CN105732642B - 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 PDFInfo
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- CN105732642B CN105732642B CN201610217050.4A CN201610217050A CN105732642B CN 105732642 B CN105732642 B CN 105732642B CN 201610217050 A CN201610217050 A CN 201610217050A CN 105732642 B CN105732642 B CN 105732642B
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- 239000002504 physiological saline solution Substances 0.000 description 1
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- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
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- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
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- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
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 a kind of eutectic crystal form, it is named as crystal form III.Crystal form III stability provided by the invention is good, and low in hygroscopicity meets medicinal requirements.There is important value to the optimization and exploitation of the following drug.
Description
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 III 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 eutectic, and this 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 meets medicinal requirements.
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 inhibitor (MEK162), 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 likely larger than 0, and corresponding eutectic is hydration at this time
The value of object, 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, are named as crystal form III, crystal form III with
The X-ray powder diffraction figure that CuK alpha rays measure is 18.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 23.1 ° ± 0.2 ° in 2theta values
Place has characteristic peak.
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. 1
Unanimously.Which show totally 41 characteristic peaks, the position of these characteristic peaks and peak intensity are as shown in table 2.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 3.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 4 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 2.
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 3.
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.
A further object of the present invention is to provide a kind of preparation method 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 dicyandiamide solution is methanol, obtained eutectic is crystal form III.
A specific aspect according to the present invention, the present invention provide a kind of preparation method of the eutectic, crystal form III's
Preparation method includes method one or method two：
Method one：By LEE011 and MEK162 eutectic crystal form I in alcohol organic solvent or alcohol organic solvent and water, ketone
It mixes in the mixed solvent system of organic solvent, ether organic solvent or nitrile organic solvent, is then obtained by the method for volatilization
To crystal form III；Crystal form I can be prepared by preparation example 1.
Method two：LEE011 and MEK162 are mixed in alcohol organic solvent, crystalline substance is then obtained by the method for volatilization
Type III.
Preferably, in method one, 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 method one, 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 method two, the mass ratio that feeds intake of the LEE011 and the MEK162 are 1:0.9~1.1.
Preferably, in method two, 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 are 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, a kind of crystal form III of present invention offer are preparing treating cancer pharmaceutical preparation
In purposes.
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.
Description of the drawings
The XRPD figures that Fig. 1 is crystal form III made from embodiment 1；
The DSC figures that Fig. 2 is crystal form III made from embodiment 1；
The TGA figures that Fig. 3 is crystal form III made from embodiment 1；
The DVS that Fig. 4 is crystal form III schemes；
Fig. 5 is that (upper figure is the XRPD figures before placing, figure below to stability contrast figure to crystal form III under the conditions of 25 DEG C/60%RH
Scheme for the XRPD after placing 30 days)；
Fig. 6 is that (upper figure is the XRPD figures before placing, figure below to stability contrast figure to crystal form III under the conditions of 40 DEG C/75%RH
Scheme for the XRPD after placing 30 days)；
Fig. 7 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 are crystal form III.In addition, the drug
Composition can also include the crystal form or amorphous article of the salt of other pharmaceutical eutectics, its salt.Optionally, crystal form of the invention
It can be used as the application of individual activating agent or they that can be administered in combination with other activating agents, including with same or similar
Therapeutic activity and for it is such combined administration be determined as safe and efficient other compounds.In special embodiment,
The co-administration of two kinds of (or a variety of) activating agents allows to significantly reduce the dosage of each activating agent used, to reduce
The side effect seen.
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,Kα
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 TAQ5000.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
Preparation example 1
The preparation method of eutectic crystal form I：
By MEK162 the and 4mL acetonitrile/waters (v of 26.6mg:V=19:1) it is placed at 50 DEG C and stirs 30 minutes, be 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 this preparation example obtains are as shown in table 1.
Table 1
| 2theta | The intervals d | Relative intensity % |
| 7.46 | 11.85 | 15.77 |
| 8.29 | 10.67 | 20.26 |
| 10.37 | 8.53 | 54.57 |
| 11.37 | 7.79 | 52.73 |
| 12.48 | 7.10 | 5.21 |
| 13.00 | 6.81 | 18.91 |
| 13.35 | 6.63 | 45.08 |
| 14.11 | 6.28 | 9.89 |
| 14.57 | 6.08 | 18.05 |
| 15.84 | 5.60 | 18.04 |
| 16.67 | 5.32 | 13.53 |
| 16.87 | 5.26 | 15.95 |
| 17.88 | 4.96 | 6.10 |
| 19.29 | 4.60 | 100.00 |
| 19.55 | 4.54 | 19.83 |
| 20.26 | 4.38 | 11.23 |
| 21.59 | 4.12 | 39.45 |
| 22.39 | 3.97 | 16.48 |
| 22.67 | 3.92 | 60.10 |
| 22.94 | 3.88 | 19.18 |
| 23.55 | 3.78 | 46.10 |
| 23.79 | 3.74 | 13.16 |
| 25.22 | 3.53 | 19.81 |
| 25.97 | 3.43 | 25.44 |
| 26.80 | 3.33 | 15.49 |
| 28.04 | 3.18 | 11.25 |
| 29.21 | 3.06 | 10.34 |
| 30.64 | 2.92 | 8.17 |
| 32.85 | 2.73 | 2.68 |
| 34.60 | 2.59 | 7.79 |
Embodiment 1
The preparation method of crystal form III：
Crystal form I made from 327mg preparation examples 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 2.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, 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 3, 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. 2, Fig. 3, Fig. 7 and do not detect solvent peak on nuclear magnetic data, lost according to TGA
The content that weight can deduce the water in crystal form III is about 2 moles.
Table 2
Embodiment 2
The preparation method of crystal form III：
5mL bottles are added in crystal form I made from 16.1mg preparation examples 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 3.
Table 3
Embodiment 3
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 4.
Table 4
| 2theta | The intervals d | Relative intensity % |
| 4.31 | 20.51 | 88.46 |
| 6.95 | 12.71 | 19.46 |
| 8.22 | 10.76 | 61.59 |
| 10.63 | 8.33 | 26.74 |
| 12.67 | 6.99 | 60.62 |
| 13.07 | 6.77 | 40.81 |
| 14.03 | 6.31 | 35.47 |
| 14.21 | 6.23 | 38.51 |
| 14.70 | 6.03 | 64.45 |
| 15.36 | 5.77 | 37.63 |
| 16.50 | 5.37 | 33.24 |
| 17.48 | 5.07 | 35.31 |
| 18.34 | 4.84 | 41.49 |
| 18.83 | 4.71 | 97.35 |
| 19.60 | 4.53 | 37.68 |
| 20.46 | 4.34 | 100.00 |
| 20.73 | 4.29 | 45.38 |
| 21.17 | 4.20 | 36.02 |
| 21.63 | 4.11 | 70.32 |
| 22.65 | 3.93 | 91.83 |
| 23.10 | 3.85 | 85.91 |
| 23.34 | 3.81 | 51.75 |
| 23.70 | 3.75 | 44.02 |
| 24.71 | 3.60 | 72.82 |
| 25.29 | 3.52 | 34.34 |
| 26.20 | 3.40 | 83.77 |
| 28.33 | 3.15 | 40.73 |
| 28.71 | 3.11 | 45.12 |
| 31.21 | 2.87 | 19.49 |
Embodiment 4
The research of MEK162 and LEE011 component molars ratio in crystal form III：
It weighs crystal form III made from the 1.504mg embodiment of the present invention 1 and vial is added, it is molten that 10mL MeOH solvents are added
Clearly, 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 5.
Table 5
| Compound | MEK162/LEE011 components |
| MEK162 concentration (mmol/L) | 0.157 |
| LEE011 concentration (mmol/L) | 0.153 |
| Molar ratio | 1:1 |
Embodiment 5
Crystal form III's draws moist research：
It takes crystal form III 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
6, DVS figures such as Fig. 4.
Table 6
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 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 6
The stability study of crystal form III：
Two parts of sample openings of crystal form III made from the embodiment of the present invention 1 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 7.
Table 7
| 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 Fig. 5) |
| Crystal form III | 40 DEG C/75%RH | 30 days | Crystal form III is remained unchanged (such as Fig. 6) |
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.
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 (12)
1. a kind of eutectic of CDK inhibitor and mek inhibitor, it is characterised in that：The structural formula of the eutectic such as formula (I) institute
Show, wherein x is the number between 0~3, and the eutectic is crystal form III, what the crystal form III was measured with CuK alpha rays
X-ray powder diffraction figure 2theta values be 18.8 ° ± 0.2 °, 20.5 ° ± 0.2 °, 23.1 ° ± 0.2 °, 22.6 ° ± 0.2 °,
There is characteristic peak at 4.3 ° ± 0.2 °, 12.7 ° ± 0.2 °
2. eutectic according to claim 1, it is characterised in that：The X-ray powder diffraction figure of the crystal form III also exists
2theta values be 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 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 III also exists
2theta values are to have characteristic peak at 26.2 ° ± 0.2 °, 24.7 ° ± 0.2 °, 21.6 ° ± 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 III, x is
Number between 2~3.
5. a kind of preparation method of eutectic according to any one of claims 1 to 4, it is characterised in that：The preparation of crystal form III
Method is method one or method two：
Method one：LEE011 and MEK162 eutectic crystal form I is organic in alcohol organic solvent or alcohol organic solvent and water, ketone
It is mixed in the mixed solvent system of solvent, ether organic solvent or nitrile organic solvent, crystalline substance is then obtained by the method for volatilization
Type III, the eutectic crystal form I the X-ray powder diffraction figure measured with CuK alpha rays 2theta values be 19.3 ° ± 0.2 °,
There is characteristic peak at 22.7 ° ± 0.2 °, 10.4 ° ± 0.2 °, 11.4 ° ± 0.2 °, 23.6 ° ± 0.2 °, 13.4 ° ± 0.2 °；
Method two：LEE011 and MEK162 are mixed in alcohol organic solvent, crystal form is then obtained by the method for volatilization
III。
6. the preparation method of eutectic according to claim 5, it is characterised in that：In method one, the crystal form I's feeds intake
Quality has with the alcohol organic solvent or alcohol organic solvent with water, organic solvent of ketone, ether organic solvent or nitrile
The volume ratio that feeds intake of the mixed solvent system of solvent is 8~25mg/mL.
7. the preparation method of eutectic according to claim 5, it is characterised in that：In method one, by the crystal form I in alcohol
It is mixed in class organic solvent, crystal form III is then obtained by the method for volatilization.
8. the preparation method of the eutectic according to claim 5 or 7, it is characterised in that：The alcohol organic solvent is first
Alcohol.
9. the preparation method of eutectic according to claim 5, it is characterised in that：In method two, the LEE011 and institute
The mass ratio that feeds intake of the MEK162 stated is 1:0.9~1.1.
10. the preparation method of eutectic according to claim 5, it is characterised in that：In method two, the throwing of the MEK162
Material quality and the volume ratio that feeds intake of the alcohol organic solvent are 6~7mg/mL.
11. 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.
12. 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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