CN105461729B - A kind of salt of EGFR inhibitor, crystal formation and application thereof - Google Patents

Abstract

The present invention relates to the crystal formation of a kind of different salt form of EGFR inhibitor and different salt form；The invention further relates to the preparation method of the various crystal formations, the pharmaceutical composition comprising the salt form or/crystal formation.Salt, crystal formation or their pharmaceutical composition of the present invention can be used for treating proliferative diseases.

Description

A kind of salt of EGFR inhibitor, crystal formation and application thereof

Technical field

The present invention relates to 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- dioxies -8- Azabicyclo [4.3.0] nonane -8- bases] propoxyl group } the different salt form of-quinazoline and the crystal formation of different salt form；The present invention also relates to And the preparation method of the salt and crystal formation, the pharmaceutical composition for including the salt and crystal formation, and 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.

The A of Chinese patent literature CN 103102344 (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 invention provides 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- 3- [(1R, 6S) -2,5- dioxies - 8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline benzene sulfonate, diphenyl sulfonate and its crystal formation.Formula (I) Shown compound is big compared with the exposed amount of free alkali into the exposed amount after salt in dog body, and bioavilability has larger improvement.

The content of the invention

Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by overall.Work as the disclosure of the specification With citation it is variant when, be defined by the disclosure of the specification.

The invention provides 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- 3- [(1R, 6S) -2,5- dioxies - 8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline benzene sulfonate, diphenyl sulfonate and its crystal formation, for controlling Treat proliferative diseases.Present invention provides the method for preparing the salt or crystal formation, is moved using the salt or crystal formation treatment lactation The method of thing, especially human pcna disease, and the medical composition and its use comprising the salt or crystal formation.

On the one hand, the present invention provides the compound shown in a kind of formula (IIb)：

Wherein, n is 1 or 2.

In some of these embodiments, the crystal formation I of the benzene sulfonate of compound shown in formula (I) of the present invention, its X ray powder Last diffracting spectrum has diffraction maximum at following 2 θ angles：4.98 ° ± 0.2 °, 9.87 ° ± 0.2 °, 10.59 ° ± 0.2 °, 11.96 ° ± 0.2 °, 13.38 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.86 ° ± 0.2 °, 19.27 ° ± 0.2 °, 20.35 ° ± 0.2 °, 21.28 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.78 ° ± 0.2 °, 23.78 ° ± 0.2 °, 24.75 ° ± 0.2 °, 26.69 ° ± 0.2 °, 32.18 ° ± 0.2 ° and 32.70 ° ± 0.2 °.

In some of these embodiments, the crystal formation I of the benzene sulfonate of compound shown in formula (I) of the present invention, its X ray powder Last diffracting spectrum has diffraction maximum at following 2 θ angles：4.98 ° ± 0.2 °, 9.87 ° ± 0.2 °, 10.59 ° ± 0.2 °, 11.96 ° ± 0.2 °, 13.38 ° ± 0.2 °, 14.09 ° ± 0.2 °, 14.91 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.86 ° ± 0.2 °, 19.27 ° ± 0.2 °, 19.72 ° ± 0.2 °, 20.15 ° ± 0.2 °, 20.35 ° ± 0.2 °, 21.28 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.78 ° ± 0.2 °, 23.03 ° ± 0.2 °, 23.78 ° ± 0.2 °, 24.06 ° ± 0.2 °, 24.75 ° ± 0.2 °, 26.06 ° ± 0.2 °, 26.69 ° ± 0.2 °, 27.58 ° ± 0.2 °, 29.31 ° ± 0.2 °, 29.73 ° ± 0.2 °, 30.09 ° ± 0.2 °, 31.04 ° ± 0.2 °, 31.69 ° ± 0.2 °, 32.18 ° ± 0.2 °, 32.70 ° ± 0.2 °, 34.47 ° ± 0.2 °, 35.71 ° ± 0.2 °, 36.22 ° ± 0.2 °, 37.88 ° ± 0.2 ° and 39.33 ° ± 0.2 °.

In some of these embodiments, the crystal formation I of the benzene sulfonate of compound shown in formula (I) of the present invention, it has base X-ray powder diffraction pattern as shown in Figure 1 in sheet.

In some of these embodiments, the crystal formation I of the benzene sulfonate of compound shown in formula (I) of the present invention, its differential are swept Retouch calorimetric curve has endothermic peak at 198.85 DEG C ± 3 DEG C.

In some of these embodiments, the crystal formation I of the benzene sulfonate of compound shown in formula (I) of the present invention, it has base Differential scanning calorimetric curve as shown in Figure 2 in sheet.

In some of these embodiments, the crystal formation I of the diphenyl sulfonate of compound shown in formula (I) of the present invention, its X ray Powder diffraction spectrum has diffraction maximum at following 2 θ angles：7.00 ° ± 0.2 °, 8.19 ° ± 0.2 °, 10.14 ° ± 0.2 °, 11.53 ° ± 0.2 °, 15.15 ° ± 0.2 °, 15.47 ° ± 0.2 °, 17.69 ° ± 0.2 °, 18.44 ° ± 0.2 °, 19.28 ° ± 0.2 °, 20.33 ° ± 0.2 °, 22.53 ° ± 0.2 °, 22.80 ° ± 0.2 °, 23.26 ° ± 0.2 °, 23.98 ° ± 0.2 °, 24.66 ° ± 0.2 °, 25.07 ° ± 0.2 °, 27.41 ° ± 0.2 °, 27.89 ° ± 0.2 ° and 28.38 ° ± 0.2 °.

In some of these embodiments, the crystal formation I of the diphenyl sulfonate of compound shown in formula (I) of the present invention, its X ray Powder diffraction spectrum has diffraction maximum at following 2 θ angles：7.00 ° ± 0.2 °, 8.19 ° ± 0.2 °, 10.14 ° ± 0.2 °, 11.53 ° ± 0.2 °, 13.75 ° ± 0.2 °, 14.13 ° ± 0.2 °, 15.15 ° ± 0.2 °, 15.47 ° ± 0.2 °, 16.52 ° ± 0.2 °, 17.69 ° ± 0.2 °, 18.44 ° ± 0.2 °, 19.28 ° ± 0.2 °, 20.33 ° ± 0.2 °, 20.97 ° ± 0.2 °, 22.53 ° ± 0.2 °, 22.80 ° ± 0.2 °, 23.26 ° ± 0.2 °, 23.98 ° ± 0.2 °, 24.66 ° ± 0.2 °, 25.07 ° ± 0.2 °, 25.49 ° ± 0.2 °, 27.41 ° ± 0.2 °, 27.89 ° ± 0.2 °, 28.38 ° ± 0.2 °, 29.49 ° ± 0.2 °, 30.68 ° ± 0.2 °, 31.57 ° ± 0.2 ° and 33.56 ° ± 0.2 °.

In some of these embodiments, the crystal formation I of the diphenyl sulfonate of compound shown in formula (I) of the present invention, it has X-ray powder diffraction pattern substantially as shown in Figure 3.

In some of these embodiments, the crystal formation I of the diphenyl sulfonate of compound shown in formula (I) of the present invention, its differential Scanning calorimetric curve has endothermic peak at 238.52 DEG C ± 3 DEG C.

In some of these embodiments, the crystal formation I of the diphenyl sulfonate of compound shown in formula (I) of the present invention, it has Differential scanning calorimetric curve substantially as shown in Figure 4.

On the one hand, the present invention provides a kind of pharmaceutical composition, and it includes the compound or this hair shown in formula (IIb) The crystal formation or combinations thereof of compound shown in Ming Dynasty style (IIb), pharmaceutically may be used wherein described pharmaceutical composition further includes The carrier of receiving, excipient, diluent, assistant agent, medium or combinations thereof.

In some of these embodiments, pharmaceutical composition of the present invention, it further includes therapeutic agent, institute State therapeutic agent and be selected from chemotherapeutic agent, antiproliferative, cytotoxic drug, signal transduction inhibitor is non-small thin for treating The medicine or combinations thereof of born of the same parents' lung cancer and epidermal carcinoma.

In other embodiments, 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 (Panitumumab), Conmana (Icotinib), hydrochloric acid Conmana (Icotinib Hydrochloride), the appropriate pearl of horse Monoclonal antibody (Matuzmab), HKI-272 (Neratinib), canertinib (Canertinib), ZD6474 (Vandetanib), AZD2171 (Cediranib), PTK787 (Vatalanib), Axitinib (Axitinib), Mo Teshani (Motesanib), Buddhist nun's trastuzumab (Nimotuzumab), Xi Li replace Buddhist nun (Theliatinib), and Buddhist nun (Epitinib) is replaced according to pyrrole, Do not replace Buddhist nun (Simotinib), Poziotinib, Varlitinib, Rociletinib, Pelitinib, AZD9291, PKI- in west 166, PD 158780, ABX-EGF, MDX447, Mab425, HM-61713, TAS-121, MM-121, ASP-8273, or they Combination.

On the other hand, the present invention provides a kind of compound using shown in formula (IIb) or formula (IIb) institute The crystal formation or pharmaceutical composition of the present invention for showing compound are used to protecting, handle or treating patient's proliferative disease to prepare Disease, and mitigate the purposes of the medicine of its order of severity.

In some of these embodiments, purposes of the present invention, wherein described proliferative diseases are metastatic carcinomas, table Skin cancer, colon cancer, sdenocarcinoma of stomach, carcinoma of urinary bladder, breast cancer, kidney, liver cancer, lung cancer, thyroid cancer, brain tumor, neck cancer, prostate cancer, pancreas Gland cancer, 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.

Compound shown in formula (IIb) includes amorphous form, crystal form, solvate, hydrate, and also includes more Crystalline forms.

In one embodiment of the invention, compound of the present invention has in crystal form and preferably at least 50% crystallinity, 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, compound of the present invention have from 50%, 60%, 70%, 80% or 90% to 95%, 96%, 97%, 98%, 99% or 100% crystallinity.

" 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.

Solid generally exists with amorphous form or crystal form.In the presence of with crystal form, molecule positioning At three-dimensional lattice point., can be with different spatial lattice arrangements knots when compound recrystallizes from solution or slurry Crystalline substance, this characteristic are called " polymorphism ", and possessed different crystal form is known respectively as a kind of " polymorph ".It is given The different polymorphic forms of material may be different from each other because one or more of physical characteristics are different, such as solubility, dissociation Degree, real density, crystal form, the stability for compressing situation, flowing property and/or solid state.A kind of chemical substance with It is unstable after fully placing a period of time at a given temperature in the presence of two kinds of (or more kind) polymorphic Forms Form be typically converted into the more stable form of thermodynamics.When this transformation is not rapidly, the form of thermodynamic instability It is referred to as " metastable " type.Usual stable type shows highest fusing point, minimum solubility and maximum chemical stability.So And metastable type can show sufficiently chemically and physically stability under normal storage requirement, so as to allow it as commodity Form uses.In this case, although metastable type is not bery stable, can also show possessed by those stable types in accordance with need The characteristic wanted, the solubility such as enhanced or preferable oral administration biaavailability.

" 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..

" solvate " refers to that crystal has solvent on the surface, in lattice or on the surface and in lattice.It is molten One specific example of agent compound is hydrate.On the surface of material, in lattice or on the surface and in lattice, water Compound can be with or without other solvents in addition to water.

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

Herein it is any be related to the present invention compound when, suitably and at one's leisure, it should be understood that be directed to corresponding Solvate such as hydrate or polymorphic modification, and it is directed to corresponding amorphous form.The compound of the present invention is preferably Exist in the form of separating and be essentially pure.

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

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

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 the A (application publication number) of patent CN 103102344 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.

Compound shown in formula (IIb) for 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 benzene sulfonate or 4- [(the chloro- 4- fluorobenzene of 3- Base) amino] -7- methoxyl groups -6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group } - Quinazoline diphenyl sulfonate.The crystal formation I of compound shown in formula (IIb) be 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups - The crystalline substance of 6- { 3- [(1R, 6S) -2,5- dioxy -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group }-quinazoline benzene sulfonate Type I.The crystal formation II of compound shown in formula (IIb) be 4- [(the chloro- 4- fluorophenyls of 3-) amino] -7- methoxyl groups -6- 3- [(1R, 6S) -2,5- dioxies -8- azabicyclos [4.3.0] nonane -8- bases] propoxyl group-quinazoline diphenyl sulfonate crystal formation II.

Compound, salt or crystal formation of the present invention, they exist with essentially pure crystal habit.

" essentially pure " refer to a kind of compound/salt/crystal formation substantially free of another or multiple compounds/ The purity at least 80% of salt/crystal formation, i.e. compound/salt/crystal formation, or at least 85%, or at least 90%, or at least 93%, or extremely Few 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 Contain other compound/salt/crystal formations in 99.8%, or at least 99.9%, or compound/salt/crystal formation, other compounds/ Percentage of the salt/crystal formation in the cumulative volume of compound/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 cumulative volume of one or more other compound/salt/crystal formations in compound/salt/crystal formation Or the percentage in gross weight is 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, formula (I) of the present invention, formula (II), formula (IIa), formula (IIb), formula (IIc), the single three-dimensional chemical isomer or its enantiomter of the compound shown in formula (IId), formula (IIe) or formula (IIf), Diastereoisomer, or the mixture of geometric isomer (or rotamer) belong to the scope of the present invention.

Unless otherwise indicated, formula (I) of the present invention, formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), All tautomeric forms of compound shown in formula (IIe) or formula (IIf) are intended to be included within the scope.In addition, Unless otherwise indicated, formula (I) described in the invention, formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), The structural formula of compound shown in formula (IIe) or formula (IIf) includes 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, 1994. formula (I)s of the present invention, formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or the compound shown in formula (IIf) can include asymmetric center or chiral centre, therefore exist different Stereoisomer.Formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or formula of the present invention (IIf) all stereoisomeric forms in any ratio of compound shown in, including but not limited to, diastereoisomer, enantiomter, resistance Turn isomers, and their mixture, such as racemic mixture, constitute a part of the invention.Many organic compounds are all Exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.It is preceding when describing optically active compound Sew D, L or R, S is used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for naming chemical combination object plane inclined The symbol of the light that shakes rotation, (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.These are three-dimensional The chemical constitution of isomers is identical, but their stereochemical structure is different.Specific stereoisomer can be mapping Body, the mixture of isomers is commonly referred to as enantiomeric mixture.50:50 mixture of enantiomers is referred to as racemic mixing Thing or racemic modification, this may cause do not have stereoselectivity or stereoselectivity in chemical reaction process.Term " mix by racemic Compound " and " racemic modification " refer to the mixture of equimolar two enantiomters, 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 is comprising compound of the present invention or originally The described crystal formation of invention, or combinations thereof, and pharmaceutically acceptable carrier, assistant agent, or excipient, these are as the present invention Applied, including any solvent, diluent, or other liquid excipients, dispersant or suspending agent, surfactant are isotonic Agent, thickener, emulsifying agent, preservative, solid binder or lubricant, etc., it is suitable for distinctive target formulation.Active component Content in the pharmaceutical composition is 1-99 weight %, 1-95 weight %, 1-90 weight %, 1-85 weight %, and 1-80 is heavy Measure %, 1-75 weight %, 1-70 weight %, 1-65 weight %, 1-60 weight %, 1-55 weight %, 1-50 weight %, 1-45 weight Measure %, 1-40 weight %, 1-35 weight %, 1-30 weight %, 1-25 weight %, 1-20 weight %, 1-15 weight %, 1-10 weight Measure %, 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, the content of comprehensive document herein, show different Carrier can be applied to the preparation and their known preparation methods of pharmaceutically acceptable composition.Except any conventional carrier The medium scope incompatible with compound of the present invention or crystal formation, for example, caused any bad biological effect or with The caused interaction in harmful manner of any other component of pharmaceutically acceptable composition, their purposes are also this The considered scope of 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 compound of the present invention or crystal formation can be administered orally, drug administration by injection, Aerosol inhalation, office Portion is administered, per rectum administration, nose administration, and buccal administration or is administered vagina administration by implantable medicine box.It is as used herein Term " 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 Administration or intravenous injection.The injection system of the composition sterile of the present invention can be water or oil suspension.These are outstanding Supernatant liquid can be manufactured according to known technology using suitable dispersant, wetting agent and suspending agent by formula.Aseptic injection can be with It is aseptic parenteral solution or suspension, is injection nontoxic acceptable diluent or solvent, such as 1,3-BDO solution.These can The excipient and solvent of receiving can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, it is sterile non-volatile Oil can be used as solvent or suspension media 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 compound 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 suppository wax, they are solid in room temperature but are then liquid under body temperature, therefore just fusing is released in vagina or cavity of tunica vaginalis Put reactive 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.

Compound of the present invention or crystal formation can be formed together with one or more excipient described in the invention Microcapsule formulations.The agent of solid dosage forms photo, lozenge, capsule, pill and granula can by coating or shell adding, as enteric coating, Controlled release coat and other known drug formulation process.In these solid dosage forms, reactive compound can be lazy with least one Property diluent mixing, such as sucrose, lactose or starch.Such formulation can also include as in general application and remove inert diluent Outside additive, such as tableting lubricant and other compression aids such as magnesium stearate and microcrystalline cellulose.As for capsule, tablet And pill, these formulations can include buffer.They can optionally include sedative, or preferably, in a certain of enteron aisle Part, the sole active agent in composition is discharged in the method arbitrarily postponed.Applicable implant compositions can include, but It is not limited to, polymer and wax.

The composition of compound of the present invention or crystal formation includes ointment by part or through percutaneous drug delivery formulation, Paste, emulsion, lotion, gel, pulvis, solution, spray, inhalant, paster.Active component under sterile conditions with medicine Acceptable carrier and any required preservative or required buffer mix on.The pharmaceutical preparation of ophthalmology, auristilla All it is the scope that the present invention considers with eye drops.In addition, present invention further contemplates that the application of transdermal patch, it is passed in control compound Being delivered to aspect in vivo has the advantages of more, such formulation can by dissolve or disperse compound into suitable medium come It is prepared.Sorbefacient can increase the flow that compound passes through skin, and through-rate controls film or divides compound Dissipate in polymer matrix or gelatin to control its speed.

Compound of the present invention or crystal formation are preferably prepared into dosage unit form to mitigate dosage by pharmaceutical formulation With the uniformity of dosage.Term " dosage " unit type " obtains the physical dispersion list of suitably medicine needed for treatment referred to herein as patient Position.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 is judged to determine.Specific effective dose level for any one special patient or organism will depend on it is many because Element includes the seriousness of treated illness and illness, the activity of particular compound, concrete composition used, the year of patient The discharge rate of age, body weight, health status, sex and eating habit, administration time, method of administration and particular compound used, The duration for the treatment of, medicinal application is combined in drug combination or with specific compound, and some other pharmaceutical field Known factor.

Carrier mass can be combined and produce the compound of the present invention of single dosage form composition or the dosage of crystal formation Change and depend on curing mainly and special mode of administration.Some of embodiments are that composition can be prepared into agent by formulation method The inhibitor in 0.01-200mg/kg body weight/days is measured, the amount of composition is received by patient to be administered.

Compound of the present invention or crystal formation with only pharmaceutical agents or combine other one or more additional treatments (pharmacy) agent is administered, and wherein drug combination causes acceptable adverse reaction, this is for high proliferative disease such as cancer Treatment has special meaning.In this case, compound of the present invention or crystal formation can combine known cell toxicant Plain agent, single transduction inhibitor or other antitumor and anticancer agents, and their mixture and combination.It is attached as used in the present invention Add the special disease of the normal drug treatment of therapeutic agent, exactly known " suitably treating disease ".It is used in the present invention " additional Therapeutic agent " includes chemotherapeutic agent or other antiproliferative medicines can combine compound of the present invention or crystal formation is treated Proliferative diseases or cancer.

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, WO2004/035525, WO 2005/030705, WO 2005/092899, and Demethylating agent includes, but is not limited to, the miscellaneous nitrogen -2 of 5- '-deoxycytidine (5-aza-dC), azacitidine (Vidaza), Compound described by his shore (Decitabine) of west and documents below：US 6,268137,US5,578,716,US 5,919, 772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US6,221, 849,US 6,953,783,US 11,393,380。

Other embodiment is that chemotherapeutic agent or other anti-proliferative drugs can combine chemical combination of the present invention Thing or crystal formation treatment proliferative diseases and cancer.Known chemotherapeutic agent includes, but is not limited to, other therapies or anticancer Agent can combine the anticancer of the present invention and include surgery, radiotherapy (a little example such as γ is radiated, neutron beam radiotherapy, Electron beam evaporation therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, Japanese yew Alkanes (taxol, Docetaxel etc.), the derivative of platinum, BRM (interferon, interleukin, tumour Necrosin (TNF), the effect of TRAIL receptor targets and medium), overheat and cold therapy, dilute the examination of any adverse reaction Agent (such as antiemetic), and the chemotherapeutic agent of other accreditations, including but not limited to, alkylating drug (mustargen, benzenebutanoic acid nitrogen Mustard, endoxan, melphalan, ifosfamide), antimetabolite (methotrexate (MTX), pemetrexed (Pemetrexed) etc. Deng), purine antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, Gemcitabine (Gemcitabine)), spindle poison (vincaleukoblastinum, vincristine, vinorelbine, taxol), podophyllotoxin (Etoposide, Irinotecan (Irinotecan), Hycamtin (Topotecan)), antibiotic (Doxorubicin (Doxorubicin), bleomycin (Bleomycin), mitomycin (Mitomycin)), nitroso ureas (BCNU (Carmustine), lomustine (Lomustine)), inorganic ions (cis-platinum, carboplatin), CDC inhibitor (KSP By mitotic kinesin inhibitors, CENP-E and CDK inhibitor), ferment (asparaginase), hormone (it not Former times sweet smell (Tamoxifen), Leuprorelin (Leuprolide), Flutamide (Flutamide), megestrol acetate (Megestrol)), Gleevec (Gleevec), adriamycin (Adriamycin), dexamethasone (Dexamethasone), and endoxan.It is anti-angiogenic Generate the factor (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 because Son) approach and other.Http sees in the wide forum for the treatment of of cancer:The oncology medicine of //www.nci.nih.gov/, FAD accreditation Thing inventory is shown in http://www.fda.gov/cder/cancer/druglist-rame.htm, and Merck Manual, the 18th edition, 2006, all contents are all combined with bibliography.

Other embodiment is that compound of the present invention or crystal formation can combine cytotoxic anticancer agent.So Anticancer can find the 13rd edition Merck index (2001) is inner.These anticancers include, but are not limited to, asparagine Enzyme (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 compound of the present invention or crystal formation drug combination, but not It is limited to, 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 suitably include new with the cytotoxin class anticancer of compound of the present invention or crystal formation use in conjunction It was found that 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 compound of the present invention or crystal formation can combine other signal transduction inhibitors. What is interesting is 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 that compound of the present invention or crystal formation combine the targeting of other signal transduction inhibitors and made For dividing the receptor kinase (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, etc.) of kinase domain family, and it Respective part.Such reagent includes, but is not limited to, antibody such as bevacizumab (Avastin).Such reagent bag Include, but be 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 compound of the present invention or crystal formation can be with bonding histone deacetylation enzyme levels Agent.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 compound of the present invention or crystal formation can combine other anticancers such as proteasome Inhibitor 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).Compound of the present invention or crystal formation can be combined with other anticancers Such as topoisomerase enzyme inhibitor, including but not limited to camptothecine.

Those additional therapeutic agents can separately be administered with the composition comprising compound of the present invention or crystal formation, as A part for more dosage regimens.Or those therapeutic agents can be a part for one-pack type, with compound of the present invention or Crystal formation mixes to form single composition.If the part as more dosage regimens is administered, two activating agents can be same When continuously or within a period of time transmit mutually, 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 compound of the present invention, or institute of the present invention The one or more for the crystal formation stated, or combinations thereof, and pharmaceutically acceptable carrier, assistant agent or excipient.The present invention Pharmaceutical composition effectively can detectably suppress protein kinase such as activity of EGFR.The pharmaceutical composition of the present invention will be applied In the treatment as antineoplastic or reduce EGFR illeffects.

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 the benzene sulfonate of compound shown in formula (I).

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

Fig. 3 is X-ray powder diffraction (XRPD) figure of the crystal formation I of the diphenyl sulfonate of compound shown in formula (I).

Fig. 4 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of the diphenyl sulfonate 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.

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 benzene sulfonate (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 (4.0g, 8.18mmol) is dissolved in ethanol (70mL), to Ethanol (10mL) solution of benzene sulfonic acid (1.42g, 9.0mmol) is added dropwise in system, continues the 9h that flows back, is cooled to room temperature, filters, very Sky is dried.

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 benzene sulfonate (crystal formation I) identification

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

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：4.98 °, 9.87 °, 10.59 °, 11.96 °, 13.38 °, 14.09 °, 14.91 °, 17.05 °, 18.86 °, 19.27 °, 19.72 °, 20.15 °, 20.35 °, 21.28 °, 22.05 °, 22.78 °, 23.03 °, 23.78 °, 24.06 °, 24.75 °, 26.06 °, 26.69 °, 27.58 °, 29.31 °, 29.73 °, 30.09 °, 31.04 °, 31.69 °, 32.18 °, 32.70 °, 34.47 °, 35.71 °, 36.22 °, 37.88 ° and 39.33 °, ± 0.2 ° of error margin be present.

3) being analyzed and identified by TA Q2000 means of differential scanning calorimetry (DSC), sweep speed is 10 DEG C/min, comprising 198.85 DEG C of endothermic peak, ± 3 DEG C of error margin be present.

Embodiment 2

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 diphenyl sulfonate (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 (500mg, 1.02mmol) is dissolved in acetone (18mL), to Acetone (6mL) solution of benzene sulfonic acid (356mg, 2.25mmol) is added dropwise in system, continues the 6h that flows back, is cooled to room temperature, filters, very Sky is dried.

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 diphenyl sulfonate (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：7.00 °, 8.19 °, 10.14 °, 11.53 °, 13.75 °, 14.13 °, 15.15 °, 15.47 °, 16.52 °, 17.69 °, 18.44 °, 19.28 °, 20.33 °, 20.97 °, 22.53 °, 22.80 °, 23.26 °, 23.98 °, 24.66 °, 25.07 °, 25.49 °, 27.41 °, 27.89 °, 28.38 °, 29.49 °, 30.68 °, 31.57 ° and 33.56 °, there is ± 0.2 ° Error margin.

3) being analyzed and identified by TA Q2000 means of differential scanning calorimetry (DSC), sweep speed is 10 DEG C/min, comprising 238.52 DEG C of endothermic peak, ± 3 DEG C of error margin be present.

Embodiment 3

The pharmacokinetic situations of compound difference salt form shown in formula (I) of the present invention

Medicine inside compound difference salt form is carried out shown in compound shown in formula (I) of the present invention and formula (I) using beasle dog For dynamic test：Each 3 of kind beasle dog, administering mode is capsule oral, is all converted according to free alkali dosage 5mg/kg Go out the dosage of salt, the oral absorption feelings of compound difference salt form shown in compound shown in Primary Study formula (I) of the present invention and formula (I) Condition.Experimental result such as table 1：

The pharmacokinetic parameter of compound and its different salt form in beasle dog body shown in 1 formula (I) of the present invention of table

Conclusion：Compound shown in formula (I) of the present invention is into the exposed amount after salt in dog body compared with the exposed amount of free alkali Greatly, bioavilability has larger improvement.

Claims (9)

1. the crystal formation I of the benzene sulfonate of compound shown in formula (I), wherein, compound shown in formula (I) and benzene sulphur in the crystal formation I The ratio of acid is 1:1, its X-ray powder diffraction pattern has diffraction maximum at following 2 θ angles：4.98 ° ± 0.2 °, 9.87 ° ± 0.2 °, 10.59 ° ± 0.2 °, 11.96 ° ± 0.2 °, 13.38 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.86 ° ± 0.2 °, 19.27 ° ± 0.2 °, 20.35 ° ± 0.2 °, 21.28 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.78 ° ± 0.2 °, 23.78 ° ± 0.2 °, 24.75 ° ± 0.2 °, 26.69 ° ± 0.2 °, 32.18 ° ± 0.2 ° and 32.70 ° ± 0.2 °,

2. the crystal formation I of the benzene sulfonate of compound shown in formula (I), wherein, compound shown in formula (I) and benzene sulphur in the crystal formation I The ratio of acid is 1:1, its X-ray powder diffraction pattern has diffraction maximum at following 2 θ angles：4.98 ° ± 0.2 °, 9.87 ° ± 0.2 °, 10.59 ° ± 0.2 °, 11.96 ° ± 0.2 °, 13.38 ° ± 0.2 °, 14.09 ° ± 0.2 °, 14.91 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.86 ° ± 0.2 °, 19.27 ° ± 0.2 °, 19.72 ° ± 0.2 °, 20.15 ° ± 0.2 °, 20.35 ° ± 0.2 °, 21.28 ° ± 0.2 °, 22.05 ° ± 0.2 °, 22.78 ° ± 0.2 °, 23.03 ° ± 0.2 °, 23.78 ° ± 0.2 °, 24.06 ° ± 0.2 °, 24.75 ° ± 0.2 °, 26.06 ° ± 0.2 °, 26.69 ° ± 0.2 °, 27.58 ° ± 0.2 °, 29.31 ° ± 0.2 °, 29.73 ° ± 0.2 °, 30.09 ° ± 0.2 °, 31.04 ° ± 0.2 °, 31.69 ° ± 0.2 °, 32.18 ° ± 0.2 °, 32.70 ° ± 0.2 °, 34.47 ° ± 0.2 °, 35.71 ° ± 0.2 °, 36.22 ° ± 0.2 °, 37.88 ° ± 0.2 ° and 39.33 ° ± 0.2 °；

3. crystal formation I according to claim 2, its differential scanning calorimetric curve has endothermic peak at 198.85 DEG C ± 3 DEG C.

4. the crystal formation I of the benzene sulfonate of compound shown in formula (I), wherein, compound shown in formula (I) and benzene sulphur in the crystal formation I The ratio of acid is 1:1, it has X-ray powder diffraction pattern substantially as shown in；

5. crystal formation I according to claim 4, it has differential scanning calorimetric curve substantially as shown in Figure 2.

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, cytotoxic drug, signal transduction inhibitor, for treating non-small cell lung cancer and epidermal carcinoma Medicine or combinations thereof.

8. pharmaceutical composition according to claim 7, wherein described therapeutic agent is adriamycin, rapamycin, Temsirolimus, everolimus, Ixabepilone, gemcitabine, endoxan, dexamethasone, Etoposide, fluorine urine are phonetic Pyridine, imatinib mesylate, Dasatinib, nilotinib, Erlotinib, Lapatinib, Iressa, Sorafenib, easypro Buddhist nun replace Buddhist nun, interferon, carboplatin, Hycamtin, taxol, vincaleukoblastinum, vincristine, Temozolomide, tositumomab, Trabedectin, Avastin, Trastuzumab, Cetuximab, Victibix, Conmana, hydrochloric acid Conmana, the appropriate pearl of horse Monoclonal antibody, HKI-272, canertinib, ZD6474, AZD2171, PTK787, Axitinib, Mo Teshani, the appropriate pearl of Buddhist nun are single Anti-, Xi Li replace Buddhist nun, and Buddhist nun is replaced according to pyrrole, western not replace Buddhist nun, Poziotinib, Varlitinib, Rociletinib, Pelitinib, AZD9291, PKI-166, PD 158780, ABX-EGF, MDX447, Mab425, HM-61713, TAS-121, MM-121, ASP- 8273, or combinations thereof.

9. a kind of usage right requires the crystal formation described in 1-5 any one or the medicine group described in claim 6-8 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.