CN105294716B - Two salicylates and its crystal formation of a kind of amino quinazoline derivative - Google Patents

Abstract

The present invention relates to the salt and its crystal formation that a kind of amino quinazoline derivative and salicylic acid are formed；The invention further relates to the preparation method of the salt and crystal formation, include the pharmaceutical composition of the salt or/and crystal formation.Salt, crystal formation or their pharmaceutical composition of the present invention can be used for treating proliferative diseases.

Description

Two salicylates and its crystal formation of a kind of amino quinazoline derivative

Technical field

The present invention relates to two salicylates and its crystal formation of a kind of amino quinazoline derivative；The invention further relates to described The preparation method of salt and crystal formation, the pharmaceutical composition for including the salt or/and crystal formation, and described salt, crystal formation or they The purposes of pharmaceutical composition.

Background technology

EGF-R ELISA (epidermal growth factor receptor, EGFR) is a kind of receptor type junket Histidine kinase, be overexpressed and (or) undergo mutation in many tumours, by signal transduction control tumour growth, and with new green blood Pipe generation, the invasion and attack of tumour and transfer etc. have close relationship.EGF-R ELISA is cell growth, differentiation and survival Important regulatory factor, its member have：ErbB-1 (EGFR, HER1), erbB-2 (EGFR, HER2), erbB-3 (EGFR, HER3) and erbB-4(EGFR,HER4).Their structures are similar, by extracellular ligand binding domain, single transmembrane area and highly conserved albumen EGFR-TK district's groups into.This structure has the function of acceptor, the energy that there is extracellular signal to be converted into intracellular effect again Power, it is a kind of novel cross-film transfer mode.Once acceptor is combined with particular ligand, it becomes possible to passes through corresponding EGFR-TK Autophosphorylation and activated receptor, so as to the signal transduction pathway in active cell.These signal transmission paths include：Ras Kinase protein and the activation for promoting cell division kinase protein MAPK, the multiple protein in activation and active cell core both this, Critical loops protein D 1 including cell cycle proliferation, so as to cause DNA synthesis, cell growth, differentiation.Growth factor receptors Excessive activation causes the proliferation out of control of cell, so as to produce various types of excessively proliferative diseases, such as non-small cell lung cancer, mammary gland Cancer, cancer of the brain etc..The suppression of growth factor receptor tyrosine kinase is proven to have the effect out of control of regulation cellular replication, therefore into For the target of new type antineoplastic medicine.

Chinese patent literature CN 103102344A (application publication number) have been disclosed for 4- in specification embodiments 6 of page 57 [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane - 8- yls] propoxyl group-quinazoline structural information, the compound is a kind of free alkali, shown in its structure such as formula (I).The compound There is very high inhibitory activity to EGFR, available for treating proliferative diseases.

The content of the invention

The present invention relates to compound 4- shown in formula (I) [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline two salicylates and its crystal formation, tool Body is related to the crystal formation I of two salicylates of compound shown in formula (I).The invention further relates to the medicine for including the salt or/and crystal formation Compositions, and the purposes of described salt, crystal formation or their pharmaceutical composition for treating patient's proliferative diseases.

On the one hand, the invention provides the salt that one kind compound as shown in formula (I) is formed with salicylic acid, the salt to have formula (II) structure shown in：

Formula (II),

Wherein m is 1,2,3 or 4；N is 1,2,3 or 4.

In certain embodiments, salt of the present invention is two salicylates of compound shown in formula (I), and the salt has Structure shown in formula (III)：

Formula (III).

On the one hand, the invention provides the crystal formation of the salt shown in formula (III), wherein the crystal formation is crystal formation I.

In certain embodiments, crystal formation of the present invention, wherein the X-ray powder diffraction pattern of the crystal formation I is under Row 2 have diffraction maximum at θ angles：6.66 ° ± 0.2 °, 8.24 ° ± 0.2 °, 10.20 ° ± 0.2 °, 13.35 ° ± 0.2 °, 13.90 ° ± 0.2 °, 15.67 ° ± 0.2 °, 16.04 ° ± 0.2 °, 16.46 ° ± 0.2 °, 17.04 ° ± 0.2 °, 17.55 ° ± 0.2 °, 18.41 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.16 ° ± 0.2 °, 19.64 ° ± 0.2 °, 19.90 ° ± 0.2 °, 20.26 ° ± 0.2 °, 20.61 ° ± 0.2 °, 21.27 ° ± 0.2 °, 21.81 ° ± 0.2 °, 22.30 ° ± 0.2 °, 22.64 ° ± 0.2 °, 22.97 ° ± 0.2 °, 23.55 ° ± 0.2 °, 24.19 ° ± 0.2 °, 24.44 ° ± 0.2 °, 24.68 ° ± 0.2 °, 24.96 ° ± 0.2 °, 25.60 ° ± 0.2 °, 26.12 ° ± 0.2 °, 26.33 ° ± 0.2 °, 26.71 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.03 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.83 ° ± 0.2 ° and 30.09 ° ± 0.2 °.

In certain embodiments, crystal formation of the present invention, wherein the X-ray powder diffraction pattern of the crystal formation I is under Row 2 have diffraction maximum at θ angles：5.86 ° ± 0.2 °, 6.66 ° ± 0.2 °, 8.24 ° ± 0.2 °, 8.42 ° ± 0.2 °, 9.64 ° ± 0.2 °, 10.20 ° ± 0.2 °, 11.82 ° ± 0.2 °, 13.35 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.87 ° ± 0.2 °, 15.17 ° ± 0.2 °, 15.67 ° ± 0.2 °, 16.04 ° ± 0.2 °, 16.46 ° ± 0.2 °, 17.04 ° ± 0.2 °, 17.55 ° ± 0.2 °, 18.41 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.16 ° ± 0.2 °, 19.64 ° ± 0.2 °, 19.90 ° ± 0.2 °, 20.26 ° ± 0.2 °, 20.61 ° ± 0.2 °, 21.27 ° ± 0.2 °, 21.56 ° ± 0.2 °, 21.81 ° ± 0.2 °, 22.30 ° ± 0.2 °, 22.64 ° ± 0.2 °, 22.97 ° ± 0.2 °, 23.55 ° ± 0.2 °, 24.19 ° ± 0.2 °, 24.44 ° ± 0.2 °, 24.68 ° ± 0.2 °, 24.96 ° ± 0.2 °, 25.60 ° ± 0.2 °, 26.12 ° ± 0.2 °, 26.33 ° ± 0.2 °, 26.71 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.03 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.83 ° ± 0.2 °, 30.09 ° ± 0.2 °, 30.58 ° ± 0.2 °, 31.12 ° ± 0.2 °, 32.02 ° ± 0.2 °, 32.39 ° ± 0.2 °, 33.16 ° ± 0.2 °, 34.53 ° ± 0.2 ° and 36.45 ° ± 0.2 °.

In certain embodiments, crystal formation of the present invention, wherein there is the crystal formation I X substantially as shown in penetrate Line powder diffraction spectrum.

In certain embodiments, crystal formation of the present invention, wherein the differential scanning calorimetric curve of the crystal formation I exists There is endothermic peak at 180.20 DEG C ± 3 DEG C.

In certain embodiments, crystal formation of the present invention, wherein the crystal formation I has difference substantially as shown in Figure 2 Show scanning calorimetric curve.

On the other hand, the present invention relates to a kind of pharmaceutical composition, it includes salt of the present invention or of the present invention Crystal formation or combinations thereof, wherein described pharmaceutical composition further includes pharmaceutically acceptable carrier, excipient, dilution Agent, assistant agent, medium or combinations thereof.

In certain embodiments, pharmaceutical composition of the present invention, it further includes therapeutic agent, the treatment Agent is selected from chemotherapeutic agent, antiproliferative, for treating the medicine or combinations thereof of non-small cell lung cancer and epidermal carcinoma.

In other embodiment, pharmaceutical composition of the present invention, wherein described therapeutic agent is adriamycin (Adriamycin), rapamycin (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabine), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), fluorouracil (Fluorouracil), imatinib mesylate (Imatinibmesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Iressa (Iressa), Sorafenib (Sorafenib), Sutent (Sunitinib), interferon (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, Vincaleukoblastinum, vincristine, Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Ah Gas fourth (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix , or combinations thereof (Panitumumab).

On the other hand, the present invention relates to one kind to use salt of the present invention or crystal formation of the present invention or institute of the present invention The pharmaceutical composition stated is used to protecting, handle or treating patient's proliferative diseases to prepare, and mitigates the medicine of its order of severity Purposes.

In certain embodiments, purposes of the present invention, wherein described proliferative diseases are metastatic carcinomas, epidermal carcinoma, Colon cancer, sdenocarcinoma of stomach, carcinoma of urinary bladder, breast cancer, kidney, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer, cancer of pancreas, CNS (central nervous system) cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

Definition and general terms

Unless otherwise indicated, all technologies and scientific terminology and ordinary skill of the art that the present invention uses What personnel were generally understood that has identical meanings.All patents of the present invention and public publication are overall by reference It is incorporated herein.Although it can be used in practice of the invention either test any to of the present invention similar or identical Method and material, but described in the present invention be preferable method, equipment and material.

The nothing that " salt that compound shown in formula (I) is formed with salicylic acid " or " salt shown in formula (III) " includes such salt is determined Shape form, crystal form, solvate, hydrate, and also include the polymorphic forms of such salt." compound shown in formula (I) Two salicylates " include amorphous form, crystal form, solvate, the hydrate of such salt, and also include such salt Polymorphic forms.

In one embodiment of the invention, salt of the invention is with crystalline nature and preferably with least 50% knot Brilliant degree, more preferably at least 60% crystallinity, still more preferably at least 70% crystallinity and most preferably at least 80% crystallinity.Crystallinity Or crystallinity can be assessed by conventional x-ray diffraction technology.

In another embodiment of the present invention, the salt have from 50%, 60%, 70%, 80% or 90% to 95%th, 96%, 97%, 98%, 99% or 100% crystallinity.

Unless otherwise indicated, in the salt of the present invention, compound shown in formula (I) can be change to the stoichiometry of acid , such as from 2:1 to 1:2, or any ratio therebetween, such as 2:1、1:1、2:3 or 1:2.The salt of the preferable present invention Example, including compound shown in formula (I) are 1 to the stoichiometry of acid:1 salt, stoichiometry of the compound shown in formula (I) to acid For 1:Compound shown in 2 salt or formula (I) is 2 to the stoichiometry of acid:3 salt.The present invention salt using when can be single Salt or several salt mixture.The salt that compound shown in formula (I) and salicylic acid are formed using when can be single The mixture of salt or the different salt into salt ratio, can also be salt that compound shown in formula (I) formed with salicylic acid and The mixture for the salt that compound shown in formula (I) is formed with other inorganic acids or organic acid.

" crystal formation " or " crystal form " refers to the solid with height rule chemical constitution, includes but is not limited to, one pack system Or multicomponent crystal, and/or the solvent of the polymorph of compound, solvate, hydrate, inclusion compound, eutectic, salt, salt The hydrate of compound, salt.The crystal form of material can be obtained by many methods known in the art.This method includes, but It is not limited to, melt crystallization, melt cooling, solvent crystallization, is crystallized in the space of restriction, for example, in nano-pore or capillary In, crystallized on surface or template, for example, on polymer, crystallizing, going in the presence of additive such as cocrystallization antimolecule Solvent, dehydration, rapid evaporation, quick cooling, Slow cooling, steam diffusion, distillation, reactive crystallization, anti-solvent add, grind and Solvent drop grinding etc..Crystal form includes anhyrous crystalline form, partially crystallizable form, the mixture of crystal form, hydrate Crystal form and crystalline solvate form.

" amorphous " or " amorphous form " refer to the particle (molecule, atom, ion) of material three-dimensional arrangement without The material formed during periodicity, it is characterized in that the X-ray powder diffraction figure for not having spike with diffusion.Amorphous is solids A kind of special physical form of matter, the architectural feature of its local order, prompts it to have the connection of countless ties with crystal-form substances System.The amorphous form of material can be obtained by many methods known in the art.This method includes, but not limited to be quenched Method, anti-solvent flocculence, ball-milling method, spray drying process, freeze-drying, wet granulation process and solid dispersions technique etc..

" solvent " refers to a kind of material (a kind of typically liquid), and the material can completely or partially dissolve another Kind material (a kind of typically solid).The solvent implemented for the present invention includes but is not limited to, water, acetic acid, acetone, second Nitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide (DMSO), 1,4- dioxane, ethanol, ethyl acetate, butanol, tertiary fourth Alcohol, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl second Base ketone, l- N-methyl-2-2-pyrrolidone Ns, mesitylene, nitromethane, polyethylene glycol, propyl alcohol, 2- acetone, pyridine, tetrahydrofuran, Toluene, dimethylbenzene, their mixture etc..

" anti-solvent " refers to the fluid for promoting product (or product precursor) to be precipitated from solvent.Anti-solvent can include cold air Body promotes the fluid of precipitation by chemically reacting or reduces the fluid of the solubility of product in a solvent；It can be with it is molten Agent identical liquid is still in different temperatures, or it can be the liquid different from solvent.

" solvate " refers to that crystal has solvent on the surface or in lattice or on the surface and in lattice, Wherein, the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide (DMSO), 1, 4- dioxane, ethanol, ethyl acetate, butanol, the tert-butyl alcohol, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, formyl Amine, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, poly- second Glycol, propyl alcohol, 2- acetone, pyridine, tetrahydrofuran, toluene, dimethylbenzene and their mixture etc..One of solvate Specific example is hydrate, wherein the solvent on the surface or in lattice or on the surface and in lattice is water. On the surface of material or in lattice or on the surface and in lattice, hydrate can be with or without except water Other solvents in addition.

Unless otherwise indicated, when referring to " solvate " and " hydrate ", this invention is intended to the sum including stoichiometry Non-stoichiometric " solvate " and " hydrate ".

The solvate of stoichiometry has the fixed ratio of solvent molecule and compound molecule.This be typically due to Bonding interaction between solvent and compound molecule.In non-stoichiometric solvate, solvent not with compound The ratio of the fixation of molecule exists and can often changed.In non-stoichiometric solvate, solvent is frequently present in crystalline substance Void space or passage within lattice.The hydrate of stoichiometry has the ratio of the fixation of hydrone and compound molecule.This It is the bonding interaction typically due between water and compound molecule.In non-stoichiometric hydrate, water not with Exist with the ratio of the fixation of compound molecule and can often change.In non-stoichiometric hydrate, water is frequently present of In the void space or passage of intracell.

Herein it is any be related to the present invention salt when, suitably and at one's leisure, it should be understood that be directed to corresponding solvent Compound such as hydrate or polymorphic modification, and it is directed to corresponding amorphous form.

Salt mixture is (i) by the difference that different anion forms single salt form, (ii) is formed by identical anion The mixture of these single salt forms of the single salt form or (iii) of ratio, such as the shape of aggregation (conglomerates) Formula.

The salt of the present invention preferably exists in the form of separating and be essentially pure.

The salt can be dry.In some embodiments, the salt is anhydrous.

The salt can be solvate or hydrate forms.The solvate of salt of the present invention and also hydrate are for example Can respectively by half-, it is single-, two-, three-, four-, five-, exist in the form of six-solvate or hydrate.In its crystal grid In can embed solvents used for crystallization, such as alcohols (such as methanol, ethanol), aldehydes, ketone (such as acetone), esters (such as acetic acid second Ester).Selected solvent or water produce solvate or hydrate or direct in crystallization and in a following processing step It is typically unpredictable to produce the degree of free alkali, and depends on treatment conditions and free cpds and selected solvent The joint of various interactions between (especially water).Experiment be must pass through to determine salt, solvate and the hydration of gained The crystallization of thing and corresponding salt/solvate or salt hydrate form or the respective stability of amorphous solid.Because at these In the case of there may be different crystalline solids and different amorphous substances, it is thus impossible to be only conceived to gained solid in The chemical composition and stoichiometric proportion of molecule.

Because the molecule in crystalline texture can be constrained by strong molecular separating force, and represent part exceptional stability The indispensable element that the structure of these crystal is formed, it is thus possible to the hydrate of the salt described in preferred corresponding hydrates.But There may also be hydrone in some lattices fettered by somewhat weak molecular separating force.The quasi-molecule is more or less incorporated into In crystal structure, a kind of relatively low energy (energetic) effect is formed., generally can be clear with crystalline hydrate The water content in amorphous solid is determined to Chu, but it depends critically upon dry and ambient conditions.On the contrary, in stable hydration There is clear stoichiometric proportion in thing, between pharmaceutically active substances and water.In many cases, these ratios can not be fully met The stoichiometric number, because some crystal defects, it is typically some relatively low approximations.For weaker combination water For, the ratio of organic molecule and hydrone can be changed to a large extent, such as can two-, three-or Extend on four-hydrate.On the other hand, in amorphous solid, the molecular structure grade of water is not stoichiometry；But its Perhaps, grade is only stoichiometry once in a while.In some cases, can not be to the accurate of hydrone because forming Rotating fields Stoichiometry is classified, so that the hydrone embedded in institute's form of Definition can not be determined.

The invention further relates to salt of the present invention or crystal formation solid state physical property.Can be by controlling with solid Form obtains the condition of salt or crystal formation to influence these properties.What the physical property of solid state included for example being ground consolidates The mobility of body.Mobility have impact on the complexity for being processed into and being handled during medicine the material.When powdery When can not easily be flowed between particle, formulation specialist has to take into account that the fact when developing tablet or capsule preparations, and its is required Use glidant such as cataloid, talcum powder, starch or calcium phosphate,tribasic.

Another important solid state property of medical compounds is its rate of dissolution or the medicine in waterborne liquid Bioavilability.Because the upper limit for the speed that its active component to oral administration can reach blood stream of patients is exerted one's influence, Therefore rate of dissolution of the active component in patient's gastric juice may have therapeutic value.

For example, for rate of dissolution and bioavilability, the different crystal forms or amorphous form of identical medicine can There can be very big difference in terms of such important pharmaceutical properties.Equally, different crystallizations or amorphous form may have Different working properties, such as hygroscopicity, mobility, these properties can influence it as the active medicine prepared for business Adaptability.

In the case of syrup, elixir and other liquid medicines is prepared, rate of dissolution is also considered.The solid-like of compound State form can also influence it to compression and the behavior of storage stability.

These actual physical characteristics in by structure cell molecular conformation and orientation influenceed, the conformation and orientation of molecule in structure cell The specific polymorphy of material is determined.

Crystal formation or it is amorphous can be differentiated by multiple technologies means, it is such as X-ray powder diffraction (XRPD), infrared Absorption spectrometry (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetry (TGA), nuclear magnetic resonance method, Raman light Spectrum, X ray single crystal diffraction, solution-reaction calorimetry, SEM (SEM), quantitative analysis, solubility and dissolution velocity etc. Deng.

X-ray powder diffraction (XRPD) can detect the information such as the change of crystal formation, crystallinity, brilliant structure state, be to differentiate crystal formation Conventional means.The peak position of XRPD collection of illustrative plates depends primarily on the structure of crystal formation, and to experimental detail relative insensitivity, and its is relative Peak height depends on many factors relevant with sample preparation and instrument geometry.Therefore, in certain embodiments, it is of the invention Crystal formation is characterized by the XRPD figures of some peak positions, and it is substantially as shown in the XRPD figures provided in accompanying drawing of the present invention. Meanwhile measuring for 2 θ of XRPD collection of illustrative plates can have experimental error, between different instruments and different samples, 2 θ's of XRPD collection of illustrative plates Difference may be slightly had by measuring, thus the numerical value of 2 θ can not be considered as it is absolute.Instrument situation is tested according to the present invention, The error margin of diffraction maximum presence ± 0.2 °.

Means of differential scanning calorimetry (DSC) is under program, by constantly heating or cooling, to measure sample and inertia reference Thing (conventional α-Al₂O₃) between a kind of technology for varying with temperature of energy difference.The fusing peak height of DSC curve depends on and sample The many factors relevant with instrument geometry are prepared, and peak position is to experimental detail relative insensitivity.Therefore, implement at some In example, crystal formation of the present invention is characterized by the DSC figures of characteristic peak positions, and it in accompanying drawing of the present invention substantially as provided DSC figures shown in.Meanwhile DSC collection of illustrative plates can have experimental error, between different instruments and different samples, the peak position of DSC collection of illustrative plates Difference may be slightly had with peak value by putting, thus the peak position of the DSC endothermic peaks or the numerical value of peak value can not be considered as it is absolute.Root Instrument situation, the error margin of melting hump presence ± 3 DEG C are tested according to the present invention.

Means of differential scanning calorimetry (DSC) can also be used to test and analyze whether crystal formation has a turn brilliant or mixed crystal phenomenon.

Chemical composition identical solid, under different thermodynamic conditions, it is different often to form the different homogeneity of crystal structure Structure body, or be variant, this phenomenon is referred to as polymorphism or homogeneity multi-phase phenomena.When temperature and pressure condition changes, become Phase co-conversion can occur between body, this phenomenon is referred to as crystal transfer.Due to crystal transfer, the property such as the mechanics of crystal, electricity, magnetics Huge change can occur.It is considerable on means of differential scanning calorimetry (DSC) figure when the temperature of crystal transfer is in the range of it can survey Observe this transition process, it is characterised in that exothermic peak of the DSC figures with this transition process of reflection, and there are two simultaneously Or multiple endothermic peaks, the feature endothermic peak of the different crystal forms before and after respectively changing.

Thermogravimetric analysis (TGA) is to determine a kind of technology that the quality of material varies with temperature under program, is applied to The forfeiture of solvent or sample distillation, the process decomposed in crystal are checked, the feelings containing the crystallization water or recrystallisation solvent in crystal can be speculated Condition.The mass change that TGA curves are shown depends on many factors such as sample preparation and instrument；Different instruments and different samples it Between, the mass change of TGA detections slightly has difference.According to present invention experiment apparatus status used, mass change presence ± 0.1% Error margin.

In the context of the present invention, 2 θ values in X-ray powder diffraction figure with spend (°) for unit.

Term " substantially as shown in the figure " refers to X-ray powder diffraction figure or DSC figures or Raman spectrogram or infrared spectrum At least 50% in figure, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% peak is shown in its figure.

When referring to spectrogram or/and appearing in the data in figure, what " peak " referred to that those skilled in the art can identify will not Belong to a feature of background noise.

It is any that there is N ± 0.01, N ± 0.02, N ± 0.03, N ± 0.05, N whenever a numeral with N values is disclosed ± 0.07, N ± 0.08, N ± 0.1, N ± 0.15, N ± 0.2, N ± 1, N ± 2, N ± 1.5, N ± 3, N ± 4, N ± 5, N ± 6, N ± The numeral of the value of 7, N ± 8, N ± 9, N ± 10, N ± 15, N ± 20 can be specifically disclosed, wherein " ± " refers to add deduct.Whenever public affairs Open a lower limit in a number range, RL, and a upper limit, RU, when, any number being within the scope of the disclosed Value can be specifically disclosed.

" compound shown in formula (I) " of the present invention is with reference to real in patent CN 103102344A (application publication number) Apply 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- that the synthetic method of example 6 obtains 3- [(1R, 6S) -2,5- dioxies - 8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline.

Two salicylates of compound shown in formula (I) or the salt shown in formula (III) are 4- [(the chloro- 4- fluorophenyls of 3-) ammonia Base] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline Two salicylates.The crystal formation I of two salicylates of compound shown in formula (I) refers to 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- first The salicylic acid of epoxide -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline two The crystal formation I of salt.The crystal formation I of salt shown in formula (III) refers to 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl group -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline two salicylate crystal formation I. They exist with essentially pure crystal habit.

" essentially pure " refers to a kind of salt/crystal formation substantially free of another or a variety of salt/crystal formations, i.e. salt/crystalline substance The purity of type at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or extremely Few 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or salt/ Contain other salt/crystal formations in crystal formation, percentage of the other salt/crystal formations in the cumulative volume of salt/crystal formation or gross weight is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

Substantially free refers to hundred of one or more other salt/crystal formations in the cumulative volume of salt/crystal formation or gross weight Divide ratio less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or Less than 0.5%, or less than 0.1%, or less than 0.01%.

" relative intensity " refers to that the intensity at the last the first peak in all diffraction maximums of X-ray powder diffraction figure (XRPD) is When 100%, the ratio of the intensity at other peaks and the intensity at the last the first peak.

In the context of the present invention, when using or regardless of whether when using the wording such as " about " or " about ", represent Within the 10% of specified value or scope, suitably within 5%, particularly within 1%.It is or common for this area For technical staff, term " about " or " about " are represented in the range of the acceptable standard error of average value.

Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.

Unless otherwise indicated, structural formula described in the invention includes all isomeric forms, (such as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism))：Such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and (Z), the rotamer of (E).Therefore, the single spatial chemistry of the compound shown in formula (I) of the present invention is different Structure body or its enantiomter, diastereoisomer, or the mixture of geometric isomer (or rotamer) belong to this hair Bright scope.

Unless otherwise indicated, all tautomeric forms of the compound shown in formula (I) of the present invention are included in this Within the scope of invention.In addition, the unless otherwise indicated, structural formula bag of compound shown in formula (I) described in the invention Include the enriched isotope of one or more different atoms.

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to documents below：S.P.Parker,Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley＆Sons, Inc., New York, the compound shown in 1994. formula (I)s of the present invention can include asymmetric center or chirality Center, therefore different stereoisomers be present.All stereoisomeric forms in any ratio of compound shown in formula (I) of the present invention, including But it is not limited to, diastereoisomer, enantiomter, atropisomer, and their mixture, such as racemic mixture, Constitute the part of the present invention.Many organic compounds all exist with optical active forms, i.e. their capable Plane of rotations The plane of polarised light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute structure at molecular chiral center Type.Prefix d, l or (+), (-) are used for the symbol for naming compound linearly polarized light to rotate, and (-) or l refer to that compound is left-handed , prefix (+) or d refer to that compound is dextrorotation.The chemical constitution of these stereoisomers is identical, but theirs is vertical Body structure is different.Specific stereoisomer can be enantiomer, and the mixture of isomers is commonly referred to as that enantiomter is mixed Compound.50:50 mixture of enantiomers is referred to as racemic mixture or racemic modification, and this may cause in chemical reaction process There is no stereoselectivity or stereoselectivity.Term " racemic mixture " and " racemic modification " refer to equimolar two mappings The mixture of isomers, lack optical activity.

Pharmaceutical composition, preparation, administration and the purposes of salt or crystal formation of the present invention

As described in the invention, the pharmaceutically acceptable composition of the present invention include salt of the present invention one kind or It is a variety of, or the one or more of crystal formation of the present invention, or combinations thereof, and pharmaceutically acceptable carrier, assistant agent, Or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, dispersant or outstanding Floating agent, surfactant, isotonic agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., is suitable for spy Some target formulations.Content of the active component in the pharmaceutical composition is 1-99 weight %, 1-95 weight %, 1-90 weight Measure %, 1-85 weight %, 1-80 weight %, 1-75 weight %, 1-70 weight %, 1-65 weight %, 1-60 weight %, 1-55 weight Measure %, 1-50 weight %, 1-45 weight %, 1-40 weight %, 1-35 weight %, 1-30 weight %, 1-25 weight %, 1-20 weight Measure %, 1-15 weight %, 1-10 weight %, 1-5 weight %.As described by documents below：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology, Eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, comprehensive document herein Content, show that different carriers can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition. Except any conventional carrier medium scope incompatible with salt of the present invention or crystal formation, for example, it is caused any bad Biological effect or any other component caused interaction in harmful manner with pharmaceutically acceptable composition, it Purposes be also the scope that is considered of the present invention.

It can be included, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, such as haemocyanin, human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturation vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose and its derivative Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Thing, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colouring agent, releasing agent, coating agents, sweetener, flavor enhancement and perfume (or spice) Material, preservative and antioxidant.

The composition of salt or crystal formation of the present invention can be administered orally, and drug administration by injection, Aerosol inhalation, locally give Medicine, per rectum administration, nose administration, buccal administration or are administered vagina administration by implantable medicine box.Term used herein " through injection " include it is subcutaneous, vein, it is intramuscular, it is IA, it is intrasternal in synovial membrane (chamber), in film, intraocular , in liver, in focus, and injection or the infusion techniques of encephalic.Preferable composition is is administered orally, to Intraperitoneal medication Or intravenous injection.The injection system of the composition sterile of the present invention can be water or oil suspension.These suspension It can be manufactured according to known technology using suitable dispersant, wetting agent and suspending agent by formula.Aseptic injection can be nothing Bacterium parenteral solution or suspension, it is injection nontoxic acceptable diluent or solvent, such as 1,3-BDO solution.These are acceptable Excipient and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, sterile non-volatile oil Solvent or suspension media can be used as by convention.

With this end in view, any gentle non-volatile oil can be the list or diphenylglycerol diester of synthesis.Fat Acid, as oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil Fat, such as olive oil or castor oil, particularly their polyoxyethylene deriv.These oil solutions or suspension can include long-chain Alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, it is generally used for the medicine system of pharmaceutically acceptable formulation Agent includes emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological medicament The hardening agent of efficiency, pharmaceutically acceptable solid, liquid, or other formulations are generally used for, and can apply to drug target The preparation of preparation.

The pharmaceutically acceptable composition of the present invention can be administered orally with any acceptable peroral dosage form, its In include, but is not limited to, capsule, tablet (tablet), pill, pulvis, sustained release agent, water suspension or solution.On Tablet is administered orally, and carrier generally comprises lactose and cornstarch.Lubricant, such as magnesium stearate, are all typically added.For Capsule oral is administered, and suitable diluent includes lactose and dry cornstarch.When it is water suspension to be administered orally, it has Effect composition is made up of emulsifying agent and suspending agent.If expecting these formulations, some sweeteners, flavor enhancement or colouring agent can also It is added.

The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspends Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can include known in general inert diluent, for example, water Or other solvents, solubilizer and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, phenmethylol, Ergol, Propane diols, 1,3-BDO, dimethylformamide, grease (particularly cottonseed, peanut, corn, microorganism, olive, castor-oil plant and Sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy Outside the diluent of property, Orally administered composition can also include assistant agent such as wetting agent, emulsifying agent or suspending agent, sweetener, flavor enhancement And aromatic.

In addition, the pharmaceutically acceptable composition of the present invention can in the form of suppository rectally.These can pass through Reagent is mixed with suitable non-perfusing adjuvant and formed, this adjuvant at room temperature for solid but at a temperature of rectum then For liquid, so as to melt in the rectum and discharge medicine.Such material includes cocoa butter, beeswax, and polyethylene glycols.This When to invent pharmaceutically acceptable composition can be local administration, particularly local application, it is related to controlling for region or organ Treat target easily to reach, such as the disease of eye, skin or lower intestinal tract.Suitable topical preparations can be prepared and be applied to These fields or organ.

Rectal suppository (see above content) or suitable enema can apply to the local application of lower intestine.Local skin Skin spot is it is also possible that medication.For local application, pharmaceutically acceptable composition can be prepared into properly by formulation method Ointment, the ointment packets are suspended or dissolved in one or more carriers containing active component.The present invention is locally administered supported Compound includes, but is not limited to mineral oil, atoleine, albolene, propane diols, polyoxyethylene, polyoxypropylene compound, breast Change wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, the lotion or emulsion include Active component is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier includes, but is not limited to, ore deposit Thing oil, Arlacel-60 (Arlacel-60), polysorbate60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, phenmethylol and water.

Preparation can be prepared into for ophthalmically acceptable, pharmaceutically acceptable composition, such as isotonic micronized suspension, pH The Sterile Saline of regulation or other aqueous solution, it is preferable that isotonic solution and the Sterile Saline or other aqueous solution of pH regulations, can be with Add disinfection preservative such as benzalkonium chloride.In addition, for ophthalmically acceptable, pharmaceutically acceptable composition can be by pharmaceutical formulation system It is standby into ointment such as vaseline oil.The pharmaceutically acceptable composition of the present invention can be carried out by the gaseous solvents or inhalant of nose to Medicine.Such composition can be prepared according to the known technology of pharmaceutical formulation, or can be prepared into salting liquid, use benzene first Alcohol or other suitable preservatives, sorbefacient, fluorocarbon or other conventional solubilizer or dispersant improve biology Availability.

Injection, as aseptic parenteral solution or oil suspension can according to known technology using suitable dispersant, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through parenterally acceptable diluent Or aseptic parenteral solution, suspension or emulsion made of solvent, for example, 1,3-BDO solution.Acceptable excipient and solvent Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, sterile non-volatile oil is by convention As solvent or suspension media.With this end in view any gentle non-volatile oil can include the list synthesized or two Portugal's bases are sweet Oily diester.In addition, aliphatic acid such as oleic acid can apply to injection.

Injection can be sterile, such as defend filter by bacterium and filter, or in the form of aseptic solid composite Bactericidal agent is mixed, can be dissolved in or be scattered in disinfectant or other sterile injectable mediums using preceding bactericidal agent.In order to prolong The effect of the compound of the long present invention, it usually needs the absorption of compound is slowed down by hypodermic injection or intramuscular injection.So It can realize solve the problems, such as crystal or non-crystalline material poorly water-soluble using liquid suspension.The absorptivity of compound depends on Its dissolution rate, successively depending on grain size and crystal shape.Furthermore it is possible to dissolved by compound in oil vehicles Or disperse to absorb to complete the delay of compound injection administration.

Injection storage form is to form chemical combination by biodegradable polymer, such as more lactic acid-polyglycolide What the microcapsule matrix of thing was completed.The controlled release ratio of compound depends on the ratio and particular polymer that compound forms polymer Property.Other biodegradable polymers include poly- (positive esters) and poly- (acid anhydrides).Injection storage form can also pass through Compound is embedded in the liposome compatible with bodily tissue or microemulsion is prepared.

Some of embodiments are, the composition of rectum or vagina administration is suppository, and suppository can be by by institute of the present invention The salt or crystal formation stated are mixed to be prepared with the auxiliary material or carrier of suitable non-perfusing, such as cocoa butter, polyethylene glycol, or bolt Agent wax, they are solid in room temperature but are then liquid under body temperature, therefore just fusing release is lived in vagina or cavity of tunica vaginalis Property compound.

The solid dosage forms of oral administration includes capsule, tablet, pill, pulvis and granula.In these formulations, active ingredient Thing mixes with least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive such as carboxymethyl cellulose, alginates are bright Glue, polyvinyl pyrrolidone, sucrose and Arabic gum, c) NMF such as glycerine, d) disintegrant such as agar, calcium carbonate, potato starch Or tapioca, alginic acid, some silicate and sodium carbonate, e) retardance agent solution such as paraffin, f) sorbefacient such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glycerin monostearate, h) absorbent such as white bole and bentonite, i) lubricant such as talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate, and their mixture.As for capsule, tablet and ball Agent, these formulations can include buffer.

The solid composite of similar type can be that filler riddles soft or hard capsule, and used auxiliary material has breast Sugared and high molecular polyethylene glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granula can pass through coating, shell adding As known coating method is prepared on enteric coating and other drugs preparation.They can optionally include opacifier, or Preferably, in certain part of enteron aisle, arbitrarily, the sole active agent in composition is discharged in the method for delay.Such as implantation Composition can include multimeric species and wax.

Salt or crystal formation of the present invention can form micro- glue together with one or more excipient described in the invention Cap dosage.The agent of solid dosage forms photo, lozenge, capsule, pill and granula can be by coating or shell addings, such as enteric coating, controlled release Coating and other known drug formulation process.In these solid dosage forms, reactive compound can be dilute with least one inertia Release agent mixing, such as sucrose, lactose or starch.Such formulation can also include besides inert diluents as in general application Additive, such as tableting lubricant and other compression aids such as magnesium stearate and microcrystalline cellulose.As for capsule, tablet and ball Agent, these formulations can include buffer.They can optionally include sedative, or preferably, certain in enteron aisle is a part of, The sole active agent in composition is discharged in the method arbitrarily postponed.Applicable implant compositions can include, but not It is limited to, polymer and wax.

The composition of salt or crystal formation of the present invention includes ointment by part or through percutaneous drug delivery formulation, pastes Agent, emulsion, lotion, gel, pulvis, solution, spray, inhalant, paster.Active component under sterile conditions with pharmacy Upper acceptable carrier and any required preservative or required buffer mix.The pharmaceutical preparation of ophthalmology, auristilla and Eye drops is all the scope that the present invention considers.In addition, present invention further contemplates that the application of transdermal patch, it is in control compound transmission There is the advantages of more to internal aspect, such formulation can be made by dissolving or disperseing compound into suitable medium It is standby to obtain.Sorbefacient can increase the flow that compound passes through skin, and through-rate controls film or disperses compound Its speed is controlled in polymer matrix or gelatin.

Salt or crystal formation of the present invention are preferably prepared into dosage unit form to mitigate dosage and agent by pharmaceutical formulation The uniformity of amount.Term " dosage " unit type " obtains the physical dispersion unit of suitably medicine needed for treatment referred to herein as patient. It should be appreciated, however, that the daily total usage of the compound or composition of the present invention will be by the doctor in charge according to reliable medical science scope Judge to determine.Specific effective dose level will depend on many factors bag for any one special patient or organism Include the seriousness of treated illness and illness, the activity of particular compound, concrete composition used, the age of patient, body The discharge rate of weight, health status, sex and eating habit, administration time, method of administration and particular compound used, treatment Duration, medicinal application are combined in drug combination or with specific compound, and known to some other pharmaceutical field Factor.

The change of the dosage of the salt or crystal formation of the present invention of the single dosage form composition of carrier mass generation can be combined Depending on curing mainly and special mode of administration.Some of embodiments are that composition can be prepared into dosage by formulation method and exist The inhibitor of 0.01-200mg/kg body weight/days, the amount of composition is received by patient to be administered.

Salt or crystal formation of the present invention are with only pharmaceutical agents or combine other one or more additional treatment (pharmacy ) agent is administered, wherein drug combination causes acceptable adverse reaction, this treatment tool for high proliferative disease such as cancer There is special meaning.In this case, salt or crystal formation of the present invention can combine known cytotoxic agent, single turn Lead inhibitor or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, additional therapeutic agent is normal The special disease of drug treatment, exactly known " suitably treating disease "." additional therapeutic agent " used in the present invention includes Chemotherapeutic agent or other antiproliferative medicines can combine salt of the present invention or crystal formation treatment proliferative diseases or cancer Disease.

Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (HDAC) inhibitor, including but simultaneously It is not limited to, SAHA, MS-275, MGO103, and the compound described by those following patents：WO 2006/010264,WO 03/024448,WO 2004/069823,US 2006/0058298,US 2005/0288282,WO 00/71703,WO 01/ 38322,WO 01/70675,WO 03/006652,WO 2004/035525,WO 2005/030705,WO 2005/092899, Included, but is not limited to demethylating agent, the miscellaneous nitrogen -2 of 5- '-deoxycytidine (5-aza-dC), azacitidine (Vidaza), Compound described by Decitabine (Decitabine) and documents below：US 6,268137,US 5,578,716,US 5, 919,772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6,221,849,US 6,953,783,US 11,393,380。

Other embodiment is, chemotherapeutic agent or other anti-proliferative drugs can combine salt of the present invention or Crystal formation treats proliferative diseases and cancer.Known chemotherapeutic agent includes, but is not limited to, and other therapies or anticancer can With the anticancer of the joint present invention and include surgery, (a little example such as γ is radiated radiotherapy, neutron beam radiotherapy, electronics Beam radiotherapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, BRM (interferon, interleukin, neoplasm necrosis The factor (TNF), the effect of TRAIL receptor targets and medium), overheat and cold therapy, dilute the reagent of any adverse reaction (such as Antiemetic), and the chemotherapeutic agent of other accreditations, including but not limited to, alkylating drug (mustargen, Chlorambucil, ring phosphorus Acid amides, melphalan, ifosfamide), antimetabolite (methotrexate (MTX), pemetrexed (Pemetrexed) etc.) is fast Purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, Ji Xita Shore (Gemcitabine)), spindle poison (vincaleukoblastinum, vincristine, vinorelbine, taxol), podophyllotoxin (relies on Moor glycosides, Irinotecan (Irinotecan), Hycamtin (Topotecan)), antibiotic (Doxorubicin (Doxorubicin), Bleomycin (Bleomycin), mitomycin (Mitomycin)), nitroso ureas (BCNU (Carmustine), Luo Mosi Spit of fland (Lomustine)), inorganic ions (cis-platinum, carboplatin), (KSP passes through mitotic kinesins to CDC inhibitor Inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), bright third Rayleigh (Leuprolide), Flutamide (Flutamide), megestrol acetate (Megestrol)), Gleevec (Gleevec), Ah mould Plain (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (Imatinib (Imatinib), Sutent (Sutent), Sorafenib (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer Disease treats wide forum and sees http:The oncologic inventory of //www.nci.nih.gov/, FAD accreditation is shown in http:// Www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18th edition, 2006, all contents All it is combined with bibliography.

Other embodiment is that salt or crystal formation of the present invention can combine cytotoxic anticancer agent.It is such anti- Cancer agent can be found the 13rd edition Merck index (2001) is inner.These anticancers include, but are not limited to, L-Asparaginasum (Asparaginase), bleomycin (Bleomycin), carboplatin, BCNU (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytarabine (Cytarabine), reach Carbazine (Dacarbazine), actinomycin D (Dactinomycin), daunorubicin (Daunorubicin), adriamycin is (more It is soft than star), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl melamine, hydroxyl Base urea, ifosfamide, Irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), first ammonia Pterin (Methotrexate), mitomycin C (Mitomycin C), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), metacortandracin (Prednisone), procarbazine (Procarbazine), Raloxifene (Raloxifen), Streptozocin (Streptozocin), TAM (Tamoxifen), thioguanine (Thioguanine), Hycamtin are long Spring alkali, vincristine, eldisine.

Include with the suitable cytotoxic drug of other of salt of the present invention or crystal formation drug combination, but it is and unlimited In these are admittedly applied to the compound of tumor disease treatment, as described in documents below：Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw- Hill.)；These anticancers include, but are not limited to, aminoglutethimide (Aminoglutethimide), ASP, sulphur Azoles purine, 5-azacitidine, Cladribine (Cladribine), busulfan (Busulfan), diethylstilbestrol, 2', 2'- difluoros are gone Oxygen CDPC, Docetaxel, red hydroxyl nonyl adenine (Erythrohydroxynonyladenine), acetylene is female Glycol, 5 FU 5 fluorouracil deoxyribonucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabine Phosphate), Fluoxymesterone (Fluoxymesterone), Flutamide (Flutamide), hydroxyprogesterone caproate, idarubicin (Idarubicin), interferon, medroxyprogesterone acetate, megestrol acetate, melphalan (Melphalan), mitotane (Mitotane), taxol, Pentostatin (Pentostatin), N- phosphates base-L-Aspartic acid (PALA), general card are mould Plain (Plicamycin), Me-CCNU (Semustine), Teniposide (Teniposide), testosterone propionate, plug replaces Send (Thiotepa), trimethyl melamine, urinate nucleosides and vinorelbine.

Other cytotoxin class anticancers suitably with salt of the present invention or crystal formation use in conjunction include new discovery Cytotoxic substance, including but being not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), macrolides antineoplastic and its natural or synthetic derivative Thing, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), support Western not monoclonal antibody (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society For Clinical Oncology, 2004,23, abstract 3181), and driving albumen spindle protein inhibitor Eg5 (Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。

Other embodiment is that salt or crystal formation of the present invention can combine other signal transduction inhibitors.It is interesting Be signal transduction inhibitor using EGFR families as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs,2000,60(Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and Their own part.Such reagent includes, but is not limited to, antibody therapy such as Trastuzumab (trastuzumab), and western appropriate former times is single Anti- (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also includes, but is not limited to, small molecule kinase suppression Preparation such as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al., Cancer Research, 2004,64,4931-4941).

Other embodiment is, salt or crystal formation of the present invention combine other signal transduction inhibitor targetings in Divide the receptor kinase (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) of kinase domain family, and they are each From part.Such reagent includes, but is not limited to, antibody such as bevacizumab (Avastin).Such reagent includes, but It is not limited to, micromolecular inhibitor such as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al., Cancer Res.2000,60 (8),2178-2189),Telatinib/BAY-57-9352,BMS-690514,BMS-540215,Axitinib/AG- 013736,Motesanib/AMG706,Sutent/Sunitinib/SU-11248,ZD-6474(Hennequin et al., 92nd AACR Meeting,New Orleans,Mar.24-28,2001,abstract 3152),KRN-951(Taguchi et al.,95th AACR Meeting,Orlando,FIa,2004,abstract2575),CP-547,632(Beebe et al.,Cancer Res.2003,63,7301-7309),CP-673,451(Roberts et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract 3989),CHIR-258 (Lee et al.,Proceedings of the American Association of Cancer Research,2004, 45,abstract 2130),MLN-518(Shen et al.,Blood,2003,102,11,abstract 476)。

Other embodiment is that salt or crystal formation of the present invention can be with bonding histone deacetylase inhibitors. Such reagent includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology,2004,23,abstract 3024),LBH-589(Beck et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract 3025),MS-275(Ryan et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract 2452),FR-901228 (Piekarz et al.,Proceedings of the American Society for Clinical Oncology, 2004,23, abstract 3028) and MGCDOI 03 (US 6,897,220).

Other embodiment is that salt or crystal formation of the present invention can combine other anticancers such as proteasome and suppress Agent and m-TOR inhibitor.These include, but are not limited to, bortezomib (Bortezomib) (Mackay et al., Proceedings of the American Society for Clinical Oncology,2004,23,Abstract , and CCI-779 (Wu et al., Proceedings of the American Association of Cancer 3109) Research,2004,45,abstract 3849).Salt or crystal formation of the present invention can be combined with other anticancers and such as opens up Flutter isomerase inhibitors, including but not limited to camptothecine.

Those additional therapeutic agents can separately be administered with the composition comprising salt of the present invention or crystal formation, as giving more A part for prescription case.Or those therapeutic agents can be a part for one-pack type, be mixed with salt of the present invention or crystal formation Single composition is formed together.If the part as more dosage regimens is administered, two activating agents can be simultaneously continuously Or transmitted mutually within a period of time, so as to obtain destination agent activity.

Can combine carrier mass produce one-pack type compound and additional therapeutic agent dosage (those include one it is additional The composition of therapeutic agent is as described in the invention) change depend on cure mainly and special mode of administration.Normally, it is of the invention The amount of composition additional therapeutic agent includes the normal amount administered of the therapeutic agent as unique activating agent using no more than composition.Separately On the one hand, the scope of the amount of existing disclosed composition additional therapeutic agent is about the 50%-100% of existing composition normal amount, Comprising reagent as sole active therapeutic agent.In the composition that those include additional therapeutic agent, additional therapeutic agent will be with this The compound of invention plays synergy.

The feature of the pharmaceutical composition of the present invention includes the one or more of salt of the present invention, or of the present invention The one or more of crystal formation, or combinations thereof, and pharmaceutically acceptable carrier, assistant agent or excipient.This present invention's Pharmaceutical composition effectively can detectably suppress protein kinase such as activity of EGFR.The pharmaceutical composition of the present invention will be applied to Treatment or reduction EGFR illeffects as antineoplastic.

The pharmaceutical composition of the present invention will be applied to, but be not limited to, and patient is given using the pharmaceutical composition of the present invention Medicine prevents or treats patient's proliferative diseases.Such disease includes cancer, especially metastatic carcinoma, non-small cell lung cancer and table Skin cancer.

The pharmaceutical composition of the present invention will include cancer and metastatic carcinoma applied to the treatment of knurl, further comprise but and unlimited In, cancer such as epidermal carcinoma, carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including ED-SCLC), cancer of the esophagus, courage Capsule cancer, oophoroma, cancer of pancreas, stomach cancer, cervical carcinoma, thyroid cancer, prostate cancer, and cutaneum carcinoma (including squamous cell carcinoma)；Leaching Bar system hematopoetic tumor (including leukaemia, the Cystic leukaemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell leaching Bar knurl, t cell lymphoma, He Jiejin (family name) lymthoma, non-hodgkin's (family name) lymthoma, hairy cell leukemia and Hugh Burkitt leaching Bar knurl)；Marrow system hematopoetic tumor (including acute and chronic myelocytic leukemia, RAEB, and it is preceding Myelocytic leukemia)；Tumour (including fibrosarcoma and the rhabdomyosarcoma, and other sarcomas, such as soft group of mesenchymal cell origin Knit and cartilage)；Maincenter peripheral nervous system knurl (including astrocytoma, neuroblastoma, glioma, and neurolemma Knurl)；With other tumours (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, Keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).

The pharmaceutical composition of the present invention can also be used to treat eye disease such as corneal graft rejection, the new vessels shape of eye Into retinal neovascularazation includes damage or metainfective new vessels is formed；Diabetic retinopathy；After crystalline lens Proliferation of fibrous tissue disease, and neovascular glaucoma；Treat retinal ischemic；Vitreous hemorrhage；Ulcer disease such as gastric ulcer；Disease The blood vessel of of science but non-malignant situation such as hemangioma, including baby's hemangioendothelioma, nasopharynx and no vascular osteonecrosis Fibroma；Female repro ductive system is disorderly such as mullerianosis.These compounds are equally also used for treating oedema and vascular is penetrating The too high situation of property.

The pharmaceutical composition of the present invention can be used for handling the situation such as diabetic retinopathy related to diabetes and Microangiopathy.The compound of the present invention is equally used for the situation of cancer patient's CBF reduction.The pharmaceutical composition pair of the present invention Patient tumors transfer, which is reduced, also beneficial effect.

The pharmaceutical composition of the present invention is except beneficial in addition to, applying also for veterinary treatment pet to human treatment, introducing The animal of kind and the animal on farm, including mammal, rodent etc..The example of other animal include horse, Dog and cat.Here, the pharmaceutical composition of the present invention includes its pharmaceutically acceptable derivates.

In the case where plural form is applied into compound, salt etc., it also means single compound, salt etc..

The treatment method of pharmaceutical composition administration comprising the present invention, further comprises to patient's additional therapeutic agent (joint Treatment) administration, wherein additional therapeutic agent is selected from：Chemotherapy, antiproliferative or antiinflammatory, wherein additional therapeutic agent are applied to The disease treated, and additional therapeutic agent can be with the pharmaceutical composition administering drug combinations of the present invention, pharmaceutical composition of the invention As single formulation, or a part of the separated composition as multi-form.Additional therapeutic agent can be with the medicine group of the present invention Compound is administered simultaneously or is not administered simultaneously.

The method of the invention for equally including the cell growth inhibition to expressing EGFR, the method include the medicine group of the present invention Compound and cells contacting, so as to suppress cell growth.The cell of growth, which can be suppressed, to be included：Epidermis cancer cell, breast cancer cell, Colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphoma cell, colon cancer cell, pancreas Cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, human osteosarcoma cell, kidney cancer cell, liver are thin Born of the same parents' cancer cell, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cells and leukaemia.

The invention provides the method for suppressing EGFR kinase activity in biological sample, the method is included the medicine of the present invention Compositions contact with biological sample.Term " biological sample " used in the present invention refers to the sample of vitro, including but It is not limited to, cell culture or cell extraction；The biopsy material obtained from mammal or its extract；Blood, saliva Liquid, urine, excrement, seminal fluid, tears, or other living tissue liquid substances and its extract.Suppress kinase activity in biological sample, Particularly EGFR kinase activity, available for multiple use known to one of ordinary skill in the art.Such purposes includes, but never It is limited to, hematometachysis, organ transplant, biological sample storage and bioassay.

" effective dose " or " effective dose " of the pharmaceutically acceptable composition of the present invention refer to handle or mitigate one or Multiple present invention are previously mentioned the effective dose of the severity of illness.The method according to the invention, composition can be any dosages With any method of administration come the order of severity that is efficiently used for handling or mitigates disease.Required accurately amount is by according to patient's Situation and change, this depend on race, the age, the general condition of patient, the order of severity of infection, special factor, to prescription Formula, etc..Composition can with one or more other therapeutic agents administering drug combinations, as discussed in the present invention.

The pharmaceutical composition of the present invention can apply to the coating of implantable medical device, such as prosthese, artificial valve, people Hematopoiesis pipe, stem and catheter.For example, vascular stem, has been used for overcoming ISR (shrinking again for vessel wall after injury).So And patient will have the risk of clot formation or platelet activation using stem or other implantable devices.These unfavorable effects It can prevent or mitigate by using the pharmaceutically acceptable pharmaceutical composition precoating device of the present invention.

Suitable coating and the coating of implantable device are typically prepared method in document US 6,099,562；US 5, 886,026；It is described with US 5,304,121, coating is the polymeric material such as hydrogel of typically bio-compatible Condensate, the poly- silicon ether of methyl two, polycaprolactone, polyethylene glycol, PLA, ethane-acetic acid ethyenyl ester, and its mixture.Bag Clothing can be covered optionally further by suitably coating, such as fluoro dimeticone, polysaccharase, polyethylene glycol, phosphatide Class, or combinations thereof, carry out the feature of performing combination thing control release.Medicine of the another aspect of the present invention including the use of the present invention The implantable device of compositions coating.The pharmaceutical composition of the present invention can also be coated in the medical instruments in implantable On, " medicine storage institute " is provided such as pearl, or with polymer or other molecular mixings, therefore with pharmaceutical aqueous solution to prescription Formula compares, it is allowed to which insoluble drug release has longer time limit.

Brief description of the drawings

Fig. 1 is X-ray powder diffraction (XRPD) figure of the crystal formation I of two salicylates of compound shown in formula (I).

Fig. 2 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of two salicylates of compound shown in formula (I).

Embodiment

The present invention is further illustrated below by the mode of embodiment, does not therefore limit the present invention to described implementation Among example scope.

X-ray powder diffraction analysis method is used in the present invention：Empyrean diffractometers, using Cu-K α radiation (45KV, 40mA) obtain X-ray powder diffraction figure.Powdered samples are prepared into straticulation on monocrystal silicon sample frame, are placed on rotary sample On platform, analyzed in the range of 3 ° -40 ° with 0.0168 ° of step-length.Data are collected using Data Collector softwares, HighScore Plus software data processings, Data Viewer softwares read data.

Means of differential scanning calorimetry used in the present invention (DSC) analysis method is：Use the TA Q2000 with heat analysis controller Module carries out means of differential scanning calorimetry.Collect data and divided using TA Instruments Thermal Solutions softwares Analysis.About 1-5mg samples are weighed in the special aluminium crucible with lid exactly, filled using 10 DEG C/min of linear heating Put, from room temperature to about 250 DEG C of progress sample analysis.During use, DSC cells are purged with drying nitrogen.

Thermal weight loss used in the present invention (TGA) analysis method is：Carried out using the TA Q500 modules with heat analysis controller Thermal weight loss.Collect data and analyzed using TA Instruments Thermal Solutions softwares.By about 10mg samples Product are weighed in platinum sample disc exactly, using 10 DEG C/min of linear heating device, from room temperature to about 300 DEG C of progress Sample analysis.During use, TGA furnace chambers are purged with drying nitrogen.

The test condition of proton nmr spectra of the present invention is：Under room temperature condition, Brooker (Bruker) 400MHz or 600MHz nuclear magnetic resonance spectrometer, with CDC1₃, d⁶- DMSO, CD₃OD or d⁶- acetone is solvent (reporting in units of ppm), uses TMS (0ppm) or chloroform (7.26ppm) are used as reference standard.When there is multiplet, following abbreviation will be used：s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, represented with hertz (Hz).

Specific implementation method

Compound 4- shown in formula (I) [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- two Oxygen -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline specific synthetic method with reference to patent CN Embodiment 6 in 103102344A (application publication number).

Embodiment

Embodiment 1

1st, 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline two salicylate (crystal formation I) preparation

Under backflow, by compound 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- bis- Oxygen -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline (1g, 2.04mmol) is dissolved in acetone (30mL), Xiang Ti Acetone (5mL) solution of salicylic acid (0.62g, 4.5mmol) is added dropwise in system, back flow reaction is overnight, is cooled to room temperature and adds stone Oily ether, there are insoluble solids to separate out, filter, vacuum drying.

2nd, 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline two salicylate (crystal formation I) identification

1) analyzed by proton nmr spectra, be 1 into salt ratio:2.

2) analyzed and identified by Empyrean X-ray powder diffractions (XRPD), radiated using Cu-K α, had following with angle Spend the characteristic peak of 2 θ expressions：5.86 °, 6.66 °, 8.24 °, 8.42 °, 9.64 °, 10.20 °, 11.82 °, 13.35 °, 13.90 °, 14.87 °, 15.17 °, 15.67 °, 16.04 °, 16.46 °, 17.04 °, 17.55 °, 18.41 °, 18.65 °, 19.16 °, 19.64 °, 19.90 °, 20.26 °, 20.61 °, 21.27 °, 21.56 °, 21.81 °, 22.30 °, 22.64 °, 22.97 °, 23.55 °, 24.19 °, 24.44 °, 24.68 °, 24.96 °, 25.60 °, 26.12 °, 26.33 °, 26.71 °, 27.73 °, 28.03 °, 28.48 °, 29.83 °, 30.09 °, 30.58 °, 31.12 °, 32.02 °, 32.39 °, 33.16 °, 34.53 ° and 36.45 °, the error for having ± 0.2 ° is held Limit.

3) being analyzed and identified by TA Q2000 means of differential scanning calorimetry (DSC), sweep speed is 10 DEG C/min, comprising 180.20 DEG C of endothermic peak, ± 3 DEG C of error margin be present.

Embodiment 2

The pharmacokinetic situations of two salicylates of compound shown in formula (I) of the present invention

The body of two salicylates of compound shown in compound shown in formula (I) of the present invention and formula (I) is carried out using beasle dog Interior pharmacokinetic trial：Each 3 of kind beasle dog, administering mode is capsule oral, is converted according to free alkali dosage 5mg/kg Go out the dosage of salt, the oral suction of two salicylates of compound shown in compound shown in Primary Study formula (I) of the present invention and formula (I) Receipts situation.Experimental result is as shown in table 1：

Compound shown in 1 formula (I) of the present invention of table and secondly pharmacokinetic parameter of the salicylate in beasle dog body

Conclusion：Exposure of exposed amount of two salicylates of compound shown in formula (I) of the present invention in dog body compared with free alkali Amount is big, and bioavilability has larger improvement.

Above said content is only the basic explanation under present inventive concept, and is appointed according to what technical scheme was made What equivalent transformation, all should belong to protection scope of the present invention.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or the feature for combining the embodiment or example description It is contained at least one embodiment or example of the present invention.In this manual, need not to the schematic representation of above-mentioned term Identical embodiment or example must be directed to.Moreover, specific features, structure, material or the feature of description can be any Combined in an appropriate manner in individual or multiple embodiments or example.In addition, in the case of not conflicting, the technology of this area Different embodiments or example and the feature of different embodiments or example described in this specification can be combined by personnel And combination.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changed, replacing and modification.

Claims (8)

1. the crystal formation of two salicylates of compound shown in formula (I), wherein the crystal formation is crystal formation I,

Wherein described crystal formation I X-ray powder diffraction pattern has diffraction maximum at following 2 θ angles：6.66 ° ± 0.2 °, 8.24 ° ± 0.2 °, 10.20 ° ± 0.2 °, 13.35 ° ± 0.2 °, 13.90 ° ± 0.2 °, 15.67 ° ± 0.2 °, 16.04 ° ± 0.2 °, 16.46 ° ± 0.2 °, 17.04 ° ± 0.2 °, 17.55 ° ± 0.2 °, 18.41 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.16 ° ± 0.2 °, 19.64 ° ± 0.2 °, 19.90 ° ± 0.2 °, 20.26 ° ± 0.2 °, 20.61 ° ± 0.2 °, 21.27 ° ± 0.2 °, 21.81 ° ± 0.2 °, 22.30 ° ± 0.2 °, 22.64 ° ± 0.2 °, 22.97 ° ± 0.2 °, 23.55 ° ± 0.2 °, 24.19 ° ± 0.2 °, 24.44 ° ± 0.2 °, 24.68 ° ± 0.2 °, 24.96 ° ± 0.2 °, 25.60 ° ± 0.2 °, 26.12 ° ± 0.2 °, 26.33 ° ± 0.2 °, 26.71 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.03 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.83 ° ± 0.2 ° and 30.09 ° ±0.2°。

2. crystal formation according to claim 1, wherein the X-ray powder diffraction pattern of the crystal formation I has at following 2 θ angles There is diffraction maximum：5.86 ° ± 0.2 °, 6.66 ° ± 0.2 °, 8.24 ° ± 0.2 °, 8.42 ° ± 0.2 °, 9.64 ° ± 0.2 °, 10.20 ° ± 0.2 °, 11.82 ° ± 0.2 °, 13.35 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.87 ° ± 0.2 °, 15.17 ° ± 0.2 °, 15.67 ° ± 0.2 °, 16.04 ° ± 0.2 °, 16.46 ° ± 0.2 °, 17.04 ° ± 0.2 °, 17.55 ° ± 0.2 °, 18.41 ° ± 0.2 °, 18.65 ° ± 0.2 °, 19.16 ° ± 0.2 °, 19.64 ° ± 0.2 °, 19.90 ° ± 0.2 °, 20.26 ° ± 0.2 °, 20.61 ° ± 0.2 °, 21.27 ° ± 0.2 °, 21.56 ° ± 0.2 °, 21.81 ° ± 0.2 °, 22.30 ° ± 0.2 °, 22.64 ° ± 0.2 °, 22.97 ° ± 0.2 °, 23.55 ° ± 0.2 °, 24.19 ° ± 0.2 °, 24.44 ° ± 0.2 °, 24.68 ° ± 0.2 °, 24.96 ° ± 0.2 °, 25.60 ° ± 0.2 °, 26.12 ° ± 0.2 °, 26.33 ° ± 0.2 °, 26.71 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.03 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.83 ° ± 0.2 °, 30.09 ° ± 0.2 °, 30.58 ° ± 0.2 °, 31.12 ° ± 0.2 °, 32.02 ° ± 0.2 °, 32.39 ° ± 0.2 °, 33.16 ° ± 0.2 °, 34.53 ° ± 0.2 ° and 36.45 ° ± 0.2 °.

3. crystal formation according to claim 1, wherein the crystal formation I has X-ray powder diffraction substantially as shown in Collection of illustrative plates.

4. crystal formation according to claim 1, wherein the differential scanning calorimetric curve of the crystal formation I is at 180.20 DEG C ± 3 DEG C Place has endothermic peak.

5. crystal formation according to claim 1, wherein the crystal formation I has means of differential scanning calorimetry substantially as shown in Figure 2 Curve.

6. a kind of pharmaceutical composition, it includes the crystal formation or combinations thereof described in claim 1-5 any one, wherein described Pharmaceutical composition further include pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or their group Close.

7. pharmaceutical composition according to claim 6, it further includes therapeutic agent, and the therapeutic agent is selected from chemistry Medicine, antiproliferative, for treating the medicine or combinations thereof of non-small cell lung cancer and epidermal carcinoma；

Wherein described therapeutic agent is adriamycin (Adriamycin), rapamycin (Rapamycin), Temsirolimus, according to Wei Mosi (Everolimus), Ixabepilone, gemcitabine (Gemcitabine), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), fluorouracil (Fluorouracil), imatinib mesylate (Imatinibmesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), Erlotinib (Erlotinib), Lapatinib (Lapatinib), Iressa (Iressa), Sorafenib (Sorafenib), Sutent (Sunitinib), interferon (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vincaleukoblastinum, vincristine, Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), western appropriate former times are single Anti- (Cetuximab), Victibix (Panitumumab), or combinations thereof.

8. a kind of usage right requires the crystal formation described in 1-5 any one or the medicine group described in claim 6-7 any one Compound is used to protecting, handle or treating patient's proliferative diseases to prepare, and mitigates the purposes of the medicine of its order of severity.