CN105503905A - Triazolo pyrazine derivative B crystal form and preparation method thereof - Google Patents
Triazolo pyrazine derivative B crystal form and preparation method thereof Download PDFInfo
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- CN105503905A CN105503905A CN201510906046.4A CN201510906046A CN105503905A CN 105503905 A CN105503905 A CN 105503905A CN 201510906046 A CN201510906046 A CN 201510906046A CN 105503905 A CN105503905 A CN 105503905A
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- crystal form
- oxazine derivative
- triazolopyridine oxazine
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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 provides a triazolo pyrazine derivative B crystal form as shown in formula (I), and the formula (I) is described in the specification. The x-ray powder diffraction (XRPD) spectrum has diffraction peaks when 2 theta is equal to 5.52, 7.954, 9.42, 10.821, 14.3, 16.18, 18.661, 19.459, 21.56, 23.461, 24.46, 26.238, 30.12, 32.521 and 32.96, wherein the error range of the 2 theta value is +/-0.2. The triazolo pyrazine derivative B crystal form has good high-humidity stability and stable solubility, can be applied to the medicines used for inhibiting c-Met activity and the medicines for treating or preventing cancers inhibiting c-Met sensitivity, and has better bioavailability; furthermore, the qualitative and quantitative information provided by the triazolo pyrazine derivative B crystal form has important significance in further studying the treatment effect of the solid medicines.
Description
Technical field
The present invention relates to a kind of polymorphic of the Triazolopyridine oxazine derivative as c-Met inhibitor, particularly, relate to a kind of Triazolopyridine oxazine derivative B crystal form and preparation method thereof.
Background technology
C-Met albumen (also referred to as pHGF (HGF) acceptor) is the cross-film 190kDa heterodimer with TYR kinase activity, and it is encoded by c-Met oncogene.Existing research display, it is active that HGF/c-Met signal path has various kinds of cell response, comprises short cell mitogen, propagation, shaping, vasculogenesis etc.Therefore, the suppression of HGF/c-Met signal path has the potentiality of significant Therapeutic cancer.
The invention provides a kind of Triazolopyridine oxazine derivative, chemistry (S)-1-(1-(imidazoles [1 by name, 2-a] pyrazine-6-base) ethyl group)-6-(1-methyl isophthalic acid H-pyrazoles-4-base)-1H-[1,2,3] triazole [4,5-b] pyrazine, shown in (I)
This compound is a kind of inhibitor of c-Met activity, may be used for the cancer for the treatment of or preventing suppressing c-Met sensitivity.In Chinese invention patent CN102906092A (WO2011/079804), disclose the preparation method and use of Triazolopyridine oxazine derivative.Repeating the preparation method of above-mentioned patent, obtain compound powder, is amorphous state after testing.As is known to the person skilled in the art, all have higher solubleness and dissolution rate than crystal formation although amorphous in most of occasion, it is unstable, and water absorbability is strong, easily transfers stable crystal formation to.Therefore, the amorphous problem that there is processing stability and package stability difference, and in process of production, the loose density of amorphous particle is less, surface free energy is high, a series of formulation problems such as also easily cause cohesion, poor fluidity, recoverable deformation strong in process of production, has a strong impact on the clinical drug use value of amorphous Triazolopyridine oxazine derivative.
As everyone knows, same medicine, crystal formation is different, also difference may be there is in its bioavailability, its stability, mobility, compressibility also may be different in addition, and the application of these physico-chemical properties on medicine produces certain impact, thus affects the curative effect of medicine.Therefore, need the crystal formation of the Triazolopyridine oxazine derivative with superior physiochemical properties, it can advantageously use in medicine processing and pharmaceutical composition.The new crystal of the Triazolopyridine oxazine derivative of the present invention's development has no report.
Summary of the invention
Problem to be solved by this invention is the unstable of existing Triazolopyridine oxazine derivative, solubleness is low and easily transfer the problem that other crystal formations etc. are unfavorable for medicine processing and use in pharmaceutical composition to, the new crystal of Triazolopyridine oxazine derivative of the present invention, the effectiveness study for solid pharmaceutical provides the problem of more qualitative, quantitative information.
In order to solve the problems of the technologies described above, the invention provides a kind of new crystal formation (hereinafter referred to as " Triazolopyridine oxazine derivative B crystal form ") of Triazolopyridine oxazine derivative, shown in (I).
Its XRPD collection of illustrative plates in 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56,23.461,24.46,26.238,30.12,32.521, there is diffraction peak at 32.96 places, wherein 2 θ value limit of error are ± 0.2.
According to Triazolopyridine oxazine derivative B crystal form of the present invention, there is the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
Present invention also offers the method preparing Triazolopyridine oxazine derivative B crystal form, comprise the following steps: the ratio with 1:150 ~ 1:250g/mL in Triazolopyridine oxazine derivative adds organic solvent, at room temperature suspend, solvent evaporated obtains solid, then vacuum-drying thus obtain the Triazolopyridine oxazine derivative B crystal form of off-white powder.
In certain embodiments, described organic solvent is that more than one fat hydrocarbons and more than one halogenated hydrocarbon solvents are with the mixed solvent of arbitrary proportion.
In some preferred embodiments, described fat hydrocarbon organic solvent is hexanaphthene; Described hydrocarbon organic solvent is methylene dichloride.And the blending ratio of hexanaphthene and methylene dichloride is 1:4 or 4:1.
In above-mentioned steps, the ratio of Triazolopyridine oxazine derivative and solvent is preferably 1:200g/mL.
Those of ordinary skill in the art according to its knowledge and experience, can adjust the consumption of the inventive method agents useful for same, and comprise and scale up or reduce raw material dosage and adjustment solvent load, the scheme of these adjustment is also contained in method of the present invention.
The compound with Triazolopyridine oxazine derivative B crystal form of the present invention is the inhibitor for suppressing c-Met activity, may be used for treating or prevention to the cancer suppressing c-Met sensitivity.
Therefore, the invention provides the purposes of Triazolopyridine oxazine derivative B crystal form in the medicine for the preparation of suppression c-Met activity; And for the preparation for the treatment of or prevention to suppress c-Met sensitivity cancer medicine in purposes.
Present invention also offers pharmaceutical composition, it comprises according to Triazolopyridine oxazine derivative B crystal form of the present invention and one or more pharmaceutically acceptable carrier, vehicle or thinner.
In some embodiments of the invention, aforementioned pharmaceutical compositions comprises other therapeutical agent further, and described therapeutical agent is selected from chemotherapy or antiproliferative, anti-inflammatory agent, immunomodulatory or immunosuppressor, neurotrophic factor, anti-tumor agents or anticancer agent etc.
According to Triazolopyridine oxazine derivative B crystal form of the present invention, there is outstanding high humidity stability, also there is stable solubleness, be conducive to medicine processing and use in pharmaceutical composition, can apply in the medicine of the cancer of c-Met sensitivity suppressing suppressing c-Met activity and treatment or prevention, and there is good bioavailability, the qualitative, quantitative information simultaneously provided, the curative effect studying this type of solid pharmaceutical is further had great importance.
Accompanying drawing explanation
Fig. 1 is the XRPD collection of illustrative plates of Triazolopyridine oxazine derivative B crystal form provided by the invention.
Fig. 2 is Triazolopyridine oxazine derivative B crystal form provided by the invention five days high-temperature stability XRPD collection of illustrative plates.
Fig. 3 is Triazolopyridine oxazine derivative B crystal form provided by the invention five days high humidity stability XRPD collection of illustrative plates.
Fig. 4 is Triazolopyridine oxazine derivative B crystal form provided by the invention five days light durability XRPD collection of illustrative plates.
Fig. 5 is Triazolopyridine oxazine derivative B crystal form provided by the invention ten days high-temperature stability XRPD collection of illustrative plates.
Fig. 6 is Triazolopyridine oxazine derivative B crystal form provided by the invention ten days high humidity stability XRPD collection of illustrative plates.
Fig. 7 is Triazolopyridine oxazine derivative B crystal form provided by the invention ten days light durability XRPD collection of illustrative plates.
Fig. 8 is the unbodied XRPD collection of illustrative plates of existing Triazolopyridine oxazine derivative.
Fig. 9 is Triazolopyridine oxazine derivative B crystal form provided by the invention and unbodied solubility curve.
Figure 10 is existing Triazolopyridine oxazine derivative unbodied five days high-temperature stability XRPD collection of illustrative plates.
Figure 11 is existing Triazolopyridine oxazine derivative unbodied five days light durability XRPD collection of illustrative plates.
Embodiment
From detailed description hereafter, above-mentioned aspect of the present invention and other aspects of the present invention will be obvious.
The preparation of embodiment 1 to 2 Triazolopyridine oxazine derivative B crystal form
Take 500mg Triazolopyridine oxazine derivative raw material in container, add the mixed solvent (analytical pure) in 100mL table 1 respectively, 35 DEG C suspend 24 hours, and solvent evaporated obtains solid, obtain off-white powder after vacuum-drying.Weigh and calculate its yield.
The preparation of table 1 Triazolopyridine oxazine derivative B crystal form
| Embodiment | Solvent | Yield |
| 1 | Methylene dichloride: hexanaphthene=1:4 | 90％ |
| 2 | Methylene dichloride: hexanaphthene=4:1 | 91％ |
Embodiment 3. characterizes Triazolopyridine oxazine derivative B crystal form by XRPD figure
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, the multifunctional assembled X-ray diffractometer of RigakuUltimaIV model is used to carry out, concrete Information Monitoring is as follows: Cu anode (40kV, 40mA), sweep velocity 20 °/minute, sweep limit (2 θ scope) 5 ~ 45 °, scanning step 0.02, slit width 0.01.Slide glass is adopted directly to process sample in test panel compacting.Thereafter XRPD collection of illustrative plates all adopts similar measuring method.
Measure the XRPD collection of illustrative plates of Triazolopyridine oxazine derivative B crystal form prepared by method according to embodiment 1, in 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56,23.461,24.46,26.238,30.12,32.521, there is diffraction peak at 32.96 places, as shown in Figure 1.Wherein 2 θ value limit of error are ± 0.2.After testing, 2 θ value limit of error also can be ± 0.15.The Triazolopyridine oxazine derivative B crystal form that according to embodiment 2 prepared by method, shown in its XRPD collection of illustrative plates with accompanying drawing 1, collection of illustrative plates is substantially identical.
It will be understood by those skilled in the art that these diffraction peaks do not represent the detailed situation of diffraction peak shown by Triazolopyridine oxazine derivative B crystal form.2 θ values of X-ray powder diffraction pattern be can along with machine and along with the change in sample preparation and batch between change and slightly changing, the value quoted is not considered as absolute value.It will also be appreciated that the relative intensity at peak may become with orientation effect, the intensity shown in XRD trace therefore contained by the present invention is exemplary, and is not used in and definitely compares.
The high-temperature stability of embodiment 4. Triazolopyridine oxazine derivative B crystal form is investigated
Triazolopyridine oxazine derivative B crystal form sample is placed in 60 DEG C of baking ovens, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 2 and Figure 5), to investigate the stability of crystal form of sample to temperature.Result shows, under hot conditions, B crystal form sample stability is general.
The high humidity study on the stability of embodiment 5. Triazolopyridine oxazine derivative B crystal form
Under Triazolopyridine oxazine derivative B crystal form sample is placed in 92.5% humidity condition, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in Figure 3 and Figure 6), to investigate the stability of crystal form of sample to humidity.Result shows, under super-humid conditions, B crystal form sample is stablized.
The light durability of embodiment 6 Triazolopyridine oxazine derivative B crystal form is investigated
Under Triazolopyridine oxazine derivative B crystal form sample is placed in 4500lux intensity of illumination, after 5 days and 10 days, sample is taken out and carry out XRPD test (as shown in figs. 4 and 7), to investigate the stability of crystal form of sample to illumination.Result shows, under illumination condition, B crystal form sample stability is general.
The unbodied preparation of comparative example 1 Triazolopyridine oxazine derivative
Synthetic method disclosed in Chinese invention patent CN102906092A, has synthesized the mixture of Triazolopyridine oxazine derivative of the present invention and chiral isomer thereof, has then been separated this mixture by chirality HPLC, obtained Triazolopyridine oxazine derivative of the present invention.After obtaining the organic solution containing Triazolopyridine oxazine derivative, by organic layer through anhydrous MgSO
4dry also vacuum-evaporation.By obtaining finalization compound after flash chromatography or preparative HPLC purifying.
As shown in Figure 8, measure through XRPD, the final product of gained is amorphous samples.
Embodiment 7 Triazolopyridine oxazine derivative B crystal form and unbodied solubleness compare
In 20mL sample bottle, add excessive B crystal form and amorphous powder respectively, add appropriate water, shake 12 hours under room temperature, adopt ultraviolet spectrophotometer to detect solubleness 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours and sampling in 12 hours respectively.Solubility curve as shown in Figure 9.
As shown in solubility curve, amorphous initial dissolution degree littlely reaches peak value constantly 1, but declines subsequently, reaches the solubleness close with B crystal form medicine near 3 hours.After 3 hours, the solubleness of B crystal form exceedes amorphous.Although amorphous drug initial dissolution curve is better than B crystal form medicine, its concrete solubleness can not be stabilized in higher level, but changes along with the drug level dissolved.This brings the stripping situation being difficult to predict to patient Shi Hui at administration solid-state drug.If with final solubleness for foundation regulation dosage, then its initial dissolution can cause local drug concentration too high, produces severe side effect; If with initial dissolution degree for foundation regulation dosage, then final drug level may be not enough, affects drug effect.In addition, also may there is crystal conversion in amorphous drug in pharmaceutical dosage form, affects its dissolved corrosion further.Therefore, adopt stable B crystal form to be processed as pharmaceutical dosage form, stable drug effect can be guaranteed, obtain better result for the treatment of.
The unbodied high-temperature stability of comparative example 2. Triazolopyridine oxazine derivative is investigated
Triazolopyridine oxazine derivative amorphous samples is placed in 60 DEG C of baking ovens, after 5 days, sample is taken out and carry out XRPD test (as shown in Figure 10), to investigate the stability of crystal form of sample to temperature.Result shows, under hot conditions, amorphous samples is unstable.
And can be found by the XRPD collection of illustrative plates comparing hot conditions unbodied XRPD collection of illustrative plates and B crystal form after lower 5 days, the amorphous of Triazolopyridine oxazine derivative at high temperature transforms other crystal formations being different from Triazolopyridine oxazine derivative B crystal form of the present invention.
The unbodied light durability of comparative example 3. Triazolopyridine oxazine derivative is investigated
Under Triazolopyridine oxazine derivative amorphous samples is placed in 92.5% humidity condition, after 5 days, sample is taken out and carry out XRPD test (as shown in figure 11), to investigate the stability of crystal form of sample to illumination.Result shows, under illumination condition, amorphous samples is unstable.
And can be found by the XRPD collection of illustrative plates comparing super-humid conditions unbodied XRPD collection of illustrative plates and B crystal form after lower 5 days, the amorphous of Triazolopyridine oxazine derivative at high temperature transforms other crystal formations being different from Triazolopyridine oxazine derivative B crystal form of the present invention.
In sum, Triazolopyridine oxazine derivative B crystal form can keep stable under high humidity conditions, is better than amorphous products.As is known to persons skilled in the art, the amorphous of instability can change other crystal formations under certain condition, and therefore stable crystal formation has advantage in the production process of pharmaceutical preparation.Due to the stability that Triazolopyridine oxazine derivative B crystal form has, it can keep stable in the medicine course of processing of various solid dosage, the crystal formation of the active constituents of medicine in the final medicine obtained can be determined, known bioavailability can be guaranteed, the drug effect difference brought because of crystal conversion can not occur.
Those skilled in the art should understand, although for illustrative purposes, this document describes the specific embodiment of the present invention, can carry out various amendment and without departing from the spirit and scope of the present invention to it.Therefore, the specific embodiment of the present invention and embodiment should not be considered as limiting the scope of the invention.The present invention is only by the restriction of claims.The all documents quoted in the application are all intactly incorporated to herein as a reference.
Claims (10)
1. a Triazolopyridine oxazine derivative B crystal form for formula (I), is characterized in that,
Its XRPD collection of illustrative plates in 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56,23.461,24.46,26.238,30.12,32.521, there is diffraction peak at 32.96 places, wherein 2 θ value limit of error are ± 0.2.
2. Triazolopyridine oxazine derivative B crystal form as claimed in claim 1, it is characterized in that, it has the XRPD collection of illustrative plates substantially the same with Figure of description Fig. 1.
3. prepare the method for Triazolopyridine oxazine derivative B crystal form as claimed in claim 1 or 2, it is characterized in that, comprise the following steps: the ratio with 1:150 ~ 1:250g/mL in Triazolopyridine oxazine derivative adds organic solvent, at room temperature suspend, solvent evaporated obtains solid, then vacuum-drying thus obtain the Triazolopyridine oxazine derivative B crystal form of off-white powder.
4. method as claimed in claim 3, is characterized in that, described organic solvent is that more than one fat hydrocarbons and more than one halogenated hydrocarbon solvents are with the mixed solvent of arbitrary proportion.
5. method as claimed in claim 4, is characterized in that,
Described fat hydrocarbon organic solvent is hexanaphthene;
Described hydrocarbon organic solvent is methylene dichloride; And
The blending ratio of hexanaphthene and methylene dichloride is 1:4 or 4:1.
6. the purposes of Triazolopyridine oxazine derivative B crystal form as claimed in claim 1 or 2 in the medicine for the preparation of suppression c-Met.
7. Triazolopyridine oxazine derivative B crystal form as claimed in claim 1 or 2 for the preparation for the treatment of or prevention to suppress c-Met sensitivity cancer medicine in purposes.
8. pharmaceutical composition, it comprises Triazolopyridine oxazine derivative B crystal form as claimed in claim 1 or 2.
9. pharmaceutical composition as claimed in claim 8, it also comprises one or more pharmaceutically acceptable carrier, vehicle or thinners.
10. pharmaceutical composition as claimed in claim 8 or 9, it comprises other therapeutical agent further, and described therapeutical agent is selected from chemotherapy or antiproliferative, anti-inflammatory agent, immunomodulatory or immunosuppressor, neurotrophic factor, anti-tumor agents or anticancer agent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127096A (en) * | 2009-12-31 | 2011-07-20 | 和记黄埔医药（上海）有限公司 | Triazole pyridine and triazole pyrazine compound and composition and application thereof |
| WO2014135876A1 (en) * | 2013-03-06 | 2014-09-12 | Astrazeneca Ab | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127096A (en) * | 2009-12-31 | 2011-07-20 | 和记黄埔医药（上海）有限公司 | Triazole pyridine and triazole pyrazine compound and composition and application thereof |
| WO2014135876A1 (en) * | 2013-03-06 | 2014-09-12 | Astrazeneca Ab | Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor |
Non-Patent Citations (2)
| Title |
|---|
| ALWIN G. SCHULLER等: "The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models", 《CLINICAL CANCER RESEARCH》 * |
| HONG JIA等: "Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine as a Highly Potent and Selective Mesenchymal-Epithelial Transition Factor Inhibitor in Clinical Development for Treatment of Cancer", 《J. MED. CHEM.》 * |
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