CN105294717A - EGFR inhibitor salt, crystal form and purpose thereof - Google Patents

EGFR inhibitor salt, crystal form and purpose thereof Download PDF

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Publication number
CN105294717A
CN105294717A CN201510796403.6A CN201510796403A CN105294717A CN 105294717 A CN105294717 A CN 105294717A CN 201510796403 A CN201510796403 A CN 201510796403A CN 105294717 A CN105294717 A CN 105294717A
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formula
crystal formation
compound
compound shown
acid
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CN105294717B (en
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章维红
刘兵
张英俊
毛洪芬
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Guangdong HEC Pharmaceutical
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Ruyuan Yao Autonomous County Dazhong Drug Trading Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to different types of salt of an EGFR inhibitor and crystal forms of different types of the salt. The invention also relates to a preparation method of various crystal forms, and a pharmaceutical composition containing the salt type or/and the crystal form. The salt, the crystal form or their pharmaceutical compositions can be used for treating proliferative disease.

Description

A kind of salt, crystal formation and uses thereof of EGFR inhibitor
Technical field
The present invention relates 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-} the different salt form of-quinazoline and the crystal formation of different salt form; The invention still further relates to the preparation method of described salt and crystal formation, comprise the pharmaceutical composition of described salt and crystal formation and the purposes of 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.
The invention provides 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-} dihydrochloride of-quinazoline, dithionate, diphosphate, benzene sulfonate, diphenyl sulfonate, dioxalic acid salt, benzoate, cinnamate, Citrate trianion or two (L-TARTARIC ACID) salt and crystal formations thereof.Exposed amount after compound salify shown in formula (I) in dog body is all large compared with the exposed amount of free alkali, and bioavailability has larger improvement.
Summary of the invention
Below only summarize aspects more of the present invention, be not limited thereto.These aspects and other parts have more complete explanation later.All reference in this specification sheets are incorporated in this by entirety.When the disclosure of the specification and citing document variant time, be as the criterion with the disclosure of the specification.
The invention provides 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-} dihydrochloride of-quinazoline, dithionate, diphosphate, benzene sulfonate, diphenyl sulfonate, dioxalic acid salt, benzoate, cinnamate, Citrate trianion or two (L-TARTARIC ACID) salt and crystal formations thereof, be used for the treatment of proliferative disease.Present invention provides the method for the described salt of preparation or crystal formation, use described salt or crystal formation treatment Mammals, the especially method of human pcna disease, and comprise the medical composition and its use of described salt or crystal formation.
On the one hand, the invention provides the compound shown in a kind of formula (II):
Wherein:
Each x and y is 1,2,3 or 4 independently;
M is mineral acid or organic acid molecule.
Wherein in some embodiments, the compound shown in formula (II), wherein mineral acid is: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, persulfuric acid, hemisulfic acid, phosphoric acid, nitric acid, thiocyanic acid or carbonic acid;
Wherein organic acid is formic acid, acetic acid, hydroxyethanoic acid, 2, 2-dichloro acetic acid, propionic acid, propanedioic acid, 3-phenylpropionic acid, pentamethylene propionic acid, isopropylformic acid, PIVALIC ACID CRUDE (25), 2-oxygen pentanedioic acid, caproic acid, hexanodioic acid, enanthic acid, sad, capric acid, sebacic acid, undeeanoic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, ethane-1, 2-disulfonic acid, Phenylsulfonic acid, naphthalene-1, 5-disulfonic acid, 2-naphthene sulfonic acid, cyclamic acid, camphorsulfonic acid, oxalic acid, lactic acid, phenylformic acid, 4-acetylamino benzoic acid, benzenebutanoic acid, alginic acid, 4-ASA, stearic acid, xitix, dextrocamphoric acid, styracin, citric acid, heavy gluconic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glactaric acid, gentisinic acid, aspartic acid, L-glutamic acid, Pidolic Acid (L-Glutimic acid), urobenzoic acid, lactobionic acid, lauric acid, oxysuccinic acid, amygdalic acid, nicotinic acid, oleic acid, vitamin B13, palmitinic acid, flutter acid, pectinic acid, picric acid, succsinic acid, tannic acid or tartrate.
Wherein in some embodiments, the compound shown in formula (II), it is hydrate, solvate, crystallization, partial crystallization, amorphous or polymorphic forms.
On the one hand, the present invention relates to a kind of pharmaceutical composition, it comprises the compound shown in formula (II), and wherein said pharmaceutical composition comprises pharmaceutically acceptable carrier further, vehicle, thinner, assistant agent, vehicle or their combination.
On the other hand, the present invention relates to a kind of pharmaceutical composition of compound shown in formula (II) that uses and come for the preparation of protection, process or treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.
On the one hand, the invention provides the compound shown in a kind of formula (IIa):
Wherein in some embodiments, the compound shown in formula (IIa), it is hydrate, solvate, crystallization, partial crystallization, amorphous or polymorphic forms.
On the other hand, the invention provides the crystal formation I of compound shown in formula (IIa).
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIa), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.67 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.22 ° ± 0.2 °, 15.03 ° ± 0.2 °, 15.24 ° ± 0.2 °, 15.58 ° ± 0.2 °, 17.35 ° ± 0.2 °, 18.62 ° ± 0.2 °, 20.35 ° ± 0.2 °, 20.59 ° ± 0.2 °, 21.26 ° ± 0.2 °, 24.08 ° ± 0.2 °, 24.44 ° ± 0.2 °, 25.37 ° ± 0.2 °, 25.68 ° ± 0.2 °, 26.66 ° ± 0.2 °, 26.83 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.48 ° ± 0.2 ° and 34.82 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIa), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.67 ° ± 0.2 °, 9.31 ° ± 0.2 °, 10.15 ° ± 0.2 °, 11.42 ° ± 0.2 °, 11.99 ° ± 0.2 °, 12.62 ° ± 0.2 °, 13.26 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.22 ° ± 0.2 °, 15.03 ° ± 0.2 °, 15.24 ° ± 0.2 °, 15.58 ° ± 0.2 °, 17.35 ° ± 0.2 °, 17.70 ° ± 0.2 °, 18.20 ° ± 0.2 °, 18.62 ° ± 0.2 °, 19.52 ° ± 0.2 °, 20.35 ° ± 0.2 °, 20.59 ° ± 0.2 °, 21.26 ° ± 0.2 °, 21.65 ° ± 0.2 °, 21.97 ° ± 0.2 °, 22.39 ° ± 0.2 °, 23.01 ° ± 0.2 °, 23.63 ° ± 0.2 °, 24.08 ° ± 0.2 °, 24.44 ° ± 0.2 °, 25.37 ° ± 0.2 °, 25.68 ° ± 0.2 °, 26.66 ° ± 0.2 °, 26.83 ° ± 0.2 °, 27.28 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.00 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.40 ° ± 0.2 °, 29.83 ° ± 0.2 °, 31.10 ° ± 0.2 °, 31.54 ° ± 0.2 °, 32.16 ° ± 0.2 °, 32.71 ° ± 0.2 °, 34.02 ° ± 0.2 °, 34.82 ° ± 0.2 °, 35.45 ° ± 0.2 °, 36.15 ° ± 0.2 °, 36.67 ° ± 0.2 °, 37.64 ° ± 0.2 °, 38.33 ° ± 0.2 °, 38.80 ° ± 0.2 ° and 39.55 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIa), it has X-ray powder diffraction pattern as shown in Figure 1 substantially.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIa), its differential scanning calorimetric curve has endotherm(ic)peak at 196.70 DEG C ± 3 DEG C places.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIa), it has differential scanning calorimetric curve as shown in Figure 2 substantially.
On the one hand, the invention provides the compound shown in a kind of formula (IIc):
On the other hand, the invention provides the crystal formation I of compound shown in formula (IIc).
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIc), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 9.07 ° ± 0.2 °, 12.45 ° ± 0.2 °, 13.96 ° ± 0.2 °, 16.50 ° ± 0.2 °, 16.78 ° ± 0.2 °, 17.93 ° ± 0.2 °, 19.37 ° ± 0.2 °, 19.84 ° ± 0.2 °, 20.33 ° ± 0.2 °, 20.84 ° ± 0.2 °, 21.85 ° ± 0.2 °, 22.10 ° ± 0.2 °, 22.26 ° ± 0.2 °, 22.96 ° ± 0.2 °, 23.67 ° ± 0.2 °, 24.04 ° ± 0.2 °, 24.62 ° ± 0.2 ° and 27.31 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIc), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 6.80 ° ± 0.2 °, 9.07 ° ± 0.2 °, 10.38 ° ± 0.2 °, 11.00 ° ± 0.2 °, 12.45 ° ± 0.2 °, 13.59 ° ± 0.2 °, 13.96 ° ± 0.2 °, 15.41 ° ± 0.2 °, 15.67 ° ± 0.2 °, 16.21 ° ± 0.2 °, 16.50 ° ± 0.2 °, 16.78 ° ± 0.2 °, 17.93 ° ± 0.2 °, 18.69 ° ± 0.2 °, 19.37 ° ± 0.2 °, 19.84 ° ± 0.2 °, 20.33 ° ± 0.2 °, 20.84 ° ± 0.2 °, 21.85 ° ± 0.2 °, 22.10 ° ± 0.2 °, 22.26 ° ± 0.2 °, 22.96 ° ± 0.2 °, 23.67 ° ± 0.2 °, 24.04 ° ± 0.2 °, 24.62 ° ± 0.2 °, 25.59 ° ± 0.2 °, 26.58 ° ± 0.2 °, 27.31 ° ± 0.2 °, 28.26 ° ± 0.2 °, 28.96 ° ± 0.2 °, 30.17 ° ± 0.2 °, 31.42 ° ± 0.2 °, 31.70 ° ± 0.2 °, 33.37 ° ± 0.2 °, 34.97 ° ± 0.2 ° and 38.18 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIc), it has X-ray powder diffraction pattern as shown in Figure 7 substantially.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIc), its differential scanning calorimetric curve has endotherm(ic)peak at 250.95 DEG C ± 3 DEG C places.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIc), it has differential scanning calorimetric curve as shown in Figure 8 substantially.
On the one hand, the invention provides the compound shown in a kind of formula (IId):
Wherein in some embodiments, the compound shown in formula (IId), it is hydrate, solvate, crystallization, partial crystallization, amorphous or polymorphic forms.
On the other hand, the invention provides the crystal formation I of compound shown in formula (IId).
Wherein in some embodiments, the crystal formation I of compound shown in formula (IId), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 5.36 ° ± 0.2 °, 10.68 ° ± 0.2 °, 14.94 ° ± 0.2 °, 16.03 ° ± 0.2 °, 16.69 ° ± 0.2 °, 19.35 ° ± 0.2 °, 21.08 ° ± 0.2 °, 21.44 ° ± 0.2 ° and 32.34 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IId), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 5.36 ° ± 0.2 °, 9.89 ° ± 0.2 °, 10.68 ° ± 0.2 °, 14.19 ° ± 0.2 °, 14.61 ° ± 0.2 °, 14.94 ° ± 0.2 °, 16.03 ° ± 0.2 °, 16.69 ° ± 0.2 °, 17.16 ° ± 0.2 °, 18.62 ° ± 0.2 °, 18.89 ° ± 0.2 °, 19.35 ° ± 0.2 °, 21.08 ° ± 0.2 °, 21.44 ° ± 0.2 °, 22.50 ° ± 0.2 °, 23.53 ° ± 0.2 °, 25.94 ° ± 0.2 °, 26.67 ° ± 0.2 °, 27.31 ° ± 0.2 °, 29.42 ° ± 0.2 °, 32.34 ° ± 0.2 ° and 33.81 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IId), it has X-ray powder diffraction pattern as shown in Figure 9 substantially.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IId), its differential scanning calorimetric curve has endotherm(ic)peak at 158.62 DEG C ± 3 DEG C places.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IId), it has differential scanning calorimetric curve as shown in Figure 10 substantially.
On the one hand, the invention provides the compound shown in a kind of formula (IIe):
Wherein in some embodiments, the compound shown in formula (IIe), it is hydrate, solvate, crystallization, partial crystallization, amorphous or polymorphic forms.
On the other hand, the invention provides the crystal formation I of compound shown in formula (IIe).
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIe), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 8.09 ° ± 0.2 °, 19.66 ° ± 0.2 °, 22.15 ° ± 0.2 °, 23.30 ° ± 0.2 °, 24.13 ° ± 0.2 °, 28.14 ° ± 0.2 °, 29.23 ° ± 0.2 ° and 31.68 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIe), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 8.09 ° ± 0.2 °, 9.69 ° ± 0.2 °, 11.64 ° ± 0.2 °, 16.20 ° ± 0.2 °, 16.56 ° ± 0.2 °, 18.69 ° ± 0.2 °, 19.66 ° ± 0.2 °, 21.31 ° ± 0.2 °, 22.15 ° ± 0.2 °, 23.30 ° ± 0.2 °, 24.13 ° ± 0.2 °, 26.24 ° ± 0.2 °, 27.18 ° ± 0.2 °, 28.14 ° ± 0.2 °, 29.23 ° ± 0.2 °, 30.05 ° ± 0.2 ° and 31.68 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIe), it has X-ray powder diffraction pattern as shown in figure 11 substantially.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIe), its differential scanning calorimetric curve has endotherm(ic)peak at 100.66 DEG C ± 3 DEG C, 146.70 DEG C ± 3 DEG C and 236.38 DEG C ± 3 DEG C places.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIe), it has differential scanning calorimetric curve as shown in figure 12 substantially.
On the one hand, the invention provides the compound shown in a kind of formula (IIf):
Wherein in some embodiments, the compound shown in formula (IIf), it is hydrate, solvate, crystallization, partial crystallization, amorphous or polymorphic forms.
On the other hand, the invention provides the crystal formation I of compound shown in formula (IIf).
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIf), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.86 ° ± 0.2 °, 9.68 ° ± 0.2 °, 13.77 ° ± 0.2 °, 14.46 ° ± 0.2 °, 18.36 ° ± 0.2 °, 19.50 ° ± 0.2 °, 20.03 ° ± 0.2 °, 20.62 ° ± 0.2 °, 21.67 ° ± 0.2 °, 22.38 ° ± 0.2 °, 22.69 ° ± 0.2 °, 23.25 ° ± 0.2 °, 24.03 ° ± 0.2 °, 25.92 ° ± 0.2 °, 26.45 ° ± 0.2 ° and 27.72 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIf), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.86 ° ± 0.2 °, 9.68 ° ± 0.2 °, 13.77 ° ± 0.2 °, 14.46 ° ± 0.2 °, 15.30 ° ± 0.2 °, 16.77 ° ± 0.2 °, 17.46 ° ± 0.2 °, 18.36 ° ± 0.2 °, 19.50 ° ± 0.2 °, 20.03 ° ± 0.2 °, 20.62 ° ± 0.2 °, 21.67 ° ± 0.2 °, 22.38 ° ± 0.2 °, 22.69 ° ± 0.2 °, 23.25 ° ± 0.2 °, 24.03 ° ± 0.2 °, 24.60 ° ± 0.2 °, 25.92 ° ± 0.2 °, 26.45 ° ± 0.2 °, 27.72 ° ± 0.2 °, 29.43 ° ± 0.2 °, 35.74 ° ± 0.2 ° and 38.16 ° ± 0.2 °.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIf), it has substantially X-ray powder diffraction pattern as shown in fig. 13 that.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIf), its differential scanning calorimetric curve has endotherm(ic)peak at 86.54 DEG C ± 3 DEG C and 114.82 DEG C ± 3 DEG C places.
Wherein in some embodiments, the crystal formation I of compound shown in formula (IIf), it has differential scanning calorimetric curve as shown in Figure 3 substantially.
On the one hand, the invention provides a kind of pharmaceutical composition, it comprises crystal formation or their combination of compound of the present invention or the compounds of this invention, wherein said pharmaceutical composition comprises pharmaceutically acceptable carrier further, vehicle, thinner, assistant agent, vehicle or their combination.
Wherein in some 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 embodiments, 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 invention provides a kind of crystal formation of the compounds of this invention or the compounds of this invention or pharmaceutical composition of the present invention of using and produce for protection, process or treatment patient proliferative disease, and alleviate the purposes of the medicine of its severity.
Wherein in some 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.
Shown in formula (II), compound, the compound shown in formula (IIa), the compound shown in formula (IIc), the compound shown in formula (IId), the compound shown in formula (IIe) or the compound shown in formula (IIf) comprise amorphous form, crystallized form, solvate, hydrate, and comprise polymorphic forms.
In one embodiment of the invention, compound of the present invention is crystallized form 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, compound of the present invention has from 50%, 60%, 70%, 80% or 90% to 95%, 96%, 97%, 98%, 99% or 100% degree of crystallinity.
" 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.
Solid exists with amorphous form or crystalline form usually.Depositing in case with crystalline form, molecule is positioned three-dimensional lattice point place.When compound is from solution or soup compound during recrystallization, can with different spatial lattice arrangements crystallizations, this characteristic is called " polymorphism ", and the different crystal form had is called as one " polymorphic form " respectively.The different polymorphic forms of given material may be different from each other, as the stability of solubleness, liberation degree, real density, crystal form, compression situation, flowing property and/or solid state because one or more physical propertys are different.Deposit in case in a kind of chemical substance with two kinds of (or more plant) polymorphic Form, after fully placing for some time at a given temperature, unstable form changes the more stable form of thermodynamics usually into.When this transformation is not very rapid, the form of thermodynamic instability is called as " metastable " type.Usual stable form demonstrates the highest fusing point, minimum solubleness and maximum chemical stability.But metastable type can demonstrate chemistry and physical stability fully under normal storage requirement, thus allows it to use as commercial form.In this case, although metastable type is not bery stable, also can demonstrate the desirable characteristic that those stable forms have, as the solubleness that enhances or oral administration biaavailability preferably.
" 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.
" solvate " refers to that crystal has solvent from the teeth outwards, in lattice or from the teeth outwards and in lattice.An object lesson of solvate is hydrate.On the surface of material, 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 ".
Any when relating to compound 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.Compound of the present invention is preferably to be separated and the existence of substantially pure form.
Described compound can be dry.In some embodiments, described compound is anhydrous.
The invention still further relates to the physical properties of compound of the present invention at solid state.These character can be affected by the condition controlling to obtain in solid form compound 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.
Compound shown in formula (II) is the salt that shown in formula (I), compound is formed with acid.
Compound shown in formula (IIa) is 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 Citrate trianion.The crystal formation I of compound shown in formula (IIa) is 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-} the crystal formation I of-quinazoline Citrate trianion.
Compound shown in formula (IIc) is 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 (L-TARTARIC ACID) salt.The crystal formation I of compound shown in formula (IIc) is 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-} the crystal formation I of-quinazoline two (L-TARTARIC ACID) salt.
Compound shown in formula (IId) is 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 benzoate.The crystal formation I of compound shown in formula (IId) is 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-} the crystal formation I of-quinazoline benzoate.
Compound shown in formula (IIe) is 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 dihydrochloride.The crystal formation I of compound shown in formula (IIe) is 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-} the crystal formation I of-quinazoline dihydrochloride.
Compound shown in formula (IIf) is 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 cinnamate.The crystal formation I of compound shown in formula (IIf) is 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-} the crystal formation I of-quinazoline cinnamate.
Compound of the present invention, salt or crystal formation, they exist with substantially pure crystal habit.
" substantially pure " refers to that a kind of compound/salt/crystal formation is substantially free of another or multiple compounds/salt/crystal formation, the i.e. purity at least 80% of compound/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 compound/salt/crystal formation in compound/salt/crystal formation, the per-cent of other compound/salt/crystal formation described in the cumulative volume or gross weight of compound/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 compound/salt/crystal formations in the cumulative volume or gross weight of compound/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 formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or the compound shown in formula (IIf) 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 formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or the compound shown in formula (IIf) are included within scope of the present invention.In addition, unless other aspects show, shown in formula (I) described in the invention, formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or formula (IIf), 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, 1994. formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or the compound shown in formula (IIf) can comprise asymmetric center or chiral centre, therefore there is different steric isomers.The stereoisomeric forms in any ratio that formula (I), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe) or the compound shown in formula (IIf) are all, include, but not limited to, diastereomer, enantiomer, atropisomer, with their mixture, as racemic mixture, constitute 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.
Salt of the present invention or crystal formation pharmaceutical composition, preparation, administration and purposes
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises compound of the present invention or 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 compound 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 compound 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.
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 compound 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.
" 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.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) figure of the crystal formation I of compound shown in formula (IIa).
Fig. 2 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of compound shown in formula (IIa).
Fig. 3 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of compound shown in formula (IIf).
Fig. 4 is thermogravimetric analysis (TGA) figure of the crystal formation I of compound shown in formula (IIe).
Fig. 5 is thermogravimetric analysis (TGA) figure of the crystal formation I of compound shown in formula (IIa).
Fig. 6 is thermogravimetric analysis (TGA) figure of the crystal formation I of compound shown in formula (IIf).
Fig. 7 is X-ray powder diffraction (XRPD) figure of the crystal formation I of compound shown in formula (IIc).
Fig. 8 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of compound shown in formula (IIc).
Fig. 9 is X-ray powder diffraction (XRPD) figure of the crystal formation I of compound shown in formula (IId).
Figure 10 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of compound shown in formula (IId).
Figure 11 is X-ray powder diffraction (XRPD) figure of the crystal formation I of compound shown in formula (IIe).
Figure 12 is means of differential scanning calorimetry (DSC) figure of the crystal formation I of compound shown in formula (IIe).
Figure 13 is X-ray powder diffraction (XRPD) figure of the crystal formation I of compound shown in formula (IIf).
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.
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 dihydrochloride (crystal formation I)
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 (0.50g, 1.02mmol) be dissolved in methyl alcohol (50mL), and this solution system is dropped to (3mol/L in the ethyl acetate solution of hydrogenchloride, 6.8mL), room temperature reaction is after 1.5 hours, be spin-dried for solvent, pull an oar by ethyl acetate, filter cake 60 DEG C of vacuum-dryings, to constant weight, obtain 0.61g faint yellow solid, productive rate: 107%.
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 dihydrochloride (crystal formation I)
1) by chromatography of ions, recording Cl-actual content is 12.66%, and when becoming two molecule hydrochlorides, Cl-theoretical content is 12.68%, and 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: 8.09 °, 9.69 °, 11.64 °, 16.20 °, 16.56 °, 18.69 °, 19.66 °, 21.31 °, 22.15 °, 23.30 °, 24.13 °, 26.24 °, 27.18 °, 28.14 °, 29.23 °, 30.05 ° and 31.68 °, 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 100.66 DEG C, 146.70 DEG C and 236.38 DEG C, there is the error margin of ± 3 DEG C.
4) carry out thermal weight loss (TGA) Analysis and Identification by TAQ500: temperature rise rate is 10 DEG C/min, in room temperature in about 75 DEG C of temperature ranges, weightlessness is 7.233%; In about 75 DEG C to 150 DEG C temperature ranges, weightlessness is 5.891%.In conjunction with the spectrum analysis of DSC and TGA, 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-} there are 3 main endothermic processes in the crystal formation I of-quinazoline dihydrochloride, first be the water or the solvent that lose free state at a lower temperature, then along with temperature raises, water or the solvent of crystal form is lost gradually, last fusion and decomposition; The endotherm(ic)peak that these three endothermic processes are respectively wider near corresponding 100.66 DEG C on DSC, the endotherm(ic)peak of 146.70 DEG C and 236.38 DEG C.
Embodiment 2
1,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} preparation of-quinazoline disulfide hydrochlorate
Under alcohol reflux, 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 (0.50g, 1.02mmol) be dissolved in ethanol (10mL), sulfuric acid (220.7mg is dripped in system, ethanol (10mL) solution 2.45mmol), back flow reaction is after 5 hours, be cooled to room temperature, suction filtration, vacuum-drying is to constant weight, obtain 536mg white solid, productive rate: 76.57%.
2,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} qualification of-quinazoline disulfide hydrochlorate
1) by chromatography of ions, SO is recorded 4 2-actual content is 26.63%, SO when becoming two molecular sulfur hydrochlorates 4 2-theoretical content is 28.63%, and salify ratio is 1:2.
2) by TAQ2000 means of differential scanning calorimetry (DSC) Analysis and Identification, sweep velocity is 10 DEG C/min, comprises the endotherm(ic)peak of 251.57 DEG C, there is the error margin of ± 3 DEG C.
Embodiment 3
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 benzoate (crystal formation I)
Under room temperature, 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 (600mg, 1.23mmol) be dissolved in ethyl acetate (100mL), phenylformic acid (329.5mg is added in above-mentioned solution, ethyl acetate (15mL) solution 2.70mmol), be warming up to 60 DEG C of heated overnight, vacuum rotary steam, the making beating of MTBE room temperature, suction filtration, vacuum-drying, obtain 650mg white solid, productive rate: 86.67%.
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 benzoate (crystal formation I)
1) by hydrogen nuclear magnetic resonance spectrum analysis, salify ratio is 1:1.
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: 5.36 °, 9.89 °, 10.68 °, 14.19 °, 14.61 °, 14.94 °, 16.03 °, 16.69 °, 17.16 °, 18.62 °, 18.89 °, 19.35 °, 21.08 °, 21.44 °, 22.50 °, 23.53 °, 25.94 °, 26.67 °, 27.31 °, 29.42 °, 32.34 ° and 33.81 °, 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 158.62 DEG C, there is the error margin of ± 3 DEG C.
Embodiment 4
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 cinnamate (crystal formation I)
At 60 DEG C, 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 (500mg, 1.02mmol) be dissolved in ethyl acetate (40mL), styracin (182mg is added in above-mentioned solution, ethyl acetate (10mL) solution 1.23mmol), continue heating 11h, be cooled to room temperature, vacuum rotary steam, obtain faint yellow solid, add sherwood oil making beating, obtain 610mg pale yellow powder shape solid, productive rate: 93.56%.
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 cinnamate (crystal formation I)
1) by hydrogen nuclear magnetic resonance spectrum analysis, salify ratio is 1:1.
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: 4.86 °, 9.68 °, 13.77 °, 14.46 °, 15.30 °, 16.77 °, 17.46 °, 18.36 °, 19.50 °, 20.03 °, 20.62 °, 21.67 °, 22.38 °, 22.69 °, 23.25 °, 24.03 °, 24.60 °, 25.92 °, 26.45 °, 27.72 °, 29.43 °, 35.74 ° and 38.16 °, 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 86.54 DEG C and 114.82 DEG C, there is the error margin of ± 3 DEG C.
4) carry out thermal weight loss (TGA) Analysis and Identification by TAQ500: temperature rise rate is 10 DEG C/min, in room temperature in about 100 DEG C of temperature ranges, weightlessness is 4.669%.In conjunction with the spectrum analysis of DSC and TGA, wherein 86.54 DEG C is solvent peak.
Embodiment 5
1,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} preparation of-quinazoline dioxalic acid salt
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 (200mg, 0.409mmol) be dissolved in methyl alcohol (10mL), oxalic acid (81mg is dripped in system, methyl alcohol (10mL) solution 0.9mmol), continue backflow 3.5h, add water (2.5mL) insoluble solids just to dissolve, be cooled to room temperature, suction filtration, vacuum-drying.
2,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} qualification of-quinazoline dioxalic acid salt
1) by hydrogen nuclear magnetic resonance spectrum analysis, salify ratio is 1:2.
2) by TAQ2000 means of differential scanning calorimetry (DSC) Analysis and Identification, sweep velocity is 10 DEG C/min, comprises the endotherm(ic)peak of 128.79 DEG C, there is the error margin of ± 3 DEG C.
Embodiment 6
1,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} preparation of-quinazoline diphosphate
At 60 DEG C, 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 (500mg, 1.02mmol) be dissolved in ethyl acetate (40mL), phosphoric acid (220.6mg is added in above-mentioned solution, ethyl acetate (10mL) solution 2.25mmol), a large amount of white solid is had to separate out, be warming up to backflow, continue heating 11h, be cooled to room temperature, suction filtration, ethyl acetate is pulled an oar, obtain 668mg white solid, productive rate: 97.52%.
2,4-[(the chloro-4-fluorophenyl of 3-) amino]-7-methoxyl group-6-{3-[(1R, 6S)-2,5-dioxy-8-azabicyclo [4.3.0] nonane-8-base] propoxy-} qualification of-quinazoline diphosphate
By chromatography of ions, record PO 4 3-actual content is 29.46%, PO when becoming two molecular phosphorus hydrochlorates 4 3-theoretical content be 27.73%, salify ratio is 1:2.
Embodiment 7
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 (L-TARTARIC ACID) salt (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 (500mg, 1.02mmol) be dissolved in ethanol (10mL), in system, slowly drip ethanol (15mL) solution of L-TARTARIC ACID (338mg, 2.25mmol), back flow reaction is spent the night, 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 (L-TARTARIC ACID) salt (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: 6.80 °, 9.07 °, 10.38 °, 11.00 °, 12.45 °, 13.59 °, 13.96 °, 15.41 °, 15.67 °, 16.21 °, 16.50 °, 16.78 °, 17.93 °, 18.69 °, 19.37 °, 19.84 °, 20.33 °, 20.84 °, 21.85 °, 22.10 °, 22.26 °, 22.96 °, 23.67 °, 24.04 °, 24.62 °, 25.59 °, 26.58 °, 27.31 °, 28.26 °, 28.96 °, 30.17 °, 31.42 °, 31.70 °, 33.37 °, 34.97 ° and 38.18 °, 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 250.95 DEG C, there is the error margin of ± 3 DEG C; This crystal formation is about 250 DEG C fusion and decomposition.
Embodiment 8
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 Citrate trianion (crystal formation I)
Under room temperature, 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 (500mg, 1.02mmol) be dissolved in methyl alcohol (50mL), citric acid (491.2mg is slowly dripped in system, methyl alcohol (10mL) solution 2.56mmol), be warming up to backflow, stirring is spent the night, cooling crystallization, obtain white solid, pull an oar with ethanol (20mL), suction filtration, vacuum-drying, obtain 510mg solid, productive rate: 73.17%.
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 Citrate trianion (crystal formation I)
1) by hydrogen nuclear magnetic resonance spectrum analysis, salify ratio is 1:1.
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: 4.67 °, 9.31 °, 10.15 °, 11.42 °, 11.99 °, 12.62 °, 13.26 °, 13.92 °, 14.22 °, 15.03 °, 15.24 °, 15.58 °, 17.35 °, 17.70 °, 18.20 °, 18.62 °, 19.52 °, 20.35 °, 20.59 °, 21.26 °, 21.65 °, 21.97 °, 22.39 °, 23.01 °, 23.63 °, 24.08 °, 24.44 °, 25.37 °, 25.68 °, 26.66 °, 26.83 °, 27.28 °, 27.73 °, 28.00 °, 28.48 °, 29.40 °, 29.83 °, 31.10 °, 31.54 °, 32.16 °, 32.71 °, 34.02 °, 34.82 °, 35.45 °, 36.15 °, 36.67 °, 37.64 °, 38.33 °, 38.80 ° and 39.55 °, 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 196.70 DEG C, there is the error margin of ± 3 DEG C.
4) carry out thermal weight loss (TGA) Analysis and Identification by TAQ500: temperature rise rate is 10 DEG C/min, in room temperature in about 170 DEG C of temperature ranges, weightlessness is 1.989%.In conjunction with the spectrum analysis of DSC and TGA, 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-} the crystal formation I of-quinazoline Citrate trianion, melting peak is 196.70 DEG C, then along with the rising of temperature, decompose gradually.
Embodiment 9
The pharmacokinetic situations of the different salt form of compound shown in formula (I)
Pharmacokinetic trial in the body adopting beasle dog to carry out the different salt form of compound shown in compound shown in formula (I) and formula (I): each 3 of kind beasle dog, administering mode is capsule oral, all convert out the dosage of salt according to free alkali dosage 5mg/kg, the oral absorption situation of compound shown in preliminary study formula (I) and the different salt form of the shown compound of formula (I).Experimental result is as table 1:
Compound and the pharmacokinetic parameter of different salt form in beasle dog body thereof shown in table 1 formula (I)
Conclusion: the exposed amount after compound salify shown in formula (I) in dog body is all large compared with the exposed amount of free alkali, and bioavailability has larger improvement.

Claims (10)

1. the compound shown in a formula (IIa):
2. the crystal formation I of compound shown in formula (IIa), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.67 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.22 ° ± 0.2 °, 15.03 ° ± 0.2 °, 15.24 ° ± 0.2 °, 15.58 ° ± 0.2 °, 17.35 ° ± 0.2 °, 18.62 ° ± 0.2 °, 20.35 ° ± 0.2 °, 20.59 ° ± 0.2 °, 21.26 ° ± 0.2 °, 24.08 ° ± 0.2 °, 24.44 ° ± 0.2 °, 25.37 ° ± 0.2 °, 25.68 ° ± 0.2 °, 26.66 ° ± 0.2 °, 26.83 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.48 ° ± 0.2 ° and 34.82 ° ± 0.2 °.
3. the crystal formation I of compound shown in formula (IIa), its X-ray powder diffraction pattern has diffraction peak at following 2 θ angle places: 4.67 ° ± 0.2 °, 9.31 ° ± 0.2 °, 10.15 ° ± 0.2 °, 11.42 ° ± 0.2 °, 11.99 ° ± 0.2 °, 12.62 ° ± 0.2 °, 13.26 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.22 ° ± 0.2 °, 15.03 ° ± 0.2 °, 15.24 ° ± 0.2 °, 15.58 ° ± 0.2 °, 17.35 ° ± 0.2 °, 17.70 ° ± 0.2 °, 18.20 ° ± 0.2 °, 18.62 ° ± 0.2 °, 19.52 ° ± 0.2 °, 20.35 ° ± 0.2 °, 20.59 ° ± 0.2 °, 21.26 ° ± 0.2 °, 21.65 ° ± 0.2 °, 21.97 ° ± 0.2 °, 22.39 ° ± 0.2 °, 23.01 ° ± 0.2 °, 23.63 ° ± 0.2 °, 24.08 ° ± 0.2 °, 24.44 ° ± 0.2 °, 25.37 ° ± 0.2 °, 25.68 ° ± 0.2 °, 26.66 ° ± 0.2 °, 26.83 ° ± 0.2 °, 27.28 ° ± 0.2 °, 27.73 ° ± 0.2 °, 28.00 ° ± 0.2 °, 28.48 ° ± 0.2 °, 29.40 ° ± 0.2 °, 29.83 ° ± 0.2 °, 31.10 ° ± 0.2 °, 31.54 ° ± 0.2 °, 32.16 ° ± 0.2 °, 32.71 ° ± 0.2 °, 34.02 ° ± 0.2 °, 34.82 ° ± 0.2 °, 35.45 ° ± 0.2 °, 36.15 ° ± 0.2 °, 36.67 ° ± 0.2 °, 37.64 ° ± 0.2 °, 38.33 ° ± 0.2 °, 38.80 ° ± 0.2 ° and 39.55 ° ± 0.2 °.
4. the crystal formation I of compound shown in formula (IIa), it has X-ray powder diffraction pattern as shown in Figure 1 substantially.
5. the crystal formation I of compound shown in formula (IIa), its differential scanning calorimetric curve has endotherm(ic)peak at 196.70 DEG C ± 3 DEG C places.
6. the crystal formation I of compound shown in formula (IIa), it has differential scanning calorimetric curve as shown in Figure 2 substantially.
7. a pharmaceutical composition, it comprises compound according to claim 1 or the crystal formation I described in claim 2-6 any one or their combination, and wherein said pharmaceutical composition comprises pharmaceutically acceptable carrier further, vehicle, thinner, assistant agent, vehicle or their combination.
8. pharmaceutical composition according to claim 7, it further comprises therapeutical agent, and described therapeutical agent is selected from chemotherapeutic agent, antiproliferative, cytotoxic drug, signal transduction inhibitor, is used for the treatment of medicine or their combination of nonsmall-cell lung cancer and epidermal carcinoma.
9. pharmaceutical composition according to claim 8, 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), Conmana (Icotinib), hydrochloric acid Conmana (IcotinibHydrochloride), horse trastuzumab (Matuzmab), HKI-272 (Neratinib), canertinib (Canertinib), ZD6474 (Vandetanib), AZD2171 (Cediranib), PTK787 (Vatalanib), Axitinib (Axitinib), Mo Teshani (Motesanib), Buddhist nun's trastuzumab (Nimotuzumab), Xi Li is for Buddhist nun (Theliatinib), according to pyrrole for Buddhist nun (Epitinib), west is not for Buddhist nun (Simotinib), Poziotinib, Varlitinib, Rociletinib, Pelitinib, AZD9291, PKI-166, PD158780, ABX-EGF, MDX447, Mab425, HM-61713, TAS-121, MM-121, ASP-8273, or their combination.
10. use the compound described in claim 1 or the crystal formation I described in claim 2-6 any one or the pharmaceutical composition described in claim 7-9 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.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106588943A (en) * 2015-10-19 2017-04-26 广东东阳光药业有限公司 Salt, crystal form and application of EGFR (epidermal growth factor receptor) inhibitor
CN108101920A (en) * 2016-11-25 2018-06-01 广东东阳光药业有限公司 Salt of amino quinazoline derivative and application thereof
JP2019530677A (en) * 2017-06-02 2019-10-24 ウーシー ショアンリャン バイオテクノロジー カンパニー，リミティド Pharmaceutical salt of EGFR inhibitor and its crystal form, production method and use
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
WO2020253836A1 (en) * 2019-06-19 2020-12-24 南京明德新药研发有限公司 Crystal form and salt of quinazoline compound and preparation method therefor
CN114685466A (en) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 Axitinib eutectic salt

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103102344A (en) * 2011-11-14 2013-05-15 广东东阳光药业有限公司 Aminoquinazoline derivative, salts thereof and application method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103102344A (en) * 2011-11-14 2013-05-15 广东东阳光药业有限公司 Aminoquinazoline derivative, salts thereof and application method

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WO2017067447A1 (en) * 2015-10-19 2017-04-27 Sunshine Lake Pharma Co., Ltd. A salt of egfr inhibitor, crystalline form and uses thereof
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
CN108101920A (en) * 2016-11-25 2018-06-01 广东东阳光药业有限公司 Salt of amino quinazoline derivative and application thereof
JP2019530677A (en) * 2017-06-02 2019-10-24 ウーシー ショアンリャン バイオテクノロジー カンパニー，リミティド Pharmaceutical salt of EGFR inhibitor and its crystal form, production method and use
US10759797B2 (en) 2017-06-02 2020-09-01 Wuxi Shuangliang Biotechnology Co., Ltd. Pharmaceutically acceptable salt of EGFR inhibitor, crystal form thereof, preparation method therefor and application thereof
WO2020253836A1 (en) * 2019-06-19 2020-12-24 南京明德新药研发有限公司 Crystal form and salt of quinazoline compound and preparation method therefor
CN114685466A (en) * 2020-12-26 2022-07-01 鲁南制药集团股份有限公司 Axitinib eutectic salt
CN114685466B (en) * 2020-12-26 2023-06-13 鲁南制药集团股份有限公司 Acetinib eutectic salt

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