CN105503905B - A kind of Triazolopyridine oxazine derivatives B crystal form and preparation method thereof - Google Patents
A kind of Triazolopyridine oxazine derivatives B crystal form and preparation method thereof Download PDFInfo
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- CN105503905B CN105503905B CN201510906046.4A CN201510906046A CN105503905B CN 105503905 B CN105503905 B CN 105503905B CN 201510906046 A CN201510906046 A CN 201510906046A CN 105503905 B CN105503905 B CN 105503905B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention provides a kind of Triazolopyridine oxazine derivatives B crystal form of formula (I),Its XRPD collection of illustrative plates has diffraction maximum at 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56,23.461,24.46,26.238,30.12,32.521,32.96, wherein 2 θ value error ranges are ± 0.2.Triazolopyridine oxazine derivatives B crystal form provided by the invention has the solubility of good high wet stability and stabilization, it can be in the active drugs of inhibition c Met and for treating or preventing to inhibiting to apply in the drug of the sensitive cancers of c Met, and there is preferable bioavilability, the qualitative, quantitative information provided simultaneously, to further studying such solid drugs the effect of, have great importance.
Description
Technical field
The present invention relates to a kind of polymorphics of the Triazolopyridine oxazine derivatives as c-Met inhibitor, and in particular, to one
Kind Triazolopyridine oxazine derivatives B crystal form and preparation method thereof.
Background technology
C-Met albumen (also referred to as hepatocyte growth factor (HGF) receptor) is the cross-film with tyrosine kinase activity
190kDa heterodimers are encoded by c-Met oncogenes.Have studies have shown that HGF/c-Met signal paths with a variety of thin
Born of the same parents respond activity, including promote cell mitogen, proliferation, forming, angiogenesis etc..Therefore, the suppression of HGF/c-Met signal paths
Fixture has the potentiality of significant treating cancer.
The present invention provides a kind of Triazolopyridine oxazine derivatives, entitled (S) -1- (1- (imidazoles [1, the 2-a] pyrazine -6- of chemistry
Base) ethyl group) -6- (1- methyl-1 H- pyrazoles -4- bases) -1H- [1,2,3] triazole [4,5-b] pyrazine, as shown in formula (I),
The compound is a kind of active inhibitor of c-Met, can be used for treating or preventing the cancer to inhibiting c-Met sensitive
Disease.In Chinese invention patent CN 102906092A (WO2011/079804), the synthesis of Triazolopyridine oxazine derivatives is disclosed
Method and purposes.The preparation method for repeating above-mentioned patent, obtains compound powder, is detected as amorphous state.Such as this field skill
Known to art personnel, although amorphous all have higher solubility and dissolution rate in most of occasions than crystal form, it is unstable
Fixed, hygroscopicity is strong, is easy to switch to stable crystal form.Therefore, it is amorphous there is a problem of processing stability and bin stability difference,
And in process of production, the bulk density of amorphous particle is smaller, surface free energy is high, also be easy to cause in process of production solidifying
It is poly-, poor fluidity, flexible deformation are strong etc., and a series of formulation problems, the drug for seriously affecting amorphous Triazolopyridine oxazine derivatives face
Bed use value.
It is well known that same drug, crystal form is different, and bioavilability may also can have difference, and in addition it is stablized
Property, mobility, compressibility may also can be different, these physicochemical properties generate certain influence to the application of drug, to shadow
The effect of ringing drug.Therefore, it is necessary to the crystal forms of the Triazolopyridine oxazine derivatives with superior physiochemical properties, can be advantageous
Ground uses in drug processing and pharmaceutical composition.The novel crystal forms for the Triazolopyridine oxazine derivatives that the present invention develops have not been reported.
Invention content
Problem to be solved by this invention is low and easy turn of unstability, the solubility of existing Triazolopyridine oxazine derivatives
The problem of being unfavorable for drug processing for other crystal forms etc. and used in pharmaceutical composition, Triazolopyridine oxazine derivatives of the invention
Novel crystal forms, for solid drugs the effect of research more qualitative, quantitative information are provided the problem of.
In order to solve the above technical problem, the present invention provides a kind of new crystal form of Triazolopyridine oxazine derivatives is (following
Claim " Triazolopyridine oxazine derivatives B crystal form "), as shown in formula (I).
Its XRPD collection of illustrative plates 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,
21.56, have diffraction maximum at 23.461,24.46,26.238,30.12,32.521,32.96, wherein 2 θ value error ranges be ±
0.2。
Triazolopyridine oxazine derivatives B crystal form according to the present invention has the XRPD substantially the same with Figure of description Fig. 1
Collection of illustrative plates.
The present invention also provides the methods for preparing Triazolopyridine oxazine derivatives B crystal form, include the following steps：In Triazolopyridine
With 1 in oxazine derivatives:150~1:Organic solvent is added in the ratio of 250g/mL, suspends at room temperature, and solvent evaporated obtains solid,
Then it is dried in vacuo to obtain the Triazolopyridine oxazine derivatives B crystal form of off-white powder.
In some embodiments, the organic solvent be more than one fat hydrocarbons and more than one halogenated hydrocarbon solvents with
The mixed solvent of arbitrary proportion.
In some preferred embodiments, the fat hydrocarbon organic solvent is hexamethylene；The hydrocarbon organic solvent is
Dichloromethane.And the mixed proportion of hexamethylene and dichloromethane is 1:4 or 4:1.
In above-mentioned steps, the ratio of Triazolopyridine oxazine derivatives and solvent is preferably 1:200g/mL.
Those of ordinary skill in the art can carry out the dosage of the method for the present invention agents useful for same according to its knowledge and experience
Adjustment, including raw material dosage and adjustment solvent dosage are scaled up or reduce, the scheme of these adjustment is also contained in the present invention
Method in.
With the present invention Triazolopyridine oxazine derivatives B crystal form compound be for inhibiting the active inhibitor of c-Met,
It can be used for treating or preventing the cancer to inhibiting c-Met sensitive.
Therefore, the present invention provides Triazolopyridine oxazine derivatives B crystal forms to prepare for inhibiting in the active drugs of c-Met
Purposes；And it is preparing for treating or preventing the purposes in the drug to inhibiting the sensitive cancers of c-Met.
The present invention also provides pharmaceutical composition, it includes Triazolopyridine oxazine derivatives B crystal form according to the present invention and
One or more pharmaceutically acceptable carriers, excipient or diluent.
In some embodiments of the invention, aforementioned pharmaceutical compositions further include other therapeutic agent, and described controls
Treat agent be selected from chemotherapy or antiproliferative, anti-inflammatory agent, immunological regulation or immunosuppressor, neurotrophic factor, anti-tumor agents or
Anticancer agent etc..
Triazolopyridine oxazine derivatives B crystal form according to the present invention has outstanding high humility stability, it may have stablizes
Solubility is conducive to drug processing and is used in pharmaceutical composition, can inhibit c-Met activity and treat or prevent to suppression
The qualitative, quantitative letter applied in the drug of the cancer of c-Met sensitivities processed, and there is preferable bioavilability, while provided
Breath, to further studying such solid drugs the effect of, have great importance.
Description of the drawings
Fig. 1 is the XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 2 is five days high-temperature stability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 3 is the five days high wet stability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 4 is five days light durability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 5 is ten days high-temperature stability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 6 is the ten days high wet stability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 7 is ten days light durability XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form provided by the invention.
Fig. 8 is the unbodied XRPD collection of illustrative plates of existing Triazolopyridine oxazine derivatives.
Fig. 9 is Triazolopyridine oxazine derivatives B crystal form provided by the invention and unbodied solubility curve.
Figure 10 is the unbodied five days high-temperature stabilities XRPD collection of illustrative plates of existing Triazolopyridine oxazine derivatives.
Figure 11 is the unbodied five days light durabilities XRPD collection of illustrative plates of existing Triazolopyridine oxazine derivatives.
Specific implementation mode
In from detailed description below, aforementioned aspect of the present invention and other aspects of the present invention will be apparent.
The preparation of 1 to 2 Triazolopyridine oxazine derivatives B crystal form of embodiment
500mg Triazolopyridine oxazine derivatives raw materials are weighed in container, the mixed solvent being separately added into 100mL tables 1 (divides
Analyse pure), 35 DEG C suspend 24 hours, and solvent evaporated obtains solid, and off-white powder is obtained after vacuum drying.It weighs and calculates its yield.
The preparation of 1 Triazolopyridine oxazine derivatives B crystal form of table
| Embodiment | Solvent | Yield |
| 1 | Dichloromethane：Hexamethylene=1:4 | 90% |
| 2 | Dichloromethane：Hexamethylene=4:1 | 91% |
Embodiment 3. characterizes Triazolopyridine oxazine derivatives B crystal form by XRPD figures
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates is penetrated using the multifunctional assembled X of Rigaku UltimaIV models
Line diffractometer carries out, and specific acquisition information is as follows：Cu anodes (40kV, 40mA), 20 °/minute of sweep speed, scanning range (2 θ
Range) 5~45 °, scanning step 0.02, slit width 0.01.It is directly suppressed to sample in test board using glass slide
Reason.Thereafter XRPD collection of illustrative plates is all made of similar measurement method.
Measure the XRPD collection of illustrative plates of Triazolopyridine oxazine derivatives B crystal form prepared according to 1 the method for embodiment, 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, there is diffraction maximum at 32.521,32.96, as shown in Figure 1.Wherein 2 θ value error ranges are ± 0.2.After testing, 2 θ values are missed
Poor range may be ± 0.15.According to Triazolopyridine oxazine derivatives B crystal form prepared by 2 the method for embodiment, XRPD figures
Spectrum is essentially identical with collection of illustrative plates shown in attached drawing 1.
It will be understood by those skilled in the art that these diffraction maximums do not represent diffraction shown by Triazolopyridine oxazine derivatives B crystal form
The detailed situation at peak.2 θ values of X-ray powder diffraction figure be can with machine and in sample preparation variation and batch
Change and slight change between secondary, cited value is not intended as absolute value.It will also be appreciated that the relative intensity at peak may be with orientation
Effect and become, therefore intensity shown in the XRD traces contained by the present invention is exemplary, and is not used to absolutely relatively.
The high-temperature stability of 4. Triazolopyridine oxazine derivatives B crystal form of embodiment is investigated
Triazolopyridine oxazine derivatives B crystal form sample is placed in 60 DEG C of baking ovens, sample is taken out after 5 days and 10 days and is carried out
XRPD tests (as shown in Figure 2 and Figure 5), to investigate stability of crystal form of the sample to temperature.The result shows that B is brilliant under hot conditions
Type sample stability is general.
The high humidity study on the stability of 5. Triazolopyridine oxazine derivatives B crystal form of embodiment
Triazolopyridine oxazine derivatives B crystal form sample is placed under 92.5% damp condition, is taken out sample after 5 days and 10 days
XRPD tests (as shown in Figure 3 and Figure 6) are carried out, to investigate stability of crystal form of the sample to humidity.The result shows that under super-humid conditions
B crystal form sample is stablized.
The light durability of 6 Triazolopyridine oxazine derivatives B crystal form of embodiment is investigated
Triazolopyridine oxazine derivatives B crystal form sample is placed under 4500lux intensities of illumination, is taken sample after 5 days and 10 days
Go out to carry out XRPD tests (as shown in figs. 4 and 7), to investigate stability of crystal form of the sample to illumination.The result shows that illumination condition
Lower B crystal form sample stability is general.
The unbodied preparation of 1 Triazolopyridine oxazine derivatives of comparative example
According to synthetic method disclosed in Chinese invention patent CN 102906092A, the Triazolopyridine of the present invention has been synthesized
Then the mixture of oxazine derivatives and its chiral isomer detaches the mixture by chiral HPLC, the triazole of the present invention is made
And pyrazines derivatives.After obtaining the organic solution containing Triazolopyridine oxazine derivatives, by organic layer through anhydrous MgSO4Drying is simultaneously
It is evaporated in vacuo.Final compound is obtained after purification by flash chromatography or preparation HPLC.
As shown in figure 8, being measured through XRPD, the final product of gained is amorphous samples.
7 Triazolopyridine oxazine derivatives B crystal form of embodiment and unbodied solubility compare
It is separately added into excessive B crystal form and amorphous powder in 20mL sample bottles, suitable water is added, shakes 12 at room temperature
Hour, it is molten in 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours and 12 hours sample detections respectively using ultraviolet specrophotometer
Xie Du.Solubility curve is as shown in Figure 9.
As shown in solubility curve, amorphous initial dissolution degree reached peak value at 1 hour, but then declined, small 3
When nearby reach and solubility similar in B crystal form drug.After 3 hours, the solubility of B crystal form is more than amorphous.Although without fixed
Shape drug initial dissolution curve is better than B crystal form drug, but its specific solubility cannot be stablized in higher level, but with
Change through the drug concentration of dissolving.This be administered solid-state drug to patient when can bring it is difficult to predict dissolution situation.If
It is foundation regulation dosage with final solubility, then its initial dissolution can cause local drug concentration excessively high, generate serious pair
Effect；If being according to regulation dosage with initial dissolution degree, final drug concentration may be insufficient, influences drug effect.In addition, nothing
Amorphous Drug is in pharmaceutical dosage form it can also happen that crystal transfer, further influences its dissolved corrosion.Therefore, using stable B
Crystal form is processed as pharmaceutical dosage form, it can be ensured that stable drug effect obtains better therapeutic effect.
The unbodied high-temperature stability of 2. Triazolopyridine oxazine derivatives of comparative example is investigated
Triazolopyridine oxazine derivatives amorphous samples are placed in 60 DEG C of baking ovens, sample is taken out after 5 days and carries out XRPD surveys
It tries (as shown in Figure 10), to investigate stability of crystal form of the sample to temperature.The result shows that amorphous samples are unstable under hot conditions
It is fixed.
Moreover, by comparing hot conditions after lower 5 days unbodied XRPD collection of illustrative plates and the XRPD collection of illustrative plates of B crystal form can send out
Existing, the amorphous conversion at high temperature of Triazolopyridine oxazine derivatives is different from Triazolopyridine oxazine derivatives B crystal form of the invention
Other crystal forms.
The unbodied light durability of 3. Triazolopyridine oxazine derivatives of comparative example is investigated
Triazolopyridine oxazine derivatives amorphous samples are placed under 92.5% damp condition, sample is taken out after 5 days and is carried out
XRPD tests (as shown in figure 11), to investigate stability of crystal form of the sample to illumination.The result shows that amorphous sample under illumination condition
Product are unstable.
Moreover, by comparing super-humid conditions after lower 5 days unbodied XRPD collection of illustrative plates and the XRPD collection of illustrative plates of B crystal form can send out
Existing, the amorphous conversion at high temperature of Triazolopyridine oxazine derivatives is different from Triazolopyridine oxazine derivatives B crystal form of the invention
Other crystal forms.
In conclusion Triazolopyridine oxazine derivatives B crystal form can keep stable under high humidity conditions, it is better than amorphous production
Object.As it is known to the person skilled in the art, it is unstable it is amorphous can be changed into other crystal forms under certain condition, therefore stablize
Crystal form in the production process of pharmaceutical preparation have advantage.Due to the stability that Triazolopyridine oxazine derivatives B crystal form has,
It can keep stable in the drug process of various solid dosages, can determine the pharmaceutical activity in the drug finally obtained
The crystal form of ingredient, it can be ensured that the drug effect difference brought because of crystal transfer will not occur for known bioavilability.
Those skilled in the art is it should be understood that although for illustrative purposes, this document describes the tools of the present invention
Body embodiment, but it can be carry out various modifications without departing from the spirit and scope of the present invention.Therefore, of the invention specific
Embodiments and examples should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (10)
1. a kind of Triazolopyridine oxazine derivatives B crystal form of formula (I), which is characterized in that
Its XRPD collection of illustrative plates 2 θ=5.52,7.954,9.42,10.821,14.3,16.18,18.661,19.459,21.56,
23.461, there is diffraction maximum at 24.46,26.238,30.12,32.521,32.96, wherein 2 θ value error ranges are ± 0.2.
2. Triazolopyridine oxazine derivatives B crystal form as described in claim 1, which is characterized in that it has and Figure of description Fig. 1
Substantially the same XRPD collection of illustrative plates.
3. the method for preparing Triazolopyridine oxazine derivatives B crystal form as claimed in claim 1 or 2, which is characterized in that including following
Step：With 1 in Triazolopyridine oxazine derivatives:150~1:Organic solvent is added in the ratio of 250g/mL, suspends at room temperature, steams
Dry solvent obtains solid, is then dried in vacuo to obtain the Triazolopyridine oxazine derivatives B crystal form of off-white powder.
4. method as claimed in claim 3, which is characterized in that the organic solvent be more than one fat hydrocarbons and it is a kind of with
Upper halogenated hydrocarbon solvent is with the mixed solvent of arbitrary proportion.
5. method as claimed in claim 4, which is characterized in that
The fat hydrocarbon organic solvent is hexamethylene；
The halogenated hydrocarbons organic solvent is dichloromethane；And
The mixed proportion of hexamethylene and dichloromethane is 1:4 or 4:1.
6. Triazolopyridine oxazine derivatives B crystal form as claimed in claim 1 or 2 is in preparing the drug for inhibiting c-Met
Purposes.
7. Triazolopyridine oxazine derivatives B crystal form as claimed in claim 1 or 2 is being prepared for treating or preventing to inhibiting c-
Purposes in the drug of the cancer of Met sensitivities.
8. pharmaceutical composition, it includes Triazolopyridine oxazine derivatives B crystal forms as claimed in claim 1 or 2.
9. pharmaceutical composition as claimed in claim 8 also includes one or more pharmaceutically acceptable carriers, excipient
Or diluent.
10. pharmaceutical composition as claimed in claim 8 or 9 further includes other therapeutic agent, therapeutic agent choosing
From chemotherapeutics, anti-inflammatory agent, immunomodulator, neurotrophic factor, anti-tumor agents.
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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 |
-
2015
- 2015-12-09 CN CN201510906046.4A patent/CN105503905B/en active Active
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 |
|---|
| 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;Hong Jia等;《J. Med. Chem.》;20140822;第57卷(第18期);第7577-7589页,尤其摘要，Table5，第7582页右栏，Scheme 4-5，第7584页左栏第一段，第7585页右栏倒数第二段 * |
| The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models;Alwin G. Schuller等;《Clinical Cancer Research》;20150316;第21卷(第12期);第2811-2819页 * |
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