CN106699736A - Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same - Google Patents
Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same Download PDFInfo
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- CN106699736A CN106699736A CN201611007536.1A CN201611007536A CN106699736A CN 106699736 A CN106699736 A CN 106699736A CN 201611007536 A CN201611007536 A CN 201611007536A CN 106699736 A CN106699736 A CN 106699736A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention provides a new crystal form gamma of compound A mesylate and application of the crystal form in preparation of drugs for prevention and/or treatment of mammalian diseases. Mammals include human, the diseases include various cancers, preferably non-small cell lung cancer, especially mutant non-small cell lung cancer. The invention also provides a pharmaceutical composition containing the new crystal form gamma of compound A mesylate. (formula I).
Description
Technical field
The invention belongs to chemicals preparation field, and in particular to a kind of crystalline substance of EGFR inhibitor compound A mesylates
Type γ and preparation method thereof, and the pharmaceutical composition containing the crystal formation.
Background technology
EGFR is the transmembrane protein tyrosine kinase members of erbB receptor families.When with growth factor part (such as epidermis
Growth factor (EGF)) when combining, acceptor can occur homologous dimerization with additional EGFR molecules, or with another family member
There is heterodimeric in (such as erbB2 (HER2), erbB3 (HER3) or erbB4 (HER4)).
The homologous dimerization and/or heterodimeric of erbB acceptors cause the phosphorylation of key tyrosine residue in Intracellular domain, and
And cause the stimulation of many Cellular Signaling Transduction Mediated paths that participation cell is bred and survived.The mistake of erbB families signal transduction
Adjust promote propagation, invade, transfer, angiogenesis and tumour cell existence, and it is many (including lung cancer, incidence cancer and
Those of breast cancer) described in human cancer.
Therefore, erbB families represent the reasonable target spot of cancer therapy drug exploitation, and many medicaments of targeting EGFR or erbB2 are present
Be it is clinically available, including Gefitinib (IRESSATM), Tarceva (TARCEVATM), Lapatinib (TYKERBTM,
TYVERBTM).The phases of New England Journal of medicine (2008) the 358th, 1160-74 and Bi DEG C of hemical
And Biophysical Research Communications (2004) Vol.319, provides in 1-11 and erbB acceptors is believed
Number conduction and its participation in tumour generation are discussed in detail.
(phases of Science [2004] the 304th, 1497-500 and New England Journal of were had been reported that in 2004
The phases of medicine [2004] the 350th, 2129-39) activated mutant of EGFR is replaced with to Ji is non-in non-small cell lung cancer (NSCLC)
The reaction of Buddhist nun's treatment is relevant.Most common EGFR activated mutants (L858R and delE746_A750) cause relative to wild type
(WT) for EGFR, the affinity of small molecule tyrosine kinase inhibitors (such as Gefitinib and Tarceva) is increased, with
And atriphos (ATP) affinity is declined.Finally, the acquired resistance treated to Gefitinib or Tarceva is produced,
For example due to the mutation of the residue T790M that guards the gate, it was reported that detect the mutation in 50% clinical resistance patient.The mutation
It is not qualified as spatially hindering the combination of Gefitinib or Tarceva and EGFR, the affinity of ATP will be only changed and arrived
Level equivalent to WTEGFR.
In view of importance of this mutation in the resistance of the existing therapy of targeting EGFR, it is believed that can suppress to include
Guard the gate gene mutation EGFR medicine it is particularly useful in the treatment of cancer.
Relative to EGFR (such as the L858R EGFR mutant or delE746_A750 mutation of activated mutant body form
Body or Exon19 missings EGFR mutant) and/or resistant mutant forms EGFR (such as T790M EGFR mutant), for
Can show to remain the compound of the selectivity of the favourable performance characteristics, and/or relative other enzyme acceptors of WT EGFR
Demand, the selectivity causes that these compounds especially are hopeful to be developed to therapeutic agent.On this point, for swashing to some
The EGFR of living or resistant mutant forms shows higher suppression while showing the compound of relatively low suppression to WT EGFR
There is demand.Because the toxicology related to Wild type EGFR suppression reduces, thus the such compound of expection can be more suitable for use
Make therapeutic agent, particularly for treatment of cancer.It is fash and/or diarrhoea that known such toxicology shows it in human body.
PCT/GB2012/051783 has found a kind of relatively some 2- of EGFR mutant forms (2,4,5- substituted anilines) pyrimidines
Compound have it is high-effect, while the display suppression relatively low to WT EGFR.With other known EGFR/EGFR mutant
Inhibitor is compared, and compound of the invention can also show favourable physical property (for example, water solubility higher, higher oozing
Permeability, and/or relatively low plasma protein combination) and/or favourable toxic characteristic (the hERG blockings tendency of such as reduction) and/or
Favourable metabolic characteristics.Therefore, such compound involves in such as treatment of cancer the activated mutant of EGFR and/or EGFR
And/or be particularly useful in the treatment of the disease condition of the resistant mutation of EGFR, the compound is specific as follows：
(compound A mesylates).
In order to improve the medicinal property of the compound, the state of the suitable preparation to its stabilization is also needed further to be ground
Study carefully.
The content of the invention
An object of the present invention is the EGFR inhibitor compound A first sulphurs for providing a kind of dissolubility and excellent in stability
The crystal formation γ of hydrochlorate, wherein：
The chemical name of compound A is：N- (2- { 2- dimethylaminoethyls-methylamino } -4- methoxyl groups -5- { [4- (1- first
Base indol-3-yl) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamides, the chemical structural formula of compound A mesylates is following formula
(I),
The crystal formation γ of the crystal formation is represented at 10.29 ± 0.2 ° and 15.17 ± 0.2 ° in X-ray diffractogram with 2 θ angles
There is characteristic peak, error is ± 0.2 °.The characteristic peak of the displacement is the most strong characteristic peak of the crystal formation X-ray, can directly represent this
Crystal formation.
Crystal formation described further also has a characteristic peak at 16.30 °, 19.46 °, 19.71 ° and 25.63 °, error for ±
0.2 °, relative absorbance intensity is more than 50%, can fully represent this crystal formation.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 7.13 °, 8.54 °,
9.46 °, 17.06 °, 17.30 °, 17.73 °, 18.21 °, 18.72 °, 20.23 °, 20.70 °, 21.65 °, 22.05 °, 22.78 ° and
23.49 ° have characteristic peak, and error is ± 0.2 °, and relative absorbance intensity is more than 10%, can in more detail distinguish other materials generation
Table this crystal formation.
It should be noted that：The different samples of specific crystal formation have same main XRPD peaks, but in coatings
Small peak may be changed.Additionally, when by those of ordinary skill in the art, the isomorphism sample obtained using correlation method uses phase
With instrument and detection method detected when, each 2 θ angle errors generally within ± 0.2 ° (each 2 θ angle errors generally ±
Implication within 0.2 ° refers to most of characteristic peak, and such as absorption intensity more than more than 80% exists more than 10% characteristic peak error
In the range of this, and accidentally there is the error of the characteristic peak of indivedual minorities beyond the scope, be considered as belonging to mutually isomorphous XRPD
Spectrogram)；And, the characteristic peak of each displacement is moderate strength absworption peak, and other weak absorbing peaks may be due to experimental implementation
There is significant change in error, other absworption peaks are absorptions unnecessary when characterizing this crystal formation to those skilled in the art
Peak.
More specifically, the X-ray diffraction diagram data of the crystal formation γ of the compound A mesylates is as shown in table 1, error
It is ± 0.2 °.Or more detailed, X-ray diffractogram such as Fig. 1 or Fig. 3 of the crystal formation γ of the compound A mesylates
It is shown.
The DSC of crystal formation described in the DSC collection of illustrative plates of the crystal formation γ of aforesaid compound A mesylates 252.1 DEG C ± 2 DEG C-
There is maximum absorption band at 252.2 DEG C ± 2 DEG C.
More detailed, the DSC spectrograms of the crystal formation γ of the compound A mesylates are as shown in Fig. 2 or Fig. 4.
X-ray diffraction testing conditions：X-ray diffraction uses sharp shadow (Empyrean) X-ray diffractometer, is penetrated in Cu target K α
Line, voltage：40.0kV, electric current：40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm, step-length
0.02 °, 2 θ scopes are determined under the conditions of often step residence time 40s：3°-50°.
DSC testing conditions：Instrument NETZSCH DSC 200F3, atmosphere N2, 20ml/min, 30 DEG C -280 DEG C of scope.
The purity of the crystal formation γ of the compound A mesylates is high and stability is high, relative to PCT/GB2012/051783
Obtained compound A mesylates advantage crystal formation B, the more conducively clinical practice of compound A mesylates fully ensures that medication
Security and validity.
Another object of the present invention is to provide a kind of preparation method of the crystal formation γ of above-claimed cpd A mesylates, should
Method process is simple, is capable of achieving under normal temperature condition.
Wherein, compound A method can be prepared according to disclosed in PCT/GB2012/051783, specific synthetic route and main
Reaction scheme it is as follows：
Wherein, compound 1 can be obtained with prior art or commercial sources.
The preparation method of the crystal formation γ of compound A mesylates is comprised the following steps：
Compound A mesylates are added in organic solvent methyl alcohol or isopropanol, wherein, compound A mesylates
Weight (g) is 1 with the volume (ml) of solvent：6-1：10, water, water and organic solvent methyl alcohol or the body of isopropanol are added at room temperature
Product compares 1：3-1：5, the stirring reaction at 50~60 DEG C is molten clear；Organic solvent methanol or isopropanol are added at 20~30 DEG C, is mended
Dosage is 1 with the volume ratio of initial incremental amount：2.5,0~10 DEG C of 6~8h of stirring is cooled to, light yellow solid is separated out, filter, use
Organic solvent methyl alcohol or isopropanol drip washing, 40~60 DEG C vacuumize baking 5h, obtain product, are compound A mesylates γ brilliant
Type.
The compound A Mesylate Form B products of prior art PCT/GB2012/051783, the crystal formation dissolubility is poor, so
And novel crystal forms of the invention improve significantly relative to it in terms of dissolubility, it is easier to which preparation is prepared and used.
Find that compound A mesylate γ crystal formations are difficult to by dissolution solvent dissolved compound A first by substantial amounts of experiment
After sulfonate, a certain amount of poor solvent crystallization is added to obtain；But, by after dissolution solvent dissolved compound A mesylates,
A certain amount of dissolution solvent is further added accidentally to obtain after adding a certain amount of poor solvent.
It is still another object of the present invention to provide a kind of drug regimen containing above-mentioned compound A Mesylate Forms γ
Thing, uses the compound A Mesylate Form γ, and more than one pharmaceutically acceptable carriers.
The carrier includes various pharmaceutic adjuvants, packaging material, tool for transmitting etc., is needed to be selected according to preparation, such as auxiliary
Material goes for oral, suction, parenteral routes or surface and uses including filler, disintegrant, adhesive, lubricant etc.；
Formulation includes but is not limited to injection, pharmaceutical solutions, tablet, capsule, granule etc..
Described pharmaceutical composition can be used for preparing EGFR and targetting causing answering for relevant disease, the particularly medicine of cancer
With, be more highly preferred to for be mutated non-small cell lung cancer.
The present invention has the advantages that following prominent and beneficial effect compared with prior art：
1st, the purity of the crystal formation γ of compound A mesylates of the invention is high, is the solid forms of steady quality, it is easier to
The configuration of pharmaceutical composition and use.
2nd, the crystal formation γ of compound A mesylates of the invention obtains compound A relative to PCT/GB2012/051783
Mesylate Form B substantially has more preferable dissolubility and stability.
3rd, the method for the crystal formation γ of prepare compound A mesylates of the present invention can simply, fast, under normal temperature condition be made
It is standby, it is easier to industrialization production.
Brief description of the drawings
Fig. 1 is the X ray diffracting spectrum of the crystal formation γ of the gained compound A mesylates of the embodiment of the present invention 2
Fig. 2 is the DSC collection of illustrative plates of the crystal formation γ of the gained compound A mesylates of the embodiment of the present invention 2
Fig. 3 is the X ray diffracting spectrum of the crystal formation γ of the gained compound A mesylates of the embodiment of the present invention 3
Fig. 4 is the DSC collection of illustrative plates of the crystal formation γ of the gained compound A mesylates of the embodiment of the present invention 3
Specific embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but the implementation method of invention is not limited to
This.
The preparation of the compound A of embodiment 1
According to PCT/GB2012/051783 specifications embodiment 28 and the method for 28A, using following technology synthetic route system
Standby compound A mesylates and its crystal formation B：
Reaction condition and parameter are：
In at 0 DEG C to N1- (2- dimethylaminoethyls) -5- methoxyl groups-N1- methyl-N4- [4- (1- methyl indol -3- bases)
Pyrimidine -2-base] benzene -1, warp of 2, the 4- triamines (intermediate 100,10g, 21.32mmol) in THF (95mL) and water (9.5mL)
3- chlorpromazine chlorides (3.28g, 25.59mmol) is added in agitating solution.The mixture is stirred into 15 minutes, Ran Houtian at room temperature
Plus NaOH (3.48g, 85.28mmol).Gained mixture is heated to 65 DEG C and is maintained 10 hours.Then the mixture is cooled down
To room temperature, CH is added3OH (40mL) and water (70mL).Gained mixture is stirred overnight.Gained solid is collected by filtration, uses
Water (25mL) is cleaned, and in being dried 12 hours at 50 DEG C, is obtained as the title compound (7.0g, 94%) of solid form.m/z
ESI-MH+=500.26.
And the method for the embodiment 28A of foundation PCT/GB2012/051783 prepares the crystal formation of compound A mesylates
B。
Method：In 70 DEG C to compound A, 20g, 36.63mmol in ethanol (120mL) and EtOAc (80mL) through stirring
Mix methanesulfonic acid (3.59g, the 36.63mmol) solution added in EtOAc (40mL) in solution.Gained mixture is stirred 1.5
Hour.Gained solid is collected by filtration, in dried in vacuum overnight at 80 DEG C, obtains and uses solid form (compound A methanesulfonic acids
The polymorph b of salt) title salt (20.5g, 94%).
The compound methanesulfonic acid salt crystal formation B passes through1H-NMR test displays find that the H of methanesulfonic acid occurs in High-Field, shows
3 hydrogen are shown with, expression products therefrom is mesylate.
1H-NMR detecting instruments and condition：Detecting instrument：The superconducting pulse Fourier of Bruker AVANCE III HD 500
Transform nuclear magnetic resonance spectrometer；Testing conditions：Solvent：MeOD-d4；Temperature：25℃；Detection foundation：JY/T 007-1996 superconduction arteries and veins
Rush Fourier-transform nuclear magnetic resonance spectral method general rule.
The preparation of the crystal formation γ of the compound A mesylates of embodiment 2
The 25g compound A mesylates that the method 1 of embodiment 1 is obtained are added in 250ml methyl alcohol, and 60ml is added at room temperature
Water, the stirring reaction 0.5h at 50~60 DEG C is molten clear；100ml methyl alcohol is added at 20~30 DEG C, 0~10 DEG C of stirring 1 is cooled to
~2h, separates out off-white powder, filters, and with 10~20ml methyl alcohol drip washing, 40~60 DEG C vacuumize baking 5h, obtain product, are first
Sulfonate γ crystal formations.
The X ray diffracting spectrum of the crystal formation γ of gained compound A mesylates is as shown in Figure 1.Specific characteristic absorption peak
Such as table 1 below, error is ± 0.2 °.
The DSC collection of illustrative plates of the crystal formation γ of gained compound A mesylates at 252.1 DEG C ± 2 DEG C as shown in Fig. 2 have maximum
Absworption peak.
The preparation of the crystal formation γ of the compound A mesylates of embodiment 3
The 25g compound A mesylates that the method 2 of embodiment 1 is obtained are added in 150ml isopropanols, are added at room temperature
The water of 50ml, the stirring reaction 0.5h at 50~60 DEG C is molten clear；60ml isopropanols are added at 20~30 DEG C, 0~10 DEG C is cooled to
6~8h of stirring, separates out light yellow solid, filters, and with 10~20ml isopropanol drip washing, 40~60 DEG C vacuumize baking 5h, are produced
Thing, is mesylate γ crystal formations.
The X ray diffracting spectrum of the crystal formation γ of gained compound A mesylates is as shown in Figure 3.Specific characteristic absorption peak
Such as table 1 below, error is ± 0.2 °.
The DSC collection of illustrative plates of the crystal formation γ of gained compound A mesylates at 252.2 DEG C ± 2 DEG C as shown in figure 4, have maximum
Absworption peak.
The X-ray diffraction of the crystal formation γ of the compound A mesylates of table 1 absorbs peak data
Wherein, No.=sequence numbers, Rel.Int.=Relative Intensity, Pos. [° 2Th.]=Position [°
2Theta], error is ± 0.2 °.Rel.Int.=Relative Intensity are it is merely meant that the substantially intensity of feature peak intensity
Situation, should not be used as the restriction of specific crystal.
X-ray diffraction testing conditions：X-ray diffraction uses sharp shadow (Empyrean) X-ray diffractometer, is penetrated in Cu target K α
Line, voltage：40.0kV, electric current：40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm, step-length
0.02 °, 2 θ scopes are determined under the conditions of often step residence time 40s：3°-50°.
DSC testing conditions：Instrument NETZSCH DSC 200F3, atmosphere N2, 20ml/min, 30 DEG C -280 DEG C of scope.
Compound crystal form γ described in embodiment 2 and 3 passes through1H-NMR test displays find that the H of methanesulfonic acid occurs in High-Field,
3 hydrogen are shown, expression products therefrom is compound A mesylates.
1H-NMR detecting instruments and condition：Detecting instrument：The superconducting pulse Fourier of Bruker AVANCE III HD 500
Transform nuclear magnetic resonance spectrometer；Testing conditions：Solvent：MeOD-d4；Temperature：25℃；Detection foundation：JY/T 007-1996 superconduction arteries and veins
Rush Fourier-transform nuclear magnetic resonance spectral method general rule.
Summarize：According to the XRD spectra and characteristic peak data of Fig. 1 and 3, with 2 θ angles represent 10.29 ± 0.2 ° and 15.17 ±
There is most strong characteristic absorption peak at 0.2 °, can substantially represent this crystal formation.
Crystal formation described further also has a characteristic peak at 16.30 °, 19.46 °, 19.71 ° and 25.63 °, error for ±
0.2 °, relative absorbance intensity is more than 50%, can fully represent this crystal formation.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 7.13 °, 8.54 °,
9.46 °, 17.06 °, 17.30 °, 17.73 °, 18.21 °, 18.72 °, 20.23 °, 20.70 °, 21.65 °, 22.05 °, 22.78 ° and
23.49 ° have characteristic peak, and error is ± 0.2 °, and relative absorbance intensity is more than 10%, can in more detail distinguish other materials generation
Table this crystal formation.
And other weak absorbing peaks may occur significant change due to experimental implementation error, to those skilled in the art
Other absworption peaks are when characterizing this crystal formation it is considered that unnecessary absworption peak.
DSC spectrograms and characteristic peak data according to Fig. 2 and 4, the DSC of the crystal formation is at 252.1 DEG C ± 2 DEG C -252.2 DEG C
There is maximum absorption band at ± 2 DEG C.
The water-soluble experiment of embodiment 4
According to《Chinese Pharmacopoeia》Ten five (2) guidance under 2010 editions second annex projects and requirement, with the He of embodiment 2
The crystal formation γ and PCT/GB2012/051783 of the 3 compound A mesylates for obtaining disclose the compound A first that method is prepared
Sulfonate crystal formation B under equal conditions carries out water-soluble experiment, and experimental technique and result are as follows：
The stability experiment of embodiment 5
With reference to Chinese Pharmacopoeia version annex XIXC bulk drugs in 2010 shadow is carried out with pharmaceutical preparation stability test guideline
Factor Experiment is rung, wherein, impurity situation of change was determined using the HPLC methods of version annex VD in 2010, chromatographic condition is：Waters
High performance liquid chromatograph, the C18 posts (50mm × 2.1mm) of 1.8 μm of particle diameter, with acetonitrile and 1% (v/v) aqueous formic acid as stream
Dynamic phase (Mobile phase B), 30min inside gradients are 10%B to 55%B, are detected under 254nm, wherein, single miscellaneous content is with addition to main peak
Maximum contaminant peak is calculated, it is total it is miscellaneous with main peak outside all impurity peaks calculate.Result is as follows：
Conclusion：Compound A Mesylate Forms γ of the invention obtains a first sulphur relative to PCT/GB2012/051783
Hydrochlorate advantage crystal formation B substantially has more preferable stability.
The preparation of the pharmaceutical composition of embodiment 6
Embodiment 2 compound A mesylates (crystal formation γ, in terms of combined alkali) 40g
Dextrin 84.00g
According to a conventional method, after above-mentioned substance is well mixed, point 1000 equal portions are respectively charged into common gelatine capsule, obtain
1000 capsules.
The preparation of the pharmaceutical composition of embodiment 7
Embodiment 3 compound A mesylates (crystal formation γ, in terms of combined alkali) 40g
Dextrin 86.00g
According to a conventional method, after above-mentioned substance is well mixed, point 1000 equal portions are respectively charged into common gelatine capsule, obtain
1000 capsules.
Above-described embodiment is the present invention preferably implementation method, but embodiments of the present invention are not by above-described embodiment
Limitation, it is other it is any without departing from Spirit Essence of the invention and the change, modification, replacement made under principle, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (10)
1. the novel crystal forms γ of a kind of compound A mesylates, the compound A mesylate structural formulas as shown in following formula I,
2. a kind of novel crystal forms γ of compound A mesylates described in a kind of claim 1, it is characterised in that the crystal formation γ is in X
Represent that error is ± 0.2 ° at 10.29 ± 0.2 ° and 15.17 ± 0.2 ° with 2 θ angles in x ray diffration pattern x.
3. a kind of novel crystal forms γ of compound A mesylates described in a kind of claim 2, it is characterised in that the crystal formation γ is in X
Represent that error is ± 0.2 °, relative absorbance also at 16.30 °, 19.46 °, 19.71 ° and 25.63 ° with 2 θ angles in x ray diffration pattern x
Intensity is more than 50%.
4. a kind of novel crystal forms γ of compound A mesylates according to Claims 2 or 3, it is characterised in that the crystal formation γ
Represented with 2 θ angles in X-ray diffractogram, further also 7.13 °, 8.54 °, 9.46 °, 17.06 °, 17.30 °, 17.73 °,
Have characteristic peak at 18.21 °, 18.72 °, 20.23 °, 20.70 °, 21.65 °, 22.05 °, 22.78 ° and 23.49 °, error for ±
0.2 °, relative absorbance intensity is more than 10%.
5. a kind of novel crystal forms γ of compound A mesylates according to claim 1, it is characterised in that the X of the crystal formation γ
X ray diffration pattern x is as shown in Fig. 1 or Fig. 3.
6. a kind of novel crystal forms γ of the compound A mesylates according to claim 1-5 any claim, its feature
It is that the DSC of crystal formation described in the DSC collection of illustrative plates of gained crystal formation γ has absorption maximum at 252.1 DEG C ± 2 DEG C -252.2 DEG C ± 2 DEG C
Peak.
7. a kind of novel crystal forms γ of the compound A mesylates according to claim 1-5 any claim, its feature
It is that the DSC collection of illustrative plates of gained crystal formation γ is as shown in figures 2 or 4.
8. a kind of novel crystal forms γ of the compound A mesylates described in claim 1-7 is preparing prevention and/or treatment lactation
The application of the medicine of Animal diseases, it is characterised in that the mammal includes people, the disease includes various cancers, preferably
Non-small cell lung cancer, the non-small cell lung cancer being particularly mutated.
9. a kind of a kind of pharmaceutical composition, it is characterised in that the compound A described in the claim 1-7 including therapeutically effective amount
The novel crystal forms γ of mesylate and more than one pharmaceutically acceptable excipient.
10. the method that one kind prepares a kind of novel crystal forms γ of the compound A mesylates described in claim 1-7, its feature exists
In, compound A mesylates are added in organic solvent methyl alcohol or isopropanol, wherein, compound A mesylate weight
G () is 1 with the volume (ml) of solvent：6-1：10, water, water and organic solvent methyl alcohol or the volume ratio of isopropanol are added at room temperature
1：3-1：5, the stirring reaction at 50~60 DEG C is molten clear；Organic solvent methanol or isopropanol, additional amount are added at 20~30 DEG C
It is 1 with the volume ratio of initial incremental amount：2.5,0~10 DEG C of 6~8h of stirring is cooled to, light yellow solid is separated out, filter, with organic
Solvent methanol or isopropanol drip washing, 40~60 DEG C vacuumize baking 5h, obtain product, are compound A mesylate γ crystal formations.
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| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
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| CN111620854A (en) * | 2019-02-28 | 2020-09-04 | 上海医药工业研究院 | 4-aminopyrimidine substituted phenylamide compound and preparation method thereof |
| CN111617083B (en) * | 2019-02-28 | 2023-10-27 | 上海医药工业研究院 | Application of methoxy substituted phenylamide aminopyrimidine derivative |
| CN110483486A (en) * | 2019-09-17 | 2019-11-22 | 鲁南制药集团股份有限公司 | A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof |
| CN110483486B (en) * | 2019-09-17 | 2024-01-26 | 鲁南制药集团股份有限公司 | Crystal form of oxtinib ketorolac and preparation method thereof |
| CN113372332A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib |
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| CN113372331B (en) * | 2020-03-10 | 2023-09-12 | 鲁南制药集团股份有限公司 | Novel crystal form of Orientinib monohydrate |
| CN113372332B (en) * | 2020-03-10 | 2023-09-12 | 鲁南制药集团股份有限公司 | Novel crystal form of octreotide |
| CN116018141A (en) * | 2020-11-19 | 2023-04-25 | 上海翰森生物医药科技有限公司 | Salt and crystal form containing indole derivatives, and preparation method and application thereof |
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