CN102180879B - Polycrystalline type alpha acetic acid solvate of hypnotic - Google Patents
Polycrystalline type alpha acetic acid solvate of hypnotic Download PDFInfo
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 148
- 239000012453 solvate Substances 0.000 title abstract description 50
- 230000000147 hypnotic effect Effects 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000002249 anxiolytic agent Substances 0.000 claims abstract description 6
- 210000002027 skeletal muscle Anatomy 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 206010021118 Hypotonia Diseases 0.000 claims description 4
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 3
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- 230000000949 anxiolytic effect Effects 0.000 claims description 3
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- 238000004458 analytical method Methods 0.000 claims description 2
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- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
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- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
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- 230000000049 anti-anxiety effect Effects 0.000 abstract 2
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- 229910052738 indium Inorganic materials 0.000 description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 3
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- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
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- 230000036506 anxiety Effects 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical group N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a polycrystalline type alpha acetic acid solvate of a hypnotic. The invention relates to an acetic acid solvate of N-methyl-N-(3-(3-[2-thienylcarbonyl]-pyrazole-[1,5-alpha]-pyrimidine-7-yl) phenyl) acetamide and further relates to the application of an acetic acid solvate of the N-methyl-N-(3-(3-[2-thienylcarbonyl]-pyrazole-[1,5-alpha]-pyrimidine-7-yl) phenyl) acetamide as a tranquilizing-hypnogenesis medicament, an antianxiety medicament, an anti-convulsion medicament and/or a skeletal muscle relaxant. The acetic acid solvate of the N-methyl-N-(3-(3-[2-thienylcarbonyl]-pyrazole-[1,5-alpha]-pyrimidine-7-yl) phenyl) acetamide has the advantages of high stability, remarkable tranquilizing-hypnogenesis, antianxiety and skeletal muscle relaxing functions, and the like.
Description
Technical field
The present invention relates to N-methyl-N-(the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) the polymorphic α of ethanamide and solvate and preparation method thereof.The invention still further relates to it as the purposes of calmness-soporific, anxiolytic, anticonvulsive drug and/or skeletal muscular relaxant.
Background technology
Insomnia seriously affects people's life, work and physical and mental health." whole world sleep investigation " result that on March 21st～25,2002 was sponsored by international mental health and neuroscience foundation (IFMHN) shows, in population of China, there is 45.4% people to have sleeping problems (wherein 28% insomnia, 17.4% suspicious insomnia).Market presents ever-increasing trend for the demand of soporific.A class novel compound of researching and developing at present is Non-benzodiazepine.Because these compounds are the α of γ-aminobutyric acid (GABA) in the combination optionally often
1Acceptor, thus the result for the treatment of that significantly is better than traditional soporific had.This compounds comprise N-methyl-N-(the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) ethanamide (hereinafter referred to as compound 1), this compound structure is as follows:
Compound 1
Compound 1 has the α of higher γ-aminobutyric acid (GABA) than other Non-benzodiazepine compound
1Receptor-selective, thereby have higher activity and lower side effect.Clinical trial proves that it is desirable calmness-soporific.
Compound 1 can be according to 4,521, No. 422 disclosed step preparations of United States Patent (USP), and when adopting this method, compound 1 exists with the form of polymorphic mixture.For increasing its solubleness, oral administration biaavailability and/or physical stability, need to improve the form of compound.In the ZL00813158.9 Chinese patent, polymorphic I and the II of compound 1 disclosed, also disclose the preparation method of I type and II type, but the method only can obtain basically pure polymorphic form.In the 03820245.X Chinese patent application, polymorph III of compound 1 and preparation method thereof is disclosed, the nucleator that the method need to add q.s carries out recrystallization again, and step is more numerous, and easily obtains the mixture of solvate and III type.
Summary of the invention
A kind of new crystal of compound 1 of the objective of the invention is to come into the open is polymorphic α, and this crystal formation has good physical and chemical stability and the advantages such as significant calmness-hypnosis, anxiety and skeletal muscle relaxation effect.The present invention also discloses a kind of easy, easy to operate, preparation method of can high yield obtaining pure polymorphic α.In addition, the invention also discloses formic acid solvent compound, acetic acid solvent compound and the acetone solvate (hereinafter to be referred as formic acid compound, acetic acid compound and acetone solvate) of compound 1 and the easy preparation method that the energy high yield obtains these pure solvates.
Formic acid compound acetic acid compound
Acetone solvate
The bulk drug of the preparation polymorphic α that the present invention is used is compound 1, is by (3-amino-1H-pyrazoles-4-yl)-2-thienyl ketone and N-[3-[3-(dimethylamino)-1-oxygen base-2-propenyl]-phenyl]-N-methylacetamide reaction obtains.In embodiment 1, (3-amino-1H-pyrazoles-4-yl)-2-thienyl ketone and N-[3-[3-(dimethylamino)-1-oxygen base-2-propenyl]-phenyl]-N-methylacetamide pyroreaction generation compound 1 in Glacial acetic acid.
The feature of polymorphic α can be described with DSC collection of illustrative plates, feature powdery diffractometry peak and monocrystalline data.Wherein the DSC collection of illustrative plates of polymorphic α is to measure with DSC (NETZSCH DSC 204, indium standard correction), and its scanning speed is 10 ℃/min, and main endotherm(ic)peak usually should be in 190～198 ℃ of scopes.Fig. 2 is the DSC collection of illustrative plates of polymorphic α, shows that main endotherm(ic)peak is at 194 ℃.
The powder diffraction data of polymorphic α is with Rigaku X-ray powder diffraction instrument (D/Max-Ra, Cu k α
1, graphite monochromator) collect, and use the silicon-dioxide standard to proofread and correct.Instrument parameter is as follows: 40KV, and 100mA, step-length 0.02 degree, 8 degrees/mins of sweep velocitys, measurement range are 3～40 degree.The powder diffraction spectrum of polymorphic α is seen Fig. 1, and its main diffraction peak is as described in Table 1.The X-ray powder diffraction spectral line of the polymorphic α that records by experiment is consistent with the theoretical powder diffraction data of the polymorphic α that calculates by the monocrystalline data, illustrate that the polymorphic α that we obtain is pure crystal formation, also further confirmed the single crystal diffraction of polymorphic α and the reliability of powdery diffractometry.Table 2 has shown the contrast at the principal character peak of the principal character peak of theoretical powdery diffractometry of polymorphic α and actual measurement.The crystalline structure of polymorphic α is measured by the single X-ray diffractometer analysis.To be of a size of the monocrystalline of 0.5x0.2x0.1mm, visit diffractometer (Bruker SMARTAPEX-CCD) with X ray CCD face, under 298 (2) K temperature
Detect and data gathering.The monocrystalline data see table 3～6 for details.
The X-ray powder diffraction spectral line measured data of table 1. polymorphic α
| 2θ° | d | Intensity | Intensity % |
| 5.946 | 14.8516 | 31743 | 100 |
| 11.487 | 7.6967 | 3649 | 11.5 |
| 13.260 | 6.6715 | 9738 | 30.7 |
| 17.431 | 5.0835 | 3339 | 10.5 |
| 17.842 | 4.9671 | 8557 | 27.0 |
| 18.474 | 4.7986 | 3853 | 12.1 |
| 19.640 | 4.5164 | 3413 | 10.8 |
| 23.105 | 3.8463 | 3739 | 11.8 |
| 26.128 | 3.4077 | 7534 | 23.7 |
The principal character peak of the theoretical powdery diffractometry of table 2. polymorphic α and measured data contrast
| The principal character peak (2 θ °) of theoretical powdery diffractometry | The contrast (2 θ °) at the principal character peak of actual measurement |
| 5.939 | 5.946 |
| 11.501 | 11.487 |
| 13.291 | 13.260 |
| 17.444 | 17.431 |
| 17.863 | 17.842 |
| 18.503 | 18.474 |
| 19.658 | 19.640 |
| 23.116 | 23.105 |
| 26.173 | 26.128 |
Atomic coordinate (the x10 of table 3. polymorphic α
4) and effective homogeneity thermal motion parameter
The bond distance of table 4. polymorphic α
And bond angle [degree]
The anisotropic thermal kinematic parameter of table 5. polymorphic α
Hydrogen atom coordinate (the x10 of table 6. polymorphic α
4) and isotropy thermal motion parameter
Compound 1 has been reported and has been had three kinds of crystal formations, i.e. polymorphic I, II and III.Polymorphic α significantly is different from this three kinds of crystal formations: compare with the III type with the I type, polymorphic α has visibly different unit cell parameters (seeing Table 7); Compare with the II type, the DSC collection of illustrative plates of polymorphic α has significantly different main endotherm(ic)peak (seeing Table 8).Therefore, polymorphic α is a kind of new crystal formation.Solubility test shows that the approximate solubility of polymorphic α in water is 31.34 μ g/ml under the room temperature, has than polymorphic I and the higher solubleness of II.
Table 7
The comparison of polymorphic α, polymorphic I and III unit cell parameters
Table 8
DCS master's endotherm(ic)peak of polymorphic α and polymorphic II relatively
| Crystal formation | Main endotherm(ic)peak scope |
| II | 172-177℃ |
| α | 190-198℃ |
The crystalline structure of the formic acid compound of compound 1, acetic acid compound and acetone solvate is by Rigaku single crystal diffractometer (Rigaku RAXIS RAPID IP), under 293 (2) K temperature
Detect and data gathering.The crystallographic dimension that is used for the formic acid compound of monocrystalline test is the monocrystalline of 0.50x0.10x0.10mm, and the monocrystalline data of acquisition see table 9～14 for details.The crystallographic dimension that is used for the acetic acid compound of monocrystalline test is the monocrystalline of 0.45x0.10x0.08mm, and the monocrystalline data of acquisition see table 15～20 for details.The crystallographic dimension that is used for the acetone solvate of monocrystalline test is the monocrystalline of 0.40x0.30x0.20mm, and the monocrystalline data of acquisition see table 21～24 for details.
Atomic coordinate (the x10 of table 9. formic acid compound
4) and effective homogeneity thermal motion parameter
The bond distance of table 10. formic acid compound
And bond angle [degree]
The anisotropic thermal kinematic parameter of table 11. formic acid compound
Hydrogen atom coordinate (the x10 of table 12. formic acid compound
4) and isotropy thermal motion parameter
The torsional angle [degree] of table 13. formic acid compound
The hydrogen bond of table 14. formic acid compound
Atomic coordinate (the x10 of table 15. acetic acid compound
4) and effective homogeneity thermal motion parameter
The bond distance of table 16. acetic acid compound
And bond angle [degree]
The anisotropic thermal kinematic parameter of table 17. acetic acid compound
Hydrogen atom coordinate (the x10 of table 18. acetic acid compound
4) and isotropy thermal motion parameter
The torsional angle [degree] of table 19. acetic acid compound
The hydrogen bond of table 20. acetic acid compound
Atomic coordinate (the x10 of table 21. acetone solvate
4) and effective homogeneity thermal motion parameter
Table 22. acetone solvate the bond distance
And bond angle [degree]
The anisotropic thermal kinematic parameter of table 23. acetone solvate
The torsional angle of table 24. acetone solvate [degree]
Can know from the monocrystalline data, contain respectively formic acid, acetic acid or acetone equal solvent molecule in the structure cell of formic acid compound, acetic acid compound and acetone solvate.And three kinds of crystal formations of the compound 1 of having reported and hydrate all are not solvent-laden crystal formation or moisture solvate.So formic acid compound, acetic acid compound and acetone solvate also are new solvates.
The problem that the preparation polymorphic often runs into is the conditional request harsh (such as temperature, rate of temperature fall) in the preparation process, but also seldom arrives highly purified sample.The invention discloses the method for preparing polymorphic α, formic acid compound, acetic acid compound and acetone solvate, these method operations very simply but can obtain pure polymorphic α, formic acid compound, acetic acid compound and the acetone solvate of high yield, so the present invention has significant superiority.
The invention provides a kind of method for preparing polymorphic α: form the crystallization solution that contains compound 1; Heat this solution; Cooling solution forms a large amount of crystal; Collect crystal.In embodiment 2, form first the hot solution that contains acetic acid and compound 1, add an amount of water, cool off again this solution, can obtain a large amount of polymorphic α.In embodiment 3, in the hot solution of acetic acid and compound 1, add an amount of water and activated carbon, cool off again this solution, can obtain a large amount of polymorphic α.Normally be heated to 40-100 ℃, then cool off with about 60-30 ℃/hour speed.Those skilled in the art can easily determine suitable Heating temperature and rate of cooling.Also can adopt other method, specific polymorphic is dropped into the recrystallisation solvent induced crystallization as crystal seed, that is: form the crystallization solution that contains compound 1; Heat this solution; The crystal seed that adds polymorphic α; Cooling solution forms a large amount of crystal; Collect crystal.In embodiment 4, by in the saturated hot acetone solution that contains compound 1, adding the crystal seed of polymorphic α, can obtain a large amount of polymorphic α.It is emphasized that if being used for the organic solvent of dissolved compound 1 is methyl alcohol, must add so polymorphic α in the solution as crystal seed, otherwise crystallized product can be the mixture of polymorphic α, II type and methylate.In embodiment 5, contain in the saturated hot methanol solution of compound 1 and do not add polymorphic α as crystal seed, cooling has obtained the mixture of polymorphic α, polymorphic II and methylate, and its DSC collection of illustrative plates is seen Fig. 3.If in containing the saturated hot methanol solution of compound 1, add an amount of polymorphic α as crystal seed, obtained pure polymorphic α after cooling off this solution.
What need to further specify is the polymorphic II that polymorphic α described in the invention reports before being not.From embodiment 4 corresponding Fig. 3, can see that polymorphic II and polymorphic α appear in the DSC collection of illustrative plates simultaneously.This collection of illustrative plates explanation: (1) exists really take the main endotherm(ic)peak 172-177 ℃ of polymorphic II as feature; (2) polymorphic II has significantly different main endotherm(ic)peak with polymorphic α.
The present invention also provides the method for preparing formic acid compound, acetic acid compound and acetone solvate: form the crystallization solution that contains compound 1; Heat this solution; Cooling solution forms a large amount of crystal; Collect crystal.In embodiment 6, form first the hot solution that contains formic acid and compound 1, cool off again this solution, can obtain a large amount of formic acid compounds.Normally be heated to 40-100 ℃, then cool off with about 30-10 ℃/hour speed.Those skilled in the art can easily determine suitable Heating temperature and rate of cooling.In embodiment 7, form first the hot solution that contains acetic acid and compound 1, cool off again this solution, can obtain a large amount of acetic acid compounds.In embodiment 8, form the hot acetone solution that contains compound 1, cool off this solution, can obtain a large amount of acetone solvates.It should be noted that acetic acid compound and polymorphic α preparation method's difference.Although both crystallization solutions are similar, its preparation method is different in Heating temperature, reduction program and other operation, thereby causes different products.
The solvent of the crystallization solution that preparation polymorphic α, formic acid compound, acetic acid compound and acetone solvate are used can or be the solvent mixture for single solvent, comprise polar solvent, non-polar solvent, protonic solvent, aprotic solvent, such as water, formic acid, acetic acid, methyl alcohol, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, hexane, diethyl ether, Virahol, toluene, ethanol, propyl alcohol, butanols, dimethyl formamide, benzene, toluene, acetone, polyoxyethylene glycol, ether etc.
The another one problem that polymorphic often runs into is the stable bad of sample.The invention discloses high temperature and illumination to the impact of polymorphic α, formic acid compound, acetic acid compound and acetone solvate, the result shows that polymorphic α, formic acid compound, acetic acid compound and acetone solvate have good physical and chemical stability.This also is one of superiority of the present invention.In embodiment 9, carried out the test under long-term placement, high temperature, illumination, grinding and pressure condition of polymorphic α, formic acid compound, acetic acid compound and acetone solvate, find that sample composition does not change.
In order to be administered into the patient, polymorphic α, formic acid compound, acetic acid compound and acetone solvate can be used as medicinal compositions and allocate.Pharmaceutical composition of the present invention comprises one or more and the pharmaceutically acceptable carrier in polymorphic α, formic acid compound, acetic acid compound and the acetone solvate, and wherein polymorphic α, formic acid compound, acetic acid compound and acetone solvate are to be present in the preparation with the amount that can effectively treat disease.Polymorphic α, formic acid compound, acetic acid compound and acetone solvate in the medicinal compositions of the present invention, according to different route of administration, its dosage can be from 0.1 milligram to 250 milligrams.Those skilled in the art can easily determine suitable concentration and dosage.The preparation technology of the Tablet and Capsula of polymorphic α is disclosed among the embodiment 10.But during practical application, formulation has more than and is limited to above-mentioned preparation.Also can be injection or other any suitable formulation.
For the preliminary activity of investigating polymorphic α, formic acid compound, acetic acid compound and acetone solvate, need to give the medicine of animal doses to observe drug effect.In embodiment 11, give polymorphic α, formic acid compound, acetic acid compound and the acetone solvate of the suitable dosage of mouse after, find that it has good calmness-hypnotic effect.
In sum, the polymorphic α of compound 1, formic acid compound, acetic acid compound and acetone solvate have the preparation method simple, easy to operate, can high productivity obtain pure sample, and have satisfactory stability and the advantages such as significant calmness-hypnosis, anxiety and skeletal muscle relaxation effect.
Description of drawings
The X-ray powder diffraction spectrum of Fig. 1 polymorphic α
The DSC collection of illustrative plates of Fig. 2 polymorphic α, wherein 194.4 ℃ is its main endotherm(ic)peak
The DSC collection of illustrative plates of the mixture of Fig. 3 polymorphic α, polymorphic II and ethylate, wherein 191.1 ℃ is the main endotherm(ic)peak of polymorphic α, and 172.1 ℃ is the main endotherm(ic)peak of polymorphic II, and 158.9 ℃ is the main endotherm(ic)peak of methylate.
Embodiment
It is unrestricted the present invention in order to illustrate that following embodiment is provided.
Embodiment
Embodiment 1
Synthesizing of compound 1
Take by weighing (3-amino-1H-pyrazoles-4-yl)-2-thienyl ketone (11.0g, 56.8mmol) and N-[3-[3-(dimethylamino)-1-oxygen base-2-propenyl]-phenyl]-N-methylacetamide (14.0g, 56.8mmol) in the 250ml there-necked flask, add Glacial acetic acid (200mL), 130 ℃ of stirring and refluxing 6 hours.Remove volatile solvent with the Rotary Evaporators evaporation after the reaction, obtain the oily residue.With obtaining granular solids after methylene dichloride (50mL) washing, add hexane (200mL), grind, filter the collecting precipitation thing, with the washing precipitation of 1: 10 dichloromethane/hexane (100mL).Vacuum-drying obtains lurid compound 1 solid (16.28g, 43.2mmol).EI-MS:376[M]
+, 334[M-CH
2CO]
+, 251[M-CH
2C α-thienyl], 110[thiophene carbonyl];
1H-NMR (ppm, CD
3OD, 600MHz): δ 1.89 (3H, s), δ 3.21 (3H, s), δ 7.18 (1H, dt, J=4,0.6Hz), δ 7.38 (1H, d, J=4Hz), δ 7.52 (1H, d, J=8Hz), δ 7.64 (1H, t, J=8Hz), δ 7.81 (1H, dd, J=5,1Hz), δ 8.02 (1H, dt, J=8Hz), δ 8.08 (1H, s), δ 8.10 (1H, dd, J=4,0.6Hz), δ 8.70 (1H, s), δ 8.76 (1H, d, J=6Hz)
Embodiment 2
The representativeness preparation of polymorphic α
(a) 10g compound 1 is dissolved in the 60mL acetic acid.
(b) this solution was heated this solution 5 minutes under 60 ℃ of temperature.Fast filtering continues heating while hot, keeps 60 ℃.Adding volume is the distilled water of 30ml.Continued heated solution 10 minutes.
(c) with 50 ℃/hour speed cooling solution to 25 ℃, form a large amount of crystal.Filter the gained solid, under 40 ℃ of temperature, the polymorphic α that the vacuum-drying previous step is collected, be 1 hour time of drying.The final pure polymorphic α of 9.2g that obtains.
Solvent also can be acetic acid aqueous solution or acetone described in the present embodiment (a), also can obtain polymorphic α equally by above-mentioned similarity method.
Embodiment 3
The representativeness preparation of polymorphic α
(a) 10g compound 1 is dissolved in the 60mL acetic acid.
(b) this solution was heated this solution 5 minutes under 60 ℃ of temperature.Fast filtering continues heating while hot, keeps 60 ℃.
(c) add a small amount of activated carbon, the amount of adding is 5mg.Adding volume is the distilled water of 30ml.Continued heated solution 10 minutes.
(d) with 50 ℃/hour speed cooling solution to 25 ℃, form a large amount of crystal.Filter the gained solid, under 40 ℃ of temperature, the polymorphic α that the vacuum-drying previous step is collected, be 1 hour time of drying.The final pure polymorphic α of 9.4g that obtains.
Solvent also can be acetic acid aqueous solution or acetone described in the present embodiment (a), also can obtain polymorphic α equally by above-mentioned similarity method.
Embodiment 4
The representativeness preparation of polymorphic α
(a) 15g compound 1 is dissolved in the 1000mL acetone.
(b) this solution was heated this solution 10 minutes under 50 ℃ of temperature.Fast filtering continues heating while hot, keeps 50 ℃.
(c) reduce temperature to 40 ℃, add the polymorphic α that obtains among a small amount of embodiment 1 as crystal seed, the amount of adding is 10mg.
(d) with 50 ℃/hour speed cooling solution, further be cooled to 5 ℃ and kept constant temperature 2 hours, form a large amount of crystal.Filter the gained solid, under 30 ℃ of temperature, the polymorphic α that the vacuum-drying previous step is collected, be 4 hours time of drying.The final pure polymorphic α of 9.4g that obtains.
Solvent also can be one or more in formic acid, acetic acid, methylene dichloride and the acetone described in the present embodiment (a), also can obtain polymorphic α equally by above-mentioned similarity method.
Resulting polymorphic α measures with DSC and X-ray powder diffraction.The DSC collection of illustrative plates of polymorphic α is to measure with DSC (NETZSCH DSC 204, indium standard correction), and its scanning speed is 10 ℃/min, and its main endotherm(ic)peak is at 194 ℃.The DSC collection of illustrative plates is seen Fig. 2.The powder diffraction data of polymorphic α is with Rigaku X-ray powder diffraction instrument (D/Max-Ra, Cuk α
1, graphite monochromator) collect, and use the silicon-dioxide standard to proofread and correct.Instrument parameter is as follows: 40KV, and 100mA, step-length 0.02 degree, 8 degrees/mins of sweep velocitys, measurement range are 3～40 degree.Powder diagram is seen Fig. 1.
The preparation process conditional of considering three kinds of crystal formations of the compound 1 of having reported requires harshness (such as temperature, rate of temperature fall); and often be mixed with other crystal formation in the product; and this method operation very simply can obtain the pure polymorphic α of high yield, so the present invention has significant superiority.
Embodiment 5
The preparation of the mixture of polymorphic α, polymorphic II and methylate
10g compound 1 is dissolved in the 700mL methyl alcohol.Then solution is heated to 70 ℃.Fast filtering while hot.Solution is Slow cooling in water-bath, and crystal is separated out gradually.After temperature is down to room temperature, put into again ice bath.Crystal is further separated out.The dry mixture that obtains 9.4g polymorphic α, polymorphic II and methylate.In the DSC collection of illustrative plates, the main endotherm(ic)peak of polymorphic α is 191.1 ℃, and the main endotherm(ic)peak of polymorphic II is 172.1 ℃, and the main endotherm(ic)peak of methylate is 158.9 ℃.Its DSC collection of illustrative plates (seeing Fig. 3) is to measure with DSC (NETZSCH DSC 204, indium standard correction), and its scanning speed is 10 ℃/min.The present embodiment has illustrated polymorphic α and the polymorphic II that has reported in DSC figure, and its main endotherm(ic)peak has obvious difference, be not polymorphic II thereby further illustrate polymorphic α.
If in above-mentioned preparation process, add 0.5mg polymorphic α as crystal seed, then can obtain the pure polymorphic α of 9.3g.
Embodiment 6
The representativeness preparation of formic acid compound
10g compound 1 is dissolved in the 60mL formic acid.This solution was heated this solution 5 minutes under 75 ℃ of temperature.Fast filtering continues heating while hot, keeps 75 ℃.With 20 ℃/hour speed cooling solutions to 25 ℃, form a large amount of crystal.Filter the gained solid, room temperature was placed 12 hours.The final pure formic acid compound of 9.3g that obtains.The preparation process conditional of considering three kinds of crystal formations of the compound 1 of having reported requires harshness (such as temperature, rate of temperature fall); and often be mixed with other crystal formation in the product; and this method operation very simply can obtain the pure formic acid compound of high yield, so the present invention has significant superiority.
Embodiment 7
The representativeness preparation of acetic acid compound
8g compound 1 is dissolved in the 60mL acetic acid.This solution was heated this solution 15 minutes under 75 ℃ of temperature.Fast filtering while hot.With 25 ℃/hour speed cooling solutions to 25 ℃, form a large amount of crystal.Filter the gained solid, under 50 ℃ of temperature, the acetic acid compound that the vacuum-drying previous step is collected, be 1 hour time of drying.The final pure acetic acid compound of 9.4g that obtains.The preparation process conditional of considering three kinds of crystal formations of the compound 1 of having reported requires harshness (such as temperature, rate of temperature fall); and often be mixed with other crystal formation in the product; and this method operation very simply can obtain the pure acetic acid compound of high yield, so the present invention has significant superiority.
Embodiment 8
The representativeness preparation of acetone solvate
6g compound 1 is dissolved in the 1000mL acetone.This solution was heated this solution 15 minutes under 70 ℃ of temperature.Fast filtering continues heating while hot, keeps 70 ℃.With 20 ℃/hour speed cooling solution, form a large amount of crystal.Further be cooled to 5 ℃ and kept constant temperature 4 hours.Crystal continues to separate out, and filters the gained solid, and room temperature was placed 12 hours.The final pure acetone solvate of 9.4g that obtains.The preparation process conditional of considering three kinds of crystal formations of the compound 1 of having reported requires harshness (such as temperature, rate of temperature fall); and often be mixed with other crystal formation in the product; and this method operation very simply can obtain the pure acetone solvate of high yield, so the present invention has significant superiority.
Embodiment 9
The stability test of polymorphic α, formic acid compound, acetic acid compound and acetone solvate
Get an amount of polymorphic α, formic acid compound, acetic acid compound and acetone solvate and be positioned in the moisture eliminator, take out sample after 6 months and carry out the X powder diffraction test.Collection of illustrative plates has no considerable change.Take by weighing each two parts of polymorphic α, formic acid compound, acetic acid compound and acetone solvates, 0.5g/ part (obtaining by the step described in the top embodiment 2) is placed in the culture dish, and every part is spread out into the thick thin layer of 8mm and tests.A copy of it sample is put in the sealing clean container, and 60 ℃ of lower placements 10 days in sampling in the 5th, 10 day, are carried out the X powder diffraction test.Collection of illustrative plates has no considerable change.The second duplicate samples was placed 10 days under 4500 ± 500lx condition, in sampling in the 5th, 10 day, carried out the X powder diffraction test.Collection of illustrative plates also has no considerable change.Other gets an amount of polymorphic α, formic acid compound, acetic acid compound and acetone solvate and places respectively in the ball mill (SQM-16 * 4, Shanghai Chinese traditional medicine machine factory), grinds sampling after 2 hours, carries out the X powder diffraction test.Collection of illustrative plates has no considerable change.Get an amount of polymorphic α, formic acid compound, acetic acid compound and each 10g of acetone solvate and starch, Microcrystalline Cellulose, Vltra tears, Magnesium Stearate and be pressed into 980 in tablet, the X powder diffraction test is carried out in sampling.Collection of illustrative plates has no considerable change.Above-mentioned high temperature, illumination, grinding and pressure test explanation polymorphic α, formic acid compound, acetic acid compound and acetone solvate have good physical and chemical stability.
Embodiment 10
The formulation of polymorphic α
Tablet
Prescription:
Preparation: first polymorphic α, lactose and starch are crossed respectively 100 mesh sieves and mix, add again 10% ethanolic soln of PVP K30, further mix, cross that 20 mesh sieves are granulated and dry.Add Magnesium Stearate 1.4g, be pressed into 1000.
Capsule
Prescription:
Preparation: the bulk drug in will write out a prescription and auxiliary material, comprise that polymorphic α, lactose, starch waited 80 mesh sieves, mixing, use the 2%HPMC aqueous solution, granulation, drying with the Magnesium Stearate mixing, is sub-packed in the capsule, every polymorphic α that contains 10mg.
Embodiment 11
The animal experiment of polymorphic α, formic acid compound, acetic acid compound and acetone solvate
The test of mouse tranquilizing soporific
Test conditions: tested medicine is polymorphic α, formic acid compound, acetic acid compound and acetone solvate.The positive control medicine is diazepam.Tested medicine and positive control drug are all used 1.5% Xylo-Mucine suspending.Laboratory animal is for supplying Kunming kind (KM) mouse.
Test grouping: blank group (abbreviation control group); Solvent control group (abbreviation group of solvents); Polymorphic α divides 4 groups, i.e. 1mg/kg group, 5mg/kg group, 10mg/kg group, 15mg/kg group; Formic acid compound, acetic acid compound and acetone solvate also are divided into 4 groups, i.e. 1mg/kg group, 5mg/kg group, 10mg/kg group, 15mg/kg group; Positive reference substance diazepam 2mg/kg group and 4mg/kg group.20 of every treated animals.Route of administration is oral (gavage) administration.Observe mouse and the tranquilizing soporific phenomenon whether occurs.
Test-results: gavage to positive control medicine diazepam after 5～10min, mouse appearance activity reduces, and reposes, closes order, bows, crouches down phenomenon, 2～4mg/kg group incidence is 20～45%.Gavage to polymorphic α, formic acid compound, acetic acid compound and acetone solvate 1,5,10,15mg/kg after 5～10min, mouse also appearance activity reduces, repose, close order, bow, crouch down phenomenon, wherein 1～5mg/kg organizes incidence 41～67%, time length≤50min; 5～10mg/kg group incidence is 89%～96%, time length 〉=45～120min.
The result shows: polymorphic α, formic acid compound, acetic acid compound and acetone solvate 1～15mg/kg have calmness and induced hypnotic effect to mouse.
It more than is the detailed description of the specific embodiment of the invention.To describe the specific embodiment of the present invention although it should be understood that the purpose this paper in order describing, can to have carried out various improvement in the situation that do not deviate from the spirit and scope of the present invention.Therefore, the present invention is not limited to this, but is limited by appending claims.
Claims (6)
- A N-methyl-N-(the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) the acetic acid solvent compound of ethanamide, it has the analysis of following monocrystalline X-radiocrystallography:
- 2. pharmaceutical composition, it comprise N-methyl-N-claimed in claim 1 (the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) ethanamide acetic acid solvent compound and pharmaceutically acceptable carrier.
- 3. the pharmaceutical composition of claim 2, wherein said composition can be made into tablet, capsule, pill, injection liquid.
- 4. the pharmaceutical composition of claim 2, wherein N-methyl-N-(the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) ethanamide acetic acid solvent compound is present in the unit dosage with unit dosage form with the amount of 0.1mg to 250mg.
- N-methyl-the N-of claim 1 (the 3-{3-[2-thienyl carbonyl]-pyrazoles-[1,5-α]-pyrimidin-7-yl phenyl) purposes of ethanamide acetic acid solvent compound in preparation calmness-hypnotic drug, anxiolytic medicament, anticonvulsant drug, skeletal muscle relaxation medicine.
- 6. the purposes of the pharmaceutical composition of the acetic acid solvent compound of claim 2 in preparation calmness-hypnotic drug, anxiolytic medicament, anticonvulsant drug, skeletal muscle relaxation medicine.
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| US6399621B1 (en) * | 1999-08-10 | 2002-06-04 | American Cyanamid Company | N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1, 5-α]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto |
| CN1678614A (en) * | 2002-08-26 | 2005-10-05 | 纽罗克里恩生物科学有限公司 | Novel polymorph of n-methyl-n-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto |
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| US6399621B1 (en) * | 1999-08-10 | 2002-06-04 | American Cyanamid Company | N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1, 5-α]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto |
| CN1678614A (en) * | 2002-08-26 | 2005-10-05 | 纽罗克里恩生物科学有限公司 | Novel polymorph of n-methyl-n-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto |
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