CN106674202A - Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate - Google Patents
Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate Download PDFInfo
- Publication number
- CN106674202A CN106674202A CN201610962661.1A CN201610962661A CN106674202A CN 106674202 A CN106674202 A CN 106674202A CN 201610962661 A CN201610962661 A CN 201610962661A CN 106674202 A CN106674202 A CN 106674202A
- Authority
- CN
- China
- Prior art keywords
- compound
- crystal formation
- dimethanesulfonate
- dimethanesulfonates
- ray diffractogram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 dimethyl sulfonate of a compound A, a crystal form of the dimethyl sulfonate, application of the dimethyl sulfonate of the compound A in preparation of a medicine for preventing and/or treating mammal diseases, and a medicinal composition containing the dimethyl sulfonate of the compound A, wherein the mammals comprise human beings, and the diseases comprise various cancers, preferably non-small cell lung cancer, particularly mutated non-small cell lung cancer.
Description
Technical field
The invention belongs to chemicals preparation field, and in particular to a kind of dimethanesulfonate of EGFR inhibitor compound A
And its crystal formation, and the pharmaceutical composition containing the salt.
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 receptor cause the phosphorylation of key tyrosine residue in Intracellular domain, and
And the stimulation of many Cellular Signaling Transduction Mediated paths for causing to breed participation cell and survive.The mistake of erbB families signal transduction
Adjust promote propagation, invade, transfer, Angiogenesiss 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 Biochemical
And Biophysical Research Communications (2004) Vol.319, provide in 1-11 and ErbB receptor are believed
Number conduction and its participation in tumour occurs 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 non-to Ji 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 to Gefitinib or Tarceva treatment 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, only the affinity of ATP will be 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 disappearance EGFR mutant) and/or resistant mutant forms EGFR (such as T790M EGFR mutant), for
The selective compound that the favourable performance characteristics to WT EGFR, and/or relative other enzyme acceptors can be shown is remained
Demand, the selectivity causes these compounds to be especially hopeful to be developed to therapeutic agent.On this point, it is sharp for 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 using
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 2- (2,4,5- substituted anilines) pyrimidine of relatively some EGFR mutant forms
Compound have it is high-effect, while showing the suppression relatively low to WT EGFR.With other known EGFR/EGFR mutant
Inhibitor is compared, the compound of the present invention also can show favourable physical property (for example, higher water solubility, higher ooze
Permeability, and/or relatively low plasma protein combination) and/or favourable toxic characteristic (the hERG blocking tendencies of such as reduction) and/or
Favourable metabolic characteristics.Therefore, such compound involves the activated mutant for having EGFR and/or EGFR in such as treatment of cancer
And/or be particularly useful in the treatment of the disease condition of the resistant mutation of EGFR, the compound is specific as follows:
(mesylates of compound A mono-).
The salt of unknown other salt for how obtaining compound A of prior art and plural number.In order to improve the compound
Medicinal property, also need further to study the state of its stable suitable preparation.
The content of the invention
In view of the defect that prior art is present, an object of the present invention is to provide a kind of dissolubility and excellent in stability
EGFR inhibitor compound A dimethanesulfonate and its crystal formation, and the pharmaceutical composition containing the salt.
The chemical name of compound A is:N- (2- { 2- dimethylaminoethyls-methylamino } -4- methoxyl group -5- { [4- (1- first
Base indol-3-yl) pyrimidine -2-base] amino } phenyl) propyl- 2- acrylamide, under the dimethanesulfonate chemical structural formula of compound A is
Formula (I),
Its1H-NMR is displayed in double methyl proton signal peaks that two methanesulfonic acids occurs in High-Field, shows there are 6 hydrogen, illustrates as diformazan
Sulfonate.
The High-Field refers to the position from 0 to concrete shift value first significantly many hydrogen peaks, specifically, the diformazan sulphur
Hydrochlorate1H-NMR is as shown in Figures 2 and 3.
1H-NMR detecting instruments:The superconducting pulse Fourier-transform nuclear magnetic resonances of Bruker AVANCE III HD 500 are composed
Instrument;Testing conditions:Solvent:MeOD-d4;Temperature:25℃;Detection foundation:JY/T 007-1996 superconducting pulse Fourier transformation cores
Magnetic resonance spectrum method general rule.
The dimethanesulfonate further includes crystal formation α.
The crystal formation α represents there is most strong characteristic absorption peak at 5.62 ± 0.2 ° in X-ray diffractogram with 2 θ angles.
Crystal formation described further also 6.53 °, 10.23 °, 13.51 °, 19.35 °, 20.01 °, 21.10 °, 22.76 °,
There is characteristic peak at 26.01 ° and 27.36 °, error is ± 0.2 °, and relative absorbance intensity is more than 50%.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 11.76 °, 12.61 °,
14.37°、15.74°、16.10°、16.72°、17.37°、17.91°、18.45°、20.38°、20.87°、22.30°、23.06°、
23.50 °, 24.22 °, 26.56 °, 27.36 °, 27.85 °, 28.43 ° and 29.62 ° have characteristic peak, and error is ± 0.2 °, relatively
Absorption intensity is more than 10%.
Specifically, the X ray diffracting data of the compound A dimethanesulfonates crystal formation α as shown in table 1, error for ±
0.2°.Specifically as illustrated in fig. 4 or 6.
The DSC of crystal formation is at 261.3 DEG C ± 2 DEG C -262.1 described in the DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation α
There is maximum absorption band at DEG C ± 2 DEG C.Specifically as shown in Fig. 5 or Fig. 7.
The dimethanesulfonate further includes compound A dimethanesulfonate tetrahydrates, its structural formula such as Formula Il institute
Show,
It passes through karl Fischer (KF methods) moisture determination and TG detections, containing the crystallization water of 4 molecules in molecule.Specifically, TG inspections
Mapping is composed as shown in Fig. 8 or 11.
Further compound A dimethanesulfonates tetrahydrate includes its crystal formation β.
The crystal formation β represented at 4.20 °, 6.67 °, 7.76 °, 14.09 °, 18.35 ° with 2 θ angles in X-ray diffractogram and
There is characteristic peak at 22.68 °, error is ± 0.2 °, and relative absorbance intensity is more than 50%.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 5.51 °, 6.44 °,
10.13°、12.52°、15.52°、15.99°、17.82°、19.53°、19.95°、20.86°、23.89°、25.28°、25.96°、
There is characteristic peak at 27.25 ° and 29.47 °, error is ± 0.2 °, and relative absorbance intensity is more than 10%.
Specifically, as shown in table 2, error is ± 0.2 ° to the X ray diffracting data of the crystal formation β.Specifically such as the institutes of Fig. 9 or 12
Show.
The DSC collection of illustrative plates of the crystal formation β has maximum absorption band at 262.9 DEG C ± 2 DEG C -263.7 DEG C ± 2 DEG C.It is concrete such as to scheme
Shown in 10 or 13.
X-ray diffraction testing conditions of the present invention:X-ray diffraction adopts sharp shadow (Empyrean) X-ray diffractometer, in Cu targets
K alpha rays, voltage:40.0kV, electric current:40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm,
0.02 ° of step-length, often walks under the conditions of time of staying 40s and determines 2 θ scopes:3°-50°.
DSC testing conditions:Instrument NETZSCH DSC 200F3, atmosphere N2, 20ml/min, 30 DEG C -280 DEG C of scope.
TG testing conditions:Instrument NETZSCH TG 209F3, atmosphere N2, 20ml/min, 33 DEG C of -400 DEG C of (10K/ of scope
min)。
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 adopts 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 the 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 are because of experimental implementation
There is significant change in error, to those skilled in the art other absworption peaks are absorptions unnecessary when characterizing this crystal formation
Peak.
The good water solubility of the compound A dimethanesulfonates and its crystal formation α and tetrahydrate crystal formation β, stability is high, relatively
The mesylate advantage crystal formation B of advantage one being obtained in PCT/GB2012/051783, there is preferably water-soluble and stability, it is more sharp
In the clinical practice of compound A, the security and validity of medication are fully ensured that.
Another object of the present invention is to provide a kind of above-claimed cpd A dimethanesulfonates and its crystal formation α and tetrahydrate
The preparation method of crystal formation β, the 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, concrete synthetic route and main
Reaction scheme it is as follows:
Wherein, compound 1 (compound A) and one mesylate can be obtained with prior art or commercial sources.
One mesylate of the compound A obtained by prior art, by further optimization preparation process, obtains chemical combination
The dimethanesulfonate of thing A, comprises the following steps that:
The mesylates of 12g compounds A mono- are added in 100~150ml ethanol and 20~30ml water, is stirred at 50~70 DEG C
0.5~1h of reaction is mixed, it is molten clear, the methanesulfonic acid of 5~6g is added dropwise, insulated and stirred is reacted 4~6h, at then moving to 15~25 DEG C 10 is stirred
~18h, separates out light yellow solid, and 35~50 DEG C of 3~5h of drying obtain compound A dimethanesulfonates.
Preferably, the preferred preparation method of compound A dimethanesulfonates crystal formation α is comprised the following steps:
10g compound A dimethanesulfonates are added in 80~100ml acetonitriles (or acetone), 20~30ml is added under room temperature
Water, 0.5~1h of stirring reaction at 45~65 DEG C is molten clear;80~100 acetonitriles (or acetone), stirring 1 are added at 20~30 DEG C
~2h, then moves to be stirred for 1~2h under ice bath, separates out light yellow solid, and 40~60 DEG C of 3~5h of drying are that dimethanesulfonate α is brilliant
Type.
Preferably, the preferred preparation method of compound A dimethanesulfonates tetrahydrate crystal formation β is comprised the following steps:
15g compound A dimethanesulfonates are added in 100~150ml tetrahydrofurans, under room temperature (20~30 DEG C) 30 are added
~40ml water, is heated to 45~65 DEG C of 0.5~1h of stirring, molten clear;1~2h is stirred under ice bath, solid is separated out, is filtered, obtained
Yellow solid, 60~80 DEG C of 5~10h of drying, are dimethanesulfonate tetrahydrate beta crystal.
One Mesylate Form B products of prior art PCT/GB2012/051783, though there is preferable purity, its water
Dissolubility is relative to poor.Synthesis is first obtained compound A dimethanesulfonates by the present invention by substantial amounts of experiment by optimize technique
And its advantage crystal formation α and tetrahydrate crystal formation β.Found by substantial amounts of experiment, directly add enough by the alkali of compound A
Acid, it is difficult to obtain highly purified compound double salt, the accidental discovery of inventor, on the basis of the mesylates of compound A mono-,
Addition acid and then further optimize technique, obtain stable dimethanesulfonate and its advantage crystal formation α and tetrahydrate crystal formation β.
It is still another object of the present invention to provide a kind of pharmaceutical composition containing above-mentioned compound A dimethanesulfonates,
Using the compound A dimethanesulfonates and its advantage crystal formation α and tetrahydrate crystal formation β, and more than one are pharmaceutically acceptable
Carrier.
The carrier includes various pharmaceutic adjuvants, packaging material, tool for transmitting etc., is needed to be selected according to preparation, such as auxiliary
Material includes filler, disintegrant, adhesive, lubricant etc., goes for oral, suction, parenteral routes or surface and uses;
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 non-small cell lung cancer being more highly preferred to, particularly for the non-small cell lung cancer of mutation.
The present invention has the advantages that compared with prior art following prominent and beneficial effect:
1st, prior art does not have the salt of other salt and plural number for obtaining compound A, and using acid more than twice
Salt manufacturing obtains plural salt, it is seen that the preparation of plural salt is difficult.Preferably preparation technology of the invention obtains compound A bis-
Mesylate.
2nd, the purity of compound A dimethanesulfonates of the invention and its advantage crystal formation α and tetrahydrate crystal formation β is high, is matter
The stable solid forms of amount, it is easier to the configuration of pharmaceutical composition and use.
3rd, compound A dimethanesulfonates of the invention and its advantage crystal formation α and tetrahydrate crystal formation β are relative to PCT/
GB2012/051783 obtains a mesylate advantage crystal formation B and substantially has preferably water-soluble and stability, more conducively ensures
The clinical efficacy and safe medication of compound A.
4th, the method for prepare compound A dimethanesulfonate crystal formation α of the present invention and tetrahydrate crystal formation β it is simple, quick, normal
Can prepare under the conditions of temperature, it is easier to industrialization production.
Description of the drawings
Fig. 1 is the mesylates of prior art compound A mono-1H-NMR collection of illustrative plates
Fig. 2 is the gained compound A dimethanesulfonates of the embodiment of the present invention 21H-NMR collection of illustrative plates
Fig. 3 is the gained compound A dimethanesulfonates of the embodiment of the present invention 41H-NMR collection of illustrative plates
Fig. 4 is the X ray diffracting spectrum of the gained compound A dimethanesulfonate crystal formation α of the embodiment of the present invention 3
Fig. 5 is the DSC collection of illustrative plates of the gained compound A dimethanesulfonate crystal formation α of the embodiment of the present invention 3
Fig. 6 is the X ray diffracting spectrum of the gained compound A dimethanesulfonate crystal formation α of the embodiment of the present invention 4
Fig. 7 is the DSC collection of illustrative plates of the gained compound A dimethanesulfonate crystal formation α of the embodiment of the present invention 4
Fig. 8 is the TG collection of illustrative plates of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 5
Fig. 9 is the X ray diffracting spectrum of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 5
Figure 10 is the DSC collection of illustrative plates of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 5
Figure 11 is the TG collection of illustrative plates of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 6
Figure 12 is the X ray diffracting spectrum of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 6
Figure 13 is the DSC collection of illustrative plates of the gained compound A dimethanesulfonate tetrahydrate crystal formation β of the embodiment of the present invention 6
Specific embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but the embodiment invented 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
The standby mesylates of compound A mono- and its crystal formation B:
Reaction condition and parameter are:
To N at 0 DEG C1- (2- dimethylaminoethyls) -5- methoxyl group-N1- methyl-N4- [4- (1- methyl indol -3- bases)
Pyrimidine -2-base] benzene -1, Jing of 2, the 4- triamines (intermediate 100,10g, 21.32mmol) in THF (95mL) and water (9.5mL)
Add 3- chlorpromazine chlorides (3.28g, 25.59mmol) in agitating solution.The mixture is stirred at room temperature 15 minutes, Ran Houtian
Plus NaOH (3.48g, 85.28mmol).Gained mixture is heated into 65 DEG C and is maintained 10 hours.Then by the mixture cooling
To room temperature, add CH3OH (40mL) and water (70mL).Gained mixture is stirred overnight.Gained solid is collected by filtration, is used
Water (25mL) clean, at 50 DEG C be dried 12 hours, obtain as solid form compound A (7.0g, 94%).m/z ESI-
MH+=500.26.
The compound is determined by nuclear-magnetism,1H-NMR tests spectrogram as shown in figure 1, showing discovery, methanesulfonic acid from figure
H occur in High-Field, show 3 hydrogen at specific displacement 3.12, expressions products therefrom is a 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.
And the method for embodiment 28A of foundation PCT/GB2012/051783 prepares the crystal formation of compound A mesylates
B。
In 70 DEG C to compound A, the agitated solution of 20g, 36.63mmol in ethanol (120mL) and EtOAc (80mL)
In be added on methanesulfonic acid (3.59g, 36.63mmol) solution in EtOAc (40mL).Gained mixture is stirred 1.5 hours.It is logical
Gained solid is collected by filtration, the dried in vacuum overnight at 80 DEG C is obtained using the title of solid form (polymorph b of a salt)
Salt (20.5g, 94%).
The preparation of the compound A dimethanesulfonates of embodiment 2
The mesylates of 12g compounds A mono- are added in 125ml ethanol and 25ml water, stirring reaction 0.75h at 60 DEG C,
It is molten clear, the methanesulfonic acid of 5.5g is added dropwise, insulated and stirred reaction 5h stirs 14h at then moving to 20 DEG C, separate out light yellow solid, and 42.5
DEG C drying 3.5h, obtain compound A dimethanesulfonates.
The compound is determined by nuclear-magnetism,1H-NMR tests spectrogram as shown in Fig. 2 showing discovery from figure, in High-Field
There are double methyl proton signal peaks of two methanesulfonic acids, show there are 6 hydrogen, represent products therefrom for double salt, i.e. dimethanesulfonates.
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 compound A dimethanesulfonate crystal formation α of embodiment 3
The 10g compound A dimethanesulfonates of embodiment 2 are added the water for adding 30ml in 100ml acetonitriles under room temperature,
Stirring reaction 0.5h at 60 DEG C, it is molten clear;100 acetonitriles are added at 30 DEG C, 1.5h is stirred, then moves to be stirred for 2h under ice bath, separated out
Light yellow solid, 50 DEG C of drying 5h, obtains product, is dimethanesulfonate alpha-crystal form.
The solid matter is defined as dimethanesulfonate alpha-crystal form.
The X ray diffracting spectrum of gained compound A dimethanesulfonate crystal formation α is as shown in Figure 4.Specific characteristic absorption peak is such as
Table 1 below, error is ± 0.2 °.
The DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation α at 262.1 DEG C ± 2 DEG C as shown in figure 5, have maximum suction
Receive peak.
The preparation of the compound A dimethanesulfonate crystal formation α of embodiment 4
The 10g compound A dimethanesulfonates of embodiment 2 are added the water for adding 20ml in 90ml acetone under room temperature, 50
Stirring reaction 1h at DEG C, it is molten clear;90ml acetone is added at 25 DEG C, 1.5h is stirred, then moves to be stirred for 1.5h under ice bath, separated out shallow
Yellow solid, 60 DEG C of drying 3h, obtains product, is dimethanesulfonate alpha-crystal form.
The compound is determined by nuclear-magnetism,1H-NMR is displayed in double methyl proton signals that two methanesulfonic acids occurs in High-Field
Peak, shows there are 6 hydrogen, as shown in figure 3, having identical result with embodiment 2, represents products therefrom for double salt, i.e. diformazan sulphurs
Hydrochlorate.
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 solid matter is defined as dimethanesulfonate alpha-crystal form.
The X ray diffracting spectrum of gained compound A dimethanesulfonate crystal formation α is as shown in Figure 6.Specific characteristic absorption peak is such as
Table 1 below, error is ± 0.2 °.
The DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation α at 261.3 DEG C ± 2 DEG C as shown in fig. 7, have maximum suction
Receive peak.
The specific characteristic absorption peak such as table 1 below of the gained compound A dimethanesulfonate crystal formation α that embodiment 3 and 4 is obtained,
Error is ± 0.2 °:
The X-ray diffraction of the compound A dimethanesulfonate crystal formation α 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 adopts sharp shadow (Empyrean) X-ray diffractometer, in Cu target K alpha rays, voltage:40.0kV, electric current:
40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm, 0.02 ° of step-length often walks the time of staying
2 θ scopes are determined under the conditions of 40s:3°-50°.
DSC testing conditions:Instrument NETZSCH DSC 200F3, atmosphere N2, 20ml/min, 30 DEG C -280 DEG C of scope.
Summarize:According to the XRD spectra and characteristic peak data of Fig. 4 and 6, represent there is most strong at 5.62 ± 0.2 ° with 2 θ angles
Characteristic absorption peak, can substantially represent this crystal formation.
Crystal formation described further also 6.53 °, 10.23 °, 13.51 °, 19.35 °, 20.01 °, 21.10 °, 22.76 °,
There is characteristic peak at 26.01 ° and 27.36 °, error is ± 0.2 °, and relative absorbance intensity is more than 50%, can fully represent this crystalline substance
Type.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 11.76 °, 12.61 °,
14.37°、15.74°、16.10°、16.72°、17.37°、17.91°、18.45°、20.38°、20.87°、22.30°、23.06°、
23.50 °, 24.22 °, 26.56 °, 27.36 °, 27.85 °, 28.43 ° and 29.62 ° have characteristic peak, and error is ± 0.2 °, relatively
Absorption intensity is more than 10%, can in more detail distinguish other materials and represent this crystal formation.
And other weak absorbing peaks occur significant change because of 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.
According to the DSC spectrograms and characteristic peak data of Fig. 5 and 7, the DSC of the crystal formation is at 261.3 DEG C ± 2-262.1 DEG C ± 2
There is maximum absorption band at DEG C.
The preparation of the compound A dimethanesulfonates tetrahydrate of embodiment 5 and its crystal formation β
The 15g compound A dimethanesulfonates of embodiment 2 are added in 100 tetrahydrofurans, at 25 DEG C of room temperature 30ml is added
Water, is heated to 50 DEG C of stirring 0.5h, molten clear;2h is stirred under ice bath, solid is separated out, is filtered, obtain yellow solid, 80 DEG C of drying
5h, obtains product.
Gained compound A dimethanesulfonates TG collection of illustrative plates as shown in figure 8, the material 80 DEG C dry to quality it is unchanged after
Carry out karl Fischer (KF methods) moisture determination and TG is determined, KF method moisture determinations result is displayed in for 9.89%, TG measurement results
The weightless ratio (9.87%) of room temperature to 70 DEG C is consistent with KF method moisture determination results, and with the theoretical water content of four hydrates
(9.47%) it is basically identical, illustrate that it is four hydrates.
So, gained compound A dimethanesulfonates should be following structural formula, be defined as compound A dimethanesulfonates four
Hydrate:
Gained compound is determined by nuclear-magnetism,1H-NMR tests are displayed in double methyl protons letter that two methanesulfonic acids occurs in High-Field
Number peak, shows there are 6 hydrogen, with the result of embodiment 2 and 4, illustrates as dimethanesulfonate.
The X ray diffracting spectrum of gained compound A dimethanesulfonate tetrahydrates is as shown in Figure 9.Specific characteristic absorption
Peak such as table 2 below, error is ± 0.2 °, is illustrated as crystal material.
The DSC collection of illustrative plates of the hydrate of gained compound A dimethanesulfonates four as shown in Figure 10, has at 263.7 DEG C ± 2 DEG C
Maximum absorption band.
The compound A dimethanesulfonates tetrahydrate is defined as tetrahydrate crystal formation β with crystalline forms presence.
The preparation of the compound A dimethanesulfonates tetrahydrate of embodiment 6 and its crystal formation β
The 15g compound A dimethanesulfonates of embodiment 2 are added in 150ml tetrahydrofurans, at 30 DEG C of room temperature 40ml is added
Water, is heated to 55 DEG C of stirring 1h, molten clear;1.5h is stirred under ice bath, solid is separated out, is filtered, obtain yellow solid, 70 DEG C of drying
10h, obtains product, is dimethanesulfonate tetrahydrate beta crystal.
The TG collection of illustrative plates of gained compound A dimethanesulfonates as shown in figure 11, at 80 DEG C dry unchanged to quality by the material
After carry out karl Fischer (KF methods) moisture determination and TG and determine, KF method moisture determinations result is displayed in for 9.0%, TG measurement results
The weightless ratio (9.00%) of room temperature to 72 DEG C is consistent with KF method moisture determination results, and with the theoretical water content of four hydrates
(9.47%) it is basically identical, illustrate that it is four hydrates.
The X ray diffracting spectrum of gained tetrahydrate crystal formation β is as shown in figure 12.Specific characteristic absorption peak such as table 2 below, by mistake
Difference is ± 0.2 °.
The DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation β as shown in figure 13, has maximum at 262.9 DEG C ± 2 DEG C
Absworption peak.
The X-ray diffraction of the compound A dimethanesulfonate tetrahydrate crystal formation β of table 2 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:
TG testing conditions:Instrument NETZSCH TG 209F3, atmosphere N2, 20ml/min, 33 DEG C of -400 DEG C of (10K/ of scope
min)。
X-ray diffraction adopts sharp shadow (Empyrean) X-ray diffractometer, in Cu target K alpha rays, voltage:40.0kV, electric current:
40.0mA, 1/32 ° of divergent slit, 1/16 ° of antiscatter slits, antiscatter slits 7.5mm, 0.02 ° of step-length often walks the time of staying
2 θ scopes are determined under the conditions of 40s:3°-50°.
DSC testing conditions:Instrument NETZSCH DSC 200F3, atmosphere N2, 20ml/min, 30 DEG C -280 DEG C of scope.
Summarize:According to the XRD spectra and characteristic peak data of Fig. 9 and 12, with 2 θ angles represent 4.20 °, 6.67 °, 7.76 °,
There is characteristic peak at 14.09 °, 18.35 ° and 22.68 °, error is ± 0.2 °, and relative absorbance intensity is more than 50%, can abundant generation
Table this crystal formation.
It is specific more detailed, compound A in X-ray diffractogram with 2 θ angles represent also 5.51 °, 6.44 °,
10.13°、12.52°、15.52°、15.99°、17.82°、19.53°、19.95°、20.86°、23.89°、25.28°、25.96°、
27.25 ° and 29.47 ° have characteristic peak, and error is ± 0.2 °, and relative absorbance intensity is more than 10%, can in more detail distinguish it
He represents this crystal formation by material.
And other weak absorbing peaks occur significant change because of 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.
According to the DSC collection of illustrative plates of Figure 10 and 13, the DSC collection of illustrative plates of the crystal formation β is at 262.9 DEG C ± 2 DEG C -263.7 DEG C ± 2 DEG C
There is maximum absorption band at place.
The water-soluble experiment of embodiment 7
According to《Chinese Pharmacopoeia》2010 editions second annex XIXC《Bulk drug instructs former in the stability test of pharmaceutical preparation
Then》Guidance, the compound A dimethanesulfonates obtained with embodiment 2,3,4,5 and 6 and its crystal formation α and β, with PCT/GB2012/
The Mesylate Form B that 051783 open method is prepared under equal conditions carries out water-soluble experiment, as a result as follows:
Remarks:
Easily dissolve:1g solutes dissolve in less than 1ml solvents;
Yi Rong:1g solutes dissolve in 1~10ml solvents;
Dissolving:1g solutes dissolve in 10~30ml solvents;
It is slightly molten:1g solutes dissolve in 30~100ml solvents;
Slightly soluble:1g solutes dissolve in 100~1000ml solvents;
Soluble,very slightly:1g solutes dissolve in 1000~10000ml solvents;
Almost insoluble or insoluble finger 1g solutes can not be completely dissolved in 10000ml solvents.
The stability experiment of embodiment 8
Shadow is carried out with reference to Chinese Pharmacopoeia version annex XIXC bulk drugs in 2010 with pharmaceutical preparation stability test guideline
Factor Experiment is rung, wherein, impurity situation of change is 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.As a result it is as follows:
AZD9291 dimethanesulfonate alpha-crystal forms | Single miscellaneous changing value % | Total miscellaneous changing value % |
Illumination | 0.02 | 0.01 |
High temperature (60 DEG C) | -0.01 | 0.01 |
AZD9291 dimethanesulfonate beta crystals/ | ||
Illumination | 0.03 | 0.05 |
High temperature (60 DEG C) | 0.02 | 0.03 |
PCT/GB2012/051783 crystal formation B | ||
Illumination | 0.11 | 0.16 |
High temperature (60 DEG C) | 0.14 | 0.20 |
Conclusion:The compound A dimethanesulfonates and its advantage crystal formation α and tetrahydrate crystal formation β of the present invention is relative to PCT/
GB2012/051783 obtains a mesylate advantage crystal formation B and substantially has more preferable stability.
The preparation of the pharmaceutical composition of embodiment 9
Compound A dimethanesulfonates (crystal formation α, in terms of the combined alkali) 40g of embodiment 3
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 10
Compound A dimethanesulfonates (tetrahydrate crystal formation β, in terms of the combined alkali) 40g of embodiment 5
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.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention not by above-described embodiment
Limit, other any Spirit Essences without departing from the present 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 (11)
1. the dimethanesulfonate of compound A, it is characterised in that chemical structural formula is lower formula (I),
2. the dimethanesulfonate of compound A according to claim 1, it is characterised in that two methanesulfonic acids of the compound A
Salt1H-NMR is displayed in double methyl proton signal peaks that two methanesulfonic acids occurs in High-Field, shows there are 6 hydrogen;It is preferred that the compound
The dimethanesulfonate of A1H-NMR is as shown in Figure 2 or Figure 3.
3. the dimethanesulfonate crystal formation α of the compound A described in a kind of claim 1-2 any claim, it is characterised in that
The crystal formation α represents there is most strong characteristic absorption peak at 5.62 ± 0.2 ° in X-ray diffractogram with 2 θ angles;It is preferred that the crystalline substance
Type α represents in X-ray diffractogram with 2 θ angles, further also 6.53 °, 10.23 °, 13.51 °, 19.35 °, 20.01 °,
There is characteristic peak at 21.10 °, 22.76 °, 26.01 ° and 27.36 °, error is ± 0.2 °, and relative absorbance intensity is more than 50%;It is more excellent
Select the crystal formation α to represent with 2 θ angles in X-ray diffractogram, further also 11.76 °, 12.61 °, 14.37 °, 15.74 °,
16.10°、16.72°、17.37°、17.91°、18.45°、20.38°、20.87°、22.30°、23.06°、23.50°、24.22°、
26.56 °, 27.36 °, 27.85 °, 28.43 ° and 29.62 ° have characteristic peak, and error is ± 0.2 °, and relative absorbance intensity is more than
10%.
4. the dimethanesulfonate crystal formation α of the compound A according to claim 1-3 any claim, it is characterised in that
The X-ray diffractogram of the compound A dimethanesulfonates crystal formation α is as illustrated in fig. 4 or 6.
5. the dimethanesulfonate crystal formation α of the compound A according to claim 1-4 any claim, it is characterised in that
The DSC of crystal formation is at 261.3 DEG C ± 2 DEG C -262.1 DEG C ± 2 DEG C described in the DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation α
There is maximum absorption band at place;It is preferred that the DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation α is as shown in Fig. 5 or Fig. 7.
6. a kind of dimethanesulfonate tetrahydrate of the compound A described in claim 1-2 any claim, its feature exists
In, its structural formula as shown in Formula Il,
7. according to right wants 6 compound A dimethanesulfonate tetrahydrate, it is characterised in that its TG detection collection of illustrative plates such as Fig. 8
Or shown in 11.
8. a kind of right wants the crystal formation β of the dimethanesulfonate tetrahydrate of compound A described in 6 or 7, it is characterised in that the crystalline substance
Type β represents at 4.20 °, 6.67 °, 7.76 °, 14.09 °, 18.35 ° and 22.68 ° that error is in X-ray diffractogram with 2 θ angles
± 0.2 °, relative absorbance intensity is more than 50%;It is preferred that the crystal formation α is represented in X-ray diffractogram with 2 θ angles, further also exist
5.51°、6.44°、10.13°、12.52°、15.52°、15.99°、17.82°、19.53°、19.95°、20.86°、23.89°、
There is characteristic peak at 25.28 °, 25.96 °, 27.25 ° and 29.47 °, error is ± 0.2 °, and relative absorbance intensity is more than 10%;It is more excellent
The X-ray diffractogram of the compound A dimethanesulfonates crystal formation β is selected as shown in Fig. 9 or Figure 12.
9. the dimethanesulfonate crystal formation β of the compound A according to claim 6-8 any claim, it is characterised in that
The DSC of crystal formation is at 262.9 DEG C ± 2 DEG C -263.7 DEG C ± 2 DEG C described in the DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation β
There is maximum absorption band at place;It is preferred that the DSC collection of illustrative plates of gained compound A dimethanesulfonate crystal formation β is as shown in Figure 10 or Figure 13.
10. the compound A dimethanesulfonates described in claim 1-9 any claim are preparing prevention and/or are treating 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.
A kind of 11. pharmaceutical compositions, it is characterised in that including therapeutically effective amount claim 1-9 any claim described in
Compound A dimethanesulfonates and more than one pharmaceutically acceptable excipient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2015107469452 | 2015-11-05 | ||
CN201510746945 | 2015-11-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106674202A true CN106674202A (en) | 2017-05-17 |
Family
ID=58840430
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610962661.1A Pending CN106674202A (en) | 2015-11-05 | 2016-11-04 | Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106674202A (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107176954A (en) * | 2017-06-02 | 2017-09-19 | 无锡双良生物科技有限公司 | Pharmaceutical salts and its crystal formation, the preparation method and application of a kind of EGFR inhibitor |
WO2018214886A1 (en) * | 2017-05-24 | 2018-11-29 | 浙江同源康医药股份有限公司 | Crystal form of deuterated azd9291, preparation method therefor, and use thereof |
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 |
US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
CN111303124A (en) * | 2020-04-08 | 2020-06-19 | 北京赛思源生物医药技术有限公司 | Novel crystal of oxitinib mesylate |
CN113801101A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | AZD 9291-2-ketoglutarate and preparation method thereof |
CN113929664A (en) * | 2020-07-13 | 2022-01-14 | 鲁南制药集团股份有限公司 | AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof |
CN113929663A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | AZD 9291-2-indole formate and preparation method thereof |
CN113968845A (en) * | 2020-07-24 | 2022-01-25 | 鲁南制药集团股份有限公司 | AZD 9291-gallate and preparation method thereof |
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 |
-
2016
- 2016-11-04 CN CN201610962661.1A patent/CN106674202A/en active Pending
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
WO2018214886A1 (en) * | 2017-05-24 | 2018-11-29 | 浙江同源康医药股份有限公司 | Crystal form of deuterated azd9291, preparation method therefor, and use thereof |
US10882845B2 (en) | 2017-05-24 | 2021-01-05 | TYK Medicines Inc. | Crystal form of deuterated AZD9291, preparation method therefor, and use thereof |
CN107176954A (en) * | 2017-06-02 | 2017-09-19 | 无锡双良生物科技有限公司 | Pharmaceutical salts and its crystal formation, the preparation method and application of a kind of EGFR inhibitor |
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 |
CN111303124A (en) * | 2020-04-08 | 2020-06-19 | 北京赛思源生物医药技术有限公司 | Novel crystal of oxitinib mesylate |
CN113801101A (en) * | 2020-06-15 | 2021-12-17 | 鲁南制药集团股份有限公司 | AZD 9291-2-ketoglutarate and preparation method thereof |
CN113929663A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | AZD 9291-2-indole formate and preparation method thereof |
CN113929664A (en) * | 2020-07-13 | 2022-01-14 | 鲁南制药集团股份有限公司 | AZD9291-3, 5-pyridine dicarboxylic acid salt and preparation method thereof |
CN113968845A (en) * | 2020-07-24 | 2022-01-25 | 鲁南制药集团股份有限公司 | AZD 9291-gallate and preparation method thereof |
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 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106674202A (en) | Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate | |
CN106699736A (en) | Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same | |
ES2643016T3 (en) | Crystalline forms of 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl) -N4- [2- (propan-2-sulfonyl) -phenyl] -pyrimidin-2,4 -diamine | |
ES2775614T3 (en) | Quinazoline derivative salts and method of preparation thereof | |
CN112851663B (en) | Parallel heterocyclic compound and application thereof | |
EP3705480B1 (en) | Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof | |
WO2021238827A1 (en) | Egfr inhibitor and preparation method and use thereof | |
CA2788774A1 (en) | Crystalline forms of sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5h-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate | |
CN106957315B (en) | N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of drug | |
WO2015096640A1 (en) | Thiazolyl-containing rapamycin derivative and application thereof | |
WO2017020869A1 (en) | B crystal form of 2-[(2r)-2-methyl-2-pyrrolidinyl]-1h-benzimidazole-7-carboxamide, preparation method and use | |
RU2712169C2 (en) | Novel polymorphic forms of icotinib phosphate and uses thereof | |
CN114685532A (en) | Macrocyclic compound and medical application thereof | |
EP4180434A1 (en) | Pb2 inhibitor, and preparation method therefor and use thereof | |
CN116096372A (en) | EGFR inhibitor, preparation method and pharmaceutical application thereof | |
KR20230008767A (en) | Crystalline forms of macrocyclic tyrosine kinase inhibitors and methods for their preparation | |
BR112017028492B1 (en) | (4-((3R,4R)-3-METHOXITETRA-HYDRO-PYRAN-4- YLAMINO)PIPERIDIN-1-YL) CITRATE (5- METHYL-6-(((2R, 6S)-6-(P- TOLIL) TETRA-HYDRO-2H-PIRAN-2-IL)METHYLAMINO)PYRIMIDIN-4-IL) METHANONE, ITS USE AND ITS PREPARATION METHOD, AND PHARMACEUTICAL COMPOSITION | |
ES2881960T3 (en) | Protein kinase inhibitors | |
CN110167917B (en) | Compound with anticancer effect and preparation method and application thereof | |
EP3941472A1 (en) | <smallcaps/>? ? ?n? ? ? ? ?crystalline and amorphous forms of-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2 <ns1:i>h</ns1:i>?-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof | |
WO2017215521A1 (en) | Plx3397 hydrochloride crystal form, preparation method therefor and use thereof | |
CN113861195B (en) | Multi-condensed-ring EGFR inhibitor as well as preparation method and application thereof | |
TWI828489B (en) | Pyrimidine-2(1H)-ketobicyclic compounds with MAT2A inhibitory activity and their uses | |
CN113980003B (en) | 2- ((2-methoxyphenyl) sulfonyl) isoindoline compound and preparation method thereof | |
WO2023041061A1 (en) | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170517 |