CN107721985A - The crystal formation of quinazolines tyrosine kinase inhibitor - Google Patents
The crystal formation of quinazolines tyrosine kinase inhibitor Download PDFInfo
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- CN107721985A CN107721985A CN201710685254.5A CN201710685254A CN107721985A CN 107721985 A CN107721985 A CN 107721985A CN 201710685254 A CN201710685254 A CN 201710685254A CN 107721985 A CN107721985 A CN 107721985A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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 crystal formation of quinazolines tyrosine kinase inhibitor.The invention belongs to field of medicaments, more particularly to a kind of Pan HER tyrosine kinase inhibitors, the crystal formation A of compound (E) N (base of 4 ((fluorophenyl of 3 chlorine 4) amino) 7 methoxyquinazoline hydrochloride 6) 4 (base of 2 azaspiros [3.3] heptane 2) 2 crotonamides, its preparation method, pharmaceutical composition i.e. shown in formula (I), and its prepare be used for treat and/or prevent hyperproliferative disease or the medicine of chronic obstructive pulmonary disease in application.
Description
1st, technical field
The present invention relates to a kind of crystal formation of quinazolines tyrosine kinase inhibitor and preparation method thereof, pharmaceutical composition,
And its prepare be used for treat and/or prevent hyperproliferative disease and/or the medicine of chronic obstructive pulmonary disease in application.
2nd, background technology
Compound (E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros
Ring [3.3] heptane -2- bases) -2- crotonamides (abbreviation formula (I) compound in specification, in patent application WO2012/159457
In have been described) for Pan-HER can not retroactive inhibition quinazoline derivative species tyrosine kinase inhibitor.Research shows, Pan-
HER tyrosine kinase irreversible inhibitors are also inhibited to HER2/4 in addition to effectively suppressing EGFR, this to HER/
There are the medicine of Irreversible inhibition in ErbB families in addition to pharmaceutical activity is improved, and also reduce the generation of drug resistance, especially
Have to the H1975 cell lines of Erlotinib resistances and significantly inhibit effect, given play to good antitumor activity.
The research of crystal formation plays an important role in drug development process, and the different crystal forms of same medicine are dissolving
Degree, stability, bioavilability etc. are there is significant difference, in order to better control over the quality of medicine, meet preparation,
The requirement of situations such as production, transport, storage, we are studied the crystal formation to formula (I) compound, good to find to have
The crystal formation of property.
3rd, the content of the invention
The present invention relates to (the 4- ((the chloro- 4- fluorophenyls of 3-) of Pan-HER tyrosine kinase inhibitors (E)-N- shown in formula (I)
Amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystal formation A, its
Preparation method, the pharmaceutical composition comprising the crystal formation, and these compounds are being prepared for treating and/or preventing hyperplasia
Application in the medicine of disease and/or chronic obstructive pulmonary disease.
Specifically, the present invention provides：
(1) the crystal formation A, described crystal formation A of a kind of formula (I) compound have following architectural feature：Radiated using Cu-K α,
The X-ray powder diffraction represented with 2 θ angles, 6.5 ± 0.2 °, 9.0 ± 0.2 °, 14.5 ± 0.2 °, 16.7 ± 0.2 °, 18.0
There is characteristic peak at ± 0.2 °.
(2) the crystal formation A of formula (I) compound described in above-mentioned (1), it has following architectural feature：Radiated using Cu-K α,
The X-ray powder diffraction represented with 2 θ angles, on the basis of comprising features described above peak, also 12.3 ± 0.2 °, 18.5 ±
There is characteristic peak at 0.2 °, 19.4 ± 0.2 °, 20.7 ± 0.2 °, 23.3 ± 0.2 °, 25.1 ± 0.2 °.
(3) the crystal formation A of formula (I) compound described in above-mentioned (2), it has following architectural feature：Radiated using Cu-K α,
The X-ray powder diffraction represented with 2 θ angles, on the basis of comprising features described above peak, also 19.7 ± 0.2 °, 22.8 ±
There is characteristic peak at 0.2 °, 24.5 ± 0.2 °, 26.5 ± 0.2 °, 27.2 ± 0.2 °.
(4) the crystal formation A of formula (I) compound described in above-mentioned (3), is radiated, the X-ray represented with 2 θ angles using Cu-K α
Powder diffraction, its X-ray powder diffraction figure are as shown in Figure 1.
(5) the crystal formation A of formula (I) compound described in above-mentioned (1)~(4), in DSC thermal maps spectrum, temperature is in about 170-190
An endothermic transition peak at DEG C be present, transition temperature when maximum is absorbed heat, i.e., the temperature at endotherm peak, be 183.89 ± 3 DEG C,
Its dsc analysis figure is as shown in Figure 2.
(6) the crystal formation A of formula (I) compound described in above-mentioned (1)~(4), in TGA collection of illustrative plates, its temperature is less than 210-
At 230 DEG C, preferably 220 DEG C, its weightlessness is 0-1%, and institute's weight loss is impurity, free water and/or organic solvent in crystal formation
Weight, during higher than the temperature, degrade, its TGA collection of illustrative plates is as shown in Figure 3.
(7) formula (I) compound described in can be prepared by the method disclosed in patent WO2012/159457, its
Compound hydrogen spectrum (1H-NMR) as shown in Figure 4.
(8) the crystal formation A of formula (I) compound described in preparation method, is prepared by following steps：
Formula (I) compound is washed and starched into 50-80h in 30-70 DEG C of organic solvent, then filtered, dries, produces crystal formation A.
The crystal formation A of described formula (I) compound preparation method, formula (I) compound is preferably in 40-60 DEG C of organic solvent
In wash and starch 60-80h.
The crystal formation A of described formula (I) compound preparation method, formula (I) compound is preferably in 45-55 DEG C of organic solvent
In wash and starch 70-75h.
The crystal formation A of described formula (I) compound preparation method, formula (I) compound is preferably in 50 DEG C of organic solvent
Wash and starch 72h.
Above-described to wash and starch what is preferably carried out under air-proof condition, described drying is preferably under vacuum, more excellent
It is selected at 45 DEG C and is dried in vacuo 16h.
The crystal formation A of described formula (I) compound preparation method, described organic solvent refer to that nitrile solvents, esters are molten
The mixed solvent of formation is combined between agent, ether solvent, ketones solvent or its two or more any solvent.
Described nitrile solvents, preferably acetonitrile or propionitrile；
Described esters solvent, including fatty esters and aromatic ester solvent, the fatty esters solvent is preferably formic acid
Methyl esters, Ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetic acid are different
Butyl ester, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, more preferably Ethyl formate, methyl acetate, acetic acid
Ethyl ester, propyl acetate, the aromatic ester solvent such as repefral；
Described ether solvent, preferably fatty ethers or cyclic ether solvents, the fatty ether solvent be preferably ether,
Dipropyl ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), ethyl-butyl ether, ethyl tert-butyl ether (ETBE), butyl oxide, more preferably diamyl ether, first
Base tertbutyl ether, ethyl-butyl ether, ethyl tert-butyl ether (ETBE), the cyclic ether solvents be preferably oxirane, 1,2- expoxy propane,
Tetrahydrofuran, 2- methylfurans, dioxolanes or Isosorbide-5-Nitrae-dioxane, more preferably tetrahydrofuran, 2- methylfurans；
Described ketones solvent, preferably alkanones and ring ketones solvent, described alkanones solvent is preferably first
Ethyl ketone, first isopropyl acetone, acetone, espeleton or methylisobutylketone, more preferably acetone, described ring ketones solvent is preferably ring
Acetone, cyclohexanone, isophorone, 1-METHYLPYRROLIDONE, more preferably 1-METHYLPYRROLIDONE；
Listed instantiation is not limited in nitrile indicated above, esters, ethers and ketones solvent, it is every
The solvent belonged in above-mentioned classification can realize the function of the present invention, that is, the crystal formation A shown in formula (I) is prepared.
Described " mixed solvent " refers to that one species or different kinds of liquid solvents are according to specific in above-mentioned organic solvent
The solvent that ratio is mixed to form.The mixed solvent that one species solvent is formed, including but not limited to example in detail below：Acetonitrile/
Propionitrile, ethyl acetate/propyl acetate, methyl tertiary butyl ether(MTBE)/ethyl-butyl ether, first isopropyl acetone/acetone, acetone/N- methylpyrroles
Alkanone.The mixed solvent that described variety classes solvent is formed, including but not limited to following mixed solvent system：Esters/nitrile,
Esters/ethers, esters/ketone, nitrile/ethers, nitrile/ketone, ketone/ethers, preferred fat esters/cyclic ketones class, cyclic ketones class/
Fatty ethers, cyclic ketones class/cyclic ethers class, alkanones/fatty ethers, alkanones/cyclic ethers class, preferably acetonitrile/N- methylpyrroles
Alkanone, acetonitrile/acetone, ethyl acetate/1-METHYLPYRROLIDONE, 1-METHYLPYRROLIDONE/methyl tertiary butyl ether(MTBE), N- methylpyrroles
Alkanone/ethyl tert-butyl ether (ETBE), 1-METHYLPYRROLIDONE/tetrahydrofuran, acetone/methyl tertiary butyl ether(MTBE), acetone/ethyl tert-butyl
Ether, acetone/tetrahydrofuran；Described solvent mixture proportions are 30:1-1:30, preferably 25:1‐1:25, preferably 20:1‐1:20.
(9) present invention also provides the crystal formation A and one or more pharmaceutical carriers and/or the medicine of diluent of formula (I) compound
Compositions, the pharmaceutical composition can be prepared into pharmaceutically acceptable any formulation, with oral, parenteral, rectum or transpulmonary
The modes such as administration, which are applied to, needs its patient.During for being administered orally, conventional solid pharmaceutical preparation is can be made into, such as tablet, capsule
Agent, pill, granule etc.；It may be made as oral liquid, such as oral solution, oral suspensions, syrup.Mouth is made
During formulation, suitable filler, adhesive, disintegrant, lubricant etc. can be added.During for parenteral, it can be made into
Injection, including parenteral solution, injection sterile powder and concentrated solution for injection.When injection is made, existing pharmacy can be used to lead
Conventional method production in domain, when preparing injection, can be added without additives, can also be added suitably according to the property of medicine
Additives.During for rectally, suppository etc. can be made into.During for transpulmonary administration, inhalant or spray etc. can be made into.
(10) present invention also provides treatment and/or the method for prevention excessively proliferative disease and/or chronic obstructive pulmonary disease, its
Including to needing patient of this treatment to give (E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyl group quinoline azoles of effective dose
Quinoline -6- bases) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystalline A form.The effective dose refers to medicine
Thing acts on body, body useful effect is occurred or the minimum effective dose of pharmacodynamics effect occurs and medicine that patient is resistant to
Thing produces the scope of dosage needed for ceiling effect.
(11) present invention also provide formula (I) compound crystal formation A prepare treatment and/or prevention excessively proliferative disease and/
Or the application in the medicine of chronic obstructive pulmonary disease.
Described excessively proliferative disease is selected from：Brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, carcinoma of urinary bladder,
Stomach cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney
Cancer, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, NHL, central nerve neuroma (glioma,
Glioblastoma multiforme, glioma sarcomatosum), prostate cancer, thyroid cancer, the hyperplasia of prostate of skin or prostate.
(12) present invention also provides the crystal formation A and the treatment preparation of one or more second of formula (I) compound composition, can
These second treatment preparations and the crystal formation A of formula (I) compound are simultaneously or sequentially administered, excessively increased for treating and/or preventing
Raw disease and/or chronic obstructive pulmonary disease.The second therapeutic agent is selected from antimetabolite, including capecitabine, gemcitabine；It is raw
Long factor inhibitors, including pazopanib, Imatinib；Antibody, including Trastuzumab, bevacizumab；Mitotic inhibitor, bag
Include taxol, vinorelbine, docetaxel, Doxorubicin；Antitumor steroids, including Letrozole, tamoxifen, fluorine dimension department
Group；Alkylating agents, including endoxan, BCNU；Metal platinum class, including carboplatin, cis-platinum, oxaliplatin；Topoisomerase
Inhibitor, including Topotecan；Immunosupress class, including everolimus.
The crystal formation A of formula (1) compound major advantage includes：
(1) compound (E)-N- (4- ((the chloro- 4- fluorobenzene of 3-) amino) -7- methoxyquinazoline hydrochlorides -6- provided by the invention
Base) -4- (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides crystal formation A preparation method it is easy to operate, be adapted to industry
Metaplasia is produced；
(2) the crystal formation A provided by the invention has good character, be easy to produce, detect, it is prepared by preparation, transport and
Storage；
(3) purity of the crystal formation A provided by the invention is high, residual solvent is few, and solubility is higher, and stability is good, quality
It is easily-controllable；
(4) the crystal formation A provided by the invention has good inhibitory activity to Pan-Her kinases, in vivo with good
Good exposed amount and/or bioavilability；
(5) the crystal formation A provided by the invention has good antitumous effect, excessive available for treatment and/or prevention
Proliferative disease and/or chronic obstructive pulmonary disease.
4th, illustrate
Fig. 1 is the crystal formation A of formula (I) compound X-ray powder diffraction collection, and ordinate represents diffracted intensity
(intensity), abscissa represents angle of diffraction (2 θ).
Fig. 2 is the crystal formation A of formula (I) compound means of differential scanning calorimetry (DSC) analysis chart, and ordinate represents hot-fluid (W/g),
Abscissa represents temperature T (DEG C).
Fig. 3 is the crystal formation A of formula (I) compound thermogravimetric analysis (TGA) curve and difference quotient thermogravimetric analysis (DTG) curve, horizontal
Coordinate is temperature (DEG C), and left side ordinate represents weight (%), and right side ordinate represents weight loss rate (%) and the relation of temperature.
Fig. 4 is formula (I) compound1H-NMR。
X-ray powder diffraction (X-ray Powder Diffraction, XRPD) refers to that beam of x-rays is irradiated to object
When upper, scattered by atom in object, each atom produces scattered wave, and these ripples interfere with each other, and as a result just produces diffraction.
The result of diffracted wave superposition makes the intensity of ray strengthen in a certain direction, weakens in the other direction.Diffraction patterns are analyzed, just
Crystal structure can be obtained.X-ray diffractometer is to utilize diffraction principle, the accurate crystal structure for determining material, texture and stress, essence
True carry out material phase analysis, qualitative analysis, quantitative analysis.For crystalline material, when crystal to be measured and incident beam are in different angle
When, those meet that the crystal face of Bragg diffraction will be detected, and it is exactly strong with different diffraction to be embodied in XRD spectrum
The diffraction maximum of degree.For amorphous material, because the long-range order of atomic arrangement in crystal structure is not present in its structure, simply exist
There is shortrange order in several atoms ranges, therefore the XRD spectrum of amorphous material is some diffusing scattering steamed bun peaks.
During with X-ray powder diffraction measure crystal formation of the invention, sometimes due to the condition of the instrument of measure or measure, right
Slightly evaluated error, the crystallization of the spectrum peak in error range it can be also covered by the present invention for the peak measured.Therefore
It is determined that during crystalline texture, it should take this error into account, therefore the applicant is it is determined that consider error model during 2 θ angles
Enclose (within ± 0.2 °).
Differential scanning calorimetry (differential scanning calorimetry, DSC) is a kind of thermal analysis system.
Under programed temperature, measurement is input to relation of the difference power (as in the form of heat) of sample and reference substance with temperature.Difference
The curve that scanning calorimeter instrument recorded claims DSC curve, and it is with hot-fluid (unit W/g, i.e. unit mass sample neither endothermic nor exothermic work(
Rate) it is ordinate, using temperature T or time t as abscissa, a variety of thermodynamics and kineticses parameters can be determined, such as specific heat capacity,
Reaction heat, the heat of transformation, phasor, reaction rate, crystalline rate, superpolymer crystal degree, sample purity etc..The method use temperature range
Wide (- 175~725 DEG C), high resolution, sample dosage are few.
Due to the influence of determining instrument or the condition of measure in DSC curve, can slightly be determined for the peak of measure
Error, the peak figure in error range, during its corresponding crystallization is intended to be included within the scope of the present invention.Therefore, it is determined that crystal knot
During structure, it should take this error into account, therefore the applicant is it is determined that produce maximum hot-fluid (the i.e. peak value at neither endothermic nor exothermic peak
Place) temperature when consider error range (within ± 3 DEG C).
Thermogravimetric analyzer (Thermogravimetric Analysis, TGA), which refers to measure under programed temperature, to be treated
The quality of test sample product and a kind of thermoanalysis technology of temperature change relation, for studying the heat endurance of material and component.Thermogravimetric
Method be under temperature programmed control, the quality of measurement of species with temperature (or time) variation relation.When measured matter is in heating process
In have distillation, when vaporizing, decompositing gas or lose the crystallization water, tested material mass will change.At this moment thermogravimetric is bent
Line is not just straight line but declined.By analyzing thermogravimetric curve, it is possible to know that measured matter produces change in how many spend
Change, and according to institute's weight loss, can calculate and how many material lost, such as the crystallization water.Help to study crystal by TGA experiments
The change of property, the physical phenomenon such as melt, evaporate, to distil and adsorb material；Also contribute to study dissociation, the oxygen of material
Change, reduction, heat endurance, decomposable process, the quantitative analysis of composition, additive and filler influence, moisture content and volatile matter, reaction
The chemical phenomenon of the materials such as dynamics.Thermogravimetric analysis is commonly divided into two classes：Dynamically (heat up) and static (constant temperature).DTG tries
The curve for testing to obtain is referred to as thermogravimetric curve (TGA curves), and TGA curves make ordinate with quality, represent Mass lost from the top down；
Abscissa is made with temperature (or time), represents temperature (or time) increase from left to right.
5th, embodiment
The embodiment of form by the following examples, the above of the present invention is made further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following examples.It is but above-mentioned interior based on the present invention
Hold realized technology and belong to the scope of the present invention.
Formula (I) compound crystal form of embodiment 1 A preparation
Formula (I) compound 200mg is added into reaction bulb, then adds listed solvent in 2.0mL following tables, is sealed, heating
To 50 DEG C of stirring 72h, solid non-dissolved clarification always, solid is filtered, obtains crystal formation A.
| Solvent is numbered | Solvent species |
| 1 | Acetonitrile |
| 2 | Ethyl acetate |
| 3 | Tetrahydrofuran (THF) |
| 4 | 1-METHYLPYRROLIDONE:Methyl tertiary butyl ether(MTBE)=1:20 |
X-ray powder diffraction determines
Crystal structure of the present invention is not limited to complete with the X-ray powder diffraction figure with being painted in accompanying drawing disclosed in the present application
Exactly the same crystal structure, as long as there is any crystal structure essentially identical with the X-ray powder diffraction figure disclosed in accompanying drawing
It is intended to be included within the scope.
XRPD test conditions：
X ray reflection parameter：Cu, K α；Entrance slit：0.6mm；Divergent slit：1mm；Scan pattern：Continuously；Scan model
Enclose：3.0~45.0 degree；Sampling step length：0.02 degree；Often walk sweep time：19.8s；Probe angle：2.0 degree.
The crystal formation A of formula (I) compound is shown in Figure 1 in X-ray powder diffraction figure, and the crystal formation is in the following θ angles of diffraction 2
There is peak at place：6.5±0.2°、9.0±0.2°、12.3±0.2°、14.5±0.2°、16.7±0.2°、18.0±0.2°、18.5±
0.2°、19.4±0.2°、19.7±0.2°、20.3±0.2°、20.7±0.2°、22.8±0.2°、23.3±0.2°、24.5±
0.2°、25.1±0.2°、26.5±0.2°、27.2±0.2°。
Means of differential scanning calorimetry is tested
The crystal formation A of formula (I) compound solid-state hot property is studied by differential scanning calorimetry (DSC).Crystal formation A DSC
Curve is shown in Fig. 2.
DSC test conditions：Purged with nitrogen with 50mL/min, with the 10 DEG C/min rates of heat addition between 25 DEG C to 250 DEG C
Data are collected, are drawn in the case of endothermic peak is directed downwardly.
Thermogravimetric analysis is tested
TGA test conditions：Purged with nitrogen with 60mL/min, room temperature between 350 DEG C with the 10 DEG C/min rates of heat addition
Collect data.Crystal formation A TGA curves show in Fig. 3.
Nmr analysis test (1H-NMR)
Instrument：Bruker Advance III 400；Solvent：Deuterated DMSO.
The nucleus magnetic hydrogen spectrum of formula (1) compound is shown in Fig. 4.
Formula (I) compound crystal form of embodiment 2 A study on the stability
Test sample：
The crystal formation A of formula (I) compound, prepared according to the method in embodiment.
Formula (I) compound, prepared according to the preparation method disclosed in WO2012/159457 specifications.
Test method：
Hot test：This product is placed in 40 DEG C of ± 2 DEG C of RH75% ± 5%, under the conditions of 60 DEG C ± 2 DEG C, in the 5th, 10 day respectively
Sampling, the investigation for carrying out character, purity in 5 days, moisturize within 10 days, XRD is investigated.The medicinal low density polyethylene (LDPE) of this product internal layer
Bag, after overcoat polyester/aluminium/polyvinyl medicine composite packing film packs, carried out character, purity, XRD in 10 days and examine
Examine.
Moisture：According to the Coulometric Titration of 0832 the first method of aquametry of Chinese Pharmacopoeia four general rules of version in 2015 2.
XRD：With reference to Chinese Pharmacopoeia four general rule 0451X ray diffraction methods measure of version in 2015.
Purity：Determined according to high performance liquid chromatography Chinese Pharmacopoeia four general rules 0512 of version in 2015.0.3mg/ml is prepared to supply
Test sample solution.Mobile phase A is 0.03mol/L diammonium hydrogen phosphate+0.02mol/L sodium perchlorates (phosphoric acid adjusts pH value to 4.0)-acetonitrile
(90:10), Mobile phase B is 0.03mol/L diammonium hydrogen phosphate+0.02mol/L sodium perchlorates (phosphoric acid adjusts pH value to 4.0) (25:
75)；Carry out linear gradient elution.
Result of the test
The formula of table 1. (I) compound crystal form A stability results
The formula of table 2. (I) compound stability result
RH：Represent humidity.
Conclusion (of pressure testing)
The crystal formation A of formula (I) compound, in 40 DEG C of RH75%, be open or remain silent under the conditions of place 5 to 10 days, it is its character, pure
Degree, moisture, XRD do not have significant change；In 60 DEG C of high temperature, be open or remain silent under the conditions of place 5 to 10 days, its character, purity, water
Divide, XRD does not have significant change yet.
Formula (I) compound, put 5 to 10 days in 40 DEG C of RH75%, the decentralization of opening condition, purity is down to by 99.0%
81.7%, under the conditions of remaining silent, there is larger improvement, but purity has still declined；5 to 10 are put in 60 DEG C of high temperature, the decentralization of opening condition
My god, purity is down to 89.0% by 99.0%, and purity is down to 77.6% by 99.0% under the conditions of remaining silent.
As a result show, formula (I) compound crystal form A of the present invention shows good stability compared with formula (I) compound, is easy to medicine
The production of product, preparation are prepared, transport and stored, and more conducively ensure validity and security that medicine uses.
Claims (9)
- Compound (E)-N- 1. shown in formula (I) (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyquinazoline hydrochloride -6- bases) -4- The crystal formation A of (2- azaspiros [3.3] heptane -2- bases) -2- crotonamides, it is characterised in that radiated using Cu-K α, with 2 θ angles The X-ray powder diffraction of expression, at 6.5 ± 0.2 °, 9.0 ± 0.2 °, 14.5 ± 0.2 °, 16.7 ± 0.2 °, 18.0 ± 0.2 ° There is characteristic peak；It is preferred that also 12.3 ± 0.2 °, 18.5 ± 0.2 °, 19.4 ± 0.2 °, 20.7 ± 0.2 °, 23.3 ± 0.2 °, 25.1 There is characteristic peak at ± 0.2 °；Further preferably also 19.7 ± 0.2 °, 22.8 ± 0.2 °, 24.5 ± 0.2 °, 26.5 ± 0.2 °, There is characteristic peak at 27.2 ± 0.2 °；Still more preferably its X-ray powder diffraction figure is substantially as shown in Figure 1.
- 2. crystal formation A as claimed in claim 1, it is characterised in that in DSC thermal maps spectrum, temperature has one at 170-190 DEG C Individual endothermic transition peak, transition temperature is 183.89 ± 3 DEG C when maximum is absorbed heat；It is preferred that its DSC collection of illustrative plates is substantially as shown in Figure 2.
- 3. crystal formation A as claimed in claim 1, it is characterised in that in TGA collection of illustrative plates, its temperature when less than 210-230 DEG C, It is preferred that 220 DEG C, its weightlessness is 0%-1%；It is preferred that its TGA collection of illustrative plates is substantially as shown in Figure 3.
- 4. prepare claim 1 described in crystal formation A method, it is characterised in that by (E)-N- (4- (the chloro- 4- fluoroanilinos of 3-)- 7- methoxyquinazoline hydrochloride -6- bases) -4- (azaspiro [3.3] heptane -2- bases) organic solvent of -2- crotonamides at 30-70 DEG C In wash and starch 50-80h, 60-80h is preferably washed and starched in 40-60 DEG C of organic solvent, is preferably starched in 45-55 DEG C of organic solvent 70-75h is washed, 72h is preferably washed and starched in 50 DEG C of organic solvents, is then filtered, dries, produces crystal formation A.
- 5. crystal formation A as claimed in claim 4 preparation method, it is characterised in that described organic solvent is in following solvent One or two kinds of or two or more solvent between any combination：(1) nitrile solvents, selected from acetonitrile or propionitrile；(2) esters solvent, including fatty esters and aromatic ester solvent, the fatty esters solvent are selected from methyl formate, formic acid Ethyl ester, propyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, propionic acid Methyl esters, ethyl propionate, propyl propionate or isopropyl propionate, the aromatic ester solvent are selected from repefral；(3) ether solvent, selected from fatty ethers and cyclic ether solvents, the fatty ether solvent is selected from ether, dipropyl ether, two different Propyl ether, methyl tertiary butyl ether(MTBE), ethyl-butyl ether, ethyl tert-butyl ether (ETBE), butyl oxide or diamyl ether, cyclic ether solvents are selected from epoxy second Alkane, 1,2 epoxy prapane, tetrahydrofuran, 2- methylfurans, dioxolanes or 1,4- dioxane；(4) ketones solvent, selected from alkanones and ring ketones solvent, described alkanones solvent is selected from MEK, first isopropyl Ketone, acetone, espeleton or methylisobutylketone, described ring ketones solvent are selected from cyclopropanone, cyclohexanone, isophorone or N- first Base pyrrolidones.
- 6. crystal formation A as claimed in claim 5 preparation method, it is characterised in that described organic solvent is in following solvent One or two kinds of or two or more solvent between the mixed solvent to be formed is combined according to special ratios：(1) nitrile solvents, selected from acetonitrile；(2) fatty esters solvent, selected from Ethyl formate, methyl acetate, ethyl acetate or propyl acetate；(3) ether solvent, selected from methyl tertiary butyl ether(MTBE), ethyl-butyl ether, ethyl tert-butyl ether (ETBE), tetrahydrofuran or 2- methyl furans Mutter；(4) ketones solvent, selected from acetone or 1-METHYLPYRROLIDONE；Described mixed solvent be selected from acetonitrile/1-METHYLPYRROLIDONE, acetonitrile/acetone, ethyl acetate/1-METHYLPYRROLIDONE, 1-METHYLPYRROLIDONE/methyl tertiary butyl ether(MTBE), 1-METHYLPYRROLIDONE/ethyl tert-butyl ether (ETBE), 1-METHYLPYRROLIDONE/tetrahydrochysene furan Mutter, the dicyandiamide solution that acetone/methyl tertiary butyl ether(MTBE), acetone/ethyl tert-butyl ether (ETBE) or acetone/tetrahydrofuran are formed；Described special ratios are selected from 30:1-1:30, preferably 25:1-1:25, preferably 20:1-1:20.
- 7. the pharmaceutical composition of the crystal formation A containing formula (I) compound described in claim any one of 1-3, it is characterised in that contain There are one or more pharmaceutical carriers, described pharmaceutical composition can be prepared into pharmaceutically acceptable any formulation.
- 8. the crystal formation A of formula (I) compound described in claim any one of 1-3 is used to treat and/or prevents excessively to increase preparing Application in terms of the medicine of raw disease and/or chronic obstructive pulmonary disease；Described excessively proliferative disease is selected from：It is brain tumor, lung cancer, non- Small cell lung cancer, squamous cell, carcinoma of urinary bladder, stomach cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, uterus Neck cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's leaching Bar knurl, central nerve neuroma (glioma, glioblastoma multiforme, glioma sarcomatosum), prostate cancer, thyroid gland The hyperplasia of prostate of cancer, skin or prostate.
- 9. the crystal formation A containing formula (I) compound described in claim any one of 1-3 treats preparation with one or more second Composition, the second therapeutic agent are selected from antimetabolite, including capecitabine, gemcitabine；Growth factor receptor inhibitors, including pa Azoles pa Buddhist nun, Imatinib；Antibody, including Trastuzumab, bevacizumab；Mitotic inhibitor, including taxol, vinorelbine, Docetaxel, Doxorubicin；Antitumor steroids, including Letrozole, tamoxifen, fulvestrant；Alkylating agents, including ring phosphorus Acid amides, BCNU；Metal platinum class, including carboplatin, cis-platinum, oxaliplatin；Topoisomerase enzyme inhibitor, including Topotecan； Immunosupress class, including everolimus.
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