pharmaceutical co-crystals, especially some water-insoluble drugs.
Acipimox is a nicotinic acid derivative, is a broad-spectrum long-acting lipid regulating drug, is used for various primary and secondary hyperlipidemias, mainly acts on adipose tissues, reduces the synthesis of plasma low-density lipoprotein and very low-density lipoprotein by inhibiting the release of free fatty acid from the adipose tissues, thereby reducing the levels of the plasma low-density lipoprotein and the very low-density lipoprotein in the plasma and simultaneously increasing the level of plasma HDL by inhibiting the activity of liver lipase. Acipimox was developed by Farmitalia carolerba company of italy and marketed in italy in 1985, and then, by virtue of its high safety and remarkable therapeutic effect, it was marketed successively in many countries and regions such as germany, chile, switzerland, hong kong of china, etc.
The pharmaceutical co-crystal can affect the physicochemical properties of the medicine, directly affect the dissolution and absorption efficiency of the medicine under the condition of physiological pH 7.4, and further affect the bioavailability, clinical curative effect and the like of the medicine. By means of drug co-crystallization, the advantages of co-crystallization can be well applied, which has very important effect on understanding and mastering the space arrangement and physicochemical properties of effective molecules of drugs.
At present, a lot of reports about acipimox exist, but reports about preparation, physicochemical properties, pharmacology and other properties are mainly about, reports about a crystal eutectic structure are less, preparation methods of acipimox are reported in patents US2005239803A1, CN 103508963A and the like, and acipimox precipitate with a crystal property obtained in patent CN86103304A is acipimox hydrate, so that the yield is low. In the previous reports, the reports of the acipimox eutectic crystal are less, and the characterization parameters of the acipimox eutectic crystal are not mentioned.
Disclosure of Invention
In view of the defects of the prior art, the invention provides a 4,4' -dipyridyl methylpyrazine derivative eutectic crystal.
The methylpyrazine derivative is acipimox, and the 4,4 '-dipyridyl methylpyrazine derivative eutectic is 4,4' -dipyridyl acipimox eutectic.
The acipimox serving as the medicinal component of the invention has the chemical name of 5-methylpyrazine-2-carboxylic acid-4-oxide, and is white or off-white crystalline powder. CAS number: 51037-30-0 molecular formula C6H6N2O3The structural formula is shown as a, the selected eutectic forming substance is 4,4' -bipyridine, and the molecular formula is C10H8N2The structural formula is shown as b.
In a first aspect of the present invention, a co-crystal of a 4,4' -bipyridylmethyl pyrazine derivative is provided. In the co-crystal, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 2: 1.
The 4,4' -dipyridyl methylpyrazine derivative eutectic uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 9.5 +/-0.2 degrees, 16.5 +/-0.2 degrees, 25.1 +/-0.2 degrees, and 27.1 +/-0.2 degrees.
Preferably, the 4,4' -bipyridyl methylpyrazine derivative eutectic has characteristic peaks at 9.5 +/-0.2 °, 10.3 +/-0.2 °, 13.9 +/-0.2 °, 16.5 +/-0.2 °, 19.2 +/-0.2 °, 20.0 +/-0.2 °, 25.1 +/-0.2 ° and 27.1 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Kalpha radiation.
Preferably, the 4,4' -bipyridine methylpyrazine derivative eutectic is irradiated by Cu-Ka, and the characteristic peak of the eutectic accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the 4,4' -dipyridyl methyl pyrazine derivative eutectic has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, which is 185.73 ℃.
Preferably, the 4,4' -dipyridyl methyl pyrazine derivative eutectic has the following crystallographic parameters: triclinic system with space group P
The unit cell parameters are:
α 73.0010(10) ° β 88.4890(10) ° γ 63.454(2) ° unit cell volume
The second aspect of the invention provides a preparation method of a 4,4' -bipyridyl methylpyrazine derivative eutectic, which comprises the following specific preparation steps: adding the methylpyrazine derivative and 4,4 '-bipyridine into an organic solvent A, heating for dissolving, clarifying the solution, performing reflux reaction, cooling for crystallization, filtering and drying to obtain the 4,4' -bipyridine methylpyrazine derivative eutectic.
Preferably, the organic solvent A is selected from one or more of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol and isopropanol.
Preferably, the organic solvent A is selected from one or two of acetonitrile, acetone and tetrahydrofuran.
Preferably, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.8-2.2: 1.
Preferably, the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.95-2.05: 1.
Preferably, the mass-to-volume ratio of the 4,4' -bipyridine to the organic solvent A in the system is 3-6: 1, wherein the mass is mg, and the volume is ml.
Preferably, the temperature for dissolving and heating is 45-75 ℃.
Preferably, the temperature for cooling and crystallizing is 0-15 ℃.
Preferably, the temperature for cooling and crystallizing is 5-10 ℃.
Preferably, the crystallization time is 40-62 hours.
Further preferably, the preparation method comprises the following steps:
dissolving the methylpyrazine derivative and 4,4 '-bipyridine in an organic solvent A, heating to dissolve at 45-75 ℃, stirring, refluxing, reacting for 7-12 hours, cooling to 0-15 ℃, crystallizing for 40-62 hours, filtering, washing a filter cake, and drying to obtain the 4,4' -bipyridine methylpyrazine derivative eutectic.
Preferably, the solvent for washing the filter cake is selected from one of acetone, acetonitrile and tetrahydrofuran.
Preferably, the drying temperature is 50-70 ℃, and the drying time is 8-12 hours.
The third aspect of the invention provides application of the 4,4' -dipyridyl methylpyrazine derivative eutectic serving as an active ingredient in preparation of a medicament for treating hypolipidemia.
Confirmation of the Crystal Structure
X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, irradiating with CuKa, collecting data in an omega scan fashion and Lp correction. The crystal structure is calculated by a ShelXT program in olex2 software, the ShelXL program is adopted to correct the structure parameters and judge the atom species by a least square method, the positions of all hydrogen atoms are obtained by a geometric calculation method and a difference Fourier method, the goodness of fit (GooF value) is 1.056 and is close to 1.0, and the weight scheme is proper and the structure is accurate.
The crystallographic data obtained by testing and analyzing the crystals of the methylpyrazine derivative prepared by the invention are (Table 1), wherein the crystallographic parameters are as follows: triclinic system with space group P
The unit cell parameters are:
α 73.0010(10) ° β 88.4890(10) ° γ 63.454(2) ° unit cell volume
The molecular formula is: [ C ]12H12N4O6·C10H8N2]The molecular weight is: 464.44. the ORTEP diagram of the eutectic crystal of 4,4 '-bipyridyl methylpyrazine derivative of the present invention shows that the methylpyrazine derivative and 4,4' -bipyridine are linked together by intramolecular hydrogen bonds, wherein the carboxyl group H3 of the methylpyrazine derivative forms a hydrogen bond with N3 on the 4,4 '-bipyridine, and the carboxyl group H6 of the other methylpyrazine derivative molecule forms an intramolecular hydrogen bond with N4 on the 4,4' -bipyridine, as shown in fig. 3. The stacking diagram of the 4,4' -dipyridyl methylpyrazine derivative of the invention is shown in figure 2.
TABLE 14, 4' -Bipyridylmethyl pyrazine derivatives Co-crystals Primary crystallography data
X-ray powder diffraction test instrument and test conditions: x-ray powder diffractometer PANalytical E; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 50 degrees.
According to the above crystallographic data, the characteristic peak of the corresponding X-ray powder diffraction pattern (Cu-Ka) is detailed in figure 1 and table 2.
TABLE 24 PXRD peaks of Co-crystals of 4,4' -bipyridylmethylpyrazine derivatives
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The eutectic TGA/DSC test result of the 4,4' -bipyridyl methyl pyrazine derivative prepared by the method is shown in figure 4, and the DSC test result has an endothermic peak with the corresponding temperature of 185.73 ℃. According to the TGA detection result, a weight loss step exists, and the DSC/TGA detection result shows that the 4,4' -bipyridyl methyl pyrazine derivative eutectic prepared by the invention does not contain other solvents.
Compared with the currently reported crystal form of the methylpyrazine derivative, the 4,4' -bipyridine methylpyrazine derivative eutectic prepared by the method has the following advantages:
(1) the stability is high. After the 4,4 '-bipyridine methylpyrazine derivative eutectic is subjected to a light test and placed in a high-temperature and high-humidity environment, the HPLC purity is still higher than 99.55%, and the solid state stability of the 4,4' -bipyridine methylpyrazine derivative eutectic is good compared with the existing methylpyrazine derivative crystal form.
(2) The drug effect is good. The 4,4' -dipyridyl methylpyrazine derivative eutectic can effectively reduce the concentration of cholesterol, triglyceride and low-density lipoprotein in the serum of a fatty liver rat.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the 4,4' -bipyridine acipimox eutectic.
FIG. 2: stacking diagram of eutectic of 4,4' -dipyridyl acipimox.
FIG. 3: ORTEP diagram of 4,4' -bipyridine acipimox cocrystal.
FIG. 4: a Differential Scanning Calorimetry (DSC) graph of the eutectic of 4,4' -bipyridyl acipimox.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and it is within the scope of the present invention to include changes and modifications apparent to those of ordinary skill in the art in light of the present invention, impurity I being 5-methylpyrazine-2-carboxylic acid, and the methylpyrazine derivative being acipimox.
Example 1:
adding 61.6mg of acipimox and 31.2mg of 4,4 '-bipyridyl into 8ml of acetonitrile, heating to 75 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to 5-10 ℃, standing at controlled temperature for crystallization for 48 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 50 ℃ for 12 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 95.33%, the purity is 99.96%, and the impurity I: 0.03 percent.
Example 2:
adding 61.6mg of acipimox and 32.0mg of 4,4 '-bipyridyl into 10ml of acetone, heating to 45 ℃, stirring for dissolving, carrying out reflux reaction for 12 hours, slowly cooling to 0-5 ℃, standing at controlled temperature for crystallization for 40 hours, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 70 ℃ for 8 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 94.56%, the purity is 99.94%, and the impurity I: 0.04 percent.
Example 3:
adding 61.6mg of acipimox and 30.5mg of 4,4 '-bipyridyl into 5ml of tetrahydrofuran, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 7 hours, slowly cooling to 10-15 ℃, standing at controlled temperature for crystallization for 62 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 60 ℃ for 10 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 93.85%, the purity is 99.92%, and the impurity I: 0.06 percent.
Example 4:
adding 61.6mg of acipimox and 34.7mg of 4,4 '-bipyridine into 8ml of methanol, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to-5-0 ℃, standing at a controlled temperature for crystallization for 35 hours, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the 4,4' -bipyridine acipimox eutectic, wherein the yield is 89.90%, the purity is 99.90%, and the impurity I: 0.08 percent.
Example 5:
adding 61.6mg of acipimox and 28.4mg of 4,4 '-bipyridyl into 4ml of ethanol, heating to 77 ℃, stirring for dissolving, carrying out reflux reaction for 8 hours, slowly cooling to 15-20 ℃, standing at controlled temperature for crystallization for 65 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 70 ℃ for 10 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 92.42%, the purity is 99.90%, and the impurity I: 0.09 percent.
Example 6:
adding 61.6mg of acipimox and 25.0mg of 4,4 '-bipyridyl into 12ml of isopropanol, heating to 80 ℃, stirring for dissolving, carrying out reflux reaction for 10 hours, slowly cooling to 5-10 ℃, standing at a controlled temperature for crystallization for 48 hours, filtering, washing a filter cake with tetrahydrofuran, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the 4,4' -bipyridyl acipimox eutectic, wherein the yield is 90.60%, the purity is 99.88%, and the impurity I: 0.11 percent.
Example 7:
adding 61.6mg of acipimox and 36.7mg of 4,4 '-bipyridyl into 10ml of mixed solvent (5ml of acetonitrile and 5ml of ethanol), heating to 55 ℃, stirring for dissolving, carrying out reflux reaction for 12 hours, slowly cooling to-5-0 ℃, standing for crystallization for 30 hours at controlled temperature, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain 4,4' -bipyridyl acipimox eutectic crystal, wherein the yield is 85.0%, the purity is 99.85%, and the impurity I: 0.12 percent.
Comparative example 1:
adding 2730ml of 98% concentrated sulfuric acid into a 10L glass reaction kettle, adding 910.0g of 5-methylpyrazine-2, 3-dicarboxylic acid under stirring, heating to 60 ℃, heating for reaction for 1h, and slowly adding 5.5kg of water and 164.9g of sodium tungstate (Na)2WO4·2H2O), 623.0g of hydrogen peroxide with the mass concentration of 30 percent, continuously heating and stirring for 8h, cooling and crystallizing for 4h under the ice bath condition, filtering the solid, drying for 12h at 100 ℃ and preparing 595g of acipimox product. The product yield in this reaction was 77.30%; HPLC purity 96.20%, impurity I: 2.80 percent.
Comparative example 2:
adding 200ml of water into 100g of the acipimox crude product, heating to 100 ℃, stirring to dissolve, adding 3.0g of activated carbon, continuing to keep the temperature and stirring for 20 minutes, and performing suction filtration; cooling the filtrate to 60 ℃ at a speed of 10 ℃/h, then dropwise adding 220g of acetone into the filtrate, cooling to 5 ℃ at a speed of 10 ℃/h for crystallization for 7h after dropwise adding, performing suction filtration, washing a filter cake with acetone, and drying (0.01MPa, 80 ℃) to obtain the off-white acipimox with a yield of 88.60%. HPLC purity: 98.30%, 5-methylpyrazine-2-carboxylic acid (impurity I): 0.50 percent.
Comparative example 3:
330mg (1mmol) of Na2WO4·2H2O was placed in a 50ml flask, dissolved in 16ml of water and fitted with mechanical stirring, reflux cooler and thermometer. 3.75ml of 40% w/v (400g/L) (44mmol) hydrogen peroxide were added to the solution, diluted H2SO4The pH was adjusted to 1.5 and 5.52g (40mmol) of 2-carboxy-5-methylpyrazine were then added.
The suspension of water produced by the reaction was heated to 70 ℃ with stirring and maintained at this temperature for 2.5 hours. Thus a gradually solubilised suspension is obtained. Finally, some product was found to precipitate. The mixture was allowed to stand at room temperature overnight to cause precipitation of the reaction product in a crystal form. This product was filtered, washed with ice water and dried on a bisque-fired plate to give 4.68g, corresponding to 4.54g, of partially hydrated (2.83%) 2-carboxy-5-methylpyrazine-4-oxide as an anhydrous product. The yield was 73.01%. HPLC purity: 95.10%, impurity I: 2.30 percent.
Comparative example 4:
250mg (0.75mg) of Na was added2WO4·2H2O was placed in a 50ml flask, dissolved in 13ml of water and fitted with mechanical stirring, reflux cooler and thermometer. 3.23ml of 40% w/v (400g/L) (38mmol) hydrogen peroxide were added to the solution, diluted H2SO4The pH was adjusted to 2.0 and then 3.76g of 98% (30mmol) 2-carboxy-5-methylpyrazine were added.
The suspension of water produced in the reaction was heated to 80 ℃ with stirring and maintained at this temperature for 2 hours. And after 45min a completely solubilized suspension was obtained. Finally, the solution was allowed to stand at room temperature overnight to cause precipitation of the reaction product in a crystal form. This product was filtered, washed with ice water and dried on a bisque-fired plate to obtain 3.02g of monohydrate of 2-carboxy-5-methylpyrazine-4-oxide (Experimental value H)2O-11.35 percent; calculated value of monohydrate product H2O-11.3%), yield 63.02%. HPLC purity: 94.21%, impurity I: 3.40 percent.
Comparative example 5:
2-carboxy-5-methylpyrazine 4-oxide (2.5g) was added to a mixed solution of methanol (60ml) and ethanolamine (1.1 ml). The mixture was heated at reflux for 20 minutes, then cooled and filtered to give after crystallization from methanol 2-carboxy-5-methylpyrazine 4-oxide ethanolamine salt (2.1g), mp.177 ° -180 ℃, yield: 60.17%, HPLC purity: 96.81%, impurity I: 2.10 percent.
Comparative example 6:
the reaction was carried out in a 500ml.x.4 neck flask equipped with a mechanical stirrer, water condenser (with gas inlet) and thermocouple under nitrogen. Sodium trimethylsilanolate (3.71g) and THF (90g) were added to the reactor, followed by ethyl 5-methylpyrazinecarboxylate-4-oxide (6.00g), the mixture was stirred at room temperature for 4 hours, and the solid was collected by filtration and rinsed with THF (3X45 g). Drying in vacuo (25 inches of mercury, 65 ℃) afforded 5.38g (yield: 92.50%) of the sodium salt as an off-white solid, HPLC purity: 96.80%, impurity I: 2.41 percent.
Stability test
Temperature, humidity and light test
The specific stability test method refers to a guidance method related to stability investigation in the fourth part of the Chinese pharmacopoeia 2015 edition, the purity detection is performed by an HPLC method, and specific test results are shown in the following table.
Table 3 stability test results of crystal forms of methylpyrazine derivatives under light, high temperature and high humidity conditions
Tests prove that all the 4,4' -dipyridyl methylpyrazine derivative eutectic prepared by the invention can achieve similar stability effects. The purity and the appearance of the 4,4 '-bipyridyl methylpyrazine derivative eutectic prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, the purity of the crystal forms in comparative examples 1 to 6 is greatly reduced under the same experimental conditions, the impurity content of the crystal forms is obviously increased, namely, the crystal forms are deteriorated, and the 4,4' -bipyridyl methylpyrazine derivative eutectic prepared by the invention has better chemical stability compared with the existing crystal forms.
Experiment of treatment effect of 4,4' -bipyridine methylpyrazine derivative eutectic on fatty liver rat
(1) Material
Medicine
I. Acipimox capsules (le zhi apple), production lot number: Z210A.
II. 4,4' -dipyridyl methyl pyrazine derivative eutectic capsule.
Preparation of 4,4' -bipyridine methylpyrazine derivative eutectic capsules was prepared according to the prescription of lezhi apple.
Reagent II: total Cholesterol (TC), Triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), alkaline phosphatase (ALP), and a blood glucose kit. Liver tissue superoxide dismutase (SOD) and Malondialdehyde (MDA) kits.
③ the instrument: an ADVIA2400 type full-automatic biochemical analyzer, an Axioskop-plus type optical microscope, a tissue embedding machine, a full-automatic tissue dehydrator, a paraffin slicer, a pathological image analysis system and the like.
(2) Animal(s) production
Male Wistar rats, after being acclimatized for 1 week, were randomly divided into a normal control group, a model group, a Lezhi apple group and a 4,4' -bipyridylmethylpyrazine derivative cocrystal group, each group containing 5 rats. Each group of rats was given free water intake, basal diet for normal control group, and high fat diet (containing 88.8% basal diet, 10% lard, 1% cholesterol, 0.2% methyl thiouracil) for the remaining 3 groups, and were fed continuously for 5 weeks. From the end of the 6 th week of the experiment, rats in each group are fed as before, and the normal control group and the model group are subjected to intragastric gavage by 1mL of physiological saline; the melezillin group is administrated with 0.06 g/(kg. d) of acipimox capsule, and the stomach is perfused with 1mL of eutectic group of 4,4 '-bipyridine methyl pyrazine derivative, and the eutectic group of 4,4' -bipyridine methyl pyrazine derivative is administrated with 0.09 g/(kg. d), so that the acipimox content administrated by each rat is ensured to be equal. The rats in 4 groups are subjected to continuous gavage for 4 weeks, killed 24h after the last gavage, blood is taken, and livers are sampled and corresponding indexes are detected.
(3) Detection of
The mental status of rats was observed, Triglyceride (TG), cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels in serum were measured, and the change in liver tissue sections of different groups was observed.
(4) Results
Mental status of rats: the early-stage food consumption of the rats fed with the high-fat feed is larger than that of the normal control group, the body mass is increased quickly, the later-stage food consumption is reduced, and the activity is reduced. The food intake and the activity of rats in the le Zhi apple group and the 4,4' -bipyridine methylpyrazine derivative eutectic group are obviously superior to those of the control group. The mass of the rat body of the 4,4' -dipyridyl methyl pyrazine derivative eutectic group is obviously lighter than that of the model group.
Liver tissue slice changes: after the rats are sacrificed, liver tissues are taken for visual observation, and the liver tissues of the normal control group are normal in color and dark red, and the section of the liver tissues is not greasy; the rats in the model group have the defects of fat liver, yellow surface and greasy section. The liver tissues of the leprosy apple group and the 4,4' -bipyridine methylpyrazine derivative cocrystal group are slightly larger, most of the liver tissues are dark red in color and are close to normal appearance. Under a light microscope, the liver tissue structure of the normal control group rat is complete and clear, the hepatic lobule structure is normal, the central vein is large and thin-walled, the liver tissue is arranged into hepatic cords, the hepatic cords are radially distributed around the central vein, and the cells are polygonal. The model group shows severe fatty liver-like change, diffuse steatosis and vacuolation-like change, the denatured liver tissue is extremely swollen and round, the volume is obviously larger than that of the normal liver tissue, the cell nucleus is extruded to one side by lipid drops, and similarly to fat cells, the liver sinus is compressed and narrowed or even disappears, and the liver cord arrangement is disordered. The apple group and the 4,4' -bipyridine methylpyrazine derivative eutectic group only have trace inflammatory cell infiltration and necrosis focus, and are close to normal performance.
Group serum lipid comparison: compared with the model group, the levels of TG, TC and LDL-C in the leprosy apple group and the 4,4' -bipyridyl methylpyrazine derivative eutectic group are obviously reduced. The results are shown in Table 4.
TABLE 4 comparison of serum lipids for each group
Note: comparing with model group, P is less than 0.05.
The research result shows that the 4,4' -bipyridine methylpyrazine derivative cocrystal group can reduce the TC, TG and LDL-C levels of the serum of a fatty liver rat and eliminate partial lipid accumulation in liver cells; the pathological histological change is obviously improved under the microscope, the liver tissues of the rats in the eutectic group of the 4,4 '-bipyridine methylpyrazine derivatives have only a small amount of lipid drops accumulated and slight steatosis, the shapes of the liver cells tend to normal cell expression, and the eutectic of the 4,4' -bipyridine methylpyrazine derivatives has better treatment effect on the fatty liver rats.
Claims (10)
1. The 4,4 '-dipyridyl methylpyrazine derivative eutectic is characterized by being formed by combining a methylpyrazine derivative and 4,4' -dipyridyl according to a molar ratio of 2: 1.
2. The co-crystal of 4,4' -bipyridylmethylpyrazine derivative according to claim 1, wherein an X-ray diffraction spectrum expressed in terms of 2 θ using Cu — ka radiation has characteristic peaks at 9.5 ± 0.2 °, 16.5 ± 0.2 °, 25.1 ± 0.2 °, and 27.1 ± 0.2 °.
3. The co-crystal of 4,4' -bipyridylmethylpyrazine derivative according to claim 2, wherein an X-ray diffraction spectrum expressed in terms of 2 θ using Cu — ka radiation has characteristic peaks at 9.5 ± 0.2 °, 10.3 ± 0.2 °, 13.9 ± 0.2 °, 16.5 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0.2 °, 25.1 ± 0.2 °, and 27.1 ± 0.2 °.
4. A co-crystal of 4,4' -bipyridylmethylpyrazine derivative according to claim 3, characterized in that it has characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1, using Cu-ka radiation.
5. 4,4' -bipyridylmethylpyrazine derivative co-crystal according to claim 1, characterized in that it has an endothermic peak at 185.73 ℃ in a Differential Scanning Calorimetry (DSC) curve.
6. A co-crystal of 4,4' -bipyridylmethylpyrazine derivative according to any of claims 1 to 5, characterized in that it has crystallographic parameters such as: triclinic system, space group of
The unit cell parameters are:
α 73.0010(10) ° β 88.4890(10) ° γ 63.454(2) ° unit cell volume
7. A preparation method of a 4,4' -dipyridyl methylpyrazine derivative eutectic is characterized by comprising the following specific preparation steps: adding the methylpyrazine derivative and 4,4 '-bipyridine into an organic solvent A, heating for dissolving, clarifying the solution, performing reflux reaction, cooling for crystallization, filtering and drying to obtain the 4,4' -bipyridine methylpyrazine derivative eutectic.
8. The preparation method of the 4,4 '-bipyridine methylpyrazine derivative eutectic compound according to claim 7, wherein the molar ratio of the methylpyrazine derivative to the 4,4' -bipyridine is 1.8-2.2: 1, preferably 1.95-2.05: 1.
9. The preparation method of the co-crystal of 4,4' -bipyridyl methylpyrazine derivatives according to claim 7, wherein the organic solvent A is one or more selected from acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, and isopropanol.
10. Use of a co-crystal of a 4,4' -bipyridylmethylpyrazine derivative according to any one of claims 1 to 5 for the preparation of a hypolipidemic agent.
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