CN105753869B - A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor - Google Patents

A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor Download PDF

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CN105753869B
CN105753869B CN201610202277.1A CN201610202277A CN105753869B CN 105753869 B CN105753869 B CN 105753869B CN 201610202277 A CN201610202277 A CN 201610202277A CN 105753869 B CN105753869 B CN 105753869B
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eutectic
crystal form
mek162
preparation
monocrystalline
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CN105753869A (en
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陈敏华
张炎锋
杨朝惠
夏楠
刘启月
张晓宇
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmatech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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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Abstract

The present invention relates to the eutectics and preparation method thereof of a kind of CDK inhibitor and mek inhibitor.Specifically, the present invention provides hydrate or anhydride crystal form, it is named as crystal form I, crystal form II and crystal form III.Eutectic stability provided by the invention is good, low in hygroscopicity, solubility higher.There is important value to the optimization and exploitation of the following drug.

Description

A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor
Technical field
The present invention relates to chemical medicines, more particularly to a kind of CDK inhibitor (LEE011) and mek inhibitor (MEK162) eutectic and preparation method thereof.
Background technology
With the emergence of melanoma resistance problems, the drug combination of multiple target drugs has become targeted therapy and grinds The main direction of development studied carefully.NRAS gene mutations are the common genetic mutation types of malignant melanoma of skin patient, are accounted for about 20%.NRAS gene mutations patient more after target therapeutic agent that is how bad, and being lack of pertinence.The study found that prominent in NRAS In the melanoma cells of change, MAPK signal path abnormal activations, and there are the imbalances of multiple cell cycle checkpoints.Therefore, together When inhibit MAPK signals critical path molecule MEK and cell cycle key to adjust kinase c DK4/6, the anti-swollen of collaboration may be played Tumor effect improves antitumor curative effect.
Novartis discloses CDK inhibitor LEE011 (Ribociclib) and mek inhibitor MEK162 (Binimetinib) and joins The I phase clinical datas of melanoma are mutated with treatment NRAS, clinic shows the composition of medicine clinical effectiveness of LEE011 and MEK162 Well, the combination at present is carrying out II phases clinic.
LEE011 is a kind of Cyclin dependent kinase 4/6 (CDK4/6) inhibitor, for treating drug resistance breast cancer With melanoma drug, is showed well in preclinical study, obtain positive achievement in research, be currently in the clinical III phases In research.The chemical name of LEE011 be 7- cyclopenta -2- (5- piperazines -1- bases-pyridine -2- bases amino) -7H- pyrrolo-es [2, 3-D] pyrimidine -6- carboxylic acid diformamides, shown in structure such as formula (Ia)：
MEK162 is a kind of oral mitogen-activated protein kinase (MEK) inhibitor, is in three phases clinic in the U.S. at present Experiment is used for NRAS gene mutation body melanomas, BRAF gene mutation body melanoma and the rudimentary blood plasma oophoroma of recurrent The treatment of patient.The chemical name of the drug is：5- [(the bromo- 2- fluorophenyls of 4-) amino] fluoro- N- of -4- (2- hydroxyl-oxethyls) - 1- methyl-1 H- benzimidazole -6- formamides, shown in structural formula such as formula (Ib)：
Patent WO2014097125A1 discloses the composition of LEE011 and MEK162, but the composition is two kinds of components Physical mixed does not form eutectic between two kinds of components, this and the present invention have the difference of essence.
Pharmaceutical co-crystals are in same crystal structure containing there are two types of the crystal of molecule.Effect between two kinds of molecules is generally non- Covalent bond (such as hydrogen bond, π-is pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals will not generally destroy the covalent of active constituents of medicine Key.Have an opportunity to improve the crystal property and physico-chemical property of drug itself, such as biology profit it has been reported that drug is made to form eutectic Expenditure (Pharmaceut.Res.23 (8), 2006, pp.1888-1897.), such as stability and technique exploitability (Int.J.Pham.320,2006, pp.114-123.).Therefore pharmaceutical co-crystals become a newly selection of pharmaceutical solid preparation.
In the prior art, pharmaceutical co-crystals are usually formed by active constituents of medicine and eutectic reagent, the pharmaceutical activity in eutectic Ingredient generally use structural rigidity is relatively strong and symmetry is higher and relative molecular mass is relatively low and containing proton good donor or The compound molecule of receptor, and eutectic reagent is mostly pharmaceutic adjuvant, vitamin, amino acid and food additives etc..Currently, not yet See and eutectic be made in two kinds of active constituents of medicine and studies the relevant report of its therapeutic effect, especially have no LEE011 and Two kinds of active constituents of medicine of MEK162 form the relevant report of eutectic.
Invention content
The present inventor is surprised to find both pharmaceutical activity of LEE011 and MEK162 by lot of experiments Ingredient can form a variety of eutectics, and this variety of eutectic has the clear superiority suitable for production and application etc..
An object of the present invention is to provide the eutectic of CDK inhibitor (LEE011) and mek inhibitor (MEK162), this hair Bright provided eutectic stability is good, and low in hygroscopicity, they are compared with LEE011 and MEK162 equimolar physical mixtures, each group Divide dissolution rate fast, solubility higher.
The two of the object of the invention are to provide the preparation method of the eutectic, although may also be likely to be obtained by other means Eutectic of the present invention, but the preparation method of eutectic of the present invention is simple, it is of low cost, to the combination medicine of the following LEE011 and MEK162 The clinical optimization and exploitation of object have important value.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of eutectic of CDK inhibitor (LEE011) and MEK (MEK162) inhibitor, the structural formula such as formula of the eutectic (I) shown in：
Wherein, x is the number between 0~3.What the x was indicated is to participate in constituting crystal lattices in every mole of eutectic molecule Water molal quantity.X may be 0, and when for 0, eutectic is anhydrous crystalline, and x is also possible to be more than 0, and corresponding eutectic is water at this time Object is closed, the value of x can be integer or non-integer.
Preferably, 0,1,2 or 3 x.
Include not only that LEE011 and MEK162 passes through conventional eutectic bond power when referring to " eutectic " according to the present invention The situation that the non-covalent bonds such as hydrogen bond are combined further includes the feelings that LEE011 and MEK162 are combined by the form of covalent bond Shape and the aforementioned simultaneous situation deposited of two kinds of situations.As long as it is combined by both drug molecules and forms eutectic, no matter its combination Which kind of form is power be, belongs to the protection category of the present invention.
A specific aspect according to the present invention, the present invention provide a kind of eutectic of hydrate form, are named as crystal form I, The X-ray powder diffraction figure that crystal form I is measured with CuK alpha rays 2theta values be 19.3 ° ± 0.2 °, 22.7 ° ± 0.2 °, There is characteristic peak at 10.4 ° ± 0.2 °.
According to a preferred aspect, the X-ray powder diffraction figure of crystal form I also 2theta values be 11.4 ° ± 0.2 °, One or more in 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, the X-ray of crystal form I Powder diagram is also to all have characteristic peak at 11.4 ° ± 0.2 °, 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 ° in 2theta values.
According to another preferred aspect, the X-ray powder diffraction figure of crystal form I also 2theta values be 21.6 ° ± 0.2 °, One or more in 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, the X-ray of crystal form I Powder diagram is also to all have characteristic peak at 21.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 ° in 2theta values.
According to third preferred aspect, the X-ray powder diffraction figure of crystal form I also 2theta values be 11.4 ° ± 0.2 °, One or more in 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 ° have Characteristic peak.
According to a most preferably aspect, the X-ray powder diffraction figure of crystal form I also 2theta values be 11.4 ° ± 0.2 °, Characteristic peak is all had at 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 °, 21.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 °.In root According in a specific implementation mode of the program, the X-ray powder diffraction figure of crystal form I is substantially consistent with Fig. 1.
According to the present invention, the content (or x values) of water is preferably any number between 0.5~3 mole in above-mentioned crystal form I. According to a specific aspect, the content (or x values) of water is 3 moles in crystal form I.
It is further preferred that the present invention crystal form I be heated to 86~95 DEG C nearby start occur first endothermic peak, 130~142 DEG C nearby start second endothermic peak occur, and differential scanning calorimetric thermogram is substantially as shown in Figure 2.
It is further preferred that the crystal form I of the present invention is when being heated to 110 DEG C nearby, it is terraced with about 5~6% weight loss Degree, thermogravimetric analysis figure are substantially as shown in Figure 3.
Another specific aspect according to the present invention, the present invention provide a kind of eutectic of anhydrous form, are named as crystal form II, should The X-ray powder diffraction figure that crystal form II is measured with CuK alpha rays 2theta values be 13.1 ° ± 0.2 °, 10.3 ° ± 0.2 °, There is characteristic peak at 16.4 ° ± 0.2 °.
According to a preferred aspect, the X-ray powder diffraction figure of crystal form II provided by the invention is also in 2theta values One or more in 19.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 14.8 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, The X-ray powder diffraction figure of crystal form II provided by the invention also 2theta values be 19.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, Characteristic peak is all had at 14.8 ° ± 0.2 °.
According to another preferred aspect, the X-ray powder diffraction figure of crystal form II provided by the invention is also in 2theta values One or more in 20.4 ° ± 0.2 °, 15.1 ° ± 0.2 °, 19.7 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, The X-ray powder diffraction figure of crystal form II provided by the invention also 2theta values be 20.4 ° ± 0.2 °, 15.1 ° ± 0.2 °, Characteristic peak is all had at 19.7 ° ± 0.2 °.
According to third preferred aspect, the X-ray powder diffraction figure of crystal form II provided by the invention is also in 2theta values 19.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 14.8 ° ± 0.2 °, 20.4 ° ± 0.2 °, 15.1 ° ± 0.2 °, 19.7 ° ± 0.2 ° one at Or many places have characteristic peak.
Also it is in 2theta values according to most preferably aspect, an X-ray powder diffraction figure of crystal form II provided by the invention Have at 19.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 14.8 ° ± 0.2 °, 20.4 ° ± 0.2 °, 15.1 ° ± 0.2 °, 19.7 ° ± 0.2 ° There is characteristic peak.According in the program a specific implementation mode, the X-ray powder diffraction figure of crystal form II substantially with Fig. 4 Unanimously.
It is further preferred that crystal form II provided by the invention be heated to 132~146 DEG C nearby start endothermic peak occur, Differential scanning calorimetric thermogram is substantially as shown in Figure 5.
It is further preferred that crystal form II provided by the invention has about 2.6~2.9% weight when being heated to 130 DEG C nearby Amount loss gradient, thermogravimetric analysis figure are substantially as shown in Figure 6.
In the present invention, from figs. 5 and 6, it can be seen that TGA weightlessness is smaller, the peak of the upper no desolventizings of DSC or dehydration, because It is anhydride that this, which can deduce crystal form II,.
In the present invention, since crystal form II can be obtained by heating eutectic crystal form I, in heating temperature not to before fusing point, altogether The molar ratio of Jingjing type II and crystal form I are identical.
Also a specific aspect, the present invention according to the present invention provide the eutectic of another hydrate form, are named as crystalline substance The X-ray powder diffraction figure that type III, crystal form III are measured with CuK alpha rays 2theta values be 18.8 ° ± 0.2 °, 20.5 ° ± There is characteristic peak at 0.2 °, 23.1 ° ± 0.2 °.
According to a preferred aspect, the X-ray powder diffraction figure of crystal form III provided by the invention is also in 2theta values One or more in 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, The X-ray powder diffraction figure of crystal form III provided by the invention also 2theta values be 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, Characteristic peak is all had at 12.7 ° ± 0.2 °.
According to another preferred aspect, the X-ray powder diffraction figure of crystal form III provided by the invention is also in 2theta values One or more in 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° are with characteristic peak.According to a specific aspect, The X-ray powder diffraction figure of crystal form III provided by the invention also 2theta values be 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, Characteristic peak is all had at 21.6 ° ± 0.2 °.
According to third preferred aspect, the X-ray powder diffraction figure of crystal form III provided by the invention is also in 2theta values One in 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 °, 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° Place or many places have characteristic peak.
Also it is in 2theta values according to most preferably aspect, an X-ray powder diffraction figure of crystal form III provided by the invention Have at 22.6 ° ± 0.2 °, 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 °, 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 0.2 ° There is characteristic peak.According in the program a specific implementation mode, the X-ray powder diffraction figure of crystal form III substantially with Fig. 7 Unanimously.Which show totally 41 characteristic peaks, the position of these characteristic peaks and peak intensity are as shown in table 5.According to the program Another specific implementation mode in, totally 38 characteristic peaks, these features are shown in the X-ray powder diffraction figure of crystal form III The position at peak and peak intensity are as shown in table 6.In the also specific implementation mode according to the program, the X-ray of crystal form III Show that totally 29 characteristic peaks, the position of these characteristic peaks and peak intensity are as shown in table 7 in powder diagram.
It is further preferred that crystal form III provided by the invention is being heated to starting first endothermic peak occur near 70~78 DEG C, Nearby start second endothermic peak occur being heated to 114~126 DEG C, differential scanning calorimetric thermogram is substantially as shown in Figure 8.
It is further preferred that crystal form III provided by the invention has about 4.4~4.8% weight when being heated to 114 DEG C nearby Amount loss gradient, thermogravimetric analysis figure are as shown in Figure 9.
According to the present invention, the content (or x values) of water is preferably any number between 0.5~3 mole in crystal form III, more Any number preferably between 2~3 moles, further preferably 2 moles or 3 moles, wherein with 2 moles for most preferably.
It is a further object to provide the eutectic monocrystalline of a kind of CDK inhibitor and mek inhibitor, which is upper Crystal form I is stated, which is the long rhabdolith of water white transparency, belongs to monoclinic system, space group P21/ c, cell parameter α=90 °, β=106.0 ± 0.2 °, γ=90 °.
Preferably, the cell parameter of the eutectic monocrystallineα= 90 °, β=105.95~106.05 °, γ=90 °.Specifically, the cell parameter of the eutectic monocrystalline α=90 °, β=105.99=~106.1 °, γ=90 °.More Specifically, the cell parameter of the eutectic monocrystalline α= 90 °, β=105.999~106.001 °, γ=90 °.In a specific embodiment, cell parameter isα=90 °, β=106.000 (6) °, γ=90 °.
A specific embodiment according to the present invention, include in the dissymmetrical structure unit of eutectic monocrystalline there are one MEK162 anion or molecule, a LEE011 cation or molecule, three hydrones；Include four in the unit cell of crystal MEK162 anion or molecule, four LEE011 cations or molecule, 12 hydrones；Its dissymmetrical structure cell schematics As shown in figure 22, unit cell schematic diagram is as shown in figure 23.
It is a further object to provide a kind of preparation methods of the eutectic comprising by LEE011 and MEK162 in alcohol organic solvent, organic solvent of ketone, ether organic solvent, nitrile organic solvent, water one kind or It is mixed in a variety of dicyandiamide solutions, the eutectic is then obtained by volatilization, stirring or cooling.
Preferably, the LEE011 and the MEK162 are mixed in the dicyandiamide solution at 0~50 DEG C.
Further, the alcohol organic solvent includes but not limited to methanol, ethyl alcohol, isopropanol etc.；The ketone Organic solvent includes but not limited to acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) etc.；The ether organic solvent includes but not It is limited to cyclic ethers class, alkyl ether etc., wherein alkyl ether such as tetrahydrofuran, Isosorbide-5-Nitrae dioxane, methyl tertiary butyl ether(MTBE)；Institute The nitrile organic solvent stated includes but not limited to acetonitrile etc..
Preferably, the dicyandiamide solution is one or more in acetonitrile, ethyl alcohol, methanol, water.
According to the present invention, when the mixed solvent that the dicyandiamide solution is water and acetonitrile or be water and ethyl alcohol mixed solvent When, obtained eutectic is crystal form I；When the dicyandiamide solution is methanol, obtained eutectic is crystal form III.
Further, it is dehydrated the crystal form I to obtain crystal form II.
A specific aspect according to the present invention, the present invention also provides a kind of preparation methods of the eutectic comprising LEE011 and MEK162 is mixed in aqueous dicyandiamide solution, crystal form I is then obtained by volatilization, stirring or cooling.
Preferably, the aqueous dicyandiamide solution be the dicyandiamide solution either water that is formed of water and alcohol organic solvent with The dicyandiamide solution that nitrile organic solvent is formed.
It is further preferable that dicyandiamide solution either water and acetonitrile that the aqueous dicyandiamide solution is water to be formed with ethyl alcohol The dicyandiamide solution of formation.
In the present invention, the ratio of both organic solvent and water mixing is not particularly limited, inventor uses respectively The mixed solvent of kind ratio is tested, and can obtain crystal form I well.
Preferably, at 0~50 DEG C by the LEE011 and MEK162 in the aqueous dicyandiamide solution Middle mixing.
Preferably, the volume ratio that feeds intake of feed intake quality and the aqueous dicyandiamide solution of the MEK162 be 6~ 10mg/mL。
Preferably, the mass ratio that feeds intake of the LEE011 and MEK162 is 1: 0.9~2.
Another specific aspect according to the present invention, the present invention also provides a kind of preparation method of the eutectic, crystal forms The preparation method of II includes step 1 or step 2：
Step 1：The crystal form I is prepared using above-mentioned preparation method, then is dehydrated the crystal form I to obtain crystal form II；
Step 2：LEE011 and MEK162 are mixed in organic solvent, crystalline substance is then obtained by volatilization, stirring or cooling Type II.
Preferably, in step 1, the crystal form I is heated to 130~140 DEG C and carries out the dehydration.
Preferably, in step 2, the organic solvent is acetonitrile or ethyl alcohol.
Third specific aspect according to the present invention, the present invention also provides a kind of preparation method of the eutectic, crystal forms The preparation method of III includes step 1 or step 2：
Step 1：The crystal form I is prepared using above-mentioned preparation method, it is then that the crystal form I is organic molten in alcohols Agent or alcohol organic solvent in the mixed solvent system of water, organic solvent of ketone, ether organic solvent or nitrile organic solvent Mixing, then obtains crystal form III by the method for volatilization；
Step 2：LEE011 and MEK162 are mixed in alcohol organic solvent, crystalline substance is then obtained by the method for volatilization Type III.
Preferably, in step 1, the quality that feeds intake of the crystal form I is organic molten with the alcohol organic solvent or alcohols Agent and water, organic solvent of ketone, ether organic solvent or nitrile organic solvent mixed solvent system the volume ratio that feeds intake be 8~ 25mg/mL。
Preferably, in step 1, the crystal form I is mixed in alcohol organic solvent, then passes through the method for volatilization Obtain crystal form III.
It is further preferable that the alcohol organic solvent includes methanol.
Preferably, in step 2, the mass ratio that feeds intake of the LEE011 and the MEK162 are 1: 0.9~1.1.
Preferably, in step 2, the volume that feeds intake of the feed intake quality and the alcohol organic solvent of the MEK162 Than for 6~7mg/mL.
Third object of the present invention is to provide a kind of Pharmaceutical compositions, including active constituent and pharmaceutically acceptable tax Shape agent, the active constituent include the eutectic.
A specific aspect according to the present invention, the present invention provide a kind of Pharmaceutical composition, including active constituent and pharmacy Upper acceptable excipient, the active constituent includes one or more in crystal form I, crystal form II, crystal form III.
Fourth object of the present invention is to provide a kind of purposes of the eutectic in preparing treating cancer pharmaceutical preparation.
A specific aspect according to the present invention, the present invention provide a kind of crystal form I, crystal form II, one kind in crystal form III or Purposes of a variety of mixtures in preparing treating cancer pharmaceutical preparation.
Fifth object of the present invention is to provide a kind of purposes of eutectic in treating cancer.
Sixth object of the present invention is to provide a kind of methods for the treatment of cancer comprising applies to patient as described above Eutectic or Pharmaceutical composition.
Further, the cancer include but not limited to melanoma, cancer of pancreas, oophoroma, breast cancer, lymthoma, Lung cancer.
Beneficial effects of the present invention are：
The present invention provides the eutectic of LEE011 and MEK162 for the first time, and research shows that these eutectics in bioavilability, control Therapeutic effect, pharmacodynamic stability and technique exploitability and storage etc. show well, and especially its therapeutic effect is bright The aobvious simple mixtures better than LEE011 and MEK162.
Description of the drawings
The XRPD figures that Fig. 1 is crystal form I made from embodiment 1；
The DSC figures that Fig. 2 is crystal form I made from embodiment 1；
The TGA figures that Fig. 3 is crystal form I made from embodiment 1；
The XRPD figures that Fig. 4 is crystal form II made from embodiment 4；
The DSC figures that Fig. 5 is crystal form II made from embodiment 4；
The TGA figures that Fig. 6 is crystal form II made from embodiment 4；
The XRPD figures that Fig. 7 is crystal form III made from embodiment 5；
The DSC figures that Fig. 8 is crystal form III made from embodiment 5；
The TGA figures that Fig. 9 is crystal form III made from embodiment 5；
The DVS that Figure 10 is crystal form I schemes；
The DVS that Figure 11 is crystal form III schemes；
Figure 12 be crystal form I under the conditions of 25 DEG C/60%RH stability contrast figure (upper figure be place 14 days after XRPD figure, Figure below is the XRPD figures before placing)；
Figure 13 be crystal form I under the conditions of 40 DEG C/75%RH stability contrast figure (upper figure be place 14 days after XRPD figure, Figure below is the XRPD figures before placing)；
Figure 14 be crystal form III under the conditions of 25 DEG C/60%RH stability contrast figure (upper figure be place before XRPD figure, under Figure is the XRPD figures after placing 30 days)；
Figure 15 be crystal form III under the conditions of 40 DEG C/75%RH stability contrast figure (upper figure be place before XRPD figure, under Figure is the XRPD figures after placing 30 days)；
Figure 16 is the solubility comparison diagram in SGF of crystal form I and physical mixture；
Figure 17 is the solubility comparison diagram in FaSSIF of crystal form I and physical mixture；
Figure 18 is that the eutectic crystal form I that MEK162 free alkalis one pack system and MEK162-LEE011 are combined by 1: 1 treats melanin The comparison diagram of the internal validity of tumor；
The DVS that Figure 19 is crystal form II schemes；
Figure 20 is that (the XRPD figures that upper figure is crystal form I, figure below are to be tried by DVS to XRPD figures of the crystal form II after DVS is tested XRPD after testing)；
Figure 21 is that (upper figure is the XRPD figures before placing, figure below to stability contrast figure to crystal form II under the conditions of 25 DEG C/25%RH Scheme for the XRPD after placing 2 days)；
Figure 22 is the dissymmetrical structure cell schematics of crystal form I；
Figure 23 is the unit cell schematic diagram of crystal form I；
Figure 24 is the nuclear-magnetism figure of crystal form III.
Specific implementation mode
Below will by specific embodiment, the present invention is further explained, but the protection domain being not intended to restrict the invention. Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.Conduct in preparation method LEE011 the and MEK162 free forms of raw material are prepared by known methods to obtain.
In the preparation method of the crystal form of the present invention：
" room temperature " refers to 15~25 DEG C.
" stirring " is completed using the conventional method of this field, such as magnetic agitation or mechanical agitation, mixing speed are 50~1800 revs/min, preferably 300~900 revs/min.
" separation " is completed using the conventional method of this field, such as centrifugation or filtering.The operation of " centrifugation " is：It will The sample to be detached is placed in centrifuge tube, is centrifuged with 10000 revs/min of rate, until solid is all sink to centrifugation bottom of the tube.
Unless stated otherwise, described " drying " can carry out at room temperature or at higher temperatures.Drying temperature room temperature~about 60 DEG C, either to 40 DEG C or to 50 DEG C.Drying time can be 2~48 hours, or overnight.Drying is in draught cupboard, air blast It is carried out in baking oven or vacuum drying oven.
In the present invention, " crystal " or " crystal form " refers to what the X-ray diffractogram characterization by shown in was confirmed.This field skill Art personnel it is understood that physicochemical property discussed herein can be characterized, experimental error therein depend on instrument condition, The preparation of sample and the purity of sample.In particular, well known to those skilled in the art, X-ray diffractogram would generally be with instrument Condition and change.In particular, it should be pointed out that the relative intensity of X-ray diffractogram may also be with the variation of experiment condition And change, so the sequence of peak intensity cannot function as unique or deciding factor.In addition, the experimental error of peak angle degree usually exists 5% or less, the error of these angles should also be considered into, allow generally for ± 0.2 ° of error.In addition, due to sample The influence of the empirical factors such as height, can cause the overall offset of peak angle degree, allow generally for certain offset.Thus, this field skill Art personnel are it is understood that the x-ray diffraction pattern of a crystal form need not be penetrated with the X in example referred herein in the present invention Ray diffraction diagram is completely the same.It is any that there is the crystal form with the same or analogous figure of characteristic peak in these collection of illustrative plates to belong to the present invention Scope within.Those skilled in the art can compare the collection of illustrative plates of collection of illustrative plates and a unknown crystal form listed by the present invention, with Confirm this two groups of collection of illustrative plates reflection is identical to be also different crystal form.
" crystal form " and " polymorphic " and other relative words refer to solid chemical compound in crystal structure in the present invention In with specific crystal form state exist.The difference of polymorphic physicochemical property can be embodied in storage stability, compressibility, close Degree, dissolution rate etc..In extreme situations, solubility or the difference of dissolution rate can cause drug inefficient, even Toxicity.
Pharmaceutical co-crystals are in same crystal structure containing there are two types of the crystal of molecule.Effect between two kinds of molecules is generally non- Covalent bond (such as hydrogen bond, π-is pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals will not generally destroy the covalent of active constituents of medicine Key.Phrase " effective therapeutic dose " or " therapeutically effective amount " used in the present invention refer to causing by researcher, animal doctor, doctor Or the activation of the biological respinse or drug response to be sought in tissue, system, animal, individual or people of other clinicians Close the amount of object or medicament.
Term " treatment " used in the present invention refers to one of the following or a variety of：(1) prevent disease；Such as can Can tend to disease, illness or obstacle, but without by or show in the lesion of the disease or the individual of symptom and prevent The disease, illness or obstacle；(2) inhibit the disease；Such as just by or show lesion or the disease of the disease, illness or obstacle Inhibit the disease, illness or obstacle in the individual of shape；And (3) improve the disease；For example, by or show the disease, disease Improve the disease, illness or obstacle (reversing lesion and/or symptom) in the individual of the lesion or symptom of disease or obstacle, such as subtracts The severity of low disease.
In some embodiments, novel crystal forms of the invention, including be it is pure, single, it is basic without mix it is any its His crystal form.In the present invention, " not having substantially " refer to when being used to refer to novel crystal forms this crystal form contain less than 20% (weight) other Crystal form is especially less than other crystal forms of 10% (weight), more refers to other crystal forms less than 5% (weight), more refer to less than 1% Other crystal forms of (weight).
It should be noted that the numerical value and numberical range that are referred in the present invention should not be narrowly interpreted as numerical value or numerical value Range itself, it should be understood by those skilled in the art that it can be according to the difference of particular technique environment, without departing substantially from essence of the invention It is floated around concrete numerical value on the basis of god and principle, in the present invention, this foreseeable floating of those skilled in the art Range is mostly indicated with term " about ".
The polymorphic of drug can be by including but not limited to that following method obtains：Melting recrystallization, melting cooling, solvent Recrystallization loses solvent, quickly volatilization, fast cooling, at a slow speed cooling, steam diffusion and distillation.Sometimes, different methods may also Obtain identical crystallization.Polymorphic can pass through X-ray powder diffraction (XRPD), differential scanning calorimetric analysis (DSC), thermogravimetric point (TGA), light microscope technique, hygroscopicity etc. are analysed to detect, find and sort out.And the crystallization mode that crystal form of the present invention uses for Volatilization, stirring and cooling method.
In addition, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes treatment and/or prevention effective dose The eutectic of the present invention, and at least one pharmaceutically acceptable excipient, above-mentioned eutectic can be crystal form I, crystal form II, crystal form One or more mixtures in III.In addition, described pharmaceutical composition can also include other pharmaceutical eutectics salt, The crystal form or amorphous article of its salt.Optionally, crystal form of the invention can be used as the application of individual activating agent or they can be with It is administered in combination with other activating agents, including is determined as safety with same or similar therapeutic activity and for such combined administration And effective other compounds.In special embodiment, the co-administration of two kinds of (or a variety of) activating agents allows to show Writing reduces the dosage of each activating agent used, to reduce seen side effect.
Aforementioned pharmaceutical compositions can be made into certain dosage form, is administered by suitable approach.Such as oral, parenteral (packet Include subcutaneous, muscle, vein or intradermal), rectum, transdermal, intranasal, the approach such as vagina.Be suitble to oral medication dosage form include tablet, Capsule, granule, powder, pill, pulvis, pastille, solution, syrup or suspension may be adapted to pharmaceutical activity as needed Quick release, sustained release or the adjusting release of ingredient；It includes aqueous or non-aqueous sterile to be suitble to the dosage form of parenteral administration Inject solution, lotion or suspension；It includes suppository or enema to be suitble to the dosage form of rectally；It is suitble to the dosage form packet of cutaneous penetration Include ointment, creme, patch；It includes aerosol, spray, nasal drop to be suitble to the dosage form of nose administration；It is suitble to the dosage form of vagina administration Including suppository, suppository, gel, paste or spray.Preferably due to the present invention crystal form have unexpected agent of low hygroscopicity and Therefore stability in water or in ethanol water is especially suitable for preparing piece agent, suspension, capsule, disintegrated tablet, i.e. It releases, be sustained and Dospan；Further preferably tablet, suspension and capsule.
Acceptable excipient in aforementioned pharmaceutical compositions Chinese pharmacology, in the case of solid oral dosage form, including but not It is limited to：Diluent, for example, starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium monohydrogen phosphate, tricalcium phosphate, Mannitol, sorbierite, sugar etc.；Adhesive, such as Arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxy propyl cellulose Element, hydroxypropyl methyl cellulose, polyethylene glycol etc.；Disintegrant, such as starch, sodium starch glycollate, pregelatinized starch, crosslinking Povidone, croscarmellose sodium, colloidal silicon dioxide etc.；Lubricant, for example, stearic acid, magnesium stearate, zinc stearate, Sodium benzoate, sodium acetate etc.；Glidant, such as colloidal silicon dioxide etc.；Complex forming agents, for example, various ranks cyclodextrin And resin；Rate of release controlling agent, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose Element, methylcellulose, methyl methacrylate, wax etc..Other available pharmaceutically acceptable excipient include but not limited to Film forming agent, plasticizer, colorant, flavoring agent, viscosity modifier, preservative, antioxidant etc..Optionally, tablet is coated and is wrapped Clothing layer, such as shellac isolation coat, sugar-coat or polymer coating are provided, the polymer such as hydroxypropyl methyl fiber in coatings Element, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose or starch can also include antisticking Agent such as silica, talcum powder, opacifiers such as titanium dioxide, colorant such as iron oxides colorant.In liquid oral dosage form In the case of, suitable excipient includes water, oils, alcohols, glycols, flavoring agent, preservative, stabilizer, colorant etc.；Water or Non-aqueous sterile suspensions can contain suspending agent and thickener；Excipient suitable for aqueous suspension includes rubber polymer or natural Glue such as gum arabic, Siberian cocklebur natural gum, alginates, glucan, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrole Alkanone or gelatin.In the case of parenteral dosage forms, the excipient of water or non-aqueous aseptic injectable solution is usually sterile Water, physiological saline or glucose solution can contain buffer, antioxidant, bacteriostatic agent and can make the pharmaceutical composition The isotonic solute with blood.Each excipient must be acceptable, can it is compatible with the other compositions in formula and for Patient is harmless.
Described pharmaceutical composition can be prepared using well known to a person skilled in the art methods in the prior art.Prepare medicine When compositions, crystal form of the present invention and one or more pharmaceutically acceptable excipient are mixed, optionally with it is a kind of or Various other active constituents of medicine mix.For example, tablet, capsule, granule can by mixing, granulation, tabletting or The techniques such as capsule are filled to prepare；Pulvis is made by mixing the finely ground active constituents of medicine to suitable size and excipient It is standby；Solution and syrup can be prepared by the way that active constituents of medicine to be dissolved in suitably seasoned water or aqueous solution；It is suspended Agent can be prepared by the way that active constituents of medicine to be scattered in pharmaceutically acceptable carrier.
It is especially mentioned that the wet granulation technology of solid pharmaceutical preparation, by taking the wet granulation of tablet as an example, preparation process is：It is mixed The dry solids such as active constituent, filler, adhesive are closed, is soaked, the solid of the wetting is made solidifying with wetting agent such as water or alcohol Polymers or granule continue wet granulation, until obtaining required uniform grading, are subsequently dried the granular product.Then will Obtained dry particle and disintegrant, lubricant, antitack agent etc. mix, the tabletting in pelleter；Optionally, with packet appropriate Clothing powder is coated.
In addition, also it is especially mentioned that oral suspensions, an advantage of this form of medication, which is patient, to be gulped down Solid form is swallowed, particularly with the patient for swallowing the elderly, children or oral cavity, injury of throat that solid form may have any problem. Suspension is the binary system for forming solid particle dispersions in a liquid, it is still kept in the water or aqueous carrier of suspension The crystal of original solid form is expected the stabilization that would be even more beneficial to keep drug products property.Other groups in oral suspensions Divide and may include buffer, surfactant, viscosity modifier, preservative, antioxidant, colorant, flavoring agent, taste masking agent Deng.
Eutectic provided by the invention has the favorable property suitable for above-mentioned dosage form.
In addition, the present invention provides purposes of the eutectic in preparing cancer drug.
" cancer " includes the pernicious or benign growths of cell in skin or biological organs, and the organ includes but unlimited In breast, prostate, lung, kidney, pancreas, stomach or intestines.Cancer is easy to invade adjacent tissue and diffusion (transfer) is to device farther out Official, such as bone, liver, lung or brain.Cancer of the present invention includes metastatic tumour cellular type, such as, but not limited to melanoma, leaching Bar tumor, leukaemia, fibrosarcoma, rhabdomyosarcoma and mastocytoma, and tissue cancer type, such as, but not limited to colon are straight Intestinal cancer, prostate cancer, Small Cell Lung Cancer and non-small cell lung cancer, breast cancer, cancer of pancreas, carcinoma of urinary bladder, kidney, gastric cancer, colloid are female thin Born of the same parents' tumor, primary carcinoma of liver, oophoroma, prostate cancer and leiomyosarcoma of uterus.
In following embodiments, the test method is usually according to normal condition or the condition of manufacturer's suggestion is implemented.
Used abbreviation is explained as follows in the present invention：
XRPD：X-ray powder diffraction
DSC：Differential scanning calorimetric analysis
TGA：Thermogravimetric analysis
DVS：Dynamic water is adsorbed
X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instruments Collection, test temperature are ordinary temperature, such as 25 DEG C.The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu, K α
1.540598；1.544426
1 intensities of K α 2/K α：0.50
Voltage：45 volt (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention acquires on TA Q2000.Differential of the present invention The method parameter for scanning thermometric analysis (DSC) is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Thermogravimetric analysis (TGA) figure of the present invention acquires on TA Q5000.Thermogravimetric analysis (TGA) of the present invention Method parameter it is as follows：
Sweep speed：10℃/min
Protective gas：Nitrogen
Dynamic water of the present invention adsorbs (DVS) figure by SMS companies (Surface Measurement Systems Ltd. it) is acquired on the Intrinsic dynamic water adsorption instruments produced.The method parameter of the dynamic water adsorption instrument is as follows：
Temperature：25℃
Carrier gas, flow velocity：N2, 200 ml/mins
Unit interval mass change：0.002%/minute
RH range：0%RH-95%RH
Embodiment 1
The preparation method of crystal form I：
MEK162 the and 4mL acetonitrile/waters (v: v=19: 1) of 26.6mg are placed at 50 DEG C and are stirred 30 minutes, are added 16.0mg LEE011, continue to be stirred overnight and slow cooling is to 20 DEG C, collect solid and can be obtained.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 1.Its XRPD figures such as Fig. 1, DSC figures Such as Fig. 2, TGA figure such as Fig. 3.As can be seen from Figure 2, the crystal form I of the present embodiment nearby starts appearance the being heated to 86~95 DEG C One endothermic peak nearby starts second endothermic peak occur at 130~142 DEG C.As can be seen from Figure 3, the crystal form I of the present embodiment is in quilt When being heated to 110 DEG C nearby, with about 5~6% weight loss gradient.
Table 1
Embodiment 2
The preparation method of crystal form I：
MEK162 the and 1mL acetonitrile/waters (v: v=1: 1) of 9.7mg are placed under room temperature (25 ± 3 DEG C) and are stirred 30 minutes, are added Enter 10.0mg LEE011, continues to be stirred overnight, you can obtain.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 2.
Table 2
Embodiment 3
The preparation method of crystal form I：
MEK162 the and 1mL ethanol/waters (v: v=9: 1) of 8.7mg are placed under room temperature (25 ± 3 DEG C) and are stirred 30 minutes, are added Enter 8.5mg LEE011, continues to be stirred overnight, you can obtain.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 3.
Table 3
Embodiment 4
The preparation method of crystal form II：
The sample of crystal form I made from 5.64mg embodiments 1 is heated to 135 DEG C with the rate of 5 DEG C/min, is put down at 135 DEG C Weigh 5min, is cooled to room temperature (25 ± 3 DEG C) and can be obtained crystal form II.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 4.Its XRPD figures such as Fig. 4, DSC figures Such as Fig. 5, TGA figure such as Fig. 6.As can be seen from Figure 5, crystal form II provided in this embodiment is being heated to 132~146 DEG C of beginnings nearby There is endothermic peak.As can be seen from Figure 6, crystal form II provided in this embodiment be heated to 130 DEG C nearby when, have about 2.6~ 2.9% weight loss gradient.
In the present embodiment, from figs. 5 and 6, it can be seen that TGA weightlessness is smaller, the peak of the upper no desolventizings of DSC or dehydration, Therefore it is anhydride that crystal form II, which can be deduced,.
In the present embodiment, since crystal form II can be obtained by heating eutectic crystal form I, in heating temperature not to before fusing point, The molar ratio of eutectic crystal form II and crystal form I are identical.
Table 4
Embodiment 5
The preparation method of crystal form III：
Crystal form I made from 327mg embodiments 1 is added in 20mL vials, the MeOH room temperature (25 ± 3 DEG C) of 15mL is added Lower dissolved clarification filters to take 4.0ml filtrates to 20ml vials, and room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, you can obtains.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 5.Its XRPD figures such as Fig. 7, DSC figures Such as Fig. 8, TGA figure such as Fig. 9.As it can be observed in the picture that crystal form III provided in this embodiment is being heated to starting near 70~78 DEG C Existing first endothermic peak nearby starts second endothermic peak occur being heated to 114~126 DEG C.As can be seen from Figure 9, the present embodiment The crystal form III of offer is when being heated to 114 DEG C nearby, with about 4.4~4.8% weight loss gradient.
In the present embodiment, it can be seen that from Fig. 8, Fig. 9, Figure 24 and do not detect solvent peak on nuclear magnetic data, according to TGA The content that weightlessness can deduce the water in crystal form III is about 2 moles.
Table 5
Embodiment 6
The preparation method of crystal form III：
5mL bottles are added in crystal form I made from 16.1mg embodiments 1, the MeOH of 2.0mL is added under room temperature (25 ± 3 DEG C) To dissolved clarification, 0.5mL filtrates are filtered to take to 1.5mL vials, room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, you can obtains.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 6.
Table 6
Embodiment 7
The preparation method of crystal form III：
The LEE011 of the MEK162 of 50.0mg and 49.3mg is added in 20mL vials, is added under room temperature (25 ± 3 DEG C) 8.0mL MeOH solvents filter to take 4.0mL filtrates to 20mL vials to dissolved clarification, and room temperature (25 ± 3 DEG C) is slowly evaporated completely solvent, It can be obtained.
The X-ray powder diffraction data for the crystal form that the present embodiment obtains are as shown in table 7.
Table 7
Embodiment 8
(1), in crystal form I MEK162 and LEE011 be total to component molar than research：
The molar ratio of MEK162 and LEE011 eutectics is dissolved in methanol, knot determining by HPLC (high performance liquid chromatography) Fruit shows that the molar ratio of MEK162 and LEE011 is 1: 1, as shown in table 8.
Table 8
Compound MEK162 and LEE011 eutectics
MEK162 concentration (mmol/L) 0.128
LEE011 concentration (mmol/L) 0.131
Molar ratio 1∶1
(2), in crystal form III MEK162 and LEE011 component molars ratio research：
It weighs crystal form III made from the 1.504mg embodiment of the present invention 5 and vial is added, 10mLMeOH solvent dissolved clarifications are added, The molar ratio of MEK162 and LEE011 in solution is tested and calculated with high performance liquid chromatograph device.As a result such as table 9.
Table 9
Compound MEK162/LEE011 components
MEK162 concentration (mmol/L) 0.157
LEE011 concentration (mmol/L) 0.153
Molar ratio 1∶1
Embodiment 9
(1), crystal form I draws moist research：
It takes crystal form I made from the about 10mg embodiment of the present invention 1 to carry out dynamic water absorption (DVS) to test.As a result such as table 10, DVS figure such as Figure 10.
Table 10
(2), crystal form II draws moist research：
It takes crystal form II made from 4 same procedure of the about 10mg embodiment of the present invention to carry out dynamic water absorption (DVS) to test.Knot Fruit such as table 11, DVS figure such as Figure 19.
Table 11
Crystal form II XRPD after DVS is tested verify crystal form and are converted to crystal form I, such as Figure 20.
(3), crystal form III draws moist research：
It takes crystal form III made from the about 10mg embodiment of the present invention 5 to carry out dynamic water absorption (DVS) to test.As a result such as table 12, DVS figures such as Figure 13.
Table 12
Define that (Chinese Pharmacopoeia version annex XIX J drugs in 2010 draw with draw moist weightening about moist feature description is drawn Moist test direction principle)：
It deliquesces：It absorbs enough moisture and forms liquid；
It is great draw it is moist：Draw wet weightening and is not less than 15%；
Have draw it is moist：Draw wet weightening less than 15% but is not less than 2%；
Slightly draw moist：Draw wet weightening less than 2% but is not less than 0.2%；
Nothing is moist almost without drawing：Draw wet weightening and is less than 0.2%.
The result shows that crystal form I of the invention increases weight 2.28% after being balanced under from 10% relative humidity to 80% relative humidity, Draw moist relatively low.And increase weight 2.77% after being balanced under from 10% relative humidity to 95% relative humidity, illustrate to be not easy by high humility It influences and deliquesces.
The result shows that crystal form III of the invention increases weight after being balanced under from 10% relative humidity to 80% relative humidity 1.12%, slightly draw moist.And increase weight 1.93% after being balanced under from 10% relative humidity to 95% relative humidity, illustrate to be not easy by High humility is influenced and is deliquesced.
Embodiment 10
(1), the stability study of crystal form I：
Two parts of sample openings of crystal form I made from the embodiment of the present invention 1 are taken to be positioned over 25 DEG C/60%RH (relative humidity), 40 DEG C/75%RH under the conditions of, after 14 days sampling survey XRPD.Experimental result such as table 13.
Table 13
Originate crystal form Placement condition Standing time Crystal form changes
Crystal form I 25 DEG C/60%RH 14 days Crystal form I is remained unchanged (such as Figure 12)
Crystal form I 40 DEG C/75%RH 14 days Crystal form I is remained unchanged (such as Figure 13)
The result shows that crystal form I of the invention is placed 14 days under the conditions of 25 DEG C/60%RH, two kinds of 40 DEG C/75%RH, it is brilliant Type does not change.
(2), the stability study of crystal form II：
Two parts of sample openings of crystal form II made from the embodiment of the present invention 4 are taken to be positioned over 25 (± 3) DEG C/25%RH (relatively wet Degree) under the conditions of, sampling survey XRPD after 2 days.Experimental result such as table 14.
Table 14
Originate crystal form Placement condition Standing time Crystal form changes
Crystal form II 25 (± 3) DEG C/25%RH 2 days Crystal form II becomes crystal form I (such as Figure 21)
The result shows that crystal form I of the invention is placed 2 days under the conditions of 25 (± 3) DEG C/25%RH, crystal form II reforms into crystalline substance Type I.
(3), the stability study of crystal form III：
Two parts of sample openings of crystal form III made from the embodiment of the present invention 5 are taken to be positioned over 25 DEG C/60%RH, 40 DEG C/75% RH, sampling survey XRPD after 30 days.Experimental result such as the following table 15.
Table 15
Originate crystal form Placement condition Standing time Crystal form changes
Crystal form III 25 DEG C/60%RH 30 days Crystal form III is remained unchanged (such as Figure 14)
Crystal form III 40 DEG C/75%RH 30 days Crystal form III is remained unchanged (such as Figure 15)
The result shows that crystal form III of the invention is placed 30 days under the conditions of 25 DEG C/60%RH, two kinds of 40 DEG C/75%RH, Crystal form does not change.
Embodiment 11
The monocrystalline of crystal form I is studied：
X-ray single crystal diffractometer：Bruker D8 Venture
X-ray light sources：Model：The micro- focusing rotary anode light source of TURBO X-RAY SOURCE type high intensity
Wavelength：Mo/Kα(λ=0.71073)
Power：2.5KW
Detector：100 type CMOS surface detectors of PHOTON
Angular instrument：Three axisAngular instrument
Test temperature：153.15K
Computer program for structure elucidation：Just solution：ShelXT (direct method),
Refine：ShelXL 2014 (least square method)
Take the sample of eutectic crystal form I made from 5.3mg embodiments 1 in 4mL THF/H2Dissolved clarification mistake in the system of O (1: 3) Filter, is then placed at room temperature, slowly volatilizees one month to obtain the final product.
Test general formula：C40H45BrF2N12O4·3H2O
Molecular weight：929.83
Crystallize color：Water white transparency
Crystal form：Length is rodlike
Crystallographic system：Monoclinic system
Space group：P21/c
Cell parameter：
α=90 °
β=106.000 (6) °
γ=90 °
Unit cell volume：
Z (number of contained experiment general formula in unit cell)：4
Calculate density：1.475g/cm3
Structure describes：Single crystal diffraction and structure elucidation show the crystal category monoclinic system, P21/ c space groups, cell parameter For α=90 °, β=106.000 (6) °, γ=90 °；}.Comprising there are one MEK162 anion or molecule, a LEE011 in the dissymmetrical structure unit of crystal Cation or molecule, three hydrones.Include four MEK162 anion or molecule, four LEE011 in the unit cell of crystal Cation or molecule, 12 hydrones, dissymmetrical structure cell schematics are as shown in figure 22, and unit cell schematic diagram is as schemed Shown in 23.
Embodiment 12
Crystal form I and physical mixture solubility comparative study：
The sample of crystal form I made from embodiment 1 and LEE011 and MEK162 equimolar physical mixtures is used into pH1.8 respectively SGF (simulated gastric fluid) and the FaSSIF (simulated intestinal fluid under fasting state) of pH6.5 be configured to saturated solution, at 30 minutes, 1 MEK162 in saturated solution is measured by high performance liquid chromatography (HPLC) method respectively after a hour, 2 hours and 24 hours Content.Solubility compares (with MEK162 densimeters) such as Figure 16 (in SGF) and Figure 17 in two samples (in FaSSIF).
It can be seen that by above-mentioned comparing result and placed 30 minutes in SGF and FaSSIF, after 1 hour, 2 hours Afterwards with after 24 hours, the solubility of crystal form I of the invention is than the two equimolar physical mixture solubility higher.
Embodiment 13
Internal evaluating drug effect
The eutectic crystal form I combined by 1: 1 to MEK162 free alkalis one pack system and MEK162-LEE011 treats melanoma Internal validity is studied respectively, and subjects are the BALB/C females that successful implantation has NRAS gene mutation melanomas Nude mice, animal model are heterograftModel；Test method be by mouse hypodermic inoculation be derived from tumor-bearing mice and The tumor mass of stripping and slicing is grouped after tumour grows to a certain size according to the mean size of tumour at random, every group eight, random to be grouped Day is calculated as 0 day, daystart gastric infusion after grouping, is administered 35 days altogether, measures tumor size in different time points, survey weekly Amount twice, the inhibiting effect of comparative assessment MEK162 one pack systems and MEK162-LEE011 eutectics to tumour；MEK162 single groups are grouped Dosage is 3.5mgkg-1(pressing free base), 2 times a day, MEK162-LEE011 eutectic group dosage are 7mgkg-1(press nothing Water eutectic meter), 2 times a day, setting blank group is the aqueous solution of 0.5% hydroxypropyl methylcellulose and 1% Tween 80, is administered daily 2 It is secondary.
As a result show (see Figure 18) compared with the mouse that MEK162 single groups are grouped, the mouse of MEK162-LEE011 eutectic groups Its gross tumor volume smaller illustrates that the antitumous effect of eutectic is better than MEK162 one-components.
Pharmacokinetics
To the equimolar physical mixture (B of MEK162 free alkalis one pack system (A groups), MEK162 and LEE011 succinates Group) and MEK162-LEE011 equimolars combine eutectic crystal form I (C groups) in rat body pharmacokinetic characteristics difference It is studied.The male SD rat of selection criteria weight be subjects, every group 3, gastric infusion.A group dosage is 5mg kg-1(pressing free base), the dosage of two component of B groups is 5mgkg-1(pressing free base), C group dosage are 10mgkg-1 (based on anhydrous eutectic), is converted by molecular weight, and the respective dosage of the two is about 5mgkg-1(pressing free base).
The results show that in the case where each component dosage is almost the same, B group physical mixed administering drug combinations and C groups two Eutectic administration is made in the free alkali of person, and individually give MEK162 has different degrees of raising to the exposed amount ratio A groups of MEK162, Area (AUC under middle B groups drug-time curve0-inf) it is 16439 ± 5461nghmL-1, C groups are 21926 ± 5875ngh mL-1, respectively A groups (AUC0-inf：11325±895ng·h·mL-1) about 1.5 and 1.9 times, thus it is speculated that MEK162 and LEE011 When co-administered, the latter may improve to the former exposed amount, after eutectic administration is especially made, MEK162's AUC0-infIt obviously increases；And the administration of C group eutectics is administered compared with B group physical mixeds, and the exposed amount of MEK162 is also improved, Qian Zheyue It is 1.3 times of the latter.
In addition, in peak time (Tmax) it is almost comparable in the case of (A groups：0.25h, B group：0.33h, C group：0.25h), C Blood peak concentration of drug (the C of MEK162 after group eutectic administrationmax) it is 10145 ± 2392ngmL-1, it is administered alone relative to A groups The C of MEK162maxFor 3242 ± 576ngmL-1, improve nearly 3 times, and B groups (Cmax：3571±630ng·mL-1) do not have then Significant change.
After can to sum up showing that eutectic administration is made in MEK162 and LEE011, the AUC of MEK1620-infAnd CmaxThere are different journeys The raising of degree is conducive to the bioavilability for improving MEK162 to a certain extent.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.

Claims (17)

1. a kind of eutectic of CDK inhibitor and mek inhibitor, it is characterised in that：Shown in the eutectic structure formula such as formula (I), Wherein, x is the number between 0-3, and the eutectic is hydrate crystal forms I, the X that the crystal form I is measured with CuK alpha rays Ray powder diffraction pattern 2theta values be 19.3 ° ± 0.2 °, 22.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.4 ° ± 0.2 °, There is characteristic peak at 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 °
2. eutectic according to claim 1, it is characterised in that：The X-ray powder diffraction figure of the crystal form I also exists 2theta values be 21.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 ° in one or more with characteristic peak.
3. eutectic according to claim 2, it is characterised in that：The X-ray powder diffraction figure of the crystal form I also exists 2theta values are to have characteristic peak at 21.6 ° ± 0.2 °, 26.0 ° ± 0.2 °, 8.3 ° ± 0.2 °.
4. eutectic according to claim 1 or 2 or 3, it is characterised in that：In the structural formula formula (I) of the crystal form I, x is choosing From the number between 0.5~3.
5. the eutectic monocrystalline of a kind of CDK inhibitor and mek inhibitor, it is characterised in that：The eutectic is to appoint in Claims 1-4 Crystal form I described in one, the eutectic monocrystalline are the long rhabdolith of water white transparency, belong to monoclinic system, space group P21/ c, unit cell Parameterα=90 °, β=106.0 ± 0.2 °, γ=90 °.
6. the eutectic monocrystalline of CDK inhibitor according to claim 5 and mek inhibitor, it is characterised in that：The eutectic monocrystalline Cell parameterα=90 °, β=105.95~106.05 °, γ =90 °.
7. the eutectic monocrystalline of CDK inhibitor according to claim 6 and mek inhibitor, it is characterised in that：The eutectic monocrystalline Cell parameterα=90 °, β=105.99~ 106.01 °, γ=90 °.
8. the eutectic monocrystalline of CDK inhibitor according to claim 7 and mek inhibitor, it is characterised in that：The eutectic monocrystalline Cell parameter α=90 °, β= 105.999~106.001 °, γ=90 °.
9. the eutectic monocrystalline of CDK inhibitor according to claim 8 and mek inhibitor, it is characterised in that：The eutectic monocrystalline Cell parameterα=90 °, β=106.000 °, γ=90 °.
10. a kind of preparation method of eutectic according to any one of claims 1 to 4, it is characterised in that：By LEE011 and MEK162 is mixed in aqueous dicyandiamide solution, then obtains crystal form I by volatilization, stirring or cooling.
11. the preparation method of eutectic according to claim 10, it is characterised in that：The aqueous dicyandiamide solution is water The dicyandiamide solution formed with alcohol organic solvent the dicyandiamide solution that either water is formed with nitrile organic solvent.
12. the preparation method of eutectic according to claim 11, it is characterised in that：The aqueous dicyandiamide solution is water The dicyandiamide solution formed with ethyl alcohol the dicyandiamide solution that either water is formed with acetonitrile.
13. the preparation method of eutectic according to claim 10, it is characterised in that：It will be described at 0~50 DEG C The LEE011 and MEK162 is mixed in the aqueous dicyandiamide solution.
14. the preparation method of eutectic according to claim 10, it is characterised in that：The MEK162 feed intake quality with The volume ratio that feeds intake of the aqueous dicyandiamide solution is 6~10mg/mL.
15. the preparation method of eutectic according to claim 10, it is characterised in that：The LEE011 and described The mass ratio that feeds intake of MEK162 is 1:0.9~2.
16. a kind of Pharmaceutical composition, including active constituent and pharmaceutically acceptable excipient, it is characterised in that：The work Property ingredient includes eutectic according to any one of claims 1 to 4.
17. a kind of purposes of eutectic according to any one of claims 1 to 4 in preparing treating cancer pharmaceutical preparation.
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WO2014147573A2 (en) * 2013-03-21 2014-09-25 Novartis Ag Combination therapy

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WO2014018725A1 (en) * 2012-07-26 2014-01-30 Novartis Ag Pharmaceutical combinations of a cdk4/6 inhibitor and a b-raf inhibitor
WO2014097125A1 (en) * 2012-12-20 2014-06-26 Novartis Ag Pharmaceutical combination comprising binimetinib
WO2014147573A2 (en) * 2013-03-21 2014-09-25 Novartis Ag Combination therapy

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