According to Shandong for Buddhist nun's new crystal and preparation method thereofTechnical field
The present invention relates to medicinal chemistry art, particularly, the present invention relates to 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino] crystal formation of-2-propylene-1-ketone, and the preparation method of new crystal and purposes.
Background technology
Replace Buddhist nun (Ibrutinib) by Pharmacyclics company of the U.S. and Johson & Johnson's joint research and development according to Shandong, commodity are called Imbruvica, its chemical name is: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, structural formula is as follows:
A kind of pioneering new drug of oral bruton's tyrosine kinase (BTK) inhibitor for Buddhist nun according to Shandong, this medicine by with target protein Btk activity site cysteine residue (Cys-481) optionally covalent attachment, non-reversibility ground suppresses BTK, thus effectively stops tumour to move to the Lymphoid tissue being adapted to tumor growth environment from B cell.In November, 2013, FDA (Food and Drug Adminstration) (FDA) ratifies its listing, be used for the treatment of a kind of rare aggressive leukemia-lymphoma mantle cell (MCL), in July, 2014, FDA ratified its treatment for lymphocytic leukemia (CLL).
The patent WO2013/184572 of Pharmacyclics company of U.S. application in 2013 discloses according to the six kind crystal formations of Shandong for Buddhist nun, wherein crystal formation D is methyl isobutyl ketone solvent compound, crystal formation E is toluene solvate, and crystal formation D is Methanol Solvate, is all not suitable for medicinal preparations.In its excess-three kind crystal formation, report crystal form B water absorbability according to WO2013/184572 larger, crystal form A is not easy moisture absorption by contrast, does not report stability and the solubility data of crystal C.
Content disclosed in WO2013/184572, in six kinds of crystal formations, crystal form A is only had to be applicable to medicinal preparations, the crystal form A of its report has three kinds of preparation methods: method one will be suspended in the organic solvent of 10 times of volumes for Buddhist nun's amorphous article according to Shandong, be heated to 50 DEG C in an oscillator, vibrate 1 hour, add the organic solvent of 30 times of volumes again, again be heated to 50 DEG C of vibrations 1 hour, then 0 DEG C is cooled to the speed of 0.1 DEG C/min, filter, the solid obtained is crystal form A, and filtrate also obtains crystal form A by pin hole slow evaporation.This kind of method complex operation, and because consumption of organic solvent be 40 times, so it is low to filter the product yield obtained for the first time, although and from filtrate, also can obtain product, consuming time oversize; Method two will be suspended in the organic solvent of 1-10 times of volume for Buddhist nun's amorphous article according to Shandong, and then sealed reaction bottle, seals 5 days in curing chamber, filters and obtains crystal form A.This kind of method is same consuming time long, and needs specific installation; Method three replaces Buddhist nun's heating for dissolving in the methyl alcohol of 10 times of volumes by according to Shandong, and add water under insulation, then heat up, be then cooled to room temperature and continue stirring 16 hours, obtaining crystal form A, yield is 80%.The complex operation of this kind of method, has intensification repeatedly and cooling in operation, the bad control of production process.
The brilliant cloud CN104327085A in Suzhou discloses another crystal form A (hereinafter referred to crystal form A '), the preparation method of its report has three kinds: method one, by according to Shandong for Buddhist nun's dissolving crude product in the mixing solutions of Virahol and normal heptane, at room temperature with the speed of per minute 750 turns stir obtain crystal form A ', high-revolving stirring industrializing implementation like this is very difficult; Method two, by according to Shandong for Buddhist nun's dissolving crude product in the mixed solvent of Virahol and normal heptane, and drop to 5 DEG C with the cooling rate of 0.1 DEG C/min from 50 DEG C and obtain crystal form A, cooling rate accurate is like this difficult to control; Method three, according to Shandong for Buddhist nun's dissolving crude product in acetone, more slowly will add normal heptane, and stirring obtains crystal form A in 1 day under the rotating speed of per minute 1000 turns, the rotating speed that this method ratio method one requires is higher, the more difficult realization of industrialization.Contriver, when repeating these methods, finds poor reproducibility, controls a little badly will obtain crystal form A disclosed in WO2013/184572.
Therefore, this area needs the new crystal formation of research and development badly, and require that preparation method is simple, Heat stability is good, water absorbability is low, is produced on a large scale.
Summary of the invention
The object of the present invention is to provide a kind of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino] crystal formation I, II of-2-propylene-1-ketone, and the preparation method of new crystal and purposes.
First aspect present invention, provides a kind of structure such as formula the crystal formation of the compound shown in X, and described crystal formation is the crystal of high stability and agent of low hygroscopicity, and described crystal formation is selected from crystal formation I and crystal form II.
In another preference, described " high stability " refers to described crystal formation I or described crystal form II to place 10 days at 60 DEG C of lower open mouths, and relative humidity is that 92% normal temperature 25 DEG C is placed 10 days, after 4500xl low temperature and irradiance places 10 days, and stable crystal form.
In another preference, described " agent of low hygroscopicity " refers to that described crystal formation I or described crystal form II are positioned over humidity is take out after 24 hours in the moisture eliminator of 80%, calculates weightening finish≤0.29%, preferably≤0.28%, more preferably≤0.27%.
In another preference, the X-ray powder diffraction pattern of described crystal formation I comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.45 °, 10.00 °, 11.28 °, 13.52 °, 16.11 °, 18.72 °, 20.82 °, 22.59 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation I comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.45 °, 9.22 °, 10.00 °, 11.28 °, 13.52 °, 14.22 °, 15.12 °, 16.11 °, 17.90 °, 18.72 °, 20.03 °, 20.82 °, 21.70 °, 22.59 °, 24.07 °, 25.49 °, 26.12 °, 28.77 °, 29.62 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation I substantially as Fig. 1 characterize.
In another preference, the dsc of described crystal formation I is analyzed collection of illustrative plates and have characteristic peak within the scope of 165 ± 5 DEG C.
In another preference, the dsc of described crystal formation I analyze collection of illustrative plates substantially as Fig. 2 characterize.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal formation I substantially as Fig. 3 characterize.
In another preference, the infrared Fourier transform spectrum of described crystal formation I comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3437.06,3305.56,3203.74,1586.83,1567.67,1519.23,1279.72,1227.67,1171.38 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal formation I comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3437.06,3305.56,3203.74,1634.38,1600.39,1586.83,1567.67,1519.23,1488.80,1479.03,1435.88,1367.99,1312.54,1300.25,1279.72,1227.67,1201.57,1171.38,1133.56,1115.39,1100.43,962.17,850.17,800.96,754.84,692.71,488.13 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal formation I substantially as shown in Figure 4.
In another preference, described crystal formation I purity is greater than 95%, and preferably, purity is greater than 97%, and more preferably, purity is greater than 99%, and most preferably, purity is greater than 99.5%.
In another preference, the X-ray powder diffraction pattern of described crystal form II comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.61 °, 10.68 °, 12.39 °, 13.09 °, 15.86 °, 18.60 °, 22.59 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal form II comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.61 °, 10.68 °, 12.39 °, 13.09 °, 15.86 °, 18.60 °, 20.08 °, 22.59 °, 23.61 °, 24.87 °, 27.75 °, 29.45 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal form II substantially as Fig. 5 characterize.
In another preference, the dsc of described crystal form II is analyzed collection of illustrative plates and have characteristic peak within the scope of 194 ± 5 DEG C.
In another preference, the dsc of described crystal form II analyze collection of illustrative plates substantially as Fig. 6 characterize.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal form II substantially as Fig. 7 characterize.
In another preference, the infrared Fourier transform spectrum of described crystal form II comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3482.37,3165.01,1632.68,1585.08,1565.09,1521.01,1310.98,1225.32,1096.00 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal form II comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3482.37,3286.46,3165.01,2946.46,1643.91,1632.68,1585.08,1565.09,1521.01,1487.93,1455.17,1393.49,1310.98,1281.66,1225.32,1201.38,1165.08,1140.46,1096.00,973.44,870.16,856.45,785.22,759.86,692.56,650.09,562.04,510.99 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal form II substantially as shown in Figure 8.
In another preference, described crystal form II purity is greater than 95%, and preferably, purity is greater than 97%, and more preferably, purity is greater than 99%, and most preferably, purity is greater than 99.5%.
Second aspect present invention, provide the preparation method of a kind of crystal formation I as described in the first aspect of the invention, described preparation method comprises the steps:
I () will be dissolved in solvent for Buddhist nun's crude product I according to Shandong, weightmeasurement ratio is about 1:1-1:20g/ml;
(ii) after being cooled to 0-25 DEG C, crystallization, thus obtain described crystal formation I;
Wherein, be describedly selected from lower group according to Shandong for Buddhist nun's crude product I: according to Shandong for Buddhist nun's crystal form A, according to Shandong for Buddhist nun's amorphous article.
In another preference, organic solvent is selected from lower group in described step (i): the mixed solvent of the mixed solvent of the mixed solvent of ether solvent, esters solvent, alcoholic solvent, ketones solvent and water, esters solvent and alkane, alcoholic solvent and alkane or its combine.
In another preference, in described step (i), organic solvent is selected from lower group: alcoholic solvent, esters solvent or its combination.
In another preference, the ether solvent described in described step (i) is selected from tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether or its combination.
In another preference, the esters solvent described in described step (i) is selected from ethyl acetate, methyl acetate, isopropyl acetate, butylacetate or its combination.
In another preference, the alcoholic solvent described in described step (i) is selected from methyl alcohol, ethanol, Virahol or its combination.
In another preference, the ketones solvent described in described step (i) is selected from lower group: acetone, methylethylketone, methyl iso-butyl ketone (MIBK), pimelinketone or its combination.
In another preference, the alkane described in described step (i) is selected from normal hexane, hexanaphthene, normal heptane or its combination.
In another preference, in described step (i), organic solvent is esters solvent, and described step (ii) the middle crystallization time is greater than 6 hours.
Third aspect present invention, provide a kind of preparation method of crystal form II as described in the first aspect of the invention, described preparation method comprises the steps:
I () will be dissolved in organic solvent for Buddhist nun's crude product II according to Shandong, weightmeasurement ratio is about 1:3-1:20g/ml;
(ii) after being cooled to 0-25 DEG C, crystallization, thus obtain described crystal form II;
Wherein, be describedly selected from lower group according to Shandong for Buddhist nun's crude product II: according to Shandong for Buddhist nun's crystal form A, according to Shandong for Buddhist nun's amorphous article or described according to Shandong for Buddhist nun's crystal formation I.
In another preference, in described step (i), organic solvent is selected from lower group: ketones solvent, esters solvent or its combination.
In another preference, the ketones solvent described in described step (i) is selected from lower group: acetone, methylethylketone, methyl iso-butyl ketone (MIBK), pimelinketone or its combination.
In another preference, the esters solvent described in described step (i) is selected from lower group: ethyl acetate, methyl acetate, isopropyl acetate, butylacetate or its combination.
In another preference, in described step (i), organic solvent is esters solvent, and described step (ii) the middle crystallization time is 1-5 hour.
Fourth aspect present invention, provides a kind of purposes of the crystal formation as described in first aspect present invention to the third aspect, for the preparation of preventing and/or treating the medicine of cancer or the medicine for the preparation of inhibition tumor cell.
In another preference, described tumour comprises lymphoma.
In another preference, described tumour cell comprises lymphoma cell.
Fifth aspect present invention, provides a kind of medical composition, and described composition comprises the crystal formation described in (a) first aspect present invention to the third aspect, and (b) pharmaceutically acceptable carrier.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 shows according to the X-ray powder diffractogram (XRPD) of Shandong for Buddhist nun's crystal formation I.
Fig. 2 shows according to the differential scanning calorimetric analysis spectrogram (DSC) of Shandong for Buddhist nun's crystal formation I.
Fig. 3 shows according to the thermogravimetic analysis (TGA) spectrogram (TGA) of Shandong for Buddhist nun's crystal formation I.
Fig. 4 shows according to the infrared Fourier transform spectrogram (FT-IR) of Shandong for Buddhist nun's crystal formation I.
Fig. 5 shows according to the X-ray powder diffractogram (XRPD) of Shandong for Buddhist nun's crystal form II.
Fig. 6 shows according to the differential scanning calorimetric analysis spectrogram (DSC) of Shandong for Buddhist nun's crystal form II
Fig. 7 shows according to the thermogravimetic analysis (TGA) spectrogram (TGA) of Shandong for Buddhist nun's crystal form II.
Fig. 8 shows according to the infrared Fourier transform spectrogram (FT-IR) of Shandong for Buddhist nun's crystal form II.
Fig. 9 shows according to Shandong for Buddhist nun's crystal formation I stability XRPD comparison diagram (a is original spectrogram, and b is that 92% normal temperature 25 DEG C places 10 days spectrograms, and c is 60 DEG C and places 10 days spectrograms, and d is illumination 10 days spectrograms).
Figure 10 shows according to Shandong for Buddhist nun's crystal form II stability XRPD comparison diagram (a is original spectrogram, and b is that 92% normal temperature 25 DEG C places 10 days spectrograms, and c is 60 DEG C and places 10 days spectrograms, and d is illumination 10 days spectrograms).
Embodiment
The present inventor is by extensive and deep research; develop two kinds of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3 first; 4-d] pyrimidine-1-base]-piperidino] crystal formation of-2-propylene-1-ketone and crystal formation I and crystal form II; all possess good thermostability and non-hygroscopic; and preparation technology is simply efficient; reproducible, large-scale industrial can be realized and produce.On this basis, the present invention is completed.
Term explanation
Unless otherwise defined, otherwise whole technology used herein and scientific terminology all have identical meanings as those skilled in the art understand usually.
As used herein, mention use in the numerical value specifically enumerated time, term " about " mean this value can from enumerate value variation no more than 1%.Such as, as used herein, statement " about 100 " comprise 99 and 101 and between whole values (such as, 99.1,99.2,99.3,99.4 etc.).
As used herein, term " contains " or " comprising (comprising) " can be open, semi-enclosed and enclosed.In other words, described term also comprise " substantially by ... form " or " by ... form ".
Polymorphic form
As used in the present invention, " crystal formation I ", " the crystal formation I of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3; 4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone ", " according to Shandong for Buddhist nun's crystal formation I " are used interchangeably, " crystal form II ", " crystal form II of 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone ", " according to Shandong for Buddhist nun's crystal form II " are used interchangeably.
In another preference, a kind of structure is such as formula the crystal formation of the compound shown in X, and described crystal formation is the crystal of high stability and agent of low hygroscopicity, and described crystal formation is selected from crystal formation I and crystal form II.
In another preference, described " high stability " refers to described crystal formation I or described crystal form II to place 10 days at 60 DEG C of lower open mouths, and relative humidity is that 92% normal temperature 25 DEG C is placed 10 days, after 4500xl low temperature and irradiance places 10 days, and stable crystal form.
In another preference, described " agent of low hygroscopicity " refers to that described crystal formation I or described crystal form II are positioned over humidity is take out after 24 hours in the moisture eliminator of 80%, calculates weightening finish≤0.29%, preferably≤0.28%, more preferably≤0.27%.
In another preference, the X-ray powder diffraction pattern of described crystal formation I comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.45 °, 10.00 °, 11.28 °, 13.52 °, 16.11 °, 18.72 °, 20.82 °, 22.59 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation I comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.45 °, 9.22 °, 10.00 °, 11.28 °, 13.52 °, 14.22 °, 15.12 °, 16.11 °, 17.90 °, 18.72 °, 20.03 °, 20.82 °, 21.70 °, 22.59 °, 24.07 °, 25.49 °, 26.12 °, 28.77 °, 29.62 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal formation I substantially as Fig. 1 characterize.
In another preference, the dsc of described crystal formation I is analyzed collection of illustrative plates and have characteristic peak within the scope of 165 ± 5 DEG C.
In another preference, the dsc of described crystal formation I analyze collection of illustrative plates substantially as Fig. 2 characterize.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal formation I substantially as Fig. 3 characterize.
In another preference, the infrared Fourier transform spectrum of described crystal formation I comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3437.06,3305.56,3203.74,1586.83,1567.67,1519.23,1279.72,1227.67,1171.38 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal formation I comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3437.06,3305.56,3203.74,1634.38,1600.39,1586.83,1567.67,1519.23,1488.80,1479.03,1435.88,1367.99,1312.54,1300.25,1279.72,1227.67,1201.57,1171.38,1133.56,1115.39,1100.43,962.17,850.17,800.96,754.84,692.71,488.13 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal formation I substantially as shown in Figure 4.
In another preference, described crystal formation I purity is greater than 95%, and preferably, purity is greater than 97%, and more preferably, purity is greater than 99%, and most preferably, purity is greater than 99.5%.
In another preference, the X-ray powder diffraction pattern of described crystal form II comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.61 °, 10.68 °, 12.39 °, 13.09 °, 15.86 °, 18.60 °, 22.59 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal form II comprises the 2 θ values that more than 3 or 3 are selected from lower group: 7.61 °, 10.68 °, 12.39 °, 13.09 °, 15.86 °, 18.60 °, 20.08 °, 22.59 °, 23.61 °, 24.87 °, 27.75 °, 29.45 ° ± 0.2 °.
In another preference, the X-ray powder diffraction pattern of described crystal form II substantially as Fig. 5 characterize.
In another preference, the dsc of described crystal form II is analyzed collection of illustrative plates and have characteristic peak within the scope of 194 ± 5 DEG C.
In another preference, the dsc of described crystal form II analyze collection of illustrative plates substantially as Fig. 6 characterize.
In another preference, the thermogravimetric analysis collection of illustrative plates of described crystal form II substantially as Fig. 7 characterize.
In another preference, the infrared Fourier transform spectrum of described crystal form II comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3482.37,3165.01,1632.68,1585.08,1565.09,1521.01,1310.98,1225.32,1096.00 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal form II comprises the charateristic avsorption band that more than 3 or 3 are selected from lower group: 3482.37,3286.46,3165.01,2946.46,1643.91,1632.68,1585.08,1565.09,1521.01,1487.93,1455.17,1393.49,1310.98,1281.66,1225.32,1201.38,1165.08,1140.46,1096.00,973.44,870.16,856.45,785.22,759.86,692.56,650.09,562.04,510.99 ± 2cm-1.
In another preference, the infrared Fourier transform spectrum of described crystal form II substantially as shown in Figure 8.
In another preference, described crystal form II purity is greater than 95%, and preferably, purity is greater than 97%, and more preferably, purity is greater than 99%, and most preferably, purity is greater than 99.5%.
Preparation method
The present invention also provides the preparation method of described crystal.
The preparation method of crystal formation I of the present invention, described preparation method comprises the steps:
I () will be dissolved in organic solvent for Buddhist nun's crude product I according to Shandong, weightmeasurement ratio is about 1:1-1:20g/ml;
(ii) after being cooled to 0-25 DEG C, crystallization, thus obtain described crystal formation I;
Wherein, be describedly selected from lower group according to Shandong for Buddhist nun's crude product I: according to Shandong for Buddhist nun's crystal form A, according to Shandong for Buddhist nun's amorphous article.
In another preference, organic solvent is selected from lower group in described step (i): the mixed solvent of the mixed solvent of the mixed solvent of ether solvent, esters solvent, alcoholic solvent, ketones solvent and water, esters solvent and alkane, alcoholic solvent and alkane or its combine.
In another preference, in described step (i), organic solvent is selected from lower group: alcoholic solvent, esters solvent or its combination.
In another preference, the ether solvent described in described step (i) is selected from tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether or its combination.
In another preference, the esters solvent described in described step (i) is selected from ethyl acetate, methyl acetate, isopropyl acetate, butylacetate or its combination.
In another preference, the alcoholic solvent described in described step (i) is selected from methyl alcohol, ethanol, Virahol or its combination.
In another preference, the ketones solvent described in described step (i) is selected from lower group: acetone, methylethylketone, methyl iso-butyl ketone (MIBK), pimelinketone or its combination.
In another preference, the alkane described in described step (i) is selected from normal hexane, hexanaphthene, normal heptane or its combination.
In another preference, in described step (i), organic solvent is esters solvent, and described step (ii) the middle crystallization time is greater than 6 hours.
The preparation method of crystal form II of the present invention, described preparation method comprises the steps:
I () will be dissolved in organic solvent for Buddhist nun's crude product II according to Shandong, weightmeasurement ratio is about 1:3-1:20g/ml;
(ii) after being cooled to 0-25 DEG C, crystallization, thus obtain described crystal form II;
Wherein, be describedly selected from lower group according to Shandong for Buddhist nun's crude product II: according to Shandong for Buddhist nun's crystal form A, according to Shandong for Buddhist nun's amorphous article, described according to Shandong for Buddhist nun's crystal formation I.
In another preference, in described step (i), organic solvent is selected from lower group: ketones solvent, esters solvent or its combination.
In another preference, the ketones solvent described in described step (i) is selected from lower group: acetone, methylethylketone, methyl iso-butyl ketone (MIBK), pimelinketone or its combination.
In another preference, the esters solvent described in described step (i) is selected from lower group: ethyl acetate, methyl acetate, isopropyl acetate, butylacetate or its combination.
In another preference, in described step (i), organic solvent is esters solvent, and described step (ii) the middle crystallization time is 1-5 hour.
Pharmaceutical composition
Present invention also offers a kind of pharmaceutical composition, it comprises the activeconstituents in safe and effective weight range, and pharmaceutically acceptable carrier.
" activeconstituents " of the present invention refer to of the present invention according to Shandong for Buddhist nun's crystal formation I and/or crystal form II.
" activeconstituents " of the present invention and pharmaceutical composition are for the preparation of preventing and/or treating the medicine of cancer or the medicine for the preparation of inhibition tumor cell.
In another preference, described tumour comprises lymphoma.
In another preference, described tumour cell comprises lymphoma cell.
" safe and effective amount " refers to: the amount of activeconstituents is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-2000mg activeconstituents/agent, more preferably, containing 10-200mg activeconstituents/agent.Preferably, described " potion " is a tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." consistency " to referred to herein as in composition each component energy and compound of the present invention and they between mutually admix, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has cellulose and its derivates (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent, wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited.The method of application of activeconstituents of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, knurl, rectum, parenteral (intravenously, intramuscular or subcutaneous) etc.The compounds of this invention can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.
In these solid dosages, activeconstituents mixes with at least one conventional inert excipients (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Described solid dosage also can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and in this composition, the release of activeconstituents can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except activeconstituents, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials.Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except activeconstituents, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The compounds of this invention can be individually dosed, or with other treatment medicine (as chemotherapeutic) Combined Preparation.
When making pharmaceutical composition, it is the Mammals (as people) being applicable to the compounds of this invention of safe and effective amount need treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1 ~ 2000mg, preferably 20 ~ 500mg.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Raw material and universal method
In embodiment raw materials used according to Shandong for Buddhist nun's crystal form A with reference to WO2013/184572 preparation, according to Shandong for Buddhist nun's amorphous article with reference to WO2008/039218 preparation.
XRD figure spectrum measuring method
X-ray powder diffractometer device: Dedye ~ ScherrerINELCPS ~ 120X-ray powder diffractometer; Source of radiation:strength ratio α 1/ α 2 is 0.5; Producer (Generator) kv:40kv; Producer (Generator) mA:30mA; Initial 2 θ: 2.000 °, sweep limit: 2.0000 ~ 50.000 °.
DSC collection of illustrative plates measuring method
Dsc (DSC) instrument: the Q2000 type of TA company of the U.S., within the scope of 20 ~ 450 DEG C, heating rate 10 DEG C/min, nitrogen flow rate 50ml/min.
TGA collection of illustrative plates measuring method
Thermogravimetric analysis (TGA) instrument: the SDTQ600 type of TA company of the U.S., within the scope of 20 ~ 450 DEG C, heating rate 10 DEG C/min, nitrogen flow rate 100ml/min.
FTIR collection of illustrative plates measuring method
Infrared spectrophotometry (FTIR) instrument: PESpectrumTwo, probe temperature 23 DEG C, relative humidity 54%, adopts pellet technique.
Major advantage of the present invention is:
(1) crystal formation I of the present invention and crystal form II all have good thermostability and non-hygroscopic.
(2) preparation method of crystal formation I of the present invention, crystal form II is simple, is applicable to large-scale industrial production.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number are weight percent and parts by weight.
Experiment material used in following examples and reagent all can obtain from commercially available channel if no special instructions.
Embodiment 1 is according to the preparation of Shandong for Buddhist nun's crystal formation I
To add in 50ml Virahol for Buddhist nun's amorphous article (10.0g) according to Shandong, and be heated to backflow and make dissolving.Until molten clear after continue stirring 30 minutes.Stop heating, with the speed of about 1 DEG C/min cooling, have solid to separate out gradually.To be cooled after room temperature, insulated and stirred 2 hours, filter, filtrate uses acetone drip washing, and filter cake obtains 8.8g product in 50 DEG C of vacuum-dryings.
Result: the x-ray diffractogram of powder of gained solid substantially as Fig. 1 characterize, substantially as shown in Figure 2, substantially as shown in Figure 3, infrared Fourier transform spectrum is substantially as shown in Figure 4 in thermogravimetric analysis for differential scanning spectrogram.
Embodiment 2 is according to the preparation of Shandong for Buddhist nun's crystal formation I
To add in 10ml isopropyl acetate for Buddhist nun's crystal form A (1.0g) according to Shandong, stirring at normal temperature is spent the night, and filtered by the suspended matter obtained, 50 DEG C of vacuum-dryings, to constant weight, obtain 720mg white solid.
Result: substantially as shown in Figure 1, substantially as shown in Figure 2, substantially as shown in Figure 3, infrared Fourier transform spectrum substantially as shown in Figure 4 in thermogravimetric analysis for differential scanning spectrogram for its x-ray diffractogram of powder.
Embodiment 3 is according to the preparation of Shandong for Buddhist nun's crystal form II
To add in 50ml ethyl acetate for Buddhist nun's amorphous article (5.0g) according to Shandong, heating for dissolving, until molten clear after, stop heating, mixture cooled to room temperature rapidly, and stirring at room temperature 2 hours, filter.Filter cake 5ml ethyl acetate drip washing, at 50 DEG C, vacuum-drying obtains 4.5g white solid.
Result: the x-ray diffractogram of powder of gained solid substantially as Fig. 5 characterize, substantially as shown in Figure 6, substantially as shown in Figure 7, infrared Fourier transform spectrum is substantially as shown in Figure 8 in thermogravimetric analysis for differential scanning spectrogram.
Embodiment 4 is according to the preparation of Shandong for Buddhist nun's crystal form II
In the 75ml acetone that will be added to for Buddhist nun's crystal form A (5.0g) according to Shandong, heating for dissolving, until molten clear after, stop heating, mixture cooled to room temperature rapidly, and in stirred overnight at room temperature, filter.Filter cake 5ml acetonitrile drip washing, at 50 DEG C, vacuum-drying obtains 4.2g white solid.
Result: the x-ray diffractogram of powder of gained solid substantially as Fig. 5 characterize, substantially as shown in Figure 6, substantially as shown in Figure 7, infrared Fourier transform spectrum is substantially as shown in Figure 8 in thermogravimetric analysis for differential scanning spectrogram.
Embodiment 5 is according to the preparation of Shandong for Buddhist nun's crystal form II
To add in 50ml ethyl acetate for Buddhist nun's crystal form A (10.0g) according to Shandong, reflux is dissolved, molten clear after with the speed cool to room temperature of 1 DEG C/min, and stirring at room temperature 4 hours, filter, filter cake ethyl acetate mixed solvent drip washing, at 50 DEG C, vacuum-drying obtains 8.5g white solid.
Result: the x-ray diffractogram of powder of gained solid substantially as Fig. 5 characterize, substantially as shown in Figure 6, substantially as shown in Figure 7, infrared Fourier transform spectrum is substantially as shown in Figure 8 in thermogravimetric analysis for differential scanning spectrogram.
Embodiment 6 stability test
Get obtained by above-described embodiment 1-5 according to Shandong for Buddhist nun's crystal formation I and crystal form II, respectively 60 DEG C of uncovered placements 10 days, relative humidity is that 92% normal temperature 25 DEG C is placed 10 days, and 4500xl low temperature and irradiance places 10 days.
Fig. 9 be the crystal formation I for preparing of embodiment 1-2 60 DEG C of uncovered placements 10 days, relative humidity is that 92% normal temperature 25 DEG C is placed 10 days, and the XRPD of 4500xl low temperature and irradiance after 10 days contrasts collection of illustrative plates.As can be seen from Figure 9, the crystal formation I crystal stability that obtains of the present invention is fine.
Figure 10 be the crystal form II prepared of embodiment 3-5 60 DEG C of uncovered placements 10 days, relative humidity is that 92% normal temperature 25 DEG C is placed 10 days, and the XRPD of 4500xl low temperature and irradiance after 10 days contrasts collection of illustrative plates.As can be seen from Figure 10, the crystal form II stability of crystal form that obtains of the present invention is also fine.
Embodiment 7 wettability test
Accurately take respectively and be laid in weighing bottle according to Shandong for Buddhist nun's crystal formation I and each 0.5 gram of crystal form II obtained by embodiment 1-5, weigh, load weighted weighing bottle opening is positioned over moisture eliminator (controlling with the saturated ammonium chloride solution) middle part that humidity is 80%, and covers moisture eliminator sealing cover; Place 24 hours, take out the weight again weighing weighing bottle, and calculate percentage weight increase with this.Wherein crystal formation I increases weight 0.27%, crystal form II weightening finish 0.26%.
The above embodiment of the present invention shows, crystal formation I and II of the present invention not only preparation technology is simple, and the agent of low hygroscopicity having high stability and be highly profitable, and especially water absorbability is much better than the crystal formation such as amorphous substance and crystal form B.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.