CN105294716A - Amino quinazoline derivative disalicylate and crystal form thereof - Google Patents

Abstract

The present invention relates to a salt formed from an amino quinazoline derivative and salicylic acid, and a crystal form thereof. The present invention further relates to preparation methods of the salt and the crystal form, and a pharmaceutical composition containing the salt and/or crystal form. According to the present invention, the salt, the crystal form or the pharmaceutical composition can be used for proliferative disease treatment.

Description

A kind of two salicylates of amino quinazoline derivative and crystal formation

Technical field

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

Background technology

EGF-R ELISA (epidermalgrowthfactorreceptor, EGFR) be a kind of receptor type tyrosine kinase, process LAN and (or) undergoing mutation in many tumours, control tumor growth by signal transduction, and generate with new vessel, the Infiltration and metastasis etc. of tumour has close relationship.EGF-R ELISA is the important regulatory factor of Growth of Cells, differentiation and survival, and its member has: erbB-1 (EGFR, HER1), erbB-2 (EGFR, HER2), erbB-3 (EGFR, and erbB-4 (EGFR, HER4) HER3).Their structural similitudies, by the protein tyrosine kinase district composition of the outer ligand binding domain of born of the same parents, single transmembrane district and high conservative.This structure has the function of acceptor, has again the ability that extracellular signal is converted into born of the same parents' internal effect, is a kind of cross-film transfer mode of novelty.Once acceptor is combined with particular ligand, just can by the autophosphorylation of corresponding Tyrosylprotein kinase activated receptor, thus the signal transduction pathway in activating cells.These signal transmission paths comprise: the activation of Ras kinase protein and short cell fission kinase protein MAPK, the multiple protein of activation both this again in activating cells core, comprise the critical loops protein D 1 of cell cycle proliferation, thus cause DNA synthesis, Growth of Cells, differentiation.The excessive activation of growth factor receptors causes the proliferation out of control of cell, thus produces various types of excessively proliferative disease, as nonsmall-cell lung cancer, mammary cancer, the cancer of the brain etc.The suppression of growth factor receptor tyrosine kinase is proved the effect having and regulate cellular replication out of control, therefore becomes the target of new type antineoplastic medicine.

Chinese patent literature CN103102344A (application publication number) has disclosed 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R in specification sheets 57 pages of embodiments 6,6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} structural information of-quinazoline, this compound is a kind of free alkali, and its structure is such as formula shown in (I).This compound has very high inhibit activities to EGFR, can be used for treating proliferative disease.

Summary of the invention

The present invention relates to compound 4-shown in formula (I) [(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-two salicylates of-quinazoline and crystal formation, be specifically related to two salicylates of compound shown in formula (I) crystal formation I.The invention still further relates to and comprise described salt or/and the pharmaceutical composition of crystal formation, and described salt, crystal formation or their pharmaceutical composition are used for the treatment of the purposes of patient's proliferative disease.

On the one hand, the invention provides a kind of salt formed by compound formula (I) Suo Shi and Whitfield's ointment, described salt has the structure shown in formula (II):

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 described salt has the 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 said crystal formation is crystal formation I.

In certain embodiments, crystal formation of the present invention, the X-ray powder diffraction pattern of wherein said crystal formation I has diffraction peak at following 2 θ angle places: 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, the X-ray powder diffraction pattern of wherein said crystal formation I has diffraction peak at following 2 θ angle places: 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 said crystal formation I has X-ray powder diffraction pattern as shown in Figure 1 substantially.

In certain embodiments, crystal formation of the present invention, the differential scanning calorimetric curve of wherein said crystal formation I has endotherm(ic)peak at 180.20 DEG C ± 3 DEG C places.

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

On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises salt of the present invention or crystal formation of the present invention or their combination, wherein said pharmaceutical composition comprises pharmaceutically acceptable carrier further, vehicle, thinner, assistant agent, vehicle or their combination.

In certain embodiments, pharmaceutical composition of the present invention, it further comprises therapeutical agent, and described therapeutical agent is selected from chemotherapeutic agent, antiproliferative, is used for the treatment of medicine or their combination of nonsmall-cell lung cancer and epidermal carcinoma.

In other embodiment, pharmaceutical composition of the present invention, wherein said therapeutical agent is Zorubicin (Adriamycin), rapamycin (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabine), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinibmesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.

On the other hand, the present invention relates to a kind of salt of the present invention or crystal formation of the present invention or pharmaceutical composition of the present invention of using and come for the preparation of protection, process or treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.

In certain embodiments, purposes of the present invention, wherein said proliferative disease is metastatic carcinoma, epidermal carcinoma, colorectal carcinoma, adenocarcinoma of stomach, bladder cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid carcinoma, brain tumor, neck cancer, prostate cancer, carcinoma of the pancreas, the cancer of CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

Definition and general terms

Except as otherwise noted, what all technology of using of the present invention and scientific terminology and those skilled in the art understood usually has identical meanings.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.Although can use and similar or identical any method of the present invention and material in practice of the present invention or test, what describe in the present invention is preferred method, equipment and material.

" salt that shown in formula (I), compound and Whitfield's ointment are formed " or " salt shown in formula (III) " comprise amorphous form, crystallized form, solvate, the hydrate of such salt, and comprise the polymorphic forms of such salt." two salicylates of compound shown in formula (I) " comprise amorphous form, crystallized form, solvate, the hydrate of such salt, and comprise the polymorphic forms of such salt.

In one embodiment of the invention, salt of the present invention has crystalline nature and preferably has at least 50% degree of crystallinity, more preferably at least 60% degree of crystallinity, still more preferably at least 70% degree of crystallinity most preferably at least 80% degree of crystallinity.Degree of crystallinity or crystallinity are assessed by conventional x-ray diffraction technology.

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

Except as otherwise noted, in salt of the present invention, shown in formula (I), compound 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 example of preferred salt of the present invention, comprising compound shown in formula (I) is the salt of 1:1 to the stoichiometry of acid, and compound shown in formula (I) is compound shown in the salt of 1:2 or formula (I) to the stoichiometry of acid is the salt of 2:3 to the stoichiometry of acid.Salt of the present invention can be single salt when using, and also can be the mixture of several salt.The salt that shown in formula (I), compound and Whitfield's ointment are formed can be single salt when using, also can be the mixture of the salt of different salify ratio, the mixture of the salt that the salt that can also to be compound shown in formula (I) be formed with Whitfield's ointment and the shown compound of formula (I) and other mineral acids or organic acid are formed.

" crystal formation " or " crystallized form " refers to the solid with height rule chemical structure, include but not limited to, single component or polycomponent crystal, and/or the polymorphic form of compound, solvate, hydrate, inclusion compound, eutectic, salt, the solvate of salt, the hydrate of salt.The crystallized form of material obtains by many methods known in the art.This method comprises, but be not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in the space limited, such as, in nanoporous or kapillary, crystallization on surface or template, such as, on polymer, crystallization under additive is as the existence of cocrystallization antimolecule, desolventizing, dehydration, rapid evaporation, cooling fast, Slow cooling, vapor diffusion, distillation, reactive crystallization, anti-solvent interpolation, grinding and solvent drip grinding etc.Crystallized form comprises anhyrous crystalline form, partial crystallization form, the mixture of crystallized form, hydrate crystalline Form and crystalline solvate form.

" amorphous " or " amorphous form " refers to the material that the particle (molecule, atom, ion) of material is formed when three-dimensional arrangement aperiodicity, it is characterized in that having the X-ray powder diffraction figure of not having a spike of diffusion.Amorphous is a kind of special physical form of solid matter, and the constitutional features of its local order, points out itself and crystal-form substances to have contacting of countless ties.The amorphous form of material obtains by many methods known in the art.This method includes, but not limited to quenching method, anti-solvent flocculence, ball milled, spray-drying process, freeze-drying, wet granulation process and solid dispersions technique etc.

" solvent " refers to a kind of material (typically a kind of liquid), and this material completely or partially can dissolve another kind of material (typically a kind of solid).Include, but are not limited to for solvent of the invention process, water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, butanols, the trimethyl carbinol, N, N-N,N-DIMETHYLACETAMIDE, DMF, methane amide, formic acid, heptane, hexane, Virahol, methyl alcohol, methyl ethyl ketone, l-N-methyl-2-2-pyrrolidone N-, sym-trimethylbenzene, Nitromethane 99Min., polyoxyethylene glycol, propyl alcohol, 2-acetone, pyridine, tetrahydrofuran (THF), toluene, dimethylbenzene, their mixture etc.

" anti-solvent " refers to the fluid promoting that product (or product precursor) precipitates from solvent.Anti-solvent can comprise cold air or promotes the fluid of precipitation by chemical reaction or reduce the fluid of product solubleness in a solvent; But it can be the liquid same with solvent phase be in differing temps, or it can be the liquid different from solvent.

" solvate " refers to that crystal from the teeth outwards, or in lattice, or from the teeth outwards and in lattice there is solvent, wherein, described solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetracol phenixin, methylene dichloride, dimethyl sulfoxide (DMSO), 1, 4-dioxane, ethanol, ethyl acetate, butanols, the trimethyl carbinol, N, N-N,N-DIMETHYLACETAMIDE, N, dinethylformamide, methane amide, formic acid, heptane, hexane, Virahol, methyl alcohol, methyl ethyl ketone, methyl-2-pyrrolidone, sym-trimethylbenzene, Nitromethane 99Min., polyoxyethylene glycol, propyl alcohol, 2-acetone, pyridine, tetrahydrofuran (THF), toluene, dimethylbenzene and their mixture etc.An object lesson of solvate is hydrate, and the solvent wherein from the teeth outwards or in lattice or from the teeth outwards and in lattice is water.On the surface of material or in lattice or from the teeth outwards and in lattice, hydrate can have or not have other solvent in addition to water.

Except as otherwise noted, when mentioning " solvate " and " hydrate ", this invention is intended to comprise stoichiometric and non-stoichiometric " solvate " and " hydrate ".

Stoichiometric solvate has the fixed ratio of solvent molecule and compound molecule.This is typically due to the Bonded Phase mutual effect between solvent and compound molecule.In non-stoichiometric solvate, solvent is not to exist with the fixing ratio of compound molecule and often can change.In non-stoichiometric solvate, solvent is often present in void space or the passage of intracell.Stoichiometric hydrate has the fixing ratio of water molecules and compound molecule.This is typically due to the Bonded Phase mutual effect between water and compound molecule.In non-stoichiometric hydrate, water is not to exist with the fixing ratio of compound molecule and often can change.In non-stoichiometric hydrate, water is often present in void space or the passage of intracell.

Any when relating to salt of the present invention here, suitable and at one's leisure, should be understood to also relate to corresponding solvate as hydrate or polymorphic modification, and also relate to corresponding amorphous form.

Salt mixture is the single salt form of the different ratios that (i) forms single salt form by different negatively charged ion, (ii) is formed by identical negatively charged ion or the mixture of (iii) these single salt forms, the such as form of aggregation (conglomerates).

Salt of the present invention is preferably to be separated and the existence of substantially pure form.

Described salt can be dry.In some embodiments, described salt is anhydrous.

Described salt can be solvate or hydrate forms.The solvate of salt of the present invention and also have hydrate such as can respectively with half-, single-, two-, three-, four-, five-, the form of six-solvate or hydrate exists.The solvent for crystallization can be embedded, as alcohols (as methyl alcohol, ethanol), aldehydes, ketone (as acetone), ester class (as ethyl acetate) in its crystal grid.Selected solvent or water in crystallization and the degree of solvate or hydrate or direct generation free alkali of producing in a following processing step normally unpredictable, and depend on the various interactional associating between treatment condition and free cpds and selected solvent (especially water).Must pass through crystallization or the amorphous solid stability separately of salt, solvate and hydrate and corresponding salt/solvate or the salt hydrate form of testing and determining gained.Because different crystalline solids and different amorphous substances may be produced in these cases, therefore, chemical constitution and the stoichiometric ratio of gained solid Middle molecule can not be only conceived to.

Because by the molecule in strong intermolecular forces constraint crystalline texture, and the essential element of the structure formation of these crystal of part exceptional stability can be represented, the therefore hydrate of the preferred salt described in corresponding hydrates of possibility.But, in some lattice fettered by intermolecular forces weak a little, also can there is water molecules.This quasi-molecule is incorporated in crystalline structure more or less, forms a kind of lower energy (energetic) effect.The same with in crystalline hydrate, usually clearly can measure the water-content in amorphous solid, but it depends critically upon drying and environmental conditions.On the contrary, in stable hydrate, between pharmaceutically active substances and water, there is clearly stoichiometric ratio.In many cases, these ratios can not meet described stoichiometric number completely, because some crystal defect, so its lower approximation.For more weak Bound moisture, the ratio of organic molecule and water molecules can change in sizable degree, such as can two-, three-or four-hydrate on extend.On the other hand, in amorphous solid, the molecular structure grade of water is not stoichiometric; But perhaps its grade is only stoichiometric once in a while.In some cases, because form layers structure, so can not classify to the precise stoichiometry of water molecules, thus make to measure the water molecules embedded in institute's form of Definition.

The invention still further relates to salt of the present invention or the crystal formation physical properties at solid state.These character can be affected by the condition controlling to obtain in solid form salt or crystal formation.The physical properties of solid state comprises the mobility of the solid such as ground.Mobility have impact on and is processed in medicine process the complexity that described material processes.When can not easily flow when between the particle of powdery, formulation specialist has to consider this fact when developing tablet or capsule preparations, and it must use glidant as colloid silica, talcum powder, starch or calcium phosphate,tribasic.

The another kind of important solid state character of medical compounds is its dissolution rate in waterborne liquid or the bioavailability of this medicine.Because the upper limit that the activeconstituents of its oral disposition administration can reach the speed of blood stream of patients is exerted one's influence, therefore the dissolution rate of activeconstituents in patient's gastric juice may have therapeutic value.

Such as, with regard to dissolution rate and bioavailability, the different crystallized form of same medicine or amorphous form may have very large difference in the pharmaceutical properties that such is important.Equally, different crystallizations or amorphous form may have different working propertiess, and as water absorbability, mobility etc., these character can affect its suitability as the active medicine prepared for business.

When obtain syrup, elixir and other liquid medicine, also dissolution rate will be considered.The solid-state form of compound also can affect its behavior to compression and stability in storage.

The physical property of these reality is subject to the impact of structure cell Middle molecule conformation and orientation, and the conformation of structure cell Middle molecule and orientation determine the specific polymorphism of material.

Crystal formation or amorphously can be differentiated by multiple technologies means, such as X-ray powder diffraction (XRPD), infrared spectroscopy (IR), melting point method, dsc (DSC), thermogravimetry (TGA), nuclear magnetic resonance method, Raman spectrum, X-ray single crystal diffraction, solution-reaction calorimetry, scanning electronic microscope (SEM), quantitative analysis, solubleness and dissolution rate etc.

X-ray powder diffraction (XRPD) can detect the information such as change, degree of crystallinity, brilliant structure state of crystal formation, is the conventional means differentiating crystal formation.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 relative peak height depends on the many factors relevant with instrument geometrical shape with sample preparation.Therefore, in certain embodiments, the feature of crystal formation of the present invention is to have the XRPD figure of some peak position, and it is substantially as shown in the XRPD figure that provides in accompanying drawing of the present invention.Meanwhile, the measuring of 2 θ of XRPD collection of illustrative plates can have experimental error, and between different instrument and different sample, measuring of 2 θ of XRPD collection of illustrative plates may slightly difference, and therefore the numerical value of described 2 θ can not be considered as absolute.Testing instrument situation according to the present invention, there is the error margin of ± 0.2 ° in diffraction peak.

Means of differential scanning calorimetry (DSC) is under program, by constantly heating or lowering the temperature, and measure sample and inertia reference substance (conventional α-Al ₂o ₃) between the temperature variant a kind of technology of energy difference.The fusing peak height of DSC curve depends on the many factors relevant with instrument geometrical shape with sample preparation, and peak position is to experimental detail relative insensitivity.Therefore, in certain embodiments, the feature of crystal formation of the present invention is to have the DSC figure of characteristic peak positions, and it is substantially as shown in the DSC figure that provides in accompanying drawing of the present invention.Meanwhile, DSC collection of illustrative plates can have experimental error, and between different instrument and different sample, the peak position of DSC collection of illustrative plates and peak value may slightly difference, and therefore the peak position of described DSC endotherm(ic)peak or the numerical value of peak value can not be considered as absolute.Testing instrument situation according to the present invention, there is the error margin of ± 3 DEG C in melting hump.

Whether means of differential scanning calorimetry (DSC) also can be used for detecting analysis crystal formation a turn brilliant or mixed crystal phenomenon.

The solid that chemical constitution is identical, under different thermodynamic conditions, often can form the different isomr of crystalline structure, or be called variant, and this phenomenon is called polymorphism or the heterogeneous phenomenon of homogeneity.When temperature and pressure condition changes, between variant, phase co-conversion can occur, this phenomenon is called crystal conversion.Due to crystal conversion, can there is huge change in the performance such as mechanics, electricity, magnetics of crystal.When the temperature of crystal conversion is when surveying in scope, means of differential scanning calorimetry (DSC) figure can be observed this transition process, it is characterized in that, DSC figure has the exothermic peak of this transition process of reflection, and there is two or more endotherm(ic)peak simultaneously, be respectively the feature endotherm(ic)peak of the different crystal forms before and after changing.

Thermogravimetric analysis (TGA) is under program, measures the temperature variant a kind of technology of quality of material, is applicable to check that the forfeiture of solvent in crystal or sample distil, the process of decomposition, can infer the situation containing crystal water or recrystallisation solvent in crystal.The quality change of TGA curve display depends on many factors such as sample preparation and instrument; Between different instruments and different sample, the quality change slightly difference that TGA detects.Testing apparatus status used according to the present invention, there is the error margin of ± 0.1% in quality change.

In the context of the present invention, 2 θ values in X-ray powder diffraction pattern are all to spend (°) for unit.

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

When mentioning spectrogram or/and when there are data in the drawings, " peak " refers to the feature that can not belong to background noise that those skilled in the art can identify.

Whenever disclosing one and having N value digital, any have N ± 0.01, N ± 0.02, N ± 0.03, N ± 0.05, N ± 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 ± 7, N ± 8, N ± 9, N ± 10, N ± 15, the numeral of N ± 20 value can be specifically disclosed, and wherein " ± " refers to and add deduct.Whenever disclosing a lower limit in a numerical range, RL, and a upper limit, RU, time, the numerical value within any scope being in the disclosed can be specifically disclosed.

" shown in formula (I) compound " of the present invention 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R for obtaining with reference to the synthetic method of embodiment 6 in patent CN103102344A (application publication number), 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-}-quinazoline.

Two salicylates of compound or the salt shown in formula (III) shown in formula (I) are 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-}-quinazoline two salicylate.Two salicylates of compound shown in formula (I) crystal formation I refer to 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy--quinazoline two salicylate crystal formation I.The crystal formation I of the salt shown in formula (III) refers to 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy--quinazoline two salicylate crystal formation I.They exist with substantially pure crystal habit.

" substantially pure " refers to that a kind of salt/crystal formation is substantially free of another or multiple salt/crystal formation, the i.e. purity at least 80% of salt/crystal formation, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 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 containing other salt/crystal formation in salt/crystal formation, the per-cent of other salt/crystal formation described in the cumulative volume or gross weight of salt/crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 3%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.

" be substantially free of " and refer to that the per-cent of one or more other salt/crystal formations in the cumulative volume or gross weight of salt/crystal formation is less than 20%, or be less than 10%, or be less than 5%, or be less than 4%, or be less than 3%, or be less than 2%, or be less than 1%, or be less than 0.5%, or be less than 0.1%, or be less than 0.01%.

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

In the context of the present invention, when using or no matter whether using the wording such as " approximately " or " about ", represent within 10% of specified value or scope, suitably within 5%, particularly within 1%.Or for those of ordinary skills, term " approximately " or " about " represent within the scope of the acceptable standard error of mean value.

Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.

Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism, with rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of the compound shown in formula (I) or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.

Unless other aspects show, all tautomeric forms of the compound shown in formula (I) are included within scope of the present invention.In addition, unless other aspects show, shown in formula (I) described in the invention, the structural formula of compound comprises the enriched isotope of one or more different atom.

The definition of neutral body chemistry of the present invention and the usual reference of the use of convention are with Publication about Document: S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, compound shown in 1994. formula (I) can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that compound shown in formula (I) is all, include, but not limited to, diastereomer, enantiomer, atropisomer, and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.

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

As described in the invention, the pharmaceutically acceptable composition of the present invention comprises one or more of salt of the present invention or one or more of crystal formation of the present invention, or their combination, and pharmaceutically acceptable carrier, assistant agent, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.The content of activeconstituents in this pharmaceutical composition is 1-99 % by weight, 1-95 % by weight, 1-90 % by weight, 1-85 % by weight, 1-80 % by weight, 1-75 % by weight, 1-70 % by weight, 1-65 % by weight, 1-60 % by weight, 1-55 % by weight, 1-50 % by weight, 1-45 % by weight, 1-40 % by weight, 1-35 % by weight, 1-30 % by weight, 1-25 % by weight, 1-20 % by weight, 1-15 % by weight, 1-10 % by weight, 1-5 % by weight.As with described by Publication about Document: InRemington:TheScienceandPracticeofPharmacy, 21stedition, 2005, ed.D.B.Troy, LippincottWilliams & Wilkins, Philadelphia, andEncyclopediaofPharmaceuticalTechnology, eds.J.SwarbrickandJ.C.Boylan, 1988-1999, MarcelDekker, NewYork, the content of comprehensive document herein, shows that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except the carrier medium of any routine and salt of the present invention or the inconsistent scope of crystal formation, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.

The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.

The composition of salt of the present invention or crystal formation can be oral administration, drug administration by injection, Aerosol inhalation, topical, per rectum administration, nose administration, containing taking administration, and vagina administration or by the administration of implantable medicine box.Term as used herein " through injection " comprises subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, intraocular, in liver, intralesional, and the injection of encephalic or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.The injection system of composition sterile of the present invention can be water or oleaginous suspension.These suspension can adopt suitable dispersion agent, wetting agent and suspension agent to manufacture by formula according to known technology.Aseptic injection can be aseptic parenteral solution or suspension, is the nontoxic acceptable thinner of injection or solvent, as 1,3 butylene glycol solution.These acceptable vehicle and solvent can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil by convention can as solvent or suspension medium.

With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Lipid acid, as oleic acid and its glyceride derivative can be used for the preparation of injectable, as natural pharmaceutically acceptable grease, as sweet oil or Viscotrol C, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain alcohol diluents or dispersion agent, and as carboxymethyl cellulose or similar dispersing agents, the pharmaceutical preparation being generally used for pharmaceutically acceptable formulation comprises emulsion and suspension.Other conventional tensio-active agents, as Tweens, the reinforcer of spans and other emulsifying agents or bioavailability, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, and can be applied to the preparation of targeted drug formulation.

The pharmaceutically acceptable composition of the present invention can be carry out oral administration with any acceptable oral dosage form, comprising, but be not limited to, capsule, tablet (tablet), pill, pulvis, sustained release agent, water suspension or solution.Orally use about tablet, carrier generally comprises lactose and W-Gum.Lubricant, as Magnesium Stearate, is all typically added.For capsule oral administration, suitable thinner comprises lactose and dry W-Gum.When oral administration is water suspension, its effective constituent is made up of emulsifying agent and suspension agent.If expect these formulations, some sweeting agent, seasonings or tinting material also can be added.

The liquid dosage form of oral administration comprises, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, and water or other solvents, solubilizing agent and emulsifying agent, as ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, grease (particularly cottonseed, Semen arachidis hypogaeae, corn, microorganism, olive, castor-oil plant and sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyoxyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except the thinner of inertia, oral compositions also can comprise assistant agent as wetting agent, emulsifying agent or suspension agent, sweeting agent, seasonings and perfume compound.

In addition, the pharmaceutically acceptable composition of the present invention can with the form rectal administration of suppository.These can form by reagent and suitable non-perfusing adjuvant being mixed with, and this adjuvant is at room temperature solid but is then liquid at the temperature of rectum, thus melts in the rectum and discharge medicine.Such material comprises cocoa butter, beeswax, and polyethylene glycols.The pharmaceutically acceptable composition of the present invention can be topical, and particularly during local application, the therapeutic goal relating to region or organ easily reaches, as the disease of eye, skin or lower intestinal tract.Suitable using topical preparations can prepare and be applied to these fields or organ.

Rectal suppository (see above content) or suitable enema can be applied to the local application of lower intestine.Local skin spot also can medication like this.For local application, pharmaceutically acceptable composition can be prepared into suitable ointment by formulation method, and this ointment packets is suspended in or is dissolved in one or more carrier containing activeconstituents.The carrier compound of topical of the present invention comprises, but is not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, and this lotion or emulsion comprise activeconstituents and is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitable carrier comprises, but is not limited to, mineral oil, Arlacel-60 (Arlacel-60), polysorbate60 (Polysorbate 60), cetyl esters wax, palmityl alcohol, 2-Standamul G, phenylcarbinol and water.

Preparation can be prepared into for eye, pharmaceutically acceptable composition; as isotonic micronized suspension, the Sterile Saline of pH regulator or other aqueous solution, preferably; the Sterile Saline of isotonic solution and pH regulator or other aqueous solution, can add disinfection preservative as benzalkonium chloride.In addition, for eye, pharmaceutically acceptable composition can be prepared into ointment as vaseline oil by pharmaceutical formulation.The pharmaceutically acceptable composition of the present invention can carry out administration by the gaseous solvents of nose or inhalation.Such composition can prepare according to the known technology of pharmaceutical formulation, maybe can be prepared into salts solution, use phenylcarbinol or other suitable sanitass, absorption enhancer, fluorocarbon or other conventional solubilizing agent or dispersion agent to improve bioavailability.

Injection, as aseptic parenteral solution or oleaginous suspension can adopt suitable dispersion agent, wetting agent and suspension agent to prepare by pharmaceutical formulation according to known technology.Aseptic injection can be nontoxic aseptic parenteral solution, suspension or the emulsion made through acceptable thinner or solvent parenterally, such as, and 1,3 butylene glycol solution.Acceptable vehicle and solvent can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention as solvent or suspension medium.With this end in view the nonvolatile oil of any gentleness can comprise list or the DG of synthesis.In addition, lipid acid such as oleic acid can be applied to injection.

Injection can be aseptic, as defended metre filter by bacterium, or mixes disinfectant with the form of aseptic solid composite, and disinfectant can be dissolved in or be scattered in sterilized water or other sterile injectable medium before use.In order to extend the effect of compound of the present invention, usually need the absorption being slowed down compound by subcutaneous injection or intramuscularly.Can realize like this utilizing liquid suspension to solve the problem of crystal or amorphous material poorly water-soluble.The specific absorption of compound depends on and depends on grain size and crystal shape successively by its dissolution rate.In addition, can be dissolved in oil vehicles by compound or disperse to have come the delay of compound injection administration to absorb.

Injection storage form is by biodegradable polymkeric substance, and the microcapsule matrix as many lactic acid-polyglycolide formation compound completes.The controlled release ratio of compound depends on the ratio of compound formation polymkeric substance and the character of particular polymer.Other biodegradable polymers comprise poly-(positive ester class) and poly-(acid anhydrides).Injection storage form also can embed the liposome compatible with bodily tissue by compound or microemulsion prepares.

Some of them embodiment is, the composition of rectum or vagina administration is suppository, suppository can prepare by the auxiliary material of salt of the present invention or crystal formation and suitable non-perfusing or carrier being mixed, as cocoa butter, polyoxyethylene glycol, or suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore in vagina or cavity of tunica vaginalis, just melt release of active compounds.

The solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granula.In these formulations, active compound mixes with the pharmaceutically acceptable inert excipient of at least one or carrier, as Trisodium Citrate or calcium phosphate or filling agent or a) weighting agent as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, b) tackiness agent is as carboxymethyl cellulose, alginate, gelatin, Povidone, sucrose and gum arabic, c) wetting Agent for Printing Inks is as glycerine, d) disintegrating agent is as agar, calcium carbonate, potato starch or tapioca (flour), Lalgine, some silicate and sodium carbonate, e) retarding agent solution is as paraffin, f) absorption enhancer is as quaternary ammonium compounds, g) wetting agent is as hexadecanol and glyceryl monostearate, h) absorption agent is as white bole and bentonite, i) lubricant is as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt, and their mixture.As for capsule, tablet and pill, these formulations can comprise buffer reagent.

The solids composition of similar type can be that weighting agent riddles soft or hard capsule, and the auxiliary material used has lactose and high molecular polyoxyethylene glycol etc.The agent of solid dosage photo, lozenge, capsule, pill and granula can by dressing, add shell such as known coating method on enteric coating and other drug preparation and prepare.They optionally can comprise opalizer, or preferably, in certain part of enteron aisle, at random, with the sole active agent in the method release composition postponed.As implant compositions can comprise multimeric species and wax.

Salt of the present invention or crystal formation can form microcapsule formulations together with one or more vehicle described in the invention.The agent of solid dosage photo, lozenge, capsule, pill and granula by dressing or can add shell, as enteric coating, controlled release coat and other known drug formulation process.In these solid dosages, active compound can mix with at least one inert diluent, as sucrose, and lactose or starch.Such formulation also can comprise substance besides inert diluents as general application, if tableting lubricant and other compression aids are as Magnesium Stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these formulations can comprise buffer reagent.They optionally can comprise tranquilizer, or preferably, in certain part of enteron aisle, with the sole active agent in the method release composition postponed arbitrarily.Applicable implant compositions can comprise, but is not limited to, polymer and wax.

The composition of salt of the present invention or crystal formation by local or formulation through percutaneous drug delivery comprise ointment, paste, emulsion, lotion, gelifying agent, pulvis, solution, sprays, inhalation, paster.Activeconstituents mixes mutually with pharmaceutically acceptable carrier and any required sanitas or required buffer reagent under sterile conditions.The pharmaceutical preparation of ophthalmology, ear drop and eye drops are all the scopes that the present invention considers.In addition, the present invention also considers the application of transdermal patch, and it is delivered in body at control compound more advantage, and such formulation can by dissolving or preparing in decentralized compound to suitable medium.Absorption enhancer can increase compound through the flow of skin, and through-rate controls film or compound is scattered in polymer matrix or gelatin to control its speed.

Salt of the present invention or crystal formation are preferably prepared into dosage unit form to alleviate the homogeneity of dosage and dosage by pharmaceutical formulation.Term " dosage " unit type " refer to that patient obtains the physical dispersion unit of the required medicine of suitably treatment herein.But, should be appreciated that compound of the present invention or composition every day total usage will judge determine according to reliable medical science scope by doctor in charge.Concrete effective dose level will depend on that many factors comprise the seriousness of illness and the illness be treated for any one special patient or organism, the activity of particular compound, concrete composition used, age of patient, body weight, healthy state, sex and food habits, administration time, the discharge rate of route of administration and particular compound used, the time length for the treatment of, medicinal application in drug combination or with specific compound coupling, and the known factor of some other pharmaceutical field.

The change that can produce the salt of the present invention of single dosage form composition or the consumption of crystal formation in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Some of them embodiment is, composition can be prepared into the inhibitor of dosage in 0.01-200mg/kg body weight/day by formulation method, and the amount being accepted composition by patient carries out administration.

Salt of the present invention or crystal formation carry out administration with only pharmaceutical agents or in conjunction with the agent of one or more other additional treatment (pharmacy), wherein drug combination causes acceptable untoward reaction, and this has special meaning for the treatment of high proliferative disease as cancer.In this case, salt of the present invention or crystal formation can in conjunction with known cytotoxic agents, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, the disease that the normal drug treatment of additional treatment agent is special is exactly known " suitably disease therapy "." additional treatment agent " used in the present invention comprises chemotherapeutic agent or other antiproliferative medicines can treat proliferative disease or cancer in conjunction with salt of the present invention or crystal formation.

Chemotherapeutic agent or other anti-proliferative drugs comprise histon deacetylase (HDAC) (HDAC) inhibitor, include, but are not limited to, SAHA, MS-275, MGO103, and those compounds described by following patent: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, comprise with demethylating agent, but be not limited to, 5-mixes nitrogen-2 '-Deoxyribose cytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and with the compound described by Publication about Document: US6, 268137, US5, 578, 716, US5, 919, 772, US6, 054, 439, US6, 184, 211, US6, 020, 318, US6, 066, 625, US6, 506, 735, US6, 221, 849, US6, 953, 783, US11, 393, 380.

Other embodiment is, chemotherapeutic agent or other anti-proliferative drugs can treat proliferative disease and cancer in conjunction with salt of the present invention or crystal formation.Known chemotherapeutic agent comprises, but be not limited to, other therapies or carcinostatic agent can be combined carcinostatic agent of the present invention and be comprised surgery, (a little example is as gamma-radiation for radiotherapy, neutron beam radiotherapy, electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (taxol, Docetaxel etc.), the derivative of platinum, biological response modifier (Interferon, rabbit, interleukin, tumour necrosis factor (TNF), the effect of TRAIL receptor target and vehicle), overheated and psychrotherapy, dilute the reagent (as antiemetic) of any untoward reaction, with the chemotherapeutic agent of other accreditations, include, but are not limited to, alkylating drug (mustargen, Chlorambucil, endoxan, melphalan, ifosfamide), metabolic antagonist (methotrexate, pemetrexed (Pemetrexed) etc.), purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vinealeucoblastine(VLB), vincristine(VCR), vinorelbine, taxol), podophyllotoxin (Etoposide, irinotecan (Irinotecan), Hycamtin (Topotecan)), microbiotic (Dx (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitrosourea (carmustine (Carmustine), lomustine (Lomustine)), mineral ion (cis-platinum, carboplatin), (KSP passes through mitotic kinesin inhibitors to cell division cycle inhibitor, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (tamoxifen (Tamoxifen), Leuprolide (Leuprolide), flutamide (Flutamide), megestrol (Megestrol)), imatinib mesylate (Gleevec), Zorubicin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (imatinib (Imatinib), Sutent (Sutent), Xarelto (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate cancer approach as mTOR, HIF (hypoxia inducible factor) approach and other.Http:// www.nci.nih.gov/ is shown in cancer therapy more widely forum, http://www.fda.gov/cder/cancer/druglist-rame.htm is shown in by the oncologic inventory of FAD accreditation, and Merck Manual, the 18 edition, 2006, all contents are all combine reference.

Other embodiment is, salt of the present invention or crystal formation can in conjunction with cytotoxic anticancer agent.Such carcinostatic agent can find the 13 edition the Merck index (2001) is inner.These carcinostatic agents comprise, but be never limited to, Asparaginase (Asparaginase), bleomycin (Bleomycin), carboplatin, carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), endoxan, cytosine arabinoside (Cytarabine), Dacarbazine (Dacarbazine), dactinomycin (Dactinomycin), daunorubicin (Daunorubicin), Zorubicin (Dx), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl trimeric cyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), methotrexate (Methotrexate), ametycin (MitomycinC), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), Procarbazine (Procarbazine), raloxifene (Raloxifen), streptozocin (Streptozocin), tamoxifen (Tamoxifen), Tioguanine (Thioguanine), Hycamtin, vinealeucoblastine(VLB), vincristine(VCR), vindesine.

Comprise with other suitable cytotoxic drugs of salt of the present invention or crystal formation drug combination, but be not limited to, these are applied to the compound of neoplastic disease treatment admittedly, as with described in Publication about Document: GoodmanandGilman'sThePharmacologicalBasisofTherapeutics (NinthEdition, 1996, McGraw-Hill.), these carcinostatic agents comprise, but be never limited to, aminoglutethimide (Aminoglutethimide), ASP, azathioprine, 5-azacytidine, CldAdo (Cladribine), busulfan (Busulfan), stilboestrol, 2', 2'-difluoro dCDP choline, Docetaxel, red hydroxyl nonyl VITAMIN B4 (Erythrohydroxynonyladenine), Ethinylestradiol, 5 FU 5 fluorouracil deoxynucleoside, floxuridine monophosphate, fludarabine phosphate (Fludarabinephosphate), Fluoxymesterone (Fluoxymesterone), flutamide (Flutamide), Hydroxyprogesterone caproate bp 98, idarubicin (Idarubicin), Interferon, rabbit, medroxyprogesterone acetate, Magace, melphalan (Melphalan), mitotane (Mitotane), taxol, pentostatin (Pentostatin), N-phosphate base-L-Aspartic acid (PALA), Plicamycin (Plicamycin), Me-CCNU (Semustine), teniposide (Teniposide), Uniteston, phosphinothioylidynetrisaziridine (Thiotepa), trimethylammonium trimeric cyanamide, urine nucleosides and vinorelbine.

What other were suitable comprises newfound cytotoxic substance with the cytotoxin class carcinostatic agent of salt of the present invention or crystal formation combined utilization, comprising, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), Macrolide antitumour drug and derivative that is natural or synthesis thereof, Temozolomide (Temozolomide) (Quinnetal., J.Clin.Oncology, 2003, 21 (4), 646-651), tositumomab (Bexxar), Trabedectin (Vidaletal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, abstract3181), with kinesin spindle body protein inhibitor Eg5 (Woodetal., Curr.Opin.Pharmacol.2001, 1, 370-377).

Other embodiment is, salt of the present invention or crystal formation can in conjunction with other signal transduction inhibitors.What is interesting is signal transduction inhibitor using EGFR family as target, as EGFR, HER-2 and HER-4 (Raymondetal., Drugs, 2000,60 (Suppl.l), 15-23; Hararietal., Oncogene, 2000,19 (53), 6102-6114) and their respective parts.Such reagent comprises, but is never limited to, antibody therapy as Trastuzumab (trastuzumab), Cetuximab (Erbitux), and handkerchief trastuzumab (Pertuzumab).Such therapy also comprises, but be never limited to, small molecule kinase inhibitors as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxleretal., CancerResearch, 2004,64,4931-4941).

Other embodiment is, salt of the present invention or crystal formation are in conjunction with receptor kinase (VEGFR, the FGFR of other signal transduction inhibitor targetings in division kinase domain family, PDGFR, flt-3, c-kit, c-fins, etc.), and their respective parts.Such reagent comprises, but is not limited to, and antibody is as rhuMAb-VEGF (Avastin).Such reagent comprises, but be never limited to, micromolecular inhibitor is as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Woodetal., CancerRes.2000, 60 (8), 2178-2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Sunitinib/SU-11248, ZD-6474 (Hennequinetal., 92ndAACRMeeting, NewOrleans, Mar.24-28, 2001, abstract3152), KRN-951 (Taguchietal., 95thAACRMeeting, Orlando, FIa, 2004, abstract2575), CP-547, 632 (Beebeetal., CancerRes.2003, 63, 7301-7309), CP-673, 451 (Robertsetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004, 45, abstract3989), CHIR-258 (Leeetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004, 45, abstract2130), MLN-518 (Shenetal., Blood, 2003, 102, 11, abstract476).

Other embodiment is, salt of the present invention or crystal formation can bonding histone deacetylase inhibitors.Such reagent comprises, but be never limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmannetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, abstract3024), LBH-589 (Becketal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, abstract3025), MS-275 (Ryanetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004, 45, abstract2452), FR-901228 (Piekarzetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004, 23, and MGCDOI03 (US6 abstract3028), 897, 220).

Other embodiment is, salt of the present invention or crystal formation can in conjunction with other carcinostatic agents as proteasome inhibitor and m-TOR inhibitor.These comprise, but be never limited to, Velcade (Bortezomib) (Mackayetal., ProceedingsoftheAmericanSocietyforClinicalOncology, 2004,23, Abstract3109), and CCI-779 (Wuetal., ProceedingsoftheAmericanAssociationofCancerResearch, 2004,45, abstract3849).Salt of the present invention or crystal formation in conjunction with other carcinostatic agents as topoisomerase enzyme inhibitor, can also include, but not limited to camptothecine.

Those additional treatment agent can separate administration with the composition comprising salt of the present invention or crystal formation, as a part for many dosage regimens.Or those therapeutical agents can be parts for one-pack type, mix with salt of the present invention or crystal formation and form single composition.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.

The change that can produce the compound of one-pack type and the consumption (those compositions comprising an additional treatment agent are as described in the invention) of additional treatment agent in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition additional treatment of the present invention agent comprises the amount of therapeutical agent as the normal administration of unique promoting agent using being no more than composition.On the other hand, the scope of the amount of existing disclosed composition additional treatment agent is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.Comprise in the composition of additional treatment agent at those, additional treatment agent will play synergy with compound of the present invention.

The feature of pharmaceutical composition of the present invention comprises one or more of salt of the present invention or one or more of crystal formation of the present invention, or their combination, and pharmaceutically acceptable carrier, assistant agent or vehicle.This pharmaceutical composition of the present invention can effectively detectably arrestin kinases as activity of EGFR.Pharmaceutical composition of the present invention using be applied to as antitumor drug treatment or reduce EGFR deleterious effect.

Pharmaceutical composition of the present invention will be applied to, but never be limited to, and use pharmaceutical composition of the present invention prevent patient's administration or treat patient's proliferative disease.Such disease comprises cancer, especially metastatic carcinoma, nonsmall-cell lung cancer and epidermal carcinoma.

The treatment being applied to knurl is comprised cancer and metastatic carcinoma by pharmaceutical composition of the present invention, includes, but are not limited to further, and cancer is as epidermal carcinoma, bladder cancer, mammary cancer, colorectal carcinoma, kidney, liver cancer, lung cancer (comprising small cell lung cancer), esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer, and skin carcinoma (comprising squamous cell carcinoma); Lymphsystem hematopoetic tumor (comprises leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, B cell lymphoma, t cell lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma); Marrow system hematopoetic tumor (comprise acute and chronic myelocytic leukemia, myelodysplastic syndrome, and promyelocitic leukemia); The tumour (comprising fibrosarcoma and rhabdosarcoma, and other sarcomas, as soft tissue and cartilage) of mesenchymal cell origin; Maincenter peripheral nervous system knurl (comprise astrocytoma, neuroblastoma, neurospongioma, and schwannoma); With other tumours (comprising melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicle knurl and Ka Bo Ji (family name) sarcoma).

Pharmaceutical composition of the present invention also can be used for treatment eye disease such as corneal graft rejection, and the new vessel of eye is formed, and retinal neovascularazation comprises damage or metainfective new vessel is formed; Diabetic retinopathy; Retrolental fibroplasia, and neovascular glaucoma; Retinal ischemia; Vitreous hemorrhage; Ulcer disease is as stomach ulcer; Pathological but non-malignant situation, as vascular tumor, comprises baby's hemangioendothelioma, the hemangiofibroma of nasopharynx and ANB; Female repro ductive system is disorderly as endometriosis.These compounds are equally also used for the treatment of oedema and the too high situation of vascular permeability.

Pharmaceutical composition of the present invention may be used for processing the situation relevant to diabetes as diabetic retinopathy and microangiopathy.Compound of the present invention is equally for the situation of cancer patients's volume of blood flow minimizing.Pharmaceutical composition of the present invention reduces patient tumors transfer also has beneficial effect.

Pharmaceutical composition of the present invention, except useful to human treatment, also can be applicable to veterinary treatment pet, the animal of introduced variety and the animal on farm, comprises Mammals, rodent etc.The example of other animal comprises horse, dog and cat.At this, pharmaceutical composition of the present invention comprises its pharmaceutically acceptable derivates.

Plural form is being applied to compound, and when salt etc., it also means single compound, salt etc.

Comprise the methods for the treatment of of pharmaceutical composition administration of the present invention, comprise the administration to patient's additional treatment agent (combination therapy) further, wherein additional treatment agent is selected from: chemotherapy, antiproliferative or anti-inflammatory agent, wherein additional treatment agent is applicable to treated disease, and additional treatment agent can with pharmaceutical composition Combined Preparation of the present invention, pharmaceutical composition of the present invention is as single formulation, or the composition separated is as a part for multi-form.Additional treatment agent can from pharmaceutical composition of the present invention administration simultaneously or different time administration.

The present invention comprises the cytostatic method to expressing EGFR equally, and this method comprises pharmaceutical composition of the present invention and cells contacting, thus cell growth inhibiting.The cell of the suppressed growth of energy comprises: epidermal carcinoma cell, breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate cancer cell, lymphoma cell, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cells, human osteosarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukemia cell.

The invention provides the method suppressing EGFR kinase activity in biological sample, this method comprises and being contacted with biological sample by pharmaceutical composition of the present invention.Term used in the present invention " biological sample " refers to the sample of vitro, include, but not limited to, cell cultures or cell extraction; From the examination of living tissue material that Mammals or its extract obtain; Blood, saliva, urine, ight soil, seminal fluid, tears, or other living tissue liquid substance and extracts thereof.Suppress kinase activity, particularly EGFR kinase activity in biological sample, can be used for the known multiple use of one of ordinary skill in the art.Such purposes comprises, but is never limited to, hematometachysis, organ transplantation, biological sample storage and biological assay.

" significant quantity " or " effective dose " of the pharmaceutically acceptable composition of the present invention refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.

Pharmaceutical composition of the present invention can be applied to the dressing of implantable medical device, as prosthese, and artificial valve, artificial blood vessel, stem and catheter.Such as, vascular stem, has been used to overcome restenosis (shrinking again of vessel wall after injury).But patient uses stem or other implantable devices to have the risk of clot formation or platelet activation.These disadvantageous effects can stop or alleviate by the application of the invention pharmaceutically acceptable pharmaceutical composition precoating device.

The general preparation method of suitable dressing and the dressing of implantable device at document US6,099,562; US5,886,026; And US5,304, described by having in 121, dressing is that biocompatible polymeric material, as hydrogel polymer, gathers methyl two silicon ether, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethane-acetic acid ethyenyl ester typically, and composition thereof.Dressing can optionally further cover by suitable dressing, as fluoro Simethicone, polysaccharidase, polyoxyethylene glycol, phospholipid, or their combination, carry out the feature of performance group compound Co ntrolled release.Another aspect of the present invention comprises the implantable device using pharmaceutical composition of the present invention coating.Pharmaceutical composition of the present invention also can be coated on the medical instruments in implantable, as pearl, or provide " medicine storage institute " with polymkeric substance or other molecular mixing, therefore compare with pharmaceutical aqueous solution administering mode, allow drug release to have longer time limit.

Accompanying drawing explanation

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

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

Embodiment

Mode below by embodiment further illustrates the present invention, does not therefore limit the present invention among described scope of embodiments.

The present invention's X-ray powder diffraction analytical procedure used is: Empyrean diffractometer, uses Cu-K α radiation (45KV, 40mA) to obtain X-ray powder diffraction figure.Powdered samples is prepared into thin layer by monocrystal silicon sample frame, is placed on specimen rotating holder, analyze with 0.0168 ° of step-length in the scope of 3 °-40 °.DataCollector software is used to collect data, HighScorePlus software data processing, DataViewer software reading of data.

The present invention's means of differential scanning calorimetry used (DSC) analytical procedure is: use the TAQ2000 module with thermal analyses controller to carry out means of differential scanning calorimetry.Collect data and use TAInstrumentsThermalSolutions software to analyze.About 1-5mg sample is weighed to exactly in the special aluminium crucible with lid, uses the linear heating device of 10 DEG C/min, carry out sample analysis from room temperature to about 250 DEG C.During use, DSC cell drying nitrogen is purged.

The present invention's thermal weight loss used (TGA) analytical procedure is: use the TAQ500 module with thermal analyses controller to carry out thermal weight loss.Collect data and use TAInstrumentsThermalSolutions software to analyze.About 10mg sample is weighed in platinum sample disc exactly, uses the linear heating device of 10 DEG C/min, carry out sample analysis from room temperature to about 300 DEG C.During use, TGA furnace chamber drying nitrogen is purged.

The test condition of proton nmr spectra of the present invention is: under room temperature condition, and the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1 ₃, d ⁶-DMSO, CD ₃oD or d ⁶-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, double doublet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).

Specific implementation method

Compound 4-shown in formula (I) [(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} the concrete synthetic method of-quinazoline is with reference to the embodiment 6 in patent CN103102344A (application publication number).

Embodiment

Embodiment 1

1,4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} preparation of-quinazoline two salicylate (crystal formation I)

Under backflow, by compound 4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-}-quinazoline (1g, 2.04mmol) be dissolved in acetone (30mL), Whitfield's ointment (0.62g is dripped in system, acetone (5mL) solution 4.5mmol), back flow reaction is spent the night, be cooled to room temperature and add sherwood oil, there are insoluble solids precipitation, suction filtration, vacuum-drying.

2,4-[(the chloro-4-fluorophenyl of 3-) is amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} qualification of-quinazoline two salicylate (crystal formation I)

1) by hydrogen nuclear magnetic resonance spectrum analysis, salify ratio is 1:2.

2) by EmpyreanX ray powder diffraction (XRPD) Analysis and Identification, use Cu-K α radiation, there is the following characteristic peak represented with angle 2 θ: 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 °, there is the error margin of ± 0.2 °.

3) by TAQ2000 means of differential scanning calorimetry (DSC) Analysis and Identification, sweep velocity is 10 DEG C/min, comprises the endotherm(ic)peak of 180.20 DEG C, there is the error margin of ± 3 DEG C.

Embodiment 2

Two salicylates of compound shown in formula (I) pharmacokinetic situations

Adopt beasle dog carry out two salicylates of compound shown in compound shown in formula (I) and formula (I) pharmacokinetic trial in body: each 3 of kind beasle dog, administering mode is capsule oral, convert out the dosage of salt according to free alkali dosage 5mg/kg, two salicylates of compound shown in compound shown in preliminary study formula (I) and formula (I) oral absorption situation.Experimental result is as shown in table 1:

Compound and the pharmacokinetic parameter of two salicylates in beasle dog body thereof shown in table 1 formula (I)

Conclusion: the exposed amount of two salicylates of compound shown in formula (I) in dog body is large compared with the exposed amount of free alkali, and bioavailability has larger improvement.

Above said content be only the present invention conceive under basic explanation, and according to any equivalent transformation that technical scheme of the present invention is done, all should protection scope of the present invention be belonged to.

In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.

Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (10)

1. the salt formed by compound formula (I) Suo Shi and Whitfield's ointment:

2. salt according to claim 1, it is two salicylates of compound shown in formula (I).

3. compound shown in formula (I) two salicylates crystal formation, wherein said crystal formation is crystal formation I;

The X-ray powder diffraction pattern of wherein said crystal formation I has diffraction peak at following 2 θ angle places: 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 °.

4. crystal formation according to claim 3, the X-ray powder diffraction pattern of wherein said crystal formation I has diffraction peak at following 2 θ angle places: 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 °, 16.46o ± 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 °.

5. crystal formation according to claim 3, wherein said crystal formation I has X-ray powder diffraction pattern as shown in Figure 1 substantially.

6. crystal formation according to claim 3, the differential scanning calorimetric curve of wherein said crystal formation I has endotherm(ic)peak at 180.20 DEG C ± 3 DEG C places.

7. crystal formation according to claim 3, wherein said crystal formation I has differential scanning calorimetric curve as shown in Figure 2 substantially.

8. a pharmaceutical composition, it comprises the salt described in claim 1 or 2 or the crystal formation described in claim 3-7 any one or their combination, and wherein said pharmaceutical composition comprises pharmaceutically acceptable carrier further, vehicle, thinner, assistant agent, vehicle or their combination.

9. pharmaceutical composition according to claim 8, it further comprises therapeutical agent, and described therapeutical agent is selected from chemotherapeutic agent, antiproliferative, is used for the treatment of medicine or their combination of nonsmall-cell lung cancer and epidermal carcinoma;

Wherein said therapeutical agent is Zorubicin (Adriamycin), rapamycin (Rapamycin), Temsirolimus, everolimus (Everolimus), Ixabepilone, gemcitabine (Gemcitabine), endoxan (Cyclophosphamide), dexamethasone (Dexamethasone), Etoposide (Etoposide), Fluracil (Fluorouracil), imatinib mesylate (Imatinibmesylate), Dasatinib (Dasatinib), nilotinib (Nilotinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib), Iressa (Iressa), Xarelto (Sorafenib), Sutent (Sunitinib), Interferon, rabbit (Interferon), carboplatin (Carboplatin), Hycamtin (Topotecan), taxol, vinealeucoblastine(VLB), vincristine(VCR), Temozolomide (Temozolomide), tositumomab (Tositumomab), Trabedectin, Avastin (Bevacizumab), Trastuzumab (Trastuzumab), Cetuximab (Cetuximab), Victibix (Panitumumab), or their combination.

10. use the salt described in claim 1 or 2 or the crystal formation described in claim 3-7 any one or the pharmaceutical composition described in claim 8-9 any one to come for the preparation of protection, process or a treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.