CN104557687A - Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form substance thereof - Google Patents

Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form substance thereof Download PDF

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Publication number
CN104557687A
CN104557687A CN201310513217.8A CN201310513217A CN104557687A CN 104557687 A CN104557687 A CN 104557687A CN 201310513217 A CN201310513217 A CN 201310513217A CN 104557687 A CN104557687 A CN 104557687A
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crystal formation
formation thing
compound
chloro
picolinamide
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吕彬华
李成伟
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Suzhou Zelgen Biopharmaceutical Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
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Priority to CN202110419553.0A priority Critical patent/CN114014804A/en
Priority to CN201310513217.8A priority patent/CN104557687A/en
Publication of CN104557687A publication Critical patent/CN104557687A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Abstract

The invention relates to a fluorine-containing deuterated omega-diphenylurea hydrate and a crystal form substance thereof. Specifically, the invention provides 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-3-fluoro-phenoxy)-2-(N-1',1',1'-tri-deuterated methyl) picolinamide monohydrate or a crystal form substance thereof and a production method thereof. The hydrate or the crystal form substance thereof is suitable for preparing pharmaceutical compositions for inhibiting tyrosine kinases (such as VEGFRs).

Description

Fluorine-containing deuterated ω-diphenyl urea hydrate and crystal formation thing thereof
Technical field
The invention belongs to field of medicaments, particularly, relate to a kind of hydrate of fluorine-containing deuterated ω-diphenyl urea and crystal formation thing thereof, and preparation method thereof, more specifically, relate to 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide monohydrate and crystal formation thing thereof, and preparation method thereof.
Background technology
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide, structure is such as formula shown in II.
The molecular formula of formula II compound is C 21h 12d 3clF 4n 4o 3, molecular weight is 485.83; Formula II compound belongs to the compound suppressing VEGFRs, is applicable to the medicine preparing Therapeutic cancer and relevant disease.
Patent WO2011/113368 describes the preparation method of formula II compound and pharmaceutically acceptable salt thereof, but is anhydrous compound for the preparation of relative medicine, does not develop hydrate and the crystal formation thing thereof of formula II compound.
Therefore, hydrate and the crystal formation thereof of researching and developing formula II compound are very necessary.
Summary of the invention
The object of this invention is to provide 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide monohydrate and method for making thereof.
Object of the present invention again provides crystal formation and the method for making thereof of described monohydrate.
In a first aspect of the present invention, provide compound shown in formula I,
In second aspect present invention, provide the preparation method of compound described in a kind of first aspect present invention,
A () described method comprises step:
(a-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is suspended in the mixed solvent of water soluble inert solvent and water, obtains suspension;
(a-2) suspension of stirring or oscillation step (a-1), thus obtain the compound described in first aspect present invention;
Or (b) described method comprises step:
(b-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide material dissolution in the mixed solvent of water soluble inert solvent and water, obtain solution;
(b-2) compound adding step (a-2) obtained in the solution obtained in step (b-1) is induced as crystal seed, and cooling is stirred or vibration, thus obtains the compound described in first aspect present invention.
In another preference, described method (a) is at room temperature carried out.
In another preference, in described step (a-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing I of picolinamide.
In another preference, in described step (a-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing II of picolinamide.
In another preference, in described step (a-1), the volume ratio of described water soluble inert solvent and water is 0.1-20:1; Preferably, be 0.5-10:1.
In another preference, in described step (a-2), a period of time was carried out in described stirring or vibration, as >=2 days; Preferably, be 4-10 days.
In another preference, in described step (a-2), also comprise step: the compound obtained is filtered and drying.
In another preference, described step (b-1) is carried out at room temperature ~ 70 DEG C.
In another preference, in described step (b-2), described cooling refers to decline 5-30 DEG C.
In another preference, in described step (b-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' of known any form, 1', the deuterated methyl of 1'-tri-) picolinamide, comprise amorphous article, crystal formation thing I, crystal formation thing II etc.
In another preference, in described step (b-1), the volume ratio of described water soluble inert solvent and water is 1-20:1; Preferably, be 2-10:1.
In another preference, in described step (b-2), a period of time was carried out in described stirring or vibration, as >=1 hour; Preferably, be 2-5 hour.
In another preference, in described step (b-2), also comprise step: the compound obtained is filtered and drying.
In another preference, described atent solvent is selected from: acetonitrile, acetone, methyl tertbutyl ketone, ethanol, methanol, isopropyl alcohol, propanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, normal heptane, normal hexane, Pentamethylene., cyclohexane extraction, toluene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxine or its combination.
In another preference, described atent solvent refers to acetonitrile, acetone, ethanol, isopropyl alcohol.
In third aspect present invention, provide the crystal formation thing of compound shown in a kind of formula I,
Described crystal formation thing has the X-ray powder diffraction characteristic peak that one or more are selected from lower group: 11.799 ± 0.2 °, 14.844 ± 0.2 ° and 25.994 ± 0.2 °.
In another preference, described crystal formation thing also has the X-ray powder diffraction characteristic peak that one or more are selected from lower group: 5.883 ± 0.2 °, 16.143 ± 0.2 °, 21.199 ± 0.2 ° and 26.213 ± 0.2 °.
In another preference, described crystal formation thing has X-ray powder diffractogram (XRPD) substantially as shown in Figure 2 a.
In another preference, the differential scanning calorimetry collection of illustrative plates (DSC) of described crystal formation thing has peak-peak at 210.0-214.3 DEG C.
In another preference, the differential scanning calorimetry collection of illustrative plates of described crystal formation thing also has peak value at 142.4-147.0 DEG C.
In another preference, the differential scanning calorimetry collection of illustrative plates of described crystal formation thing substantially as shown in Figure 2 b.
In fourth aspect present invention, provide the preparation method of crystal formation thing described in a kind of third aspect present invention,
(I) described method comprises step:
(I-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is suspended in the mixed solvent of water soluble inert solvent and water, obtains suspension;
(I-2) suspension of stirring or oscillation step (I-1), crystallize, thus obtain the crystal formation thing described in third aspect present invention;
Or (II) described method comprises step:
(II-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide material dissolution in the mixed solvent of water soluble inert solvent and water, obtain solution;
(II-2) compound adding step (I-2) obtained in the solution obtained in step (II-1) is induced as crystal seed, and cooling is stirred or vibration, crystallize, thus obtains the crystal formation thing described in third aspect present invention.
In another preference, described method (I) is at room temperature carried out.
In another preference, in described step (I-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing I of picolinamide.
In another preference, in described step (a-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing II of picolinamide.
In another preference, in described step (I-1), the volume ratio of described water soluble inert solvent and water is 0.1-20:1; Preferably, be 0.5-10:1.
In another preference, in described step (I-2), a period of time was carried out in described stirring or vibration, as >=2 days; Preferably, be 4-10 days.
In another preference, in described step (I-2), also comprise step: the compound obtained is filtered and drying.
In another preference, described step (II-1) is carried out at room temperature ~ 70 DEG C.
In another preference, in described step (II-2), described cooling refers to decline 5-30 DEG C.
In another preference, in described step (II-1), described 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' of known any form, 1', the deuterated methyl of 1'-tri-) picolinamide, comprise amorphous article, crystal formation thing I, crystal formation thing II etc.
In another preference, in described step (II-1), the volume ratio of described water soluble inert solvent and water is 1-20:1; Preferably, be 2-10:1.
In another preference, in described step (II-2), a period of time was carried out in described stirring or vibration, as >=1 hour; Preferably, be 2-5 hour.
In another preference, in described step (II-2), also comprise step: the compound obtained is filtered and drying.
In another preference, described atent solvent is selected from: acetonitrile, acetone, methyl tertbutyl ketone, ethanol, methanol, isopropyl alcohol, propanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, normal heptane, normal hexane, Pentamethylene., cyclohexane extraction, toluene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxine or its combination.
In another preference, described atent solvent refers to acetonitrile, acetone, ethanol, isopropyl alcohol.
In fifth aspect present invention, provide the purposes of crystal formation thing described in compound described in a kind of first aspect present invention or third aspect present invention, for the preparation of the pharmaceutical composition suppressing tyrosine kinase (as VEGFRs).
In another preference, described pharmaceutical composition is also used for the treatment of and prophylaxis of cancer.
In sixth aspect present invention, provide a kind of pharmaceutical composition, comprise:
(1) compound described in first aspect present invention and/or the crystal formation thing described in third aspect present invention are as active component; And (2) pharmaceutically acceptable carrier.
In another preference, be made up of the crystal formation thing described in third aspect present invention and pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition is also containing other cancer therapy drug.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 a shows the X-ray powder diffraction pattern of formula II compound crystal form thing I.
Fig. 1 b shows the differential scanning calorimetry figure of formula II compound crystal form thing I.
Fig. 1 c shows the NMR figure of formula II compound crystal form thing I.
Fig. 2 a shows the X-ray powder diffraction pattern of the crystal formation thing of formula I.
Fig. 2 b shows the differential scanning calorimetry figure of the crystal formation thing of formula I.
Fig. 2 c shows the thermogravimetric analysis figure of the crystal formation thing of formula I.
Fig. 2 d shows the NMR figure of the crystal formation thing of formula I.
Detailed description of the invention
The present inventor is by long-term and deep research, have unexpectedly discovered that a kind of 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide monohydrate (formula I, its water content is 3.6%) and the preparation method of crystal formation thing, inventor is by strictly controlling preparation condition (as specific mixed solvent, mixing time etc.) to have purity high for obtained formula I or its crystal formation thing, the advantages such as good stability, and it is suitable for preparing the pharmaceutical composition suppressing tyrosine kinase (as VEGFRs), thus be more conducive to the diseases such as Therapeutic cancer.In addition, crystal formation thing of the present invention, in the medicine manufacture processes such as subpackage, is not easily kicked up, and easily collecting, not easily causes waste, and contributes to the healthy of protection operator.On this basis, inventor completes the present invention.
As used herein, " formula II compound " refer to 4-shown in structural formula as I I (4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide.
As used herein, " formula I " refer to 4-shown in structural formula as I (4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) monohydrate of picolinamide.
As used herein, " VEGFRs " refers to vascular endothelial growth factor receptor (vascular endothelial growth factor receptor).
As used herein, described " 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1'; 1'; the deuterated methyl of 1'-tri-) picolinamide raw material " can be 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' of known any form, 1', the deuterated methyl of 1'-tri-) picolinamide, as its amorphous article, crystal formation thing I, crystal formation thing II etc., or see the crystal formation that patent CN201210143861.6 obtains.
Polymorph
Solid is not be exactly exist with the form of crystallization with unbodied form.When crystal form, molecule is positioned in three-dimensional lattice case.When compound crystallizes out from solution or serosity, space lattice arrangement crystallization (this character is referred to as " polymorphism ") that it can be different, form the crystal with different crystal forms, this various crystal form is referred to as " polymorph ".The different polymorphs of given material can in one or more physical attribute (as dissolubility and rate of dissolution, true specific gravity, crystal form, accumulation mode, mobility and/or solid-state stability) different from each other.
Crystallization
Can working solution be passed through, the solubility limit of compound of interest is exceeded, thus complete production-scale crystallization.This can have been come by multiple method, and such as, dissolved compound at relatively high temperature, then below cooling solution to saturation limit.Or reduce liquid volume by boiling, atmospheric evaporation, vacuum drying or the certain methods by other.By adding solvent resistant or compound has the solvent of low dissolubility or the mixture of such solvent wherein, reduce the dissolubility of compound of interest.Another kind of optional method is that adjust ph is to reduce dissolubility.About the detailed description of crystallization aspect refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN0750611294.
If expect that the formation of salt and crystallization occur simultaneously, if salt is less than material dissolution degree in reaction medium, so add the direct crystallization that suitable acid or alkali can cause required salt.Equally, in the medium that the form finally wanted is less than reactants dissolved degree, completing of synthetic reaction can make end product direct crystallization.
The optimization of crystallization can comprise and being inoculated in crystallization medium as crystal seed with the crystal of desired form.In addition, many method for crystallising use the combination of above-mentioned strategy.An embodiment is at high temperature by interested compound dissolution in a solvent, is added the solvent resistant of proper volume subsequently, to make system just in time under saturated level by controlled way.Now, the crystal seed (and keeping the integrity of crystal seed) of desired form can be added, by system cooling to complete crystallization.
As used herein, term " room temperature " refers generally to 4-30 DEG C, preferably refers to 20 ± 5 DEG C.
Crystal formation thing of the present invention
As used herein, term " crystal formation thing of the present invention " refers to the crystal formation thing of formula I.
The qualification of crystal formation thing and character
The present invention, after the crystal formation thing of preparation I compound, adopts following various ways and instrument to be studied its character.
X-ray powder diffraction
The method measuring the X-ray powder diffraction of crystal formation is well known in the art.Such as use the x-ray powder diffraction instrument of Rigaku D/max2550VB/PC model, with 2 ° of scanning speeds per minute, adopt copper radiation target to obtain collection of illustrative plates.
The crystal formation thing of formula I of the present invention, has specific crystal formation form, in X-ray powder diffraction (XRPD) figure, have specific characteristic peak.
Described crystal formation thing has the X-ray powder diffraction characteristic peak that one or more are selected from lower group: 11.799 ± 0.2 °, 14.844 ± 0.2 ° and 25.994 ± 0.2 °.
In another preference, described crystal formation thing also has the X-ray powder diffraction characteristic peak that one or more are selected from lower group: 5.883 ± 0.2 °, 16.143 ± 0.2 °, 21.199 ± 0.2 ° and 26.213 ± 0.2 °.
In another preference, described crystal formation thing has X-ray powder diffractogram substantially as shown in Figure 2 a.
Differential scanning calorimetry
Also known as " differential scanning calorimetry " (DSC), be in heating process, measure a kind of technology of relation between energy difference between measured matter and reference substance and temperature.Peak position on DSC collection of illustrative plates, shape are relevant with the character of material with peak number order, therefore can be used for qualitatively identifying material.The many kinds of parameters such as phase transition temperature, glass transition temperature, reaction heat that the method carrys out detection material is commonly used in this area.
DSC assay method is well known in the art.Such as can use NETZSCH DSC204F1 differential scanning calorimetry (DSC), with 10 DEG C of heating rates per minute, be warming up to 350 DEG C from 25 DEG C, obtain the DSC scanning spectra of crystal formation.
The crystal formation thing of formula I of the present invention, has specific characteristic peak in differential scanning calorimetry (DSC) figure.
The differential scanning calorimetry collection of illustrative plates of described crystal formation thing has peak-peak at 210.0-214.3 DEG C.
In another preference, described crystal formation thing has differential scanning calorimetry collection of illustrative plates (DSC) substantially as shown in Figure 2 b.
Nuclear magnetic resonance, NMR
Also can adopt nuclear magnetic resonance, NMR (NMR) to assist and determine crystalline structure, its assay method is well known in the art.The present invention preferably adopts Bruker Avance III plus-400MHz.
Elementary analysis
Also can adopt elementary analysis to assist and determine crystalline structure, its assay method is well known in the art.The present invention preferably adopts German element vario EL cube.
Active component
As used herein, term " active component " or " reactive compound " refer to formula I of the present invention and/or crystal formation thing of the present invention.
Pharmaceutical composition and application process
Because reactive compound of the present invention has the excellent inhibit activities to tyrosine kinase (Kinase) such as VEGFRs, therefore reactive compound of the present invention and can be used for treating containing the pharmaceutical composition that this reactive compound is main active, prevention and alleviate the disease mediated by tyrosine kinase (Kinase) such as VEGFRs.According to prior art, reactive compound of the present invention can be used for treating following disease: cancer, cardiovascular disease, obesity, diabetes etc.
Pharmaceutical composition of the present invention comprises crystal formation thing of the present invention in safe and effective weight range and pharmaceutically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound (or crystal formation thing) is enough to obviously improve the state of an illness, and is unlikely to produce serious side effect.Usually, pharmaceutical composition contains 1-2000mg crystal formation thing/agent of the present invention, more preferably, containing 10-200mg crystal formation thing/agent of the present invention.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." compatibility " to referred to herein as in compositions each component energy and active component of the present invention and they between mutually admix, and the drug effect of not obvious reduction active component.Pharmaceutically acceptable carrier part example have cellulose and its derivates (as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Talcum, kollag (as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (as wetting agent (as sodium lauryl sulphate), disintegrating agent, coloring agent, flavoring agent, stabilizing agent, antioxidant, antiseptic, apirogen water etc.
The method of application of crystal formation thing of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and topical.
Solid dosage forms for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosage formss, active component mixes with at least one conventional inert excipients (or carrier), as sodium citrate or dicalcium phosphate, or mix with following compositions: (a) filler or bulking agent, such as, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binding agent, such as, hydroxy methocel, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum; (c) wetting agent, such as, glycerol; (d) disintegrating agent, such as, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as spermol and glyceryl monostearate; (h) adsorbent, such as, Kaolin; (i) lubricant, such as, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and in this compositions, the release of active component can discharge in certain part in a delayed fashion in digestive tract.The example of adoptable embedding component is polymeric material and Wax.If desired, active component also can form microencapsulation form with one or more in above-mentioned excipient.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except active component, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami or these materials.
Except these inert diluents, compositions also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and spice.
Except active component, suspension can comprise suspending agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline Cellulose, aluminium methoxide and agar or these materials.
Compositions for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, diluent, solvent or excipient comprise water, ethanol, polyhydric alcohol and suitable mixture thereof.
Dosage form for the crystal formation thing of the present invention of topical comprises ointment, powder, patch, propellant and inhalant.Active component aseptically with physiologically acceptable carrier and any antiseptic, buffer agent, or the propellant that may need if desired is mixed together.
Crystal formation thing of the present invention can be individually dosed, or with other pharmaceutically acceptable compound administering drug combinations.
When making pharmaceutical composition, it is the mammal (as people) being applicable to the crystal formation thing of the present invention of safe and effective amount need treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1 ~ 2000mg, preferably 10 ~ 500mg.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
Major advantage of the present invention has:
1. provide novel 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1 ', 1 ', 1 '-three deuterated methyl) picolinamide monohydrate or its crystal formation thing.
2. additionally provide the purposes of described hydrate or its crystal formation thing, can be used for preparing the pharmaceutical composition suppressing tyrosine kinase (as VEGFRs), thus be used for the treatment of the diseases such as cancer.
Below in conjunction with concrete enforcement, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise percentage ratio and number calculate by weight.If not the raw materials used special instruction of the present invention, all commercially.
Embodiment 14-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing I of picolinamide (formula II compound)
4-(4-amino-3-fluorophenoxy)-N-(methyl-d is added to four mouthfuls of round-bottomed flasks 3) ascorbyl palmitate (4.0g, 15.14mmol), oxolane (36g), drips the anhydrous toluene solution (3.74g is dissolved in 4.3g toluene) of 4-chloro-3-trifluoromethylbenzene based isocyanate under uniform stirring, to dropwise under rear nitrogen protection uniform stirring 3 hours;
HPLC detection display consumption of raw materials is complete, add the mixed liquor of oxolane and methanol, stir after 5 minutes, 1.8g chloroacetic chloride is slowly instilled in mixture, within about 5 minutes, drips and finish, uniform stirring, a large amount of pale precipitation is separated out, continue stirring 1.5 hours, filter, the mixed liquor washing of solid oxolane and acetone;
Solid proceeds to there-necked flask, adds acetone (53.7g) and pure water (11.2g), adds sodium hydrate aqueous solution (1.7g immediately, 45%w/w), be heated to 40 degree, Keep agitation 30 minutes, sample is clearly molten, and cooling is stirred to 20 degree, adds 6.7g pure water, there is muddy appearance, continue to be cooled to about 3 degree, uniform stirring about 1 hour, a large amount of solid is separated out, sucking filtration, and the cold acetone/water mixed solvent of solid washs, 30 degree of vacuum dryings 8 hours, obtain pale solid 4.9g, yield: 67%.
Sampling warp 1h NMR, X-ray powder diffraction, differential scanning calorimetry etc. detect to be proved, described solid is title compound.
1H NMR（CD 3OD，400MHz）:δ6.99-7.02(m,1H),7.09(dd,J=2.4Hz,6.8Hz,1H),7.12(d,J=2.4Hz,1H),7.53(d,J=8.4Hz,1H),7.60(d,J=2.8Hz,1H),7.65(dd,J=2.8Hz,8.4Hz,1H),8.04(d,J=2.4Hz,1H),8.20(t,J=8.8Hz,1H),8.51(d,J=5.6Hz,1H)。
Its X-ray powder diffraction pattern is shown in Fig. 1 a, and the parameter at each peak is as shown in table 1, and differential scanning calorimetry figure (DSC) is shown in Fig. 1 b, 1fig. 1 c is shown in by the collection of illustrative plates of H NMR.
Table 1
Peak number 2θ(°) Peak height Relative intensity (I%) Peak number 2θ(°) Peak height Relative intensity (I%)
1 7.259 16006 100.0 19 23.786 1219 7.6
2 8.584 757 4.7 20 24.240 1512 9.4
3 10.653 553 3.5 21 24.794 1147 7.2
4 11.492 565 3.5 22 25.840 1678 10.5
5 12.044 532 3.3 23 26.373 2382 14.9
6 13.399 3654 22.8 24 27.110 1050 6.6
7 13.598 859 5.4 25 27.436 3054 19.1
8 14.543 11121 69.5 26 28.126 806 5.0
9 14.761 2266 14.2 27 29.314 991 6.2
10 15.609 1220 7.6 28 30.374 792 4.9
11 16.502 1205 7.5 29 31.582 1208 7.5
12 17.230 2410 15.1 30 32.707 521 3.3
13 18.574 1891 11.8 31 35.115 696 4.3
14 18.847 2388 14.9 32 38.763 527 3.3
15 19.818 2859 17.9 33 39.750 549 3.4
16 21.871 762 4.8 34 40.979 494 3.1
17 22.831 795 5.0 35 43.145 459 2.9
18 23.427 3359 21.0
Embodiment 24-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing of monohydrate (formula I) of picolinamide
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' prepared by embodiment 1 is added to single necked round bottom flask, 1', the deuterated methyl of 1'-tri-) the crystal formation thing I (1g) of picolinamide, add the mixed solvent (20mL of acetonitrile/water immediately, v:v=1:1), after sealing, room-temperature, homogenous stirs one week, filters, and under room temperature, high vacuum dry obtains off-white color solid sample for 6 hours and is about 952mg; HPLC purity >=99.5%.
Sampling warp 1h NMR, mass spectrum, X-ray powder diffraction, DSC, TGA, elementary analysis, Ka Er-Fischer moisture mensuration etc. detect proof and obtain title compound.
1H NMR（CD 3OD，400MHz）:δ6.99-7.02(m,1H),7.09(dd,J=2.4Hz,6.8Hz,1H),7.12(d,J=2.4Hz,1H),7.53(d,J=8.4Hz,1H),7.60(d,J=2.8Hz,1H),7.65(dd,J=2.8Hz,8.4Hz,1H),8.04(d,J=2.4Hz,1H),8.20(t,J=8.8Hz,1H),8.50(d,J=5.6Hz,1H)。MS（ESI,m/z）:486[M+H] +。
Results of elemental analyses:
Element C% H% N%
Measured value 50.10 3.64 11.11
Theoretical value 50.06 4.00 11.12
Its X-ray powder diffraction pattern is shown in Fig. 2 a, and the parameter at each peak is as shown in table 2, means of differential scanning calorimetry
Method figure (DSC) is shown in Fig. 2 b, and Fig. 2 c is shown in thermogravimetric analysis (TGA), 1fig. 2 d is shown in by the collection of illustrative plates of H NMR.
Embodiment 34-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing of monohydrate (formula I) of picolinamide
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' prepared by embodiment 1 is added to single necked round bottom flask, 1', the deuterated methyl of 1'-tri-) the crystal formation thing I (100mg) of picolinamide, add the mixed solvent (4mL of acetone/water immediately, v:v=4:1), after sealing, room-temperature, homogenous stirs one week, filter, under room temperature, high vacuum dry obtains off-white color solid sample for 6 hours and is about 55mg title compound.
Comparative example 1
4-prepared by embodiment 1 (4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) the crystal formation thing I of picolinamide (400mg) is suspended in the mixed solvent (15mL of acetone/water, v:v=4:1) in, stirred at ambient temperature 24 hours, filter, the mixed solvent washing of the solid acetone/water obtained, 30 DEG C of vacuum dryings obtain off-white color solid in 6 hours.Sampling warp 1h NMR, X-ray powder diffraction, DSC etc. detect proof, obtain the crystal formation thing I as the formula II compound in embodiment 1.
Relatively comparative example 1 and embodiment 2-3 known: the crystal formation thing of formula I finds in the accident stirring (at least 2 days) under the sufficiently long time.
Embodiment 44-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing of monohydrate (formula I) of picolinamide
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' is added to single necked round bottom flask, 1', the deuterated methyl of 1'-tri-) picolinamide (400mg), mixed solvent (the 4.5:1 of 16mL acetone/water is added under room temperature, w/w), be stirred to sample clearly molten, filter, filtrate adds the mixed solvent (4.5:1 of 3mL acetone/water, w/w), the crystal seed adding embodiment 2 preparation after stirred at ambient temperature 5min is about 10mg, be cooled to 20 DEG C of stirrings, crystal is slowly had to separate out, continue to be cooled to about 3 DEG C, filter after stirring 30min, the cold acetone/water mixed solvent of solid washs, under room temperature, high vacuum dry obtains off-white color solid sample 314mg in 6 hours, HPLC purity is greater than>=and 99.5%, sampling warp 1h NMR, X-ray powder diffraction, DSC, TGA etc. detect proof and obtain title compound.
Embodiment 54-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing of monohydrate (formula I) of picolinamide
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' is added to single necked round bottom flask, 1', the deuterated methyl of 1'-tri-) picolinamide (400mg), mixed solvent (the 4.5:1 of 16mL acetone/water is added under room temperature, w/w), be heated to 50 DEG C, be stirred to sample clearly molten, filter, the crystal seed adding embodiment 2 preparation after being cooled to 30 DEG C is about 10mg, be cooled to 20 DEG C of stirrings, crystal is slowly had to separate out, continue to be cooled to about 3 DEG C, stir after 1 hour and filter, the cold acetone/water mixed solvent of solid washs, under room temperature, high vacuum dry obtains off-white color solid sample 314mg in 6 hours, sample and obtain title compound through the detection such as X-ray powder diffraction, DSC, TGA proof.
Comparative example 2
By 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) picolinamide (400mg) joins acetone/water (8mL, 4:1, w/w) in, be warmed up to 60 DEG C, stirring and dissolving is clarified, and filters, filtrate cool to room temperature also stirs 1 hour, solid is separated out, and filter, 30 DEG C of vacuum dryings obtain off-white color solid in 6 hours.Sample and detect proof through X-ray powder diffraction, DSC etc., obtain the crystal formation thing I as the formula II compound in embodiment 1.
Relatively comparative example 2 and embodiment 4-5 known: at 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) picolinamide compound solution in do not add formula I the induction of crystal formation thing can not get the crystal formation thing of formula I.
Embodiment 64-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', the deuterated methyl of 1', 1'-tri-) the crystal formation thing of monohydrate (formula I) of picolinamide
4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1' is added to single necked round bottom flask, 1', the deuterated methyl of 1'-tri-) the crystal formation thing II (200mg of picolinamide, preparation method is see the embodiment 1 of patent CN201210143861.6), add the mixed solvent (5mL of acetonitrile/water immediately, v:v=1:1), after sealing, room-temperature, homogenous stirs 4 days, filter, under room temperature, high vacuum dry obtains off-white color solid sample 125mg in 6 hours; Sample and obtain title compound through the detection such as X-ray powder diffraction, DSC, TGA proof.
The stability of embodiment 74-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl) uride) the fluoro-phenoxy group of-3-)-2-(the deuterated methyl of N-1', 1', 1'-tri-) picolinamide monohydrate crystal form thing
After the accelerated test (experimental condition 40 DEG C, 75%RH) of 6 months, result shows: 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl) uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) crystal formation of picolinamide monohydrate crystal form thing is very stable, 95% (effective crystal form content can pass through this area conventional method, as the method such as XRPD, solid-state nmr calculates) is greater than containing crystal formation thing content described in title; And freshly prepd (0 month) crystal formation thing of comparing, after 6 months, described crystal formation thing HPLC purity is greater than 99%, and impurity content change is less than 1%.
Embodiment 8 pharmaceutical composition
According to a conventional method, after above-mentioned substance mix homogeneously, tabletting, obtains 1000 tablets.
Embodiment 9 is for c-Kit, PDGFR-β protein tyrosine kinase molecular level inhibit activities
1, experimental technique
The present embodiment adopts enzyme linked immunosorbent assay (Enzyme-Linked Immunosorbent Assay, ELISA) to measure formula I to c-Kit, PDGFR-β protein tyrosine kinase molecular level inhibit activities.
The compound measured: formula I crystal formation thing.
Main agents:
Reaction substrate Poly (Glu, Tyr) 4:1available from Sigma; The monoclonal antibody PY99 of anti phosphotyrosine is purchased from Santa Cruz company; The IgG of horseradish peroxidase-labeled sheep anti mouse is purchased from Calbiochem company; ATP, DTT, OPD are purchased from Amresco company; ELISA Plate is purchased from Corning company; Su11248 is purchased from Merck company.
Experimental technique:
See Roskoski, R., Jr.Sunitinib:a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor.Biochem Biophys Res Commun, 356:323-328,2007, specifically comprise:
Kinase reaction substrate Poly (Glu, Tyr) 4:120 μ g/ml are diluted to, coated elisa plate with the PBS without potassium ion.At bag, by adding given the test agent in good ELISA Plate hole, (given the test agent is first mixed with 10 with DMSO -2the storage liquid of M, is diluted to desired concn with reaction buffer before use, adds in experimental port, makes it be 10 at the final concentration of 100 μ l reaction systems -5mol/L).Set up Positive control wells simultaneously, add positive reference compound Su11248.
Add the ATP solution (ATP final concentration 5 μMs) with reaction buffer dilution, finally, add the tested tyrosine kinase with reaction buffer dilution.Reaction system cumulative volume is 100 μ l.Set up negative control hole and without enzyme control wells simultaneously.
Reaction system be placed in wet box, 37 DEG C of shaking table lucifuge reaction 1h, reaction terminates rear T-PBS and washes plate three times.Add antibody PY99100 μ l/ hole, 37 DEG C of shaking table reaction 30min.T-PBS washes plate three times.Add the IgG100 μ l/ hole of the sheep anti mouse of horseradish peroxidase-labeled, 37 DEG C of shaking table reaction 30min.T-PBS washes plate three times.Add OPD nitrite ion 100 μ l/ hole, room temperature lucifuge reaction 1-10min.Add 2M H 2sO 450 μ l stopped reactions, with wavelengthtunable decline orifice plate microplate reader VERSAmax survey A 492value.
Suppression ratio by following formulae discovery sample:
2, experimental result
Above experimental result is the average of twice test.
3, evaluation criterion and evaluation of result
Meet the prerequisite of term of reference at the inhibit activities of positive reference compound under, test-compound is at experimental concentration 10 -5under mol/L, suppression ratio is greater than 50% judgement, and it is effective; It is invalid that suppression ratio is less than 50% judgement.
Result shows, and the suppression ratio of formula I crystal formation thing to protein tyrosine kinase c-Kit, PDGFR-β is greater than 50%, therefore has significantly for the inhibit activities of c-Kit, PDGFR-β tyrosine kinase at molecular level.
In sum, crystal formation thing of the present invention is highly stable, is very suitable for pharmaceutical composition.And crystal formation thing of the present invention is in the medicine manufacture processes such as subpackage, not easily kicks up, easily collecting, not easily causes waste, and contributes to the healthy of protection operator.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (11)

1. compound shown in formula I,
2. a preparation method for compound as claimed in claim 1, is characterized in that,
A () described method comprises step:
(a-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is suspended in the mixed solvent of water soluble inert solvent and water, obtains suspension;
(a-2) suspension of stirring or oscillation step (a-1), thus obtain compound according to claim 1;
Or (b) described method comprises step:
(b-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide material dissolution in the mixed solvent of water soluble inert solvent and water, obtain solution;
(b-2) compound adding step (a-2) obtained in the solution obtained in step (b-1) is induced as crystal seed, and cooling is stirred or vibration, thus obtains compound according to claim 1.
3. preparation method as claimed in claim 2, it is characterized in that, described atent solvent is selected from: acetonitrile, acetone, methyl tertbutyl ketone, ethanol, methanol, isopropyl alcohol, propanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, normal heptane, normal hexane, Pentamethylene., cyclohexane extraction, toluene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxine or its combination.
4. a crystal formation thing for compound shown in formula I, is characterized in that,
Described crystal formation thing has the X-ray powder diffraction characteristic peak that one or more are selected from lower group: 11.799 ± 0.2 °, 14.844 ± 0.2 ° and 25.994 ± 0.2 °.
5. crystal formation thing as claimed in claim 4, it is characterized in that, the differential scanning calorimetry collection of illustrative plates (DSC) of described crystal formation thing has peak-peak at 210.0-214.3 DEG C.
6. a preparation method for crystal formation thing as claimed in claim 4, is characterized in that,
(I) described method comprises step:
(I-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide raw material is suspended in the mixed solvent of water soluble inert solvent and water, obtains suspension;
(I-2) suspension of stirring or oscillation step (I-1), crystallize, thus obtain crystal formation thing according to claim 4;
Or (II) described method comprises step:
(II-1) by 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride) the fluoro-phenoxy group of-3-)-2-(N-1', 1', the deuterated methyl of 1'-tri-) picolinamide material dissolution in the mixed solvent of water soluble inert solvent and water, obtain solution;
(II-2) compound adding step (I-2) obtained in the solution obtained in step (II-1) is induced as crystal seed, and cooling is stirred or vibration, crystallize, thus obtains crystal formation thing according to claim 4.
7. preparation method as claimed in claim 6, it is characterized in that, described atent solvent is selected from: acetonitrile, acetone, methyl tertbutyl ketone, ethanol, methanol, isopropyl alcohol, propanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, normal heptane, normal hexane, Pentamethylene., cyclohexane extraction, toluene, ethyl acetate, Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxine or its combination.
8. a purposes for crystal formation thing described in compound described in claim 1 or claim 4, is characterized in that, for the preparation of the pharmaceutical composition suppressing tyrosine kinase (as VEGFRs).
9. a pharmaceutical composition, is characterized in that, comprises:
(1) compound according to claim 1 and/or crystal formation thing according to claim 4 are as active component; And (2) pharmaceutically acceptable carrier.
10. pharmaceutical composition as claimed in claim 9, is characterized in that, be made up of crystal formation thing according to claim 4 and pharmaceutically acceptable carrier.
11. pharmaceutical compositions as claimed in claim 9, is characterized in that, described pharmaceutical composition is also containing other cancer therapy drug.
CN201310513217.8A 2013-10-25 2013-10-25 Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form substance thereof Pending CN104557687A (en)

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