CN109438371A - A kind of methylpyrazine derivative arginine hydrate - Google Patents
A kind of methylpyrazine derivative arginine hydrate Download PDFInfo
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- CN109438371A CN109438371A CN201811648347.1A CN201811648347A CN109438371A CN 109438371 A CN109438371 A CN 109438371A CN 201811648347 A CN201811648347 A CN 201811648347A CN 109438371 A CN109438371 A CN 109438371A
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- methylpyrazine derivative
- arginine
- methylpyrazine
- hydrate
- arginine hydrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- A—HUMAN NECESSITIES
- 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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- 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 pharmaceutical technology field, specifically provide a kind of methylpyrazine derivative arginine hydrate, preparation method and its preparing the purposes in hypolipidemic.Methylpyrazine derivative arginine hydrate prepared by the present invention is radiated using Cu-K α, and the X-ray diffraction spectrogram indicated with 2 θ exists: 5.7 ± 0.2 °, 9.1 ± 0.2 °, 16.2 ± 0.2 °, there is characteristic peak at 24.5 ± 0.2 °, 24.8 ± 0.2 °, 27.8 ± 0.2 °.Methylpyrazine derivative arginine hydrate stability prepared by the present invention is high, dissolved state and solid state are placed purity and are basically unchanged, its solubility in different media is 2.5 times of existing crystal form, and bioavilability with higher, has preferable prospects for commercial application.
Description
Technical field
The invention belongs to technical field of organic pharmaceutical co-crystal, in particular to a kind of methylpyrazine derivative arginine hydration
Object.
Background technique
Pharmaceutical co-crystals are to pass through the molecular recognition of intermolecular mutual synergistic effect progress based on supramolecular chemistry principle
And Supramolecular self assembly.Active pharmaceutical ingredient (API) and suitable eutectic formation (cocrystal former, CCF) pass through
H-bonding self-assembly, or non-covalent bond (Van der Waals force of such as aromatic hydrocarbons or phenyl ring, the pi-conjugated work of π-with saturability and directionality
With with halogen key) a kind of new structure for being formed of assembling, i.e. pharmaceutical co-crystals.It neither needs to form new be total to based on hydrogen bond
Valence link, and do not need to destroy existing covalent bond, while retaining the pharmacological action of drug itself, and the object of energy modified medicaments
Physicochemical property, such as improve the stability of drug, reduce its draw it is moist, improve dissolubility, improve bioavilability, it is total for drug
Application of the crystalline substance in terms of pharmaceuticals industry provides vast potential for future development.In recent years, pharmaceutical co-crystals research was increasingly by people
Concern.At this stage, external that the research of pharmaceutical co-crystals is started gradually to increase and be goed deep into；And the country is studied it also relatively
It is few.For imitation medicine, the research of pharmaceutical co-crystals can also break patent protection of the Yuan Yan medicine company to drug crystal forms, be conducive to
Imitation medicine is introduced to the market.Therefore, obtain more has important reality meaning with novel, practical and creative pharmaceutical co-crystals
Justice, especially some water-insoluble drugs.
Acipimox is nicotinic acid derivates, is a kind of broad-spectrum long-acting lipid regulating agent, is used for various primary and secondary height
Pionemia mainly acts on adipose tissue, by inhibiting adipose tissue to discharge free fatty acid, reduces plasma low density lipoprotein
And the synthesis of very low density lipoprotein, so that the level of plasma low density lipoprotein and very low density lipoprotein in blood plasma is reduced,
Simultaneously by inhibiting hepatic lipase activity to increase plasma HDL levels.Acipimox is by Italian Farmitalia Carlo
Erba company develops, and listed in 1985 in Italy, then, relies on its higher safety and significant curative effect, phase
It is listed after in multiple countries and regions such as Germany, Chile, Switzerland, Hong-Kong.
Pharmaceutical co-crystals will affect the physicochemical property of drug, directly affect dissolution and suction of the drug under the conditions of physiological pH 7.4
It produces effects rate, and then influences the bioavilability of drug, clinical efficacy etc..By way of pharmaceutical co-crystals, it can be very good to apply
Eutectic advantage, this has very important work for the spatial arrangement and physicochemical property that understand and grasp the effective molecule of drug
With.
It is more about the relevant report of Acipimox at present, but primarily with regard to its preparation, preparation, physicochemical property and medicine
The report of the properties such as reason, the report about its crystal form eutectic structure is less, patent US2005239803A1, CN 103508963A
Deng the preparation method for reporting Acipimox, patent CN86103304-2 obtains the Acipimox sediment of crystal character, is
It is hydrated Acipimox, yield is lower.In report before, less, Acipimox crystallography is reported for Acipimox eutectic
Characterization parameter does not refer to.
Summary of the invention
In view of the deficiencies in the prior art, the one side of the application provides a kind of methylpyrazine derivative arginine hydration
Object.
Signified methylpyrazine derivative is Acipimox in the present invention, and signified methylpyrazine derivative arginine hydrate is
Acipimox arginine hydrate.
Acipimox is white as drug ingedient of the invention, the entitled Acipimox of chemistry
Color or off-white color crystalline powder.No. CAS: 51037-30-0, molecular formula C6H6N2O3, structural formula is as shown in a, the present invention
Selected in eutectic formation be arginine, molecular formula C6H14N4O2, its structural formula is shown as b.
According to the first aspect of the invention, methylpyrazine derivative arginine hydrate crystal forms are provided.In the crystal,
Methylpyrazine derivative: arginine: the molar ratio of water is 1:1:1.
The methylpyrazine derivative arginine hydrate crystal forms, are radiated using Cu-K α, are spread out with the X-ray that 2 θ are indicated
Penetrating spectrogram has spy at 5.7 ± 0.2 °, 9.1 ± 0.2 °, 16.2 ± 0.2 °, 24.5 ± 0.2 °, 24.8 ± 0.2 °, 27.8 ± 0.2 °
Levy peak.
Preferably, the methylpyrazine derivative arginine hydrate crystal forms, are radiated, the X indicated with 2 θ using Cu-K α
X ray diffraction spectrogram at 5.7 ± 0.2 °, 9.1 ± 0.2 °, 16.2 ± 0.2 °, 17.4 ± 0.2 °, 18.3 ± 0.2 °, 19.6 ±
There is characteristic peak at 0.2 °, 21.1 ± 0.2 °, 24.5 ± 0.2 °, 24.8 ± 0.2 °, 25.5 ± 0.2 °, 27.8 ± 0.2 °.
Preferably, the methylpyrazine derivative arginine hydrate crystal forms, are radiated using Cu-K α, characteristic peak symbol
Close X-ray powder diffraction pattern as shown in Figure 1.
Preferably, the methylpyrazine derivative arginine hydrate crystal forms, in differential scanning calorimetric curve (DSC)
There are two endothermic peak, respectively 187.11 DEG C, 214.47 DEG C；There are a heat releases in differential scanning calorimetric curve (DSC) for it
Peak is 242 DEG C.
Preferably, the methylpyrazine derivative arginine hydrate crystal forms, crystallographic parameter is: monoclinic system,
Space group: P21, cell parameter are as follows:α=
90.00 °, β=104.762 (2) °, γ=90.00 °, unit cell volumeMolecular formula is: C12H22N6O6, point
Son amount is: 346.35.
The second aspect of the application provides a kind of preparation method of methylpyrazine derivative arginine hydrate crystal forms, specifically
Preparation step includes: to be dissolved in methylpyrazine derivative and arginine in the mixed solution of organic solvent and water, is dissolved by heating, molten
After liquid clarification, cool down crystallization, and filtration drying obtains methylpyrazine derivative arginine hydrate crystal forms.
The organic solvent is selected from methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, acetone, acetonitrile, tetrahydrofuran, formic acid first
The one or more of ester, ethyl acetate, Ethyl formate, methyl acetate, butyl acetate.
It is further preferred that organic solvent is selected from one or both of methanol, ethyl acetate and tetrahydrofuran.
Preferably, the volume ratio of organic solvent and water is 25~500:1.
The methylpyrazine derivative and arginic molar ratio are 1:0.8~2.
Preferably, methylpyrazine derivative and arginic molar ratio are 1:1.0~1.5.
In the system mass volume ratio of methylpyrazine derivative and solution be 40~200mg/ml, wherein quality with
Mg meter, volume is in terms of ml.
The mass volume ratio of arginine and organic solvent is 36~450:1 in the system, and wherein quality is in terms of mg, volume
In terms of ml.
The temperature of the dissolution heating is 45~85 DEG C.
The cooling crystallization temperature is 0~30 DEG C.
Preferably, cooling crystallization temperature is 5~20 DEG C.
The crystallization time is 10~72 hours.
It is further preferred that the preparation method comprises the following steps:
Methylpyrazine derivative and arginine are dissolved in the mixed solution of organic solvent and water, 45~85 DEG C of heating are molten
Solution is cooled to 0~30 DEG C of crystallization 10~72 hours after solution clarification, filters, and washs filter cake, dry methylpyrazine derivative
Arginine hydrate crystal.
The solvent of the washing filter cake is selected from one of methanol, ethyl alcohol and ethyl acetate.
The drying temperature is 50~80 DEG C, and drying time is 8~12 hours.
Present invention also provides another preparation methods of methylpyrazine derivative arginine hydrate, specifically include as follows
Step:
After mixing by methylpyrazine derivative and arginine, organic solvent and water is added dropwise, starts to grind, grind
Finish, dry methylpyrazine derivative arginine hydrate crystal.
Preferably, the organic solvent is in methanol, ethyl alcohol, the tert-butyl alcohol, tetrahydrofuran, methyl formate and ethyl acetate
One or more.
Preferably, the volume ratio of organic solvent and water is 25~500:1.
Preferably, the methylpyrazine derivative and arginic molar ratio are 1:1~1.5.
Preferably, the mass volume ratio of the methylpyrazine derivative and organic solvent is 2~8:1, wherein quality is with g
Meter, volume is in terms of ml.
Preferably, the mass volume ratio of the arginine and organic solvent is 2~12:1, wherein quality is in terms of g, volume
In terms of ml.
Preferably, milling time is 5~30min.
The third aspect of the application provides a kind of pharmaceutical composition, and the composition is derivative containing methylpyrazine of the present invention
Object arginine hydrate crystal, and include other pharmaceutically acceptable auxiliary material components.
Preferably, pharmaceutical composition of the invention preparation is as follows: using standard and conventional technique, makes the compounds of this invention
In conjunction with solid acceptable on galenic pharmacy or liquid-carrier, and be allowed to arbitrarily with adjuvant acceptable on galenic pharmacy and
Excipient combines and is prepared into available dosage form.
Preferably, other components include other active constituents, excipient, the filler etc. that can be used in combination.
Preferably, the pharmaceutical composition is spray, tablet, capsule, powder-injection, liquid injection agent etc..
The fourth aspect of the application provides a kind of methylpyrazine derivative arginine hydrate crystal as active constituent system
Application in standby treatment hypolipidemic.
The confirmation of crystal structure
X-ray crystal data is collected on Rigaku XtaLAB Synergy model instrument, test temperature 293 (2) K,
It is radiated with CuKa, data are collected with ω scanning mode and carries out Lp correction.With direct method analytic structure, difference Fourier method is found out
Whole non-hydrogen atoms, the hydrogen atom on all carbon and nitrogen are obtained using theoretical plus hydrogen, carry out essence to structure using least square method
It repairs.
Testing and parse crystallographic data obtained by methylpyrazine derivative arginine hydrate crystal prepared by the present invention is (table
1): its crystallographic parameter is: monoclinic system, chiral space group P21；It is derivative that methylpyrazine prepared by the present invention is tested and parsed to crystalline substance
Crystallographic data obtained by object crystal is (table 1): cell parameter are as follows: α=90.00 °, β=104.762 (2) °, γ=90.00 °, unit cell volumeMolecular formula
It is: C12H22N6O6, molecular weight is: 346.35.The structure elucidation photo of methylpyrazine derivative eutectic of the invention shows that this is total
There are 1 molecules for Jingjing body, as shown in Fig. 3.The hydrogen bond figure of methylpyrazine derivative crystal form of the invention, as shown in Fig. 2.
1 methylpyrazine derivative arginine hydrate crystal forms predominant crystal data of table
According to above-mentioned crystallographic data, in corresponding X-ray powder diffraction figure (Cu-K α) characteristic peak be detailed in attached drawing 1 and
Table 2.
The peak PXRD of 2 methylpyrazine derivative arginine hydrate crystal forms of table
Prepared all samples crystallographic parameter all having the same and X-ray powder diffraction spectrogram in embodiment.
The methylpyrazine derivative arginine hydrate crystal forms of the method for the invention preparation, differential scanning calorimetric curve
(DSC) as shown in figure 4, having 2 endothermic peaks and an exothermic peak in differential scanning calorimetric curve (DSC), first is inhaled result
Thermal spike is 187.11 DEG C, is in methylpyrazine derivative eutectic caused by the reduction of water, and second endothermic peak is 214.47 DEG C, is first
The fusing weightlessness of base pyrazines derivatives eutectic is volatilized, and exothermic peak occurs at 242 DEG C, illustrates that heat required for volatilizing is greater than altogether
Crystalline substance melts the heat of release.Its thermogravimetric analysis (TGA) only exists two weightless steps, and first step is to lose crystallization water mistake
Journey, second step are to melt weightless process.The methylpyrazine derivative arginine hydrate crystal forms exist as shown in Figure 4
DSC/TGA map.
The methylpyrazine derivative arginine hydrate crystal forms of herein described method preparation are relative to the first reported at present
Base pyrazines derivatives crystal form has the advantage that
(1) stability is high.Methylpyrazine derivative arginine hydrate is either equal in solid state or dissolved state
Stability with higher.When in solution state, with the extension of dissolution time, impurity 5-Methylpyrazine-2-carboxylic acid contains
Amount is lower than 0.12%, and less, total impurities content is lower than 0.14% for variation.When in solid state, by illumination, high temperature, high humidity
After test, HPLC purity is still higher than 99.20%.
(2) solubility is good.The solubility of methylpyrazine derivative arginine hydrate is 2.5 times of existing crystal form solubility
Left and right, the solubility of methylpyrazine derivative arginine hydrate in different media are above the solubility of existing crystal form.
(3) bioavilability is high.Rats with Fatty Liver serum can be effectively reduced in methylpyrazine derivative arginine hydrate
In cholesterol, triglycerides, low-density lipoprotein concentration.
Detailed description of the invention
Fig. 1: the PXRD figure of methylpyrazine derivative arginine hydrate crystal forms.
Fig. 2: the hydrogen bond figure of methylpyrazine derivative arginine hydrate crystal forms.
Fig. 3: the ORTEP figure of methylpyrazine derivative arginine hydrate crystal forms.
Fig. 4: the TGA/DSC figure of methylpyrazine derivative arginine hydrate crystal forms.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration,
It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention
It is also contained within the scope of the invention, impurity I is 5-Methylpyrazine-2-carboxylic acid, and methylpyrazine derivative is Acipimox.
Embodiment 1:
5.0g (32.4mmol) methylpyrazine derivative and 5.6g (32.4mmol) arginine are dissolved in methanol aqueous solution
In (50ml methanol+0.5ml water), 60 DEG C of dissolutions are heated to, after solution clarification, are cooled to 20 DEG C, static crystallization 52 hours filters
Dry methylpyrazine derivative arginine hydrate 10.9g, yield 97.1%, HPLC:99.94%, impurity I:0.05%.
Embodiment 2:
5.0g (32.4mmol) methylpyrazine derivative and 11.2g (48.6mmol) arginine are dissolved in 50ml ethyl acetate
In aqueous solution (50ml ethyl acetate+2ml water), it is heated to 75 DEG C of dissolutions and is cooled to 15 DEG C, static crystallization 48 after solution clarification
Hour, filtration drying obtains methylpyrazine derivative arginine hydrate 11.0g, yield 98.0%, HPLC:99.93%, impurity I:
0.06%.
Embodiment 3:
10.0g (64.8mmol) methylpyrazine derivative and 13.4g (77.8mmol) arginine amine are dissolved in tetrahydrofuran
In aqueous solution (50ml tetrahydrofuran+0.1ml water), it is heated to 65 DEG C of dissolutions and is cooled to 10 DEG C, static crystallization after solution clarification
36 hours, filtration drying obtained methylpyrazine derivative arginine hydrate 21.6g, yield 96.3%, HPLC:99.92%, impurity
I:0.07%.
Embodiment 4:
It is water-soluble that 2.0g (13.0mmol) methylpyrazine derivative and 4.5g arginine (26.0mmol) are dissolved in 50ml ethyl alcohol
In liquid (50ml ethyl alcohol+1ml water), 70 DEG C of dissolutions are heated to, after solution clarification, are cooled to 0 DEG C, static crystallization 24 hours filters
Dry methylpyrazine derivative arginine hydrate 4.3g, yield 95.3%, HPLC:99.91%, impurity I:0.08%.
Embodiment 5:
8.0g (51.9mmol) methylpyrazine derivative and 7.2g arginine (41.5mmol) are dissolved in 50ml isopropanol,
It is heated to 80 DEG C of dissolutions and is cooled to 30 DEG C, static crystallization 48 hours, filtration drying obtains methylpyrazine derivative after solution clarification
Arginine hydrate 13.4g, yield 93.6%, HPLC:99.90%, impurity I:0.09.
Embodiment 6:
5.0g (32.4mmol) methylpyrazine derivative and 8.5g arginine (48.6mmol) are dissolved in 50ml Ethyl formate
In, 45 DEG C of dissolutions are heated to, after solution clarification, are cooled to -5 DEG C, static crystallization 12 hours, it is derivative that filtration drying obtains methylpyrazine
Object arginine hydrate 10.4g, yield 92.8%, HPLC:99.90%, impurity I:0.09.
Embodiment 7:
It is water-soluble that 5.0g (32.4mmol) methylpyrazine derivative and 8.5g arginine (48.6mmol) are dissolved in methyl acetate
In liquid (methyl acetate 20ml+ water 1ml), it is heated to 55 DEG C of dissolutions and is cooled to 35 DEG C after solution clarification, static crystallization 8 hours,
Filtration drying obtains methylpyrazine derivative arginine hydrate 10.3g, yield 91.8%, HPLC:99.89%, impurity I:
0.10%.
Embodiment 8:
5.0g (32.4mmol) methylpyrazine derivative and 5.6g arginine (32.4mmol) are added in ball mill, stirring
It after uniformly, is added dropwise methanol aqueous solution (1ml methanol+0.01ml water), starts to grind 5min, finish, it is dry that methylpyrazine is derivative
Object arginine hydrate 10.7g, yield 95.8%, HPLC:99.93%, impurity I:0.05%.
Embodiment 9:
After mixing by 5.0g (32.4mmol) methylpyrazine derivative and 8.4g arginine (48.6mmol), second is added dropwise
Acetoacetic ester aqueous solution (2.5ml ethyl acetate+0.1ml water) starts to grind 30min, finish, dry that methylpyrazine derivative is smart
Propylhomoserin hydrate 10.6g, yield 94.7%, HPLC:99.90%, impurity I:0.10%.
Comparative example 1:
The concentrated sulfuric acid that 2730ml mass concentration is 98% is added in 10L glass reaction kettle, is added under stirring condition
5- methylpyrazine -2,3- dicarboxylic acids of 910.0g, is heated to 60 DEG C, heating reaction 1h, be then slowly added into 5.5kg water,
164.9g sodium tungstate (Na2WO4·2H2O), the hydrogen peroxide that 623.0g mass concentration is 30% continues heating stirring 8h, ice bath item
Cooling crystallization 4h under part, filters solid, and dry 12h at 100 DEG C prepares product Acipimox 595g.Product is received in the reaction
Rate 77.3%；HPLC purity 96.2%, impurity I:2.8%.
Comparative example 2:
200ml water is added into 100g Acipimox crude product, is heated to 100 DEG C, 3.0g active carbon is added after stirring and dissolving
Continue insulated and stirred 20 minutes, filters；Filtrate is cooled to 60 DEG C with 10 DEG C/h, 220g acetone is then added dropwise thereto, drop finishes,
Be cooled to 5 DEG C of crystallization 7h with 10 DEG C/h, filter, with acetone washing filter cake, dry (0.01MPa, 80 DEG C) up to off-white color Ah
Former times does not take charge of, yield 88.6%.HPLC purity: 98.3%, 5-Methylpyrazine-2-carboxylic acid (impurity I): 0.5%.
Comparative example 3:
By the Na of 330mg (1mmol)2WO4·2H2O is placed in 50ml flask, dissolved and be equipped with 16ml water mechanical stirring,
Reflux cooler and thermometer.The hydrogen peroxide of 40% weight/volume of 3.75ml (400g/L) (44mmol) is incorporated in solution
In, with dilute H2SO4Being adjusted to pH value is 1.5, and the 2- carboxyl -5- methylpyrazine of 5.52g (40mmol) is then added.
The suspended matter for reacting the water generated is heated to 70 DEG C under stiring and maintains this temperature 2.5 hours.Thus obtain
Gradually solubilized suspended matter.Finally discovery has portion of product precipitating.Mixture is stood overnight at room temperature, and generates crystal shape
The precipitating of the reaction product of shape.This product is washed through filtering and with ice water, then is placed in drying on porous plate and can be obtained part and be
2- carboxyl -5- methylpyrazine -4- oxide the 4.68g of hydrate form (2.83%), be equivalent to 4.54g without aquatic products.Yield is
73%.HPLC purity: 95.1%, impurity I:2.3%.
Comparative example 4:
By the Na of 250mg (0.75mg)2WO4·2H2O is placed in 50ml flask, is dissolved with 13ml water and is equipped with machinery and stirred
It mixes, reflux cooler and thermometer.The hydrogen peroxide of 40% weight/volume of 3.23ml (400g/L) (38mmol) is incorporated in
In solution, with dilute H2SO4Being adjusted to pH value is 2.0, and the 2- carboxyl -5- methylpyrazine of 3.76g 98% (30mmol) is then added.
The suspended matter for reacting the water generated is heated to 80 DEG C under stiring and maintains this temperature 2 hours.And after 45min i.e.
It can get the suspended matter of solubilising completely.Finally, solution stands overnight at room temperature and generates the heavy of the reaction product of crystal shape
It forms sediment.This product is washed through filtering and with ice water, then is placed on porous plate dry acquisition 3.02g 2- carboxyl -5- methylpyrazine -4-
Monohydrate (the experiment value H of oxide2O-11.35%；The calculated value H of monohydrate product2O-11.3%), yield 63%.
HPLC purity: 94.2%, impurity I:3.4%.
Comparative example 5:
2- carboxyl -5- methylpyrazine 4- oxide (2.5g) is added to the mixed of methanol (60ml) and ethanol amine (1.1ml)
It closes in solution.Mixture is heated to reflux 20 minutes, is then cooled down and is filtered, 2- carboxyl -5- methyl pyrrole is obtained after methanol crystallization
Piperazine 4- oxide ethanolamine salt (2.1g), mp.177 °~180 DEG C, yield: 60.17%, HPLC purity: 96.8%, impurity I:
2.1%.
Comparative example 6:
Under nitrogen protection, in the 500mL.x.4 equipped with mechanical agitator, water condenser (having gas access) and thermocouple
It is reacted in neck bottle.Trimethyl silicane sodium alkoxide (3.71g) and THF (90g) are added into reactor, 5- methylpyrazine is then added
Mixture is stirred at room temperature 4 hours carboxylic acid -4- oxide ethyl ester (6.00g), solid is collected by filtration and with THF (3x45g)
It rinses.It is dried in vacuo (25 inches of mercury, 65 DEG C), obtaining 5.38g, (yield: 92.5%) sodium salt, is pale solid, and HPLC is pure
Degree: 96.8%, impurity I:2.4%.
Stability test
1, study on the stability of the methylpyrazine derivative arginine hydrate in solution state
The methylpyrazine derivative sample that Example 1-7 and comparative example 1-6 are prepared is dissolved in the water, by methyl pyrrole
Oxazine derivatives solution is placed in 25 DEG C of environment, investigates stability of the methylpyrazine derivative crystal form under solution state, often
Every the content of two hours sampling and testings wherein impurity, test result is shown in Table 3.
Stability test result of the 3 methylpyrazine derivative crystal form of table under solution state
Through testing, all methylpyrazine derivative arginine hydrates of the present invention program preparation are reachable in solution state
To similar stabilizing effect.As shown in Table 3, it is known that existing methylpyrazine derivative crystal form its impurity I (5- methylpyrazine-
2- carboxylic acid) and total miscellaneous content height, and impurity I content and the content of total impurities all increase with the extension of dissolution time.Through trying
It tests and learns, methylpyrazine derivative arginine hydrate prepared by the present invention, the content and total impurities of sample purity and impurity I contains
Amount is not substantially change；And 1 crystal form of comparative example to 6 crystal form of comparative example under identical condition, the content of impurity I and total
The content of impurity is constantly increasing, it can be seen that, compared to existing methylpyrazine derivative crystal form, first prepared by the present invention
Base pyrazines derivatives arginine hydrate has preferable stability under solution state.
2, temperature and humidity and exposure experiments to light
Specific stability testing method is referring to 2015 editions the 4th guidance methods in relation to study on the stability of Chinese Pharmacopoeia
It carries out, purity detecting is detected with HPLC method, and specific test result see the table below.
Stability test result of the 4 methylpyrazine derivative crystal form of table under illumination, high temperature and super-humid conditions
Through testing, all methylpyrazine derivative arginine hydrates of the present invention program preparation can reach similar steady
Qualitative effect.The methylpyrazine derivative arginine hydrate that the present invention is prepared is under conditions of illumination, high temperature and high humidity
Obvious variation do not occur for its purity, appearance, and comparative example 1 to 6 crystal form of comparative example under identical experiment condition its
Purity is greatly reduced, and impurity content has obvious raising, that is, rotten situation occurs, it is seen that first prepared by the present invention
Base pyrazines derivatives arginine hydrate has preferable chemical stability compared to existing crystal form.
Solubility experiment
Specific dissolubility test refers to Chinese Pharmacopoeia 2015.Accurate embodiment 1-7 and the comparative example of weighing respectively
Methylpyrazine derivative crystal is excessive, is placed in small cillin bottle, and it is slow to be separately added into water, 0.1mol/L hydrochloric acid, the phosphate of pH7.4
Solution is rushed, methylpyrazine derivative saturated solution is configured to, shakes up dissolution, is filtered, according to UV-VIS spectrophotometry (general rule
0401) absorbance is measured at the wavelength of 270nm, to calculate its solubility.
The solubility of 5 methylpyrazine derivative crystal form of table in different media
Through testing, all methylpyrazine derivative arginine hydrates of the present invention program preparation can reach similar molten
Solution property effect.By table 5 as it can be seen that the methylpyrazine derivative arginine hydrate of the present invention program preparation is in different pH solution
Solubility is above the crystal form of comparative example 1 to comparative example 6, and methylpyrazine derivative crystal form prepared by the present invention is relative to existing crystalline substance
Type, dissolubility with higher.
Bioavilability experiment: experiment of the methylpyrazine derivative arginine hydrate to Rats with Fatty Liver therapeutic effect
(1) material
1. drug
I, Acipimox Capsules (Le Zhiping), product batch number: Z210A.
II, methylpyrazine derivative arginine hydrate.
2. reagent: total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein level
White cholesterol (HDL-C), alanine aminotransferase (ALT), aspartic transaminase (AST), alkaline phosphatase (ALP) and blood
Sugared kit.Liver superoxide dismutase (SOD) and malonaldehyde (MDA) kit.
3. instrument: ADVIA2400 type full-automation Biochemical Analyzer, Axioskop-plus type optical microscopy, tissue packet
Bury machine, Automation-tissue-dehydrating machine, paraffin slicing machine, Pathologic image analysis system etc..
(2) animal
Male Wistar rat after adaptive feeding 1 week, is randomly divided into Normal group, model group, pleasure and knows apple group and first
Base pyrazines derivatives arginine hydrate group, every group 5.Every group of rat freely takes the photograph water, and Normal group gives basal feed,
Remaining 3 groups are given high lipid food (containing 88.8% basal feed, 10% lard, 1% cholesterol, 0.2% methylthiouracil), even
Continuous feeding 5 weeks.From testing for the 6th weekend, each group rat is still fed such as preceding method, Normal group and model group physiological saline
1mL stomach-filling；Pleasure knows that apple group and methylpyrazine derivative arginine hydrate group give methylpyrazine derivative 0.06/ (kgd)
Stomach-filling 1mL.The equal continuous gavage of 4 groups of rats 4 weeks, puts to death for 24 hours after last stomach-filling, takes blood to take liver and carries out corresponding index detection.
(3) it detects
Observe mental status, measurement Triglycerides in Serum (TG) of rat, cholesterol (TC), low-density lipoprotein
(LDL-C), high-density lipoprotein cholesterol (HDL-C) is horizontal, observes different groups of hepatic tissue sections variations.
(4) result
Rat mental status: high lipid food feeds appetite rat early period and is greater than Normal group, and weight increases comparatively fast, after
Phase appetite reduces, and activity is reduced.Happy rat appetite, the activity for knowing apple group and methylpyrazine derivative arginine hydrate group
It is significantly better than that control group.Methylpyrazine derivative arginine hydrate group rat weight is obviously lighter than control group.
Hepatic tissue section situation of change: taking hepatic tissue to visually observe after putting to death rat, finds Normal group hepatic tissue color
It is damp normal, it is in kermesinus, section is without greasy feeling；Model group rats liver is loose, surface is turned to be yellow, and section is greasy.It is happy know apple group and
Methylpyrazine derivative arginine hydrate group hepatic tissue is slightly biased big, and most of color is dark red, close to Normal appearances.
Each group serum lipids compare: compared with model group, pleasure knows apple group and methylpyrazine derivative arginine hydrate group
TG, TC, LDL-C, level are decreased obviously.It the results are shown in Table 6.
The comparison of 6 each group serum lipids of table
This result of study display, methylpyrazine derivative arginine hydrate can reduce Rats with Fatty Liver serum TC, TG and
LDL-C is horizontal, removes liver cell inner part lipid accumulation；Show that Histopathologic changes are obviously improved under mirror, methylpyrazine spreads out
Biological arginine hydrate group liver tissues of rats only has a small amount of fat drips accumulation, Minimal fatty denaturation, and liver cell form tends to be normal
Cells show, methylpyrazine derivative arginine hydrate group have preferable therapeutic effect to Rats with Fatty Liver.
Claims (10)
1. a kind of methylpyrazine derivative arginine hydrate, which is characterized in that be by methylpyrazine derivative: arginine: water
1:1:1 is combined and is formed in molar ratio, is radiated using Cu-K α, the X-ray diffraction spectrogram indicated with 2 θ exists: 5.7 ± 0.2 °, 9.1 ±
There is characteristic peak at 0.2 °, 16.2 ± 0.2 °, 24.5 ± 0.2 °, 24.8 ± 0.2 °, 27.8 ± 0.2 °.
2. methylpyrazine derivative arginine hydrate as described in claim 1, which is characterized in that it is radiated using Cu-K α, with
2 θ indicate X-ray diffraction spectrogram at 5.7 ± 0.2 °, 9.1 ± 0.2 °, 16.2 ± 0.2 °, 17.4 ± 0.2 °, 18.3 ± 0.2 °,
There is characteristic peak at 19.6 ± 0.2 °, 21.1 ± 0.2 °, 24.5 ± 0.2 °, 24.8 ± 0.2 °, 25.5 ± 0.2 °, 27.8 ± 0.2 °.
3. methylpyrazine derivative arginine hydrate as claimed in claim 2, which is characterized in that it is radiated using Cu-K α,
Characteristic peak meets X-ray powder diffraction pattern as shown in Figure 1.
4. methylpyrazine derivative arginine hydrate as described in claim 1, which is characterized in that it is in differential scanning calorimetry
There are two endothermic peaks, respectively 187.11 DEG C, 214.47 DEG C in curve (DSC)；It is in differential scanning calorimetric curve (DSC)
There are an exothermic peaks, are 242 DEG C.
5. methylpyrazine derivative arginine hydrate according to any one of claims 1-4, which is characterized in that its crystallography
Parameter is: monoclinic system, chiral space group P21；Methylpyrazine derivative crystal form prepared by the present invention institute is tested and parsed to crystalline substance
Obtaining crystallographic data is (table 1): cell parameter are as follows:
α=90.00 °, β=104.762 (2) °, γ=90.00 °, unit cell volume
6. a kind of preparation method of methylpyrazine derivative arginine hydrate, which is characterized in that specific preparation step include: by
Methylpyrazine derivative and arginine are dissolved in the mixed solution of organic solvent and water, are dissolved by heating, after solution clarification, cooling analysis
Crystalline substance, filtration drying obtain methylpyrazine derivative arginine hydrate.
7. the preparation method of methylpyrazine derivative arginine hydrate as claimed in claim 6, which is characterized in that methyl pyrrole
Oxazine derivatives and arginic molar ratio are 1:0.8~2, preferably 1:1.0~1.5.
8. a kind of preparation method of methylpyrazine derivative arginine hydrate, which is characterized in that specific preparation step include: by
Methylpyrazine derivative and arginine after mixing, are added dropwise organic solvent and water, start to grind, and grinding finishes, dry first
Base pyrazines derivatives arginine hydrate.
9. a kind of pharmaceutical composition, it includes methylpyrazine derivative arginine of any of claims 1-4 hydrations
Object, and include other pharmaceutically acceptable auxiliary material components.
10. methylpyrazine derivative arginine hydrate of any of claims 1-4 is used for hypolipidemic in preparation
In application.
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| CN113121456A (en) * | 2020-01-15 | 2021-07-16 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| WO2021203572A1 (en) * | 2020-04-08 | 2021-10-14 | 山东新时代药业有限公司 | 1,2-bis(4-pyridyl)ethane-acipimox co-crystal |
| CN113121456B (en) * | 2020-01-15 | 2024-04-26 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
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