CN109503475B - Isonicotinamide methylpyrazine derivative eutectic I - Google Patents
Isonicotinamide methylpyrazine derivative eutectic I Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines, and particularly provides an isonicotinamide methylpyrazine derivative eutectic I, a preparation method thereof and application thereof in preparing a blood fat reducing medicine. The isonicotinamide methylpyrazine derivative eutectic I prepared by the invention uses Cu-Kalpha radiation, and an X-ray diffraction spectrogram expressed by 2 theta is as follows: characteristic peaks are at 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 14.5 +/-0.2 degrees and 16.2 +/-0.2 degrees. The isonicotinamide methylpyrazine derivative eutectic prepared by the invention has good stability in a medium, and after the solid state is placed, the product has high purity and good stability, and the bioavailability is high through animal test verification. 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 an isonicotinamide methylpyrazine derivative co-crystal I.
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 physical and chemical 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 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 caro Erba company of italy, 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 of germany, chile, switzerland, hong kong, 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 of the acipimox are mainly about, reports about a crystal eutectic structure of the acipimox are less, the patent US2005239803A1, the patent CN 103508963A and the like report a preparation method of the acipimox, and the patent CN86103304-2 obtains an acipimox precipitate with a crystal property, which is acipimox hydrate, and has low yield. 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 application provides an isonicotinamide methylpyrazine derivative eutectic I.
The methylpyrazine derivative is acipimox, the isonicotinamide methylpyrazine derivative eutectic I is isonicotinamide acipimox eutectic I, and the meaning of the eutectic I is the same as that of the eutectic crystal I.
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, and the selected eutectic forming substance isIsonicotinamide of formula C6H6N2And O, the structural formula of which is shown as b.
According to a first aspect of the present invention, there is provided isonicotinamide methylpyrazine derivative cocrystal form I. In the eutectic, the molar ratio of the methylpyrazine derivative to the isonicotinamide is 1:1.
According to the isonicotinamide methylpyrazine derivative eutectic crystal I, Cu-Kalpha radiation is used, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 14.5 +/-0.2 degrees and 16.2 +/-0.2 degrees.
Preferably, the isonicotinamide methylpyrazine derivative eutectic crystal form I has characteristic peaks at 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 10.2 +/-0.2 degrees, 13.0 +/-0.2 degrees, 14.5 +/-0.2 degrees, 14.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 19.5 +/-0.2 degrees, 26.1 +/-0.2 degrees and 30.1 +/-0.2 degrees by using Cu-Kalpha radiation and an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the isonicotinamide methylpyrazine derivative eutectic crystal form I is irradiated by Cu-Ka, and the characteristic peak of the crystal form I accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the isonicotinamide methylpyrazine derivative eutectic crystal form I has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, and is 210.08 ℃.
Preferably, the isonicotinamide methylpyrazine derivative eutectic crystal form I has the crystallographic parameters: monoclinic system, chiral space group P21C; the unit cell parameters are:
α is 90.00 °, β is 93.6670(13 °), γ is 90.00 °, unit cell volume
The second aspect of the application provides a preparation method of an isonicotinamide methylpyrazine derivative eutectic crystal form I, and the specific preparation steps comprise: adding the methylpyrazine derivative and isonicotinamide into an organic solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain the isonicotinamide methylpyrazine derivative eutectic crystal form I.
The organic solvent A is selected from one or more of methanol, ethanol, isopropanol, methyl formate, ethyl acetate, ethyl formate, methyl acetate and butyl acetate.
Further preferably, the organic solvent A is selected from one or two of methanol and ethyl acetate.
The molar ratio of the methylpyrazine derivative to the isonicotinamide is 1: 0.8-2.
Preferably, the molar ratio of the methylpyrazine derivative to the isonicotinamide is 1: 1.0-1.5.
The mass-volume ratio of the methylpyrazine derivative to the organic solvent A in the system is 40-200: 1, wherein the mass is in mg and the volume is in ml.
The mass-volume ratio of isonicotinamide to organic solvent A in the system is 25-320: 1, wherein the mass is in mg and the volume is in ml.
The temperature for dissolving and heating is 45-85 ℃.
The cooling crystallization temperature is 0-30 ℃.
Preferably, the temperature reduction and crystallization temperature is 5-20 ℃.
The crystallization time is 10-72 hours.
Further preferably, the preparation method comprises the following steps:
adding the methylpyrazine derivative and isonicotinamide into an organic solvent A, heating to 45-85 ℃ for dissolving, cooling to 0-30 ℃ after the solution is clarified, crystallizing for 10-72 hours, filtering, washing a filter cake, and drying to obtain the isonicotinamide methylpyrazine derivative eutectic crystal form I.
The solvent for washing the filter cake is selected from one of methanol, ethanol and ethyl acetate.
The drying temperature is 50-80 ℃, and the drying time is 8-12 hours.
The invention also provides another preparation method of the isonicotinamide methylpyrazine derivative crystal form I, which comprises the following steps:
uniformly mixing the methyl pyrazine derivative and isonicotinamide, dropwise adding an organic solvent B, starting grinding, and drying to obtain the isonicotinamide methyl pyrazine derivative eutectic crystal form I after grinding is finished.
Preferably, the organic solvent B is selected from one or more of methanol, ethanol, tert-butanol, methyl formate and ethyl acetate.
Preferably, the molar ratio of the methylpyrazine derivative to the isonicotinamide is 1: 1-1.5.
Preferably, the mass-to-volume ratio of the methylpyrazine derivative to the organic solvent B is 2-8: 1, wherein the mass is g and the volume is ml.
Preferably, the mass-to-volume ratio of the isonicotinamide to the organic solvent B is 2-12: 1, wherein the mass is g, and the volume is ml.
Preferably, the grinding time is 5-30 min.
In a third aspect of the application, a pharmaceutical composition is provided, wherein the composition contains the isonicotinamide methylpyrazine derivative eutectic crystal form I, and other pharmaceutically acceptable auxiliary material components.
Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.
Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
The fourth aspect of the application provides an application of the isonicotinamide methylpyrazine derivative eutectic crystal form I as an active ingredient in preparation of a medicament for treating and reducing blood fat.
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. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
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: monoclinic system, chiral space group is P21/c; the unit cell parameters are:
α is 90.00 °, β is 103.494(5 °), γ is 90.00 °, unit cell volume
The molecular formula is: c12H11N4O4The molecular weight is: 276.26. the structural analysis photo of the isonicotinamide methylpyrazine derivative eutectic crystal shows that the crystal does not contain a solvent, as shown in figure 3. The hydrogen bond diagram of the isonicotinamide methylpyrazine derivative eutectic crystal is shown in the attached figure 2.
Table 1 main crystallographic data of isonicotinamide methylpyrazine derivative eutectic crystal form I
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 2 PXRD peaks of isonicotinamide methylpyrazine derivative eutectic crystal form I
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns.
The Differential Scanning Calorimetry (DSC) result of the isonicotinamide methylpyrazine derivative eutectic crystal form I prepared by the method is shown in figure 4, only one endothermic peak in the Differential Scanning Calorimetry (DSC) is 210.08 ℃, and the melting point of the organic pharmaceutical eutectic of the isonicotinamide methylpyrazine derivative is shown; thermogravimetric analysis (TGA) of the methyl pyrazine derivative only has one weight loss step, and the results show that the methyl pyrazine derivative organic drug eutectic has no solvent and has a stable structure. The methylpyrazine derivative organic drug co-crystal has a DSC/TGA spectrum shown in figure 4.
Compared with the currently reported crystal form of the methylpyrazine derivative, the isonicotinamide methylpyrazine derivative eutectic crystal form I prepared by the method has the following advantages:
(1) the stability is high. The isonicotinamide methylpyrazine derivative eutectic crystal form I has higher stability in a solid state or a dissolved state. In a dissolved state, along with the prolonging of the dissolving time, the content of the impurity 5-methylpyrazine-2-carboxylic acid is less than 0.13 percent, the change is not large, and the total impurity content is less than 0.22 percent. In a solid state, after the isonicotinamide methylpyrazine derivative eutectic crystal I is subjected to a light test and is placed in a high-humidity environment, the HPLC purity is still higher than 99%, and compared with the existing methylpyrazine derivative crystal form, the solid state stability is good.
(2) Has high bioavailability. The isonicotinamide methylpyrazine derivative 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 isonicotinamide methylpyrazine derivative eutectic crystal form I.
FIG. 2: hydrogen bond diagram of isonicotinamide methylpyrazine derivative eutectic crystal form I.
FIG. 3: an ORTEP diagram of an isonicotinamide methylpyrazine derivative eutectic crystal form I.
FIG. 4: a Differential Scanning Calorimetry (DSC) graph of the isonicotinamide methylpyrazine derivative eutectic crystal form I.
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:
dissolving 5.0g (32.4mmol) of methylpyrazine derivative and 4.0g (32.4mmol) of isonicotinamide in 50ml of methanol, heating to 60 ℃ for dissolution, cooling to 20 ℃ after the solution is clarified, standing for crystallization for 48 hours, filtering and drying to obtain 8.6g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 96.5%, and HPLC: 99.96%, impurity I: 0.03 percent.
Example 2:
dissolving 5.0g (32.4mmol) of methylpyrazine derivative and 6.0g (48.6mmol) of isonicotinamide in 50ml of ethyl acetate, heating to 77 ℃ for dissolution, cooling to 15 ℃ after the solution is clarified, standing for crystallization for 52 hours, filtering and drying to obtain 8.8g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 98.0%, and HPLC: 99.93%, impurity I: 0.05 percent.
Example 3:
dissolving 10.0g (64.8mmol) of methylpyrazine derivative and 9.6g (77.8mmol) of isonicotinamide in 50ml of methanol, heating to 65 ℃ for dissolution, cooling to 10 ℃ after the solution is clarified, standing for crystallization for 36 hours, filtering and drying to obtain 17.2g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 96.0%, and HPLC: 99.91%, impurity I: 0.07 percent.
Example 4:
dissolving 2.0g (13.0mmol) of methylpyrazine derivative and 3.2g of isonicotinamide (26.0mmol) in 50ml of ethanol, heating to 70 ℃ for dissolution, cooling to 0 ℃ after the solution is clarified, standing for crystallization for 24 hours, filtering and drying to obtain 3.4g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 94.2%, and HPLC: 99.88%, impurity I: 0.09 percent.
Example 5:
dissolving 8.0g (51.9mmol) of methylpyrazine derivative and 4.0g of isonicotinamide (41.5mmol) in 50ml of isopropanol, heating to 80 ℃ for dissolving, cooling to 30 ℃ after the solution is clarified, standing for crystallization for 48 hours, filtering and drying to obtain 10.7g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 93.1%, and HPLC: 99.86%, impurity I: 0.10 percent.
Example 6:
dissolving 5.0g (32.4mmol) of methylpyrazine derivative and 6.0g of isonicotinamide (48.6mmol) in 50ml of ethyl formate, heating to 45 ℃ for dissolution, cooling to-5 ℃ after the solution is clarified, standing for crystallization for 12 hours, filtering and drying to obtain 8.2g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 91.2%, and HPLC: 99.84%, impurity I: 0.10 percent.
Example 7:
dissolving 5.0g (32.4mmol) of methylpyrazine derivative and 6.0g of isonicotinamide (48.6mmol) in 20ml of methyl acetate, heating to 55 ℃ for dissolution, cooling to 35 ℃ after the solution is clarified, standing for crystallization for 8 hours, filtering and drying to obtain 8.0g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 90.0%, and HPLC: 99.82%, impurity I: 0.11 percent.
Example 8:
uniformly mixing 5.0g (32.4mmol) of methylpyrazine derivative and 4.0g of isonicotinamide (32.4mmol), dropwise adding 1ml of methanol, starting grinding for 5min, drying to obtain 8.6g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 95.1%, and performing HPLC: 99.85%, impurity I: 0.09 percent.
Example 9:
adding 5.0g (32.4mmol) of methylpyrazine derivative and 6.0g (48.6mmol) of isonicotinamide into a ball mill, stirring uniformly, dropwise adding 1.5ml of ethyl formate, starting grinding for 5min, drying to obtain 8.8g of isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the yield is 96.9%, and HPLC: 99.80%, 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 77.3%; HPLC purity 96.2%, impurity I: 2.8 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 88.6%. HPLC purity: 98.3%, 5-methylpyrazine-2-carboxylic acid (impurity I): 0.5 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 4.62g, corresponding to 4.48g, of partially hydrated (2.83%) 2-carboxy-5-methylpyrazine-4-oxide as an anhydrous product. The yield was 72%. HPLC purity: 95.1%, impurity I: 2.3 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 give 3.00g 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 62.6%. HPLC purity: 94.2%, impurity I: 3.4 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: 96.8%, impurity I: 2.1 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: 92.5%) of the sodium salt as an off-white solid, HPLC purity: 96.8%, impurity I: 2.4 percent.
Stability test
1. Stability investigation of isonicotinamide methylpyrazine derivative eutectic crystal form I in solution state
Samples of the methylpyrazine derivatives prepared in examples 1 to 9 and comparative examples 1 to 6 were dissolved in water, the methylpyrazine derivative solution was placed in an environment at 25 ℃, the stability of different crystal forms of the methylpyrazine derivatives in the solution state was examined, samples were taken every two hours to test the content of impurities therein, and the test results are shown in table 3.
Table 3 stability test results of crystal forms of methylpyrazine derivatives in solution state
Tests prove that all the isonicotinamide methylpyrazine derivative eutectic crystal forms I prepared by the scheme of the invention can achieve similar stability effects in a solution state. As can be seen from table 3, the existing crystal form of methylpyrazine derivative has high contents of impurity I (5-methylpyrazine-2-carboxylic acid) and total impurities, and the contents of impurity I and total impurities both increase with the increase of the dissolution time. Experiments show that the purity of the sample, the content of the impurity I and the total impurity content of the isonicotinamide methylpyrazine derivative eutectic crystal I prepared by the invention are not obviously changed; compared with the existing crystal form of the methylpyrazine derivative, the isonicotinamide methylpyrazine derivative eutectic crystal form I prepared by the invention has better stability in a solution state.
2. 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 4 stability test results of crystal forms of methylpyrazine derivatives under light, high temperature and high humidity conditions
Tests prove that all the prepared isonicotinamide methylpyrazine derivative eutectic crystal forms I can achieve similar stability effects. The purity and the appearance of the prepared isonicotinamide methylpyrazine derivative eutectic crystal form I 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, and the crystal forms are deteriorated.
Bioavailability experiment: experiment of therapeutic action of isonicotinamide methylpyrazine derivative on fatty liver rat
(1) Material
Medicine
I. Acipimox capsules (le zhi apple), production lot number: Z210A.
II. Isonicotinamide methylpyrazine derivatives.
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 ADVIA 2400 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 an isonicotinamide methylpyrazine derivative group, and 5 rats were administered to each group. 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 melezhi apple group and the isonicotinamide methylpyrazine derivative group are administrated with 0.06/(kg. d) of methylpyrazine derivative and are intragastrically filled by 1 mL. 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 isonicotinamide methylpyrazine derivative group are obviously superior to those of the control group. The isonicotinamide group rats had significantly lower body mass than the control 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 apple group and the isonicotinamide methylpyrazine derivative group are slightly larger, most of the liver tissues are dark red, and the appearance is close to normal.
Group serum lipid comparison: compared with the model group, the levels of TG, TC and LDL-C in the le-know apple group and the isonicotinamide methylpyrazine derivative group are obviously reduced. The results are shown in Table 5.
TABLE 5 comparison of serum lipids for each group
The research result shows that the isonicotinamide methylpyrazine derivative can reduce TC, TG and LDL-C levels of serum of fatty liver rats and eliminate partial lipid accumulation in liver cells; pathological histological change is obviously improved under a mirror, liver tissues of rats with isonicotinamide methylpyrazine derivatives only have a small amount of lipid drops accumulated, slight steatosis and hepatic cell morphology tends to normal cell expression, and the isonicotinamide methylpyrazine derivatives have a good treatment effect on fatty liver rats.
Claims (11)
1. An isonicotinamide methylpyrazine derivative eutectic crystal form I is characterized in that Cu-Kalpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta is as follows: characteristic peaks are arranged at 7.2 +/-0.2 degrees, 8.1 +/-0.2 degrees, 14.5 +/-0.2 degrees and 16.2 +/-0.2 degrees, wherein the methylpyrazine derivative is acipimox, the isonicotinamide methylpyrazine derivative eutectic I is isonicotinamide acipimox eutectic I,
2. the isonicotinamide methylpyrazine derivative eutectic crystal form I of claim 1, wherein an X-ray diffraction spectrum expressed in terms of 2 Θ using Cu-ka radiation has characteristic peaks at 7.2 ± 0.2 °, 8.1 ± 0.2 °, 10.2 ± 0.2 °, 13.0 ± 0.2 °, 14.5 ± 0.2 °, 14.9 ± 0.2 °, 16.2 ± 0.2 °, 19.5 ± 0.2 °, 26.1 ± 0.2 °, 30.1 ± 0.2 °.
3. The isonicotinamide methylpyrazine derivative eutectic crystalline form I according to claim 2, characterized in that with Cu-ka radiation its characteristic peaks follow the X-ray powder diffraction pattern as shown in figure 1.
4. The isonicotinamide methylpyrazine derivative eutectic crystal form I as claimed in claim 1, characterized in that it has an endothermic peak at 210.08 ℃ in the differential scanning calorimetry curve.
5. Isoniacinamide methylpyrazine derivative cocrystal form I according to anyone of claims 1 to 4, characterised in that it has crystallographic parameters: monoclinic system, chiral space group P21C; the unit cell parameters are: a = 4.19222(7) a, b = 12.20130(16) a, c = 24.4548(3) a, a = 90.00 °, b = 93.6670(13) ° g = 90.00 °, unit cell volume V = 1248.31(3) a3。
6. A preparation method of the isonicotinamide methylpyrazine derivative eutectic crystal form I as claimed in any one of claims 1 to 4, characterized in that the specific preparation steps comprise: adding the methylpyrazine derivative and isonicotinamide into an organic solvent A, heating to dissolve, cooling to crystallize after the solution is clarified, filtering and drying to obtain the isonicotinamide methylpyrazine derivative eutectic crystal form I, wherein the organic solvent A is selected from one or more of methanol, ethanol, isopropanol, methyl formate, ethyl acetate, ethyl formate, methyl acetate and butyl acetate.
7. The preparation method of the isonicotinamide methylpyrazine derivative eutectic crystal I as claimed in claim 6, wherein the molar ratio of the methylpyrazine derivative to isonicotinamide is 1: 0.8-2.
8. The method for preparing the isonicotinamide methylpyrazine derivative eutectic crystal form I as claimed in claim 7, wherein the molar ratio of the methylpyrazine derivative to isonicotinamide is 1:1.0 to 1.5.
9. A preparation method of the isonicotinamide methylpyrazine derivative eutectic crystal form I as claimed in any one of claims 1 to 4, characterized in that the specific preparation steps comprise: uniformly mixing the methylpyrazine derivative and isonicotinamide, dropwise adding an organic solvent B, starting grinding, and drying to obtain the isonicotinamide methylpyrazine derivative eutectic crystal I after grinding is finished, wherein the organic solvent B is selected from one or more of methanol, ethanol, tert-butyl alcohol, methyl formate and ethyl acetate.
10. A pharmaceutical composition comprising the isonicotinamide methylpyrazine derivative co-crystal form I according to any one of claims 1 to 4 together with other pharmaceutically acceptable auxiliary components.
11. Use of the isonicotinamide methylpyrazine derivative co-crystal form I according to any one of claims 1 to 4 for the preparation of a hypolipidemic agent.
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