CN106188017B - R configuration 4- (substituted anilinic) quinazoline derivant and its preparation method and application - Google Patents
R configuration 4- (substituted anilinic) quinazoline derivant and its preparation method and application Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical chemistry technology, more particularly to the polymorph of the R type isomers of medical compounds N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine, its xylenesulfonate (Formula II) and the xylenesulfonate, and specifically disclose preparation method.Biological test statistics indicate that, the crystal form A that R type isomeric compound and its xylenesulfonate provided by the invention all show preferable inhibitory activity, especially compound shown in Formula II to EGFR and Her2 tyrosine kinase obviously has preferably absorption and exposed amount.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5-
((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine R type stereoisomer, its dimethylbenzene
The polymorphic of sulfonate and the xylenesulfonate, and specifically disclose preparation method and as tyrosinase inhibitor
Purposes.
Background technique
Tumour is one of the important diseases for seriously threatening human health and life at present.Traditional oncotherapy is to pass through hair
Existing tumour is simultaneously destroyed come what is realized, deepens continuously now with what is studied cell signaling pathway, people are to tumour cell
Internal oncogene and antioncogene acts on the more and more deep of understanding, new for the specific molecular shot design of tumour
More and more attention has been paid to have become a hot topic of research field, and anti-tumor drugs targeting is as a kind of new treatment to anti-tumor drug
Method has also been applied to clinic, and has obtained significant progress in recent years.
In recent years, people are dedicated to inhibiting cellular signal transduction pathways to develop novel target spot anti-tumor drug.Small molecule
Tyrosine kinase inhibitor opens a fan new window as new anti-tumor drugs targeting, for the treatment and prevention of tumour, and
And its side effect is slight, there is good tolerance.Patent document CN102030742A is specifically disclosed to be inhibited as tyrosinase
4- (substituted anilinic) quinazoline derivant of agent, and specifically disclose compound N-(4- (3- fluorine benzyloxy) -3- chlorphenyl) -
6- (5- ((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine, the compound to EGFR and
Her2 all has higher external inhibitory activity；Existing test data shows the compound than similar commercialized product
LapatinibHave the function of preferably inhibiting tumour growth and good safety.Patent document
CN103304544A discloses N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethylamino)
Methyl) -2- furyl)-quinazoline -4- amine raceme xylenesulfonate and polymorphic.For more preferable, more effectively developmental research
The compound simultaneously can be potentially applied to clinic, the present invention to the optical isomer of the compound and its xylenesulfonate into
It has gone research, and the application is completed based on the research.
Summary of the invention
The present inventor is to develop with good physicochemical property or/and excellent pharmacological curative effect and be suitable for being prepared into pharmaceutical compositions
For the purpose of the compound of object form, to N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl
Amino) methyl) -2- furyl) stereoisomer of-quinazoline -4- amine studied, obtain its R- type isomers, institute
State the xylenesulfonate of isomers and the crystal form of the xylenesulfonate.Test data show the isomers and
Its xylenesulfonate has good bioactivity and cell inhibitory effect effect, and its xylenesulfonate and polymorphic
Also have better stability and medicine for characteristic, such as higher exposed amount and half-life period, is more suitable for preparation for preventing or treating
The drug of cancer, the present invention are based on this and complete.
First aspect present invention provides compound (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- shown in a kind of Formulas I
(5- ((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine or its pharmaceutically acceptable salt；
Second aspect of the present invention provides (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- shown in Formula II
(methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine xylenesulfonate, i.e. compound shown in Formulas I
Xylenesulfonate:
The present inventor is it has surprisingly been found that compound shown in Formula II can be deposited with more than one polymorph
, and two different crystal forms are prepared, it is respectively designated as crystal form A, crystal form B.Crystal form A and B is shown in water
Preferable dissolubility out is conducive to body absorption, distribution, has better stability, is conducive to pack and store.It is especially aobvious
Landing, which improves medicine, such as increases internal exposed amount for property, extends half-life period etc., be more applicable for preparation for prevent or
The drug for the treatment of cancer.For this purpose, the present invention provides the crystal forms of compound shown in Formula II.
Third aspect present invention provides the crystal form A of compound shown in Formula II, and the crystal form A is radiated using Cu-K α, with 2 θ
X-ray powder diffraction (i.e. X-RPD) map that angle indicates is at 4.6 ° ± 0.2 °, 4.8 ° ± 0.2 °, 9.2 ° ± 0.2 °, 12.6 °
± 0.2 °, 15.0 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.6 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ±
There is characteristic diffraction peak at 0.2 °.
Specifically, the crystal form A, is radiated using Cu-K α, and the X-ray powder diffraction collection indicated with 2 θ angles is at 4.6 °
± 0.2 °, 4.8 ° ± 0.2 °, 9.2 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.5 ± 0.2 °, 15.0 ° ± 0.2 °, 15.9 ° ± 0.2 °,
17.5 ° ± 0.2 °, 18.9 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.5 °
± 0.2 °, 20.9 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.7 ° ±
There is characteristic peak at 0.2 °, 27.0 ° ± 0.2 °, 27.3 ° ± 0.2 °.
In one embodiment of the invention, the crystal form A has X-RPD map as shown in Figure 1.
Crystal form A of the present invention is analyzed through differential scanning calorimetry (DSC), and map is at 140~158 DEG C, 242~250 DEG C
Occurs endothermic peak in range respectively；More specifically, the peak value of its endothermic peak respectively appears in 149.2 ± 2 DEG C, 249.7 ± 2 DEG C；
In one embodiment of the invention, crystal form A of the present invention has DSC map as shown in Figure 2.
Fourth aspect present invention provides the crystal form B of compound shown in Formula II, and the crystal form B is radiated using Cu-K α, with 2 θ
Angle indicate X-ray powder diffraction collection at 4.6 ° ± 0.2 °, 8.5 ° ± 0.2 °, 9.1 ° ± 0.2 °, 11.9 ° ± 0.2 °,
13.5 ° ± 0.2 °, 15.2 ° ± 0.2 °, 16.1 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.1 °
± 0.2 °, 19.4 ° ± 0.2 °, 19.6 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.3 ° ± 0.2 °, 22.8 ° ±
There is characteristic diffraction peak at 0.2 °, 22.9 ° ± 0.2 °, 26.3 ° ± 0.2 °, 27.1 ° ± 0.2 °.
Specifically, the crystal form B, is radiated using Cu-K α, and the X-ray powder diffraction collection indicated with 2 θ angles is at 4.6 °
± 0.2 °, 7.5 ° ± 0.2 °, 8.5 ° ± 0.2 °, 9.1 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.5 ° ± 0.2 °,
14.6 ° ± 0.2 °, 15.2 ° ± 0.2 °, 15.5 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.4 ° ± 0.2 °, 17.1 °
± 0.2 °, 17.5 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.4 ° ±
0.2 °, 19.6 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.3 ° ± 0.2 °,
22.8 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.4 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.8 ° ± 0.2 °, 26.3 ° ± 0.2 °, 27.1 °
There is characteristic peak at ± 0.2 °, 27.6 ° ± 0.2 °, 29.2 ° ± 0.2 °.
In one embodiment of the invention, the crystal form B has X-RPD map as shown in Figure 3.
Crystal form B of the present invention is analyzed through differential scanning calorimetry (DSC), and map is at 121~148 DEG C, 235~250 DEG C
Occurs endothermic peak in range respectively；More specifically, the peak value of its endothermic peak respectively appears in 131.8 ± 2 DEG C, 247.1 ± 2 DEG C；
In one embodiment of the invention, crystal form B of the present invention has DSC map as shown in Figure 4.
Fifth aspect present invention provides compound and its xylenesulfonate (chemical combination shown in Formula II shown in a kind of preparation formula I
Object) method, method includes the following steps:
(1) by (R) -2- first sulfoxide group ethamine (CAS:84104-28-9) and 5- (4- (4- (3- fluorine benzyloxy) -3- chlorobenzene
Amido) -6- quinazolyl) after furans -2- formaldehyde tosilate reacts under the effect of suitable alkali, then restore through reducing agent
To compound shown in Formulas I；Wherein, the suitable alkali be selected from triethylamine, diisopropyl ethyl amine, ammonium hydroxide, sodium carbonate, potassium carbonate,
One of sodium bicarbonate, saleratus are a variety of；The reducing agent is selected from sodium borohydride, Sodium triacetoxyborohydride, cyano
One of sodium borohydride is a variety of.
Or ((((methyl is sub- by 2- by 5- by chiral column resolving racemic N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6-
Sulfuryl) ethylamino) methyl) -2- furyl)-quinazoline -4- amine obtain Formulas I shown in compound.
(2) compound shown in Formulas I is reacted with p-methyl benzenesulfonic acid (i.e. TsOH), obtains compound shown in Formula II；
Preferably, the specific steps of step (2) are as follows: by (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5-
((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine be added tetrahydrofuran in, stirring and dissolving,
The ethanol solution of p-methyl benzenesulfonic acid is added, solid is precipitated, filtering obtains Formula II compound represented.
Sixth aspect present invention provides the method for the crystal form A of compound shown in preparation formula II a kind of, and this method includes following
Step:
Formula II compound represented is added in the mixed solution of tetrahydrofuran and water, heating stirring dissolution, cooling analysis
Crystalline substance, filtering, 60~100 DEG C of vacuum drying obtain the crystal form A of compound shown in Formula II；Wherein, the volume ratio of tetrahydrofuran and water is
3~15:1, preferably 5~10:1.
Seventh aspect present invention provides the method for the crystal form B of compound shown in preparation formula II a kind of, and this method includes following
Step:
Compound shown in Formula II is added in the mixed solution of second alcohol and water, heating stirring dissolution, cool down crystallization, mistake
Filter, 60~100 DEG C of vacuum drying, obtains the crystal form B of compound shown in Formula II；Wherein the volume ratio of second alcohol and water is 3~15:1,
It is preferred that 5~10:1.
Eighth aspect present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes Formulas I institute of the present invention
Show compound or its pharmaceutically acceptable salt and at least one optional pharmaceutically acceptable carrier or excipient；?
In a preferred embodiment of the invention, the pharmaceutically acceptable salt is xylenesulfonate；It is highly preferred that the dimethylbenzene
Sulfonate is one of crystal form A, crystal form B or its mixed crystal.
Ninth aspect present invention provides to be changed shown in compound shown in formula I or its pharmaceutically acceptable salt, Formula II
Object and its crystal form A, crystal form B are closed in preparation for treating and/or preventing mammal (including people) and receptor tyrosine kinase phase
Purposes in the disease of pass or the drug of illness.
Tenth aspect present invention provide eight, the nine aspect described pharmaceutical compositions of the invention preparation for treating and/or
Prevent the purposes in the drug of mammal (including people) disease relevant to receptor tyrosine kinase or illness.
Tenth one side of the invention provides a kind of for treating and/or preventing and receptor junket in mammal in need
The method of the relevant disease of histidine kinase or illness, this method include to the sheet of mammal in need application therapeutically effective amount
This hair of compound shown in invention Formulas I or its pharmaceutically acceptable salt or Formula II compound represented or effective dose
Pharmaceutical composition described in bright 8th or nine aspect.
In the present invention, described " disease relevant to receptor tyrosine kinase or illness " is preferably " by receptor tyrosine kinase
The tumour that enzyme mediates ", " by the proliferation and migration of the tumour cell of receptor tyrosine kinase driving ", more preferable erbB receptor junket ammonia
Acid kinase cancer susceptible, as EGFR or Her2 high expression and EGF drive tumour, specifically include entity tumor, as bile duct, bone,
Bladder, brain/central nervous system, breast, Colon and rectum, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung
Cancer), the cancer of neuron, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid gland, uterus and vulva etc., and
Non-solid tumors, such as leukaemia, Huppert's disease or lymthoma.According to the present invention completely it is expected that the compounds of this invention
It can be used for the prevention and/or treatment of above-mentioned disease or illness.
It should be noted that in the present invention, " compound shown in Formulas I " has the same meaning with " compound I ", refers to
Compound (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide with stereochemical structure shown in Formulas I
Base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine；" compound shown in Formula II " has identical with " compound II "
Meaning, refer to compound (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- with stereochemical structure shown in Formula II
((2- (methyl sulfoxide base) ethylamino) methyl) -2- furyl)-quinazoline -4- amine xylenesulfonate；The present invention is used
Raw material or reagent be all it is known in the art that can be prepared by disclosed prior art or can be with
It is commercially available by commercial system.For example, 5- (4- (4- (3- fluorine benzyloxy) -3- chloroanilino) -6- quinazolyl) furans -2-
Formaldehyde tosilate can be purchased from Shanghai Da Rui fine chemicals Co., Ltd or Shanghai Han Xiang Biotechnology Co., Ltd
It can buy, (R) -2- first sulfoxide group ethamine is referred to existing literature (Lim, Chin-Chin et al.Resolution and
Enantiomeric purities of [2- (methylsulfinyl) ethyl] amine, Tetrahedron:Asymmetry,
5 (1994): 1883-1886) it is prepared.
Compound shown in Formulas I of the present invention or its xylenesulfonate polymorph are for treating and/or preventing
When above-mentioned related disease or when being used to prepare pharmaceutical composition, it can be used as unique active pharmaceutical ingredient and be used alone,
Can with other active ingredient combinations or be used in combination, as long as it does not generate other detrimental effects, such as allergic reaction.Combining makes
With can by by each therapeutic component simultaneously, sequence or separate administration and realize.
Term used herein " composition " mean include comprising specified amount each specified ingredient product, and directly
Or any product generated indirectly from the combination of each specified ingredient of specified amount.Those skilled in the art can be by changing this hair
The actual dose of each active constituent is horizontal in bright pharmaceutical composition, so that resulting reactive compound amount can effectively be suffered from for specific
Person, composition and administration mode obtain required therapeutic response.Dosage level need to be according to the activity of particular compound, administration way
Diameter, the patient's condition of the severity of the treated patient's condition and patient to be treated and medical history are selected.But the way of this field
It is that the dosage of compound gradually increases dosage, until obtaining since less than obtaining required therapeutic effect and desired level
Required effect.In the present invention, described pharmaceutical composition can especially particular formulation in solid or liquid form for take orally to
Medicine, for parental injection or for rectally.
Compound shown in the Formulas I of the present invention of term " treatment and/or prevention effective dose " or its is pharmaceutically acceptable
Salt refer to be suitable for the compound of the reasonable effect of any therapeutic treatment and/or prevention/Hazard ratio treatment obstacle sufficient amount.
It is to be understood that total consumption per day of compound shown in formula I or its pharmaceutically acceptable salt and composition must be examined by master
Doctor makes decision in reliable medical judgment scope.For any specific patient, specific treatment effective dose is horizontal
Must be depending on many factors, the factor includes the severity of treated obstacle and the obstacle；Used materialization
Close the activity of object；Used concrete composition；Age, weight, general health, gender and the diet of patient；It is used
Particular compound administration time, administration route and excretion rate；Duration for the treatment of；It is combined with used particular compound
Using or the drug that uses simultaneously；And similar factor well known to medical field.For example, the way of this field is, the agent of compound
It measures since less than obtaining required therapeutic effect and desired level, dosage is gradually increased, until obtaining required effect.One
As in fact, the dosage of compound shown in formula I or its pharmaceutically acceptable salt for mammal especially people can be with
Between 0.001~1000mg/kg body weight/day, such as between 0.01~100mg/kg body weight/day, such as between 0.01~10mg/
Kg body weight/day.
Biological activity test of the present invention statistics indicate that, shown in compound shown in Formulas I or its pharmaceutically acceptable salt, Formula II
Compound all shows preferable inhibitory activity to EGFR and Her2 tyrosine kinase, and to EGFR and Her2 tyrosine kinase
Highly expressed cell strain has an inhibiting effect, and with raceme N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (first
Base sulfoxide group) ethylamino) methyl) -2- furyl)-quinazoline -4- amine compares, two compound in dissolution dissolution, stablize
Property, vitro kinase activity, the inhibiting effect (such as tumor control rate) of part specific tumors cell strain, cytotoxicity, medicine are for power
Learning (such as drug absorption, exposed amount) etc. has different degrees of raising and improvement；Therefore, compound shown in formula I
With compound shown in Formula II can be used for EGFR and Her2 receptor tyrosine kinase individually or part mediate disease, mainly pass through suppression
One or more EGFR families tyrosine kinase is made, and is made by inhibiting the activity of kinases to generate antiproliferative, anti-migration, promoting apoptosis
With.Specifically, compound shown in Formulas I or its pharmaceutically acceptable salt can pass through the inhibition to EGFR and Her2 tyrosine kinase
Effect, for preventing and treating the tumour of one or more erbB receptor tyrosine kinase sensitivities, especially EGFR or Her2 high
The tumour of expression and EGF driving.Including entity tumor such as bile duct, bone, bladder, brain/central nervous system, breast, Colon and rectum, son
Endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neuron, esophagus, ovary, pancreas, prostate, kidney,
Skin, testis, thyroid gland, uterus and vulva cancer, non-solid tumors such as leukaemia, Huppert's disease or lymthoma.
Detailed description of the invention
The X-RPD map for the crystal form A that Fig. 1 embodiment 4 obtains；
The DSC-TGA map for the crystal form A that Fig. 2 embodiment 4 obtains；
The X-RPD map for the crystal form B that Fig. 3 embodiment 5 obtains；
The DSC-TGA map for the crystal form B that Fig. 4 embodiment 5 obtains.
Specific embodiment
Below by way of specific embodiment, above content of the invention is described in further detail, but should not be incited somebody to action
This is interpreted as any restrictions to the scope of the present invention.All technical solutions realized based on above content of the present invention are belonged to
The scope of the present invention.The present invention to used in test to material and test method carry out general and/or specifically retouch
It states.If not specified during the present invention is described below, the operation carried out is the progress under room temperature of this field routine, institute
Room temperature is stated with art-recognized meanings well known in the art, generally refers to 20~35 DEG C, preferably 20~30 DEG C, more preferable 20~25 DEG C.
Inspection apparatus used in the present invention:
(1) nuclear magnetic resoance spectrum
Instrument model: Varian INOVA-600 Nuclear Magnetic Resonance
Test condition: solvent DMSO-d6
(2) mass spectroscopy molecular measures fixed
Instrument model: Agilent 1100LC/MSD LC-MS instrument
Test condition: ESI
(3) specific rotation
Instrument model: Rudoiph (Rudolph) company Autopol IV automatic polarimeter
Test condition: temperature: 20 DEG C, D lamp wavelength: 589nm, methanol solution, concentration: 1mg/ml
(4) thermogravimetric and differential thermal
Instrument model: 1 synchronous solving of METTLER TOLEDO TGA/DSC
Test condition: 30~270 DEG C of temperature range, 10 DEG C/min of heating rate
(5) crystal form X-ray powder diffraction
Instrument model: PANalytical x-ray powder diffraction instrument (model: X ' Pert PRO MPD)
Test condition: radiation source: Cu KαRay, 40kV, 40mA；Divergent slit: 1/8 °；Antiscatter slits: 1/4 °；It sweeps
Retouch mode: continuous scanning；Scanning range (2 θ): 3~45 °；Scanning step (2 θ): 0.026 °；Scanning speed: 8 °/min；
Embodiment 1:(R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl) and-quinazoline -4- amine (compound I) preparation:
By 5- (4- (4- (3- fluorine benzyloxy) -3- chloroanilino) -6- quinazolyl) furans -2- formaldehyde tosilate
(16g) is dissolved in methylene chloride/methanol (VMethylene chloride: VMethanolIn mixed solution for 3:1), 12ml triethylamine is added and is stirred to react
10min is added (R) -2- first sulfoxide group ethamine (8.0g), reaction is stirred at room temperature, TLC detects raw material after completion of the reaction, under ice bath
It is added portionwise sodium borohydride (4.0g), TLC detects end of reaction, and 500ml methylene chloride, isometric saturated ammonium chloride solution is added
Washing, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, and decompression steams solvent, and residue chromatographs to obtain yellow solid through column
13.3g, as ((R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethylamino) first
Base) -2- furyl)-quinazoline -4- amine xylenesulfonate (compound I), HPLC purity 97.03%.
1H-NMR(600MHz,DMSO-d6,δppm): 9.92 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.16 (d, 1H,
), J=8.4Hz 8.01 (s, 1H), 7.79 (d, 1H, J=8.8Hz), 7.75 (dd, 1H, J=2.0Hz, J=8.4Hz), 7.47
(m, 1H), 7.28-7.35 (m, 3H), 7.19 (m, 1H), 7.05 (d, 1H, J=2.4Hz), 6.48 (d, 1H, J=2.4Hz),
5.27(s,2H),3.84(s,2H),2.94(m,3H),2.83(m,1H),2.56(s,3H).[a]D=33.883 ± 0.847.Rt
=17.613；
ESI-MS(m/z):[M+H]+: 565.1.
Embodiment 2:(R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl) and-quinazoline -4- amine (compound I) preparation
By N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethylamino) methyl) -2-
Furyl)-quinazoline -4- amine raceme (R/S isomer proportion 49.55/50.45, preparation method such as patent CN102030742
It is described) by partly preparing chiral column fractionation, splitting condition is as follows: instrument: high performance liquid chromatograph, UV detector；Chromatographic column:
Surface apply (the 3,5- xylyl carbamate) silica gel of amylose-three be filler (AD-H, 20 ×
250mm)；Column temperature: 30 DEG C；Mobile phase: dehydrated alcohol-n-hexane (32:28) of 0.2% diethylamine；Detection wavelength: 220nm；Stream
Speed: 1.0ml/min.Wherein (R)-N- (4- (3- fluorine benzyloxy) 3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl)-quinazoline -4- amine is first eluted out.[a]D=35.016 ± 0.385 (HPLC purity
98.93%).
Embodiment 3:(R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl) and-quinazoline -4- amine xylenesulfonate (compound II) preparation
Compound I (4g, 7.08mmol) prepared in embodiment 1 is added in 10ml tetrahydrofuran, stirring and dissolving adds
The ethanol solution (10ml) for entering p-methyl benzenesulfonic acid (3.66g, 21.02mmol), is precipitated rapidly yellow solid, filters, dries, obtain
6.04g amorphous solid is (R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl
Amino) methyl) -2- furyl)-quinazoline -4- amine xylenesulfonate (compound II), yield 94.1%.
Embodiment 4:(R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl) and-quinazoline -4- amine xylenesulfonate (compound II) crystal form A preparation
Gained compound II (2g) in embodiment 3 is added in the mixed solution of 40ml tetrahydrofuran and 5ml water, heating is stirred
After mixing dissolution, cool down crystallization, filters, and 80 DEG C of vacuum dryings obtain 1.49g yellow crystalline powder, and yield 74.5%, HPLC is pure
Degree 97.09%；After measured, X-RPD map is as shown in Figure 1, its DSC-TGA map is as shown in Figure 2.
Crystal form A:1H-NMR(400MHz,DMSO-d6,δppm): 11.34 (s, 1H), 9.29 (s, 2H), 9.02 (s, 1H),
8.93 (s, 1H), 8.43 (d, 1H, J=8.8Hz), 7.93 (d, 1H, J=8.8Hz), 7.88 (d, 1H, J=1.6Hz), 7.62
(dd, 1H, J=1.6Hz, J=8.4Hz), 7.49 (m, 1H), 7.48 (d, 4H, J=7.6Hz), 7.34 (m, 3H), 7.25 (d,
1H, J=2.8Hz), 7.22 (m, 1H), 7.10 (d, 4H, J=7.6Hz), 6.89 (d, 1H, J=1.2Hz), 5.32 (s, 2H),
(4.47 s, 2H), 3.48 (m, 2H), 3.24 (m, 2H), 3.06 (m, 2H), 2.66 (s, 3H), 2.28 (s, 6H) .Rt=17.707；
[a]D=25.671 ± 0.519.
Embodiment 5:(R)-N- (4- (3- fluorine benzyloxy) -3- chlorphenyl) -6- (5- ((2- (methyl sulfoxide base) ethyl ammonia
Base) methyl) -2- furyl) and-quinazoline -4- amine xylenesulfonate (compound II) crystal form B preparation
Gained compound II (2g) in embodiment 3 is added in the mixed solution of 40ml ethyl alcohol and 6ml water, heating stirring is molten
Xie Hou, cool down crystallization, filters, and 80 DEG C of vacuum dryings obtain 1.62g yellow crystalline powder, yield 81%, HPLC purity
99.37%；After measured, X-RPD map is as shown in figure 3, its DSC-TGA map is as shown in Figure 4.
Crystal form B:1H-NMR(400MHz,DMSO-d6,δppm): 11.40 (s, 1H), 9.30 (s, 2H), 9.04 (s, 1H),
8.94 (s, 1H), 8.44 (d, 1H, J=8.8Hz), 7.93 (d, 1H, J=8.4Hz), 7.87 (d, 1H, J=2.0Hz), 7.62
(dd, 1H, J=1.6Hz, J=8.4Hz), 7.49 (m, 1H), 7.48 (d, 4H, J=7.6Hz), 7.34 (m, 3H), 7.26 (d,
1H, J=3.2Hz), 7.21 (m, 1H), 7.10 (d, 4H, J=7.6Hz), 6.89 (d, 1H, J=2.8Hz), 5.32 (s, 2H),
(4.48 s, 2H), 3.49 (m, 2H), 3.24 (m, 2H), 3.06 (m, 2H), 2.66 (s, 3H), 2.28 (s, 6H) .Rt=17.656；
[a]D=27.112 ± 0.551.
By preparing different crystal, it has been found that an interesting phenomenon: the optical purity and raw material of the crystal form A of precipitation
The optical purity of (compound I) is approximate；The crystal form B optical purity of precipitation is higher, is higher than the optical purity of raw material (compound I),
It is easier to prepare.
Dissolubility test
The present invention respectively studies the solubility of compound I, compound II crystal form A, compound II crystal form B, side
Method are as follows: take sample Compound Compound I (2.5mg), compound II crystal form A (250mg), compound II crystal form B (250mg), set
In the iodine flask of 250ml, water is added to be settled to 250ml, at interval of strength shaking in 5 minutes 30 seconds, observation 30 at 25 DEG C ± 2 DEG C
Dissolution situation in minute.Test result is shown in Table 1.
Table 1, solubility test test result
| Sample ID | Test specimen quality | Dissolve situation | Solubility |
| Compound I | 2.5mg | Non- Quan Rong | It is insoluble |
| Compound II crystal form A | 250mg | Dissolution | Slightly soluble |
| Compound II crystal form B | 250mg | Dissolution | Slightly soluble |
The result shows that: compound I is insoluble in water, crystal form A, B of compound II slightly soluble in water, illustrates that crystal form A, B have
There is better dissolubility, is more advantageous to the dissolution of drug in vivo than compound I.
Biological test
For it is more preferable, compound crystal form A, Formula II shown in compound shown in Formulas I of the present invention, Formula II are studied deeper into ground
The biological activity and pharmacokinetic characteristics of shown compound crystal form B, experiment is to measure institute of the present invention below the present inventor
Compound is stated in vitro to press down the proliferation of EGFR/HER2 high expression cancer cell (A431, SKOV-3, N87 cell and BT474 cell)
Production is used and pharmacokinetic characteristics.
A) cell inhibitory effect is tested
With reference to Rusnak etc., Cell Prolif, method described in 2007,40,580-594 is tested.Cell Proliferation
Tumor cell line A431, SKOV-3, BT474 and the NCI-N87 for inhibiting test to be overexpressed using EGFR or HER2.
Eagle culture medium is improved in the Dulbecco containing 10% fetal calf serum, 2mM glutamine and nonessential amino acid
(DMEM) in, in 37 DEG C, 5%CO2Cell is cultivated in cell incubator, using trypsase/ethylenediamine tetra-acetic acid (EDTA) from
Cell is harvested in Tissue Culture Flask.Cell is adherent overnight with 4000/ hole (0.1ml culture medium) addition, 96 porocyte culture plates, adds
Enter the dilution of 0.1ml untested compound, the ultimate density of DMSO is 0.25%, by tissue culture plate in 37 DEG C, 5% CO2
Under the conditions of cultivate 72h, observe the variation of cellular morphology under the microscope, discard culture solution, then 10% trichlorine is added in every hole
Acetic acid (TCA) fixes cell, and 4 DEG C of placement 1h, each hole of culture plate is rinsed 5 times with deionized water, and to remove TCA, drying, air is done
It is dry to without wet mark.Every hole adds mass fraction to be 0.4% 100 μ l of SRB (Sulforhodamine B), is placed at room temperature for 20min, discards each
It is rinsed 5 times after liquid with 1% acetic acid in hole, uses 10mM Tris (trishydroxymethylaminomethane, pH 10.5) after being air-dried
150 μ l extraction, detects the absorbance at 550nm wavelength, with the logarithm (lg [concentration]) of compound concentration for abscissa, inhibits
Rate is ordinate, then does dose-effect curve fitting using 5 software of GRAPHPAD PRISM, calculates to obtain IC50It is worth (nM).Knot
Fruit is shown in Table 2.
The test of 2 cell inhibitory effect of table
Above-mentioned test result shows that the compounds of this invention I, compound II crystal form A, compound II crystal form B are effective junket
Histidine kinase inhibitor, can be realized to EGFR/HER2 high expression cancer cell (A431, SKOV-3, NCI-N87 and BT474 are thin
Born of the same parents) Proliferation Ability, and in-vitro multiplication inhibitory effect is approximate.
B) Pharmacokinetic Evaluation:
Healthy SD rat 9, male, weight 200-220g is randomly divided into 3 groups (every group 3), and single oral gavage is given respectively
Compound crystal form A shown in Formula II, compound crystal form B shown in Formula II, dosage are 100mg/kg, drug is with 10% tween
80 add 90% deionized water to prepare.Fasting 12h, free water before testing.2h is unified after administration feeds.After administration 0,1.0,
3.0,10 and blood 0.3ml is taken through rat eye rear vein beard for 24 hours, set in heparinised tubes, 5min is centrifuged with 11000rpm speed,
Separated plasma, 20 DEG C of preservations.With the compound I and its metabolite Lapatinib in liquid chromatography tandem mass spectrometry measurement blood plasma
(Lapatnib) concentration investigates the Pharmacokinetic Characteristics and internal metabolic stability of crystal form A and B, the results are shown in Table 3:
The pharmacokinetics of 3 drug metabolite of table is tested
*The metabolite Lapatinib detected in blood plasma
It is calculated with compound I and active metabolite, crystal form A obviously has preferably absorption and exposed amount, Isodose
Under, maximum plasma concentration or area under the drug-time curve are about 1.3 times of crystal form B.It is expected that crystal form A has better body than crystal form B
Interior anti-tumor activity.
Claims (19)
1. a kind of crystal form A of compound shown in Formula II, is radiated using Cu-K α, the X-ray powder diffraction figure indicated with 2 θ angles
It composes at 4.6 ° ± 0.2 °, 4.8 ° ± 0.2 °, 9.2 ° ± 0.2 °, 12.6 ° ± 0.2 °, 15.0 ° ± 0.2 °, 19.1 ° ± 0.2 °,
There is characteristic diffraction peak at 19.6 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °,
2. crystal form A described in claim 1 is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angles is at 4.6 °
± 0.2 °, 4.8 ° ± 0.2 °, 9.2 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.5 ± 0.2 °, 15.0 ° ± 0.2 °, 15.9 ° ± 0.2 °,
17.5 ° ± 0.2 °, 18.9 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.6 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.5 °
± 0.2 °, 20.9 ° ± 0.2 °, 21.5 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.8 ° ± 0.2 °, 24.7 ° ±
There is characteristic peak at 0.2 °, 27.0 ° ± 0.2 °, 27.3 ° ± 0.2 °.
3. crystal form A described in claim 1 has X-RPD map as shown in Figure 1.
4. described in any item crystal form A according to claim 1~3, which is characterized in that the DSC map of the crystal form A 140~
Occurs endothermic peak respectively within the scope of 158 DEG C, 242~250 DEG C.
5. any one crystal form A according to claim 1~3, which is characterized in that the endothermic peak of the DSC map of the crystal form A
Peak value respectively appears in 149.2 ± 2 DEG C, 249.7 ± 2 DEG C.
6. any one crystal form A according to claim 1~3, which is characterized in that the crystal form A has DSC as shown in Figure 2
Map.
7. a kind of crystal form B of compound shown in Formula II, is radiated using Cu-K α, the X-ray powder diffraction figure indicated with 2 θ angles
It composes at 4.6 ° ± 0.2 °, 8.5 ° ± 0.2 °, 9.1 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.5 ° ± 0.2 °, 15.2 ° ± 0.2 °,
16.1 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.6 °
± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.3 ° ± 0.2 °, 22.8 ° ± 0.2 °, 22.9 ° ± 0.2 °, 26.3 ° ±
There is characteristic diffraction peak at 0.2 °, 27.1 ° ± 0.2 °,
8. crystal form B described in claim 7 is radiated using Cu-K α, the X-ray powder diffraction collection indicated with 2 θ angles is at 4.6 °
± 0.2 °, 7.5 ° ± 0.2 °, 8.5 ° ± 0.2 °, 9.1 ° ± 0.2 °, 11.9 ° ± 0.2 °, 12.9 ° ± 0.2 °, 13.5 ° ± 0.2 °,
14.6 ° ± 0.2 °, 15.2 ° ± 0.2 °, 15.5 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.1 ° ± 0.2 °, 16.4 ° ± 0.2 °, 17.1 °
± 0.2 °, 17.5 ° ± 0.2 °, 18.2 ° ± 0.2 °, 18.4 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.1 ° ± 0.2 °, 19.4 ° ±
0.2 °, 19.6 ° ± 0.2 °, 20.0 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.6 ° ± 0.2 °, 22.3 ° ± 0.2 °,
22.8 ° ± 0.2 °, 22.9 ° ± 0.2 °, 23.4 ° ± 0.2 °, 25.0 ° ± 0.2 °, 25.8 ° ± 0.2 °, 26.3 ° ± 0.2 °, 27.1 °
There is characteristic peak at ± 0.2 °, 27.6 ° ± 0.2 °, 29.2 ° ± 0.2 °.
9. crystal form B described in claim 7 has X-RPD map as shown in Figure 3.
10. the crystal form B according to claim 7~9, which is characterized in that the DSC map of the crystal form B 121~148 DEG C,
Occurs endothermic peak respectively within the scope of 235~250 DEG C.
11. according to the described in any item crystal form B of claim 7~9, which is characterized in that the DSC map endothermic peak of the crystal form B
Peak value respectively appear in 131.8 ± 2 DEG C, 247.1 ± 2 DEG C.
12. according to the described in any item crystal form B of claim 7~9, which is characterized in that the crystal form B has as shown in Figure 4
DSC map.
13. a kind of method for preparing any one of claim 1~6 crystal form A, method includes the following steps:
Formula II compound represented is added in the mixed solution of tetrahydrofuran and water, heating stirring dissolution, cool down crystallization, mistake
Filter, 60~100 DEG C of vacuum drying, obtains the crystal form A of compound shown in Formula II.
14. according to the method for claim 13, which is characterized in that the volume ratio of tetrahydrofuran and water is 3~15:1.
15. according to the method for claim 13, which is characterized in that the volume ratio of tetrahydrofuran and water is 5~10:1.
16. a kind of method for preparing any one of claim 7~12 crystal form B, method includes the following steps:
Compound shown in Formula II being added in the mixed solution of second alcohol and water, heating stirring dissolution, cool down crystallization, filtering, and 60
~100 DEG C of vacuum drying, obtain the crystal form B of compound shown in Formula II.
17. according to the method for claim 16, which is characterized in that the volume ratio of second alcohol and water is 3~15:1.
18. according to the method for claim 16, which is characterized in that the volume ratio of second alcohol and water is 5~10:1.
19. a kind of pharmaceutical composition, it includes any selected from any one of the claim 1~6 crystal form A, claim 7~12
One of described crystal form B of item or its mixed crystal and at least one optional pharmaceutically acceptable carrier or excipient.
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