CN109485599A - A kind of Src tyrosine kinase inhibitor crystal form, preparation method and pharmaceutical composition - Google Patents
A kind of Src tyrosine kinase inhibitor crystal form, preparation method and pharmaceutical composition Download PDFInfo
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- CN109485599A CN109485599A CN201811277770.5A CN201811277770A CN109485599A CN 109485599 A CN109485599 A CN 109485599A CN 201811277770 A CN201811277770 A CN 201811277770A CN 109485599 A CN109485599 A CN 109485599A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The present invention provides the hydrochloride Form of the compound with Formulas I structure and phosphate crystal form, with good stability and dissolubility, preparation method is easy to operate, can stably obtain above-mentioned crystal form.Preparation method product yield 93~96% in the present invention, purity are 99.8% or more.By dissolubility and Detection of Stability, the hydrochloride Form and phosphate crystal form of the compound with Formulas I structure in the application are soluble easily in water, by 3 months accelerated stability tests, moisture content change amount is between 0.15~0.2%, maximum single each impurity content variation is 0.01%, and total impurities changes of contents is 0.01~0.04%.The present invention also provides a kind of preparation method of Src tyrosine kinase inhibitor crystal form and contain the pharmaceutical composition of the Src tyrosine kinase inhibitor crystal form.
Description
Technical field
The invention belongs to drug crystal forms technical field more particularly to a kind of Src tyrosine kinase inhibitor crystal forms, its preparation
Method and pharmaceutical composition.
Background technique
It is directed in the signal transduction pathway (growth of such as cell is broken up, survival, migration etc.) of various normal cells
Kinases, kinases are considered playing a role in various diseases and obstacle.Maximum group is protein kinase in kinases, effect
In specific protein and correct the activity of the specific protein.They are widely used in the transmission and control of signal
Intracellular complicated reaction.Tyrosine kinase is a kind of tyrosine that phosphate can be transmitted to protein from adenosine triphosphate
Enzyme on residue can be divided into the kinases that cytoplasm protein kinases is connected with across membrane receptor.About 50% known carcinogenophore
Because product is protein tyrosine kinase.Protein tyrosine kinase (PTK) can be divided into two types, membrane receptor protein junket
Histidine kinase (e.g., growth factor receptor protein tyrosine kinase) and non-receptor protein tyrosine kinase (e.g., proto-oncogene
Src family in product).In a variety of human cancers, the overactivity of Src, including colon cancer, breast cancer, lung are reported
Cancer, bladder cancer, cutaneum carcinoma and gastric cancer etc., Src can be used as the general target spot for the treatment of of cancer.
Biaryl compound, chemical name are as follows: 2- (5- (4- (2- beautiful jade base oxethyl) phenyl) pyridine -2- base)-N- benzene
Methyl acetamide has structure shown in formula I.
Structural compounds and its pharmaceutically acceptable salt shown in Formulas I are effective Src tyrosine kinase inhibitors, can be with
Disease and disorder of the effective treatment by Src kinase regulatory.The compound currently used for treat the research of photochemical keracele into
Enter III phase clinical stage, the research there are also part for solid tumor has entered I phase or II phase clinical stage.
There are polymorphisies for the free alkali of structural compounds shown in Formulas I, and different salt forms also can be generated.Sameization
The different crystal forms of object are closed, chemical composition is identical, but microcosmic crystal structure is different, thus causes them in mode of appearance, physics and chemistry
It is had differences in property and bioactivity.But the salt form of structural compounds shown in presently disclosed Formulas I such as fumarate, Malaysia
Hydrochlorate etc., stability is poor.The preparation processing performance of drug is directly affected, and will affect the stability of drug, solubility
And bioavilability, and then influence quality, safety, validity and its application of drug.
Summary of the invention
The purpose of the present invention is to provide a kind of Src tyrosine kinase inhibitor crystal form, preparation method and pharmaceutical compositions
Object, the present invention in Src tyrosine kinase inhibitor crystal form have good solvent borne and stability.
The present invention provides a kind of Src tyrosine kinase inhibitor crystal form, the XRPD figure of the Src tyrosine kinase inhibitor
Spectrum 2 θ angle values be 14.41 ± 0.2 °, 16.88 ± 0.2 °, 17.46 ± 0.2 °, 18.05 ± 0.2 °, 18.98 ± 0.2 °,
21.21 ± 0.2 °, 22.48 ± 0.2 °, 23.18 ± 0.2 °, 23.89 ± 0.2 °, 25.36 ± 0.2 °, 29.74 ± 0.2 ° of position
There is diffraction maximum.
Preferably, the DSC map of the Src tyrosine kinase inhibitor crystal form has endothermic peak at 130 ± 5 DEG C.
The present invention provides a kind of Src tyrosine kinase inhibitor crystal form, the Src tyrosine kinase inhibitor crystal form
XRPD map 2 θ angle values be 4.55 ± 0.2 °, 17.22 ± 0.2 °, 17.60 ± 0.2 °, 18.70 ± 0.2 °, 19.12 ±
0.2°、20.18±0.2°、20.96±0.2°、21.24±0.2°、21.52±0.2°、22.98±0.2°、23.24±0.2°、
23.50 ± 0.2 °, 25.18 ± 0.2 °, 25.42 ± 0.2 ° of position have diffraction maximum.
Preferably, the DSC map of the Src tyrosine kinase inhibitor has endothermic peak at 191 ± 5 DEG C.
The present invention provides a kind of preparation method of Src tyrosine kinase inhibitor crystal form, comprising the following steps:
A) compound with Formulas I structure is mixed with acetone, stirring is complete to dissolving；
The temperature of the dissolution is 45~56 DEG C；
B acid) is added dropwise under stirring conditions, acid stirs after being added dropwise to be reacted, and crystallization is precipitated, obtains Src junket ammonia
Acid kinase inhibitor crystal form；
The acid is hydrochloric acid or phosphoric acid；
Preferably, the amount ratio of the compound and acetone with Formulas I structure is 1g:(30~55) mL.
Preferably, the molar ratio of the compound with Formulas I structure and acid is 1:(1.1~1.5)；The dropwise addition of the acid
Speed is (0.5~10) mL/min.
Preferably, the step B) in react pH value be 3~6.
Preferably, the step B) in react temperature be 20~35 DEG C.
The present invention provides a kind of pharmaceutical composition, including Src tyrosine kinase inhibitor crystal form described above.
The present invention provides the hydrochloride Forms of the compound with Formulas I structure and phosphate crystal form, have good steady
Qualitative and dissolubility, preparation method is easy to operate, can stably obtain above-mentioned crystal form.Preparation method product in the present invention
Yield 93~96%, purity are 99.8% or more.By dissolubility and Detection of Stability, in the application with Formulas I structure
The hydrochloride Form and phosphate crystal form of compound are soluble easily in water, by 3 months accelerated stability tests, moisture content change amount
Between 0.15~0.2%, maximum single each impurity content variation is 0.01%, and total impurities changes of contents is 0.01~0.04%.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The embodiment of invention for those of ordinary skill in the art without creative efforts, can also basis
The attached drawing of offer obtains other attached drawings.
Fig. 1 is the XRPD figure of the crystal form for the hydrochloride with formula (I) structural compounds that the embodiment of the present invention 1 is prepared
Spectrum；
Fig. 2 is the DSC and TGA for the crystal form that the hydrochloride with formula (I) structural compounds is prepared in the embodiment of the present invention 1
Map；
Fig. 3 is the XRPD figure for the phosphatic crystal form with formula (I) structural compounds that the embodiment of the present invention 3 is prepared
Spectrum；
Fig. 4 is the DSC and TGA that the phosphatic crystal form with formula (I) structural compounds is prepared in the embodiment of the present invention 3
Map.
Specific embodiment
The present invention provides a kind of Src tyrosine kinase inhibitor crystal form, and the Src tyrosine kinase inhibitor is with formula
The hydrochloride of the compound of structure shown in I, the XRPD map of the Src tyrosine kinase inhibitor 2 θ angle values be 14.41 ±
0.2°、16.88±0.2°、17.46±0.2°、18.05±0.2°、18.98±0.2°、21.21±0.2°、22.48±0.2°、
23.18 ± 0.2 °, 23.89 ± 0.2 °, 25.36 ± 0.2 °, 29.74 ± 0.2 ° of position have diffraction maximum.
Its DSC map has endothermic peak at 130 ± 5 DEG C.
The present invention also provides another crystal form of Src tyrosine kinase inhibitor, the Src tyrosine kinase inhibitor
XRPD map for the phosphate of the compound with structure shown in Formulas I, the Src tyrosine kinase inhibitor is in 2 θ angle values
4.55±0.2°、17.22±0.2°、17.60±0.2°、18.70±0.2°、19.12±0.2°、20.18±0.2°、20.96
±0.2°、21.24±0.2°、21.52±0.2°、22.98±0.2°、23.24±0.2°、23.50±0.2°、25.18±
0.2 °, 25.42 ± 0.2 ° of position have diffraction maximum.
Its DSC map has endothermic peak at 191 ± 5 DEG C.
The present invention provides a kind of preparation method of Src tyrosine kinase inhibitor crystal form, comprising the following steps:
A) compound with Formulas I structure is mixed with acetone, stirring is complete to dissolving；
The temperature of the dissolution is 45~56 DEG C；
B acid) is added dropwise under stirring conditions, acid stirs after being added dropwise to be reacted, and crystallization is precipitated, obtains Src junket ammonia
Acid kinase inhibitor crystal form；
The acid is hydrochloric acid or phosphoric acid；
The present invention mixes the compound with Formulas I structure with acetone, and to dissolving completely, the temperature of the dissolution is for stirring
45~56 DEG C, preferably 48~55 DEG C, specifically, in an embodiment of the present invention, can be 48 DEG C, 50 DEG C, 52 DEG C or 55 DEG C.
In the present invention, the ratio between the quality of the compound with Formulas I structure and the volume of acetone preferably 1g:(30~55)
ML, more preferably 1g:(35~50) mL, most preferably 1g:(40~45) mL can be with specifically, in an embodiment of the present invention
It is 1g:38mL, 1g:43mL, 1g:40mL or 1g:50mL.
Described there will be Formulas I structural compounds in acetone after dissolved clarification, the present invention is dripped in the solution under stirring conditions
Acid adding, after acid is added dropwise, stirring is reacted, and crystallization is precipitated in reaction process, after the crystallization is carried out suction filtration drying,
The salt of the compound with structure shown in Formulas I, i.e. Src tyrosine kinase inhibitor crystal form can be obtained.
In the present invention, the Src tyrosine kinase inhibitor crystal form is the hydrochloric acid of the compound with structure shown in Formulas I
Salt crystal form or phosphate crystal form.
In the present invention, the acid is that can form pharmaceutically acceptable salt with the compound with structure shown in Formulas I
Acid；The molar ratio of the compound with Formulas I structure and acid is preferably 1:(1.1~1.5), more preferably 1:(1.2~
1.4), most preferably 1:1.3；The rate of addition of the acid is preferably (0.5~10) mL/min, more preferably (1~8) mL/
Min, most preferably (3~5) mL/min；The pH value being stirred to react is preferably 3~6, and more preferably 4~5, specifically,
In the embodiment of the present invention, it can be 4,4.5,4.7 or 6.
In the present invention, after dripped acid, the pH value of reaction system can use not within the scope of 3~6
The pH value of reaction system is adjusted to 3~6 within the scope of this by the mode for adding acid, the type of the acid added preferably with make
The type of the acid of dropwise addition is consistent.
In the present invention, the temperature of the acid adding reaction is preferably 20~35 DEG C, and more preferably 25~30 DEG C.
It in the present invention, is preferably vacuum drying to the drying precipitated crystal, the temperature of the drying is preferably 40
~55 DEG C, more preferably 45~50 DEG C.
The present invention provides the hydrochloride Forms of the compound with Formulas I structure and phosphate crystal form, have good steady
Qualitative and dissolubility, preparation method is easy to operate, can stably obtain above-mentioned crystal form.Preparation method product in the present invention
Yield 93~96%, purity are 99.8% or more.By dissolubility and Detection of Stability, in the application with Formulas I structure
The hydrochloride Form and phosphate crystal form of compound are soluble easily in water, by 3 months accelerated stability tests, moisture content change amount
Between 0.15~0.2%, maximum single each impurity content variation is 0.01%, and total impurities changes of contents is 0.01~0.04%.
In order to further illustrate the present invention, with reference to embodiments to a kind of Src tyrosine kinase suppression provided by the invention
Preparation crystal form, preparation method and pharmaceutical composition are described in detail, but cannot be understood as to the scope of the present invention
Restriction.
Embodiment 1
2- (5- (4- (2- beautiful jade base oxethyl) phenyl) pyridine -2- base)-N- benzyl acetamide hydrochloride crystal form (has
Have the hydrochloride Form of formula (I) structural compounds) preparation
Structural compounds shown in Formulas I (3.0g) are placed in 500ml round-bottomed flask, with 150ml acetone solution, are warming up to 50
DEG C, stirring to abundant dissolved clarification, then the lower 0.72g that is added dropwise of stirring analyzes pure hydrochloric acid, and drop is down to after finishing and 30min is stirred at room temperature, and tests
After pH value is 7.5, adding hydrochloric acid to pH value is 4.Continue stirring and crystallizing, filters, 45 DEG C of vacuum dryings, obtained solid is Formulas I
The hydrochloride Form of shown structural compounds.Yield 95%, it is 99.89% that HPLC, which detects purity,.
The preparation of the hydrochloride Form of structural compounds shown in 2 Formulas I of embodiment
Structural compounds shown in Formulas I (3.0g) are placed in 250ml round-bottomed flask, with 120ml acetone solution, are warming up to 55
DEG C, stirring to abundant dissolved clarification, then the lower 0.79g that is added dropwise of stirring analyzes pure hydrochloric acid, and drop is down to after finishing and 30min is stirred at room temperature, and tests
PH value is 4.5.Continue stirring and crystallizing, filters, 45 DEG C of vacuum dryings, obtained solid is the hydrochloric acid of structural compounds shown in Formulas I
Salt crystal form.Yield 93%, it is 99.85% that HPLC, which detects purity,.
3 2- of embodiment (5- (4- (2- beautiful jade base oxethyl) phenyl) pyridine -2- base)-N- benzyl acetyl amine phosphate
The preparation of crystal form (i.e. with the phosphate crystal form of formula (I) structural compounds)
Structural compounds shown in Formulas I (3.0g) are placed in 250ml round-bottomed flask, with 130ml acetone solution, are warming up to 48
DEG C, stirring to abundant dissolved clarification, then the lower 0.84g that is added dropwise of stirring analyzes pure phosphoric acid, and drop is down to after finishing and 20min is stirred at room temperature, and tests
PH value is 6.Continue stirring and crystallizing, filters, 45 DEG C of vacuum dryings, obtained solid is the phosphate of structural compounds shown in Formulas I
Crystal form.Yield 96%, it is 99.92% that HPLC, which detects purity,.
The preparation of the phosphate crystal form of structural compounds shown in 4 Formulas I of embodiment
Structural compounds shown in Formulas I (3.0g) are placed in 250ml round-bottomed flask, with 115ml acetone solution, are warming up to 52
DEG C, stirring to abundant dissolved clarification, then the lower 0.87g that is added dropwise of stirring analyzes pure phosphoric acid, and drop is down to after finishing and 30min is stirred at room temperature, and tests
PH value is 4.7.Continue stirring and crystallizing, filters, 45 DEG C of vacuum dryings, obtained solid is the phosphoric acid of structural compounds shown in Formulas I
Salt crystal form.Yield 95%, it is 99.83% that HPLC, which detects purity,
The detection of the hydrochloride Form of structural compounds shown in 5 Formulas I of embodiment
The hydrochloride Form of structural compounds shown in Formulas I made from Example 1 examines it using XRPD method
It surveys.The RIGAKU TTR type III X-ray powder diffraction instrument used, determination condition and method: Cu (target), 40KV~30mA (work
Make voltage and electric current), 2 θ=2~50 degree (scanning range), 4.0deg/min. (scanning speed), obtained map is shown in Fig. 1.By
Fig. 1 is it is found that the XRPD map of the hydrochloride Form of structural compounds shown in the Formulas I that embodiment 1 provides is in 2 θ ± 0.2o
14.41, there is peak in 16.88,17.46,18.05,18.98,21.21,22.48,23.18,23.89,25.36,29.74 position.
The present invention additionally use DSC-TGA method to the hydrochloride Forms of structural compounds shown in Formulas I provided by the invention into
Detection is gone.The instrument and equipment used be Mei Tele-support benefit TGA-DSC, 25~400 DEG C of temperature range, heating rate 10
DEG C/min, obtained map is shown in Fig. 2.As shown in Figure 2, the hydrochloride Form of structural compounds shown in the Formulas I that embodiment 1 provides
DSC map has endothermic peak 130 DEG C of positions, and TGA map is before 200 DEG C without obvious weightless.
The detection of structural compounds phosphate crystal form shown in 6 Formulas I of embodiment
The phosphate crystal form of structural compounds shown in Formulas I made from Example 3, examines it using XRPD method
It surveys.The RIGAKU TTR type III X-ray powder diffraction instrument used, determination condition and method: Cu (target), 40KV~30mA (work
Make voltage and electric current), 2 θ=2~50 degree (scanning range), 4.0deg/min. (scanning speed), obtained map is shown in Fig. 3.By
Fig. 3 it is found that embodiment 3 provide Formulas I shown in structural compounds phosphate crystal form XRPD map 2 θ ± 0.2o be 4.55,
17.22、17.60、18.70、19.12、20.18、20.96、21.24、21.52、22.98、23.24、23.50、25.18、25.42
Position have peak.
The present invention additionally use DSC-TGA method to the phosphate crystal forms of structural compounds shown in Formulas I provided by the invention into
Detection is gone.The instrument and equipment used be Mei Tele-support benefit TGA-DSC, 25-400 DEG C of temperature range, heating rate 10
DEG C/min, obtained map is shown in Fig. 4.As shown in Figure 4, the phosphate crystal form of structural compounds shown in the Formulas I that embodiment 3 provides
DSC map has endothermic peak about 191 DEG C of positions, and TGA map is before 200 DEG C without obvious weightless.
The dissolubility of the crystal salt of structural compounds shown in 7 Formulas I of embodiment detects
Knot shown in the Formulas I that structural compounds hydrochloride Form shown in the Formulas I that Example 1 provides and embodiment 3 provide
The phosphate of structure compound carries out dissolubility test, the results are shown in Table 1；
The dissolubility of the crystal salt of structural compounds shown in 1 Formulas I of table detects
Wherein, almost insoluble: solute 1g (mL) cannot be completely dissolved in solvent 10000ml；Slightly soluble: solute 1g (mL),
It can be in solvent 100~less than being dissolved in 1000mL；It is slightly molten: solute 1g (mL), it can be in solvent 30~less than being dissolved in 100mL；Easily
It is molten: solute 1g (mL), it can be in solvent 1~less than being dissolved in 10mL.
The Detection of Stability of structural compounds crystal salt shown in 8 Formulas I of embodiment
The hydrochloride and embodiment 3 of structural compounds shown in the Formulas I that Example 1 provides provide structuring shown in Formulas I
The phosphate for closing object carries out stability test.Contrast sample is to prepare according to preparation method disclosed in US20090318450A1
Formulas I shown in structural compounds diphosphate.The normal storage temperature of structural compounds salt shown in Formulas I is -20 DEG C.It will implement
Example 1 provide Formulas I shown in structural compounds hydrochloride and embodiment 3 provide Formulas I shown in structural compounds phosphate with
And contrast sample is protected from light storage under conditions of 25 DEG C of temperature, relative humidity RH60%, carries out accelerated stability experiment.Measurement
In 0 month, 1 month, 2 months and 3 months moisture content, purity, maximum single impurity and total impurities content, experimental result is shown in
Table 2.
The crystal salt stability test of structural compounds shown in 2 Formulas I of table
As shown in Table 2, the phosphate and hydrochloride of the novel crystal forms prepared in the application, compare existing contrast sample,
With better stability.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of Src tyrosine kinase inhibitor crystal form, the XRPD map of the Src tyrosine kinase inhibitor is in 2 θ angle values
For 14.41 ± 0.2 °, 16.88 ± 0.2 °, 17.46 ± 0.2 °, 18.05 ± 0.2 °, 18.98 ± 0.2 °, 21.21 ± 0.2 °,
22.48 ± 0.2 °, 23.18 ± 0.2 °, 23.89 ± 0.2 °, 25.36 ± 0.2 °, 29.74 ± 0.2 ° of position have diffraction maximum.
2. Src tyrosine kinase inhibitor crystal form according to claim 1, which is characterized in that the Src tyrosine kinase
The DSC map of inhibitor crystal form has endothermic peak at 130 ± 5 DEG C.
3. a kind of Src tyrosine kinase inhibitor crystal form, the XRPD map of the Src tyrosine kinase inhibitor crystal form is at 2 angles θ
Angle value be 4.55 ± 0.2 °, 17.22 ± 0.2 °, 17.60 ± 0.2 °, 18.70 ± 0.2 °, 19.12 ± 0.2 °, 20.18 ± 0.2 °,
20.96±0.2°、21.24±0.2°、21.52±0.2°、22.98±0.2°、23.24±0.2°、23.50±0.2°、25.18
± 0.2 °, 25.42 ± 0.2 ° of position have diffraction maximum.
4. Src tyrosine kinase inhibitor crystal form according to claim 3, which is characterized in that the Src tyrosine kinase
The DSC map of inhibitor has endothermic peak at 191 ± 5 DEG C.
5. a kind of preparation method of Src tyrosine kinase inhibitor crystal form, comprising the following steps:
A) compound with Formulas I structure is mixed with acetone, stirring is complete to dissolving；
The temperature of the dissolution is 45~56 DEG C；
B acid) is added dropwise under stirring conditions, acid stirs after being added dropwise to be reacted, and crystallization is precipitated, obtains Src tyrosine-kinase
Enzyme inhibitor crystal form；
The acid is hydrochloric acid or phosphoric acid；
6. preparation method according to claim 5, which is characterized in that the compound and acetone with Formulas I structure
Amount ratio is 1g:(30~55) mL.
7. preparation method according to claim 5, which is characterized in that the compound with Formulas I structure rubs with acid
You are than being 1: (1.1~1.5)；The rate of addition of the acid is (0.5~10) mL/min.
8. preparation method according to claim 5, which is characterized in that the step B) in react pH value be 3~6.
9. preparation method according to claim 5, which is characterized in that the step B) in react temperature be 20~35
℃。
10. a kind of pharmaceutical composition, including Src tyrosine-kinase described in claim 1~2 or claim 3~4 any one
Src tyrosine kinase inhibitor made from preparation method described in crystal form or claim 5~9 any one of enzyme inhibitor is brilliant
Type.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090318450A1 (en) * | 2006-12-28 | 2009-12-24 | Kinex Pharmaceuticals, Llc | Compositions for modulating a kinase cascade and methods of use thereof |
| CN101616915A (en) * | 2006-12-28 | 2009-12-30 | 金克斯医药品有限公司 | The composition and the method for regulation and control kinase cascade |
-
2019
- 2019-01-16 CN CN201811277770.5A patent/CN109485599A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090318450A1 (en) * | 2006-12-28 | 2009-12-24 | Kinex Pharmaceuticals, Llc | Compositions for modulating a kinase cascade and methods of use thereof |
| CN101616915A (en) * | 2006-12-28 | 2009-12-30 | 金克斯医药品有限公司 | The composition and the method for regulation and control kinase cascade |
Non-Patent Citations (1)
| Title |
|---|
| TAO LIU ET AL.: ""Targeting Src and Tubulin in Mucinous Ovarian Carcinoma"", 《CLINICAL CANCER RESEARCH》 * |
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Application publication date: 20190319 |