CN110023318A - The crystal form of compound - Google Patents
The crystal form of compound Download PDFInfo
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- CN110023318A CN110023318A CN201780074441.8A CN201780074441A CN110023318A CN 110023318 A CN110023318 A CN 110023318A CN 201780074441 A CN201780074441 A CN 201780074441A CN 110023318 A CN110023318 A CN 110023318A
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- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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
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Abstract
The invention belongs to pharmaceutical fields, provide compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form, its pharmaceutical composition, and its preparation method and application.
Description
The invention belongs to pharmaceutical fields, provide compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide novel crystal forms, its pharmaceutical composition, and its preparation method and application.
Epidermal growth factor (EGF) and EGF-R ELISA (EGFR) combination can activate tyrosine kinase activity, to cause the reaction for leading to cell Proliferation.The overexpression and/or overactivity of EGFR can lead to cell division out of control, and cell division out of control can be the inducement of cancer.Therefore, can inhibit the compound of EGFR overexpression and/or overactivity is the candidate for treating tumour.
Related compound (3aR of the present invention, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide, its chemical structure is shown in formula A, has the function of effectively inhibiting EGFR overexpression and/or overactivity.Therefore, it can be used for the treatment with the overexpression of EGFR and/or overactivity related disease, such as the treatment of cancer.
Before the crystal form for finding a kind of compound, it is difficult to predict (1) specific compound with the presence or absence of crystal form；(2) unknown crystal form how is made；(3) what kind of the property of crystal form can be, such as stability, bioavilability etc..
Since the characteristic of solid depends on the property of structure and compound itself, the different solid forms of compound often show different physics and chemical property.The difference of chemical property can be measured, be analyzed and be compared by a variety of analytical technology means, and these differences may finally be used to distinguish these existing different solid forms.The difference of physical property, such as solubility and bioavilability, it is also critically important when describing the solid forms of medical compounds.Similarly, in medical compounds, such as the exploitation of formula A compound, the new crystal of medical compounds and unformed form are also critically important.
Patent CN102906086A discloses compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide and preparation method thereof.
Summary of the invention
It summarizes
By a large amount of exploratory developments, we have found that formula A compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide) may exist crystalline form.We have conducted extensive research formula A compound, determine and the crystalline form for meeting medicinal demand is prepared.Based on these researchs, the present invention provides the crystal form I of formula A compound.
On the one hand, the present invention provides (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide I type crystal, i.e. the crystal form I of formula A compound.
The crystal form I of formula A compound provided by the invention has good crystallinity, no hygroscopicity and stable characteristic, and has acceptable oral administration biaavailability.
On the other hand, the present invention provides the preparation method of the crystal form I of formula A compound, these preparation methods are repeatable, and easily operated.
Another aspect, the present invention provides pharmaceutical composition, the pharmaceutical composition contains the crystal form I of a effective amount of formula A compound and at least one pharmaceutically acceptable carrier of surplus.
It treats the present invention also provides a kind of on the method for inhibiting EGF-R ELISA overexpression and/or the influential cancer of overactivity.This method includes that the crystal form I of a effective amount of formula A compound is applied to individual in need.
The present invention also provides the purposes that the crystal form I of formula A compound is used to prepare drug, the drug is for treating on EGF-R ELISA overexpression and/or the influential cancer of overactivity is inhibited, such as lung cancer, head and neck cancer, colorectal cancer, pharynx cancer, epidermoid carcinoma and cancer of pancreas.
Fig. 1 shows the powder x-ray diffraction figure of the crystal form I of formula A compound, horizontal axis (X- axis) is 2 θ of angle of diffraction, and the longitudinal axis (Y- axis) is diffracted intensity.
The differential scanning calorimetry figure of the crystal form I of Fig. 2 expression A compound, horizontal axis (X- axis) are temperature, and the longitudinal axis (Y- axis) is hot-fluid.
The thermogravimetric analysis figure of the crystal form I of Fig. 3 expression A compound, horizontal axis (X- axis) are temperature, and the longitudinal axis (Y- axis) is weight percent.
Definition
Unless otherwise stated, following abbreviation used in the application (including specification and claims) or term have definition given below.It must be noted that singular used in this specification and the appended claims also includes plural form, unless context clearly show that it is really not so.
" crystal form of the invention " used herein refers to formula A compound crystal form crystal form I.
" formula A compound " used herein or " (3aR, 6aR)-N- (4- (3- ethynylanilino) -7-
Methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide " refer to the compound (alternatively referred to as compound A) such as following formula A chemical structure:
" C used herein1-6Alkylol " refers to the fully saturated linear or branched alkyl group alcohol with 1,2,3,4,5 or 6 carbon atom.The example includes but is not limited to methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, n-hexyl alcohol etc..
It is used herein to refer to the fully saturated hydrocarbon with 1 or 2 carbon atom " less than the halogenated alkane of three carbon atoms ", replaced by one or more halogen atoms selected from F, Cl, Br or I.The example includes methylene chloride, chloroform, carbon tetrachloride, 1,2- dichloroethanes etc..
It is used herein " about " to refer to the numerical value at most ± 10% for deviateing and specifically giving.
" solution " used herein refers to mixture of the one or more of solutes of certain purposes in one or more of solvents.Solution means to include homogeneous mixture and multiphase mixture, is such as beaten liquid or other contain the suspension mixture of insoluble matter.
" organic solvent " used herein refers to any appropriate organic solvent for certain purposes in text.
" dissolution solvent " used herein refers under proper condition, such as amount appropriate, temperature appropriate, such as room temperature or heating, any appropriate organic solvent that can partly or entirely dissolve solute.
" anti-dissolution solvent " used herein refers to that any appropriate organic solvent, substance are less than the solubility in dissolution solvent in solubility wherein.
" effective quantity " of the crystal form of formula A compound and formula A compound, shows patient takes one
A medication amount, it can effectively mitigate under this quantity, improve certain to inhibiting EGF-R ELISA overexpression and/or the influential cancer of overactivity, taking individual can be people, it is also possible to the subjects such as animal, wherein on inhibiting EGF-R ELISA overexpression and/or the influential cancer of overactivity to may be, but not limited to, lung cancer, head and neck cancer, colorectal cancer, pharynx cancer, epidermoid carcinoma and cancer of pancreas etc.." effective quantity " will change with many factors such as the judgements of compound, the morbid state treated, the severity of disease treated, the age of individual and related health conditions, administration method and form, attending physician or veterinary practitioner.
" individual " used herein means mammal and nonmammalian.Mammal means any member of mammal, including but not limited to people；Non-human primate such as chimpanzee and other apes and monkey class；Farm-animals such as ox, horse, sheep, goat and pig；Domestic animal such as rabbit, dog and cat；Laboratory animal, including rodent, such as rat, mouse and cavy；Deng.The example of nonmammalian includes but is not limited to birds etc..Term " individual " is not offered as specific age or gender.
Detailed description of the invention
The present invention provides compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide novel crystal forms.
The characteristic that crystal form I of the invention has good crystallinity, no hygroscopicity and stability good, and there is acceptable oral administration biaavailability, it is suitble to prepare oral drug preparation.Repeatability amplification production crystal form I may be implemented in the favorable reproducibility of crystal form I of the invention；And its in ordinary preparation stablize, thus facilitate preparation produce and treatment disease when use.In addition, crystal form I purity is high of the invention；Dissolvent residual is few, meets bulk pharmaceutical chemicals quality requirement, such as the requirement of ICH Q3A.
Those skilled in the art can the conventional method based on test method disclosed in pharmacopeia, its alternative or this field the above advantage of crystal form of the present invention is verified.
As described herein, crystal form of the invention can be carried out by the method that one or more of solid-states are analyzed
Identification.For example, crystal form of the invention can be identified by one or more methods, such as powder x-ray diffraction, the lattice parameter of monocrystalline, FTIR spectrum, differential scanning calorimetric analysis data and/or thermogravimetric curve.And if the discriminatory analysis result of one of method is consistent with crystal form of the invention, it is inconsistent with crystal form of the invention for being not offered as the qualification result of other any methods.
As described herein, novel crystal forms can be composed by powder x-ray diffraction and be identified.However, one skilled in the art will appreciate that the peak intensity and/or peak situation of powder x-ray diffraction may be different because of the difference of experiment condition, such as different diffraction test conditions and/or orientation priority scheduling.Simultaneously because the accuracy of different instruments is different, the 2 θ values measured have the error of about ± 0.2 2 θ.However, it is known that the relative intensity value at peak relys more on certain properties of measured sample than the position at peak, such as the size of crystal, the purity of the orientation effect of crystallization and analyzed material in sample, therefore shown peak intensity deviation is likely to occur about ± 20% or wider.But despite the presence of test error, instrument error and orientation priority scheduling, the information for the enough identification crystal form I of XRPD data acquisition that those skilled in the art still can provide from this patent.
Crystal form I
The present invention provides the crystal form I of formula A compound.
In some embodiments, the crystal form I of formula A compound can be identified by X-ray powder diffraction.In some embodiments, the powder x-ray diffraction characteristic diffraction angles (2 θ) of the crystal form I of formula A compound are 5.4 degree, 6.5 degree, 10.1 degree, 12.2 degree, 13.1 degree, 16.2 degree, and the 2 θ values measured have the error of about ± 0.2 2 θ.
In some embodiments, the powder x-ray diffraction characteristic diffraction angles (2 θ) of crystal form I are 5.4 degree, 6.5 degree, 8.0 degree, 10.1 degree, 10.8 degree, 12.2 degree, 13.1 degree, 14.8 degree, 16.2 degree, 22.6 degree, 25.4 degree, and the 2 θ values measured have the error of about ± 0.2 2 θ.
In some embodiments, the powder x-ray diffraction feature diffraction of the crystal form I of formula A compound
Angle (2 θ) is 5.4 degree, 6.5 degree, 8.0 degree, 10.1 degree, 10.8 degree, 12.0 degree, 12.2 degree, 13.1 degree, 14.8 degree, 16.2 degree, 17.3 degree, 18.1 degree, 20.5 degree, 22.6 degree, 23.1 degree, 25.4 degree, 26.6 degree, and the 2 θ values measured have the error of about ± 0.2 2 θ.
In some embodiments, the powder x-ray diffraction characteristic diffraction angles (2 θ) of the crystal form I of formula A compound are 5.4 degree, 6.5 degree, 8.0 degree, 10.1 degree, 10.8 degree, 12.0 degree, 12.2 degree, 13.1 degree, 14.8 degree, 16.2 degree, 17.3 degree, 18.1 degree, 18.8 degree, 20.5 degree, 21.1 degree, 22.6 degree, 23.1 degree, 24.1 degree, 25.4 degree, 26.6 degree, 27.2 degree, and the 2 θ values measured have the error of about ± 0.2 2 θ.
In some embodiments, the powder x-ray diffraction characteristic diffraction angles (2 θ) of the crystal form I of formula A compound are 5.4 degree, 6.5 degree, 8.0 degree, 10.1 degree, 10.8 degree, 12.0 degree, 12.2 degree, 13.1 degree, 14.4 degree, 14.8 degree, 16.2 degree, 17.3 degree, 18.1 degree, 18.8 degree, 20.5 degree, 21.1 degree, 22.6 degree, 23.1 degree, 24.1 degree, 25.4 degree, 26.6 degree, 27.2 degree, 29.9 degree, 30.7 degree.The 2 θ values measured have the error of about ± 0.2 2 θ.
In some embodiments, the crystal form I of formula A compound has diffraction spectrogram as shown in Figure 1.Despite the presence of test error, instrument error and orientation priority scheduling, the information of the crystal form I for the enough duscriminant A compounds of XRPD data acquisition that those skilled in the art still can provide from this patent.
In some embodiments, the crystal form I of formula A compound can be identified with differential scanning calorimetric analysis.In some embodiments, the crystal form I of formula A compound has differential scanning calorimetric analysis curve as shown in Figure 2.In DSC spectrogram, the endothermic peak of the crystal form I of formula A compound is at about 259.4-261.7 DEG C.
In some embodiments, the crystal form I of formula A compound can be identified with thermogravimetric analysis.In some embodiments, the crystal form I of formula A compound has thermal gravimetric analysis curve as shown in Figure 3, shows that crystal form I is anhydride or pure crystalline substance.
In some embodiments, such as the crystal form I weight content of formula A compound is at least up to 99%,
At least 95%, at least 90%, or more down to 80%.Or the crystal form I weight content of formula A compound is at least up to 70%, or at least 60%.Or further, the crystal form I weight content of formula A compound is at least up to 50%.
The preparation method of crystal form I
Method A
This patent is related to the preparation method of the crystal form I of formula A compound, comprising:
(1) by compound (3aR, 6aR) simultaneously [3,4-b] pyrroles -5 (1H)-formamide is suspended in the in the mixed solvent of a kind of suitable solvent or several solvents to-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo；Wherein, the solvent is selected from dissolution solvent (such as n,N-dimethylacetamide, C1-6Alkylol, tetrahydrofuran, the halogenated alkane less than three carbon atoms, acetone, butanone, acetonitrile and toluene) or water-miscible organic solvent and water composition mixed solvent；
(2) suspension that whipping step (1) obtains；
(3) isolated (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form I solid；
(4) drying steps (3) obtained solid.
In some embodiments, step (1) compound used therefor (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide is preferably solid, such as a kind of single crystal form, such as crystal form I, it is also possible to the mixture of two or more crystal forms.
In some embodiments, in the step (1), compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide is not completely dissolved in suspending system, i.e., and part of compound is existing in solid form.
In some embodiments, the water-miscible organic solvent accounts for the volume hundred of the mixed solvent
Score is less than about 95%.
In some embodiments, the water-miscible organic solvent is selected from acetone, methanol, ethyl alcohol, isopropanol, tetrahydrofuran, n,N-dimethylacetamide and acetonitrile.When selected water-miscible organic solvent is ethyl alcohol, percent by volume shared by ethyl alcohol is no less than about 10%.
In some embodiments, the water-miscible organic solvent and water mix in appropriate proportions.In some embodiments, the volume ratio of water-miscible organic solvent and water is about 9:1 to about 1:9 or about 1:1, such as (volume ratio is about 9:1 to about 1:9) to ethanol/water.
In some embodiments, in the step (2), stir suspension while can be heated, heating temperature should be not higher than dicyandiamide solution boiling point, for example, about 40 degree, about 60 degree and about 80 degree.The heating can promote the crystal form I of solid transformation accepted way of doing sth A compound in suspending system.
In some embodiments, in the step (2), the time for stirring suspension can be 20-100 hours, for example, at least 24 hours, at least 48 hours, at least 60 hours, at least 72 hours.
Method B
This patent is related to another preparation method of the crystal form I of formula A compound, comprising:
(1) by compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide is mixed at least one dissolution solvent, and it then heats mixture and obtains the 1st kind of solution；
(2) at least one anti-dissolution solvent is added in the 1st solution of Xiang Suoshu, obtains the 2nd solution；
(3) by the 2nd solution cooled to room temperature；Then
(4) isolated (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form I solid；
(5) drying steps (4) obtained solid.
In some embodiments, wherein the dissolution solvent is selected from n,N-Dimethylformamide or N, N-
Dimethyl acetamide.
In some embodiments, the anti-dissolution solvent is selected from acetonitrile.
In some embodiments, the volume ratio of the dissolution solvent and anti-dissolution solvent is from about 1:10 to about 5:1, such as 0.3/1.
The feature being related in each embodiment of the above-mentioned preparation method of the crystal form of formula A compound can be arbitrarily combined with each other, each scheme that these intercombinations obtain is included within the scope of the invention, and just as specifically and seriatim listing herein, the scheme that these intercombinations obtain is the same.
Pharmaceutical composition and treatment method
The crystal form I of formula A compound is used to treat disease, such as cancer.The cancer includes but is not limited to lung cancer, head and neck cancer, colorectal cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, gastric cancer, kidney, liver cancer, the cancer of the brain, cancer of the esophagus, osteocarcinoma and sarcoma, such as soft tissue sarcoma and leukaemia.
There is provided herein treatments on the method for inhibiting EGF-R ELISA overexpression and/or the influential cancer of overactivity, including applying the active pharmaceutical ingredient formed by formula A compound, the crystal form I of its pharmaceutically acceptable salt or formula A compound of the invention.
In some embodiments, this treatment method is at least for a kind of on the method for inhibiting EGF-R ELISA overexpression and/or the influential disease of overactivity, such as cancer.Wherein, it applies a effective amount of pharmaceutical composition of the invention to individual in need to be treated, the crystal form I in described pharmaceutical composition comprising at least one pharmaceutical acceptable carrier and formula A compound.
The dosage that at least one active pharmaceutical ingredient of crystal form I selected from formula A compound and/or its pharmaceutically acceptable salt or formula A compound reaches expected physiological action depends on many factors, for example, using purpose, the clinical condition of administration mode and patient.Daily dosage may be example
Such as, range from 0.01mg to 3g daily (such as daily from 0.05mg to 2g, or even from 100mg to 1g daily).The unit dose formulations of Orally-administrable include, such as tablet or capsule.
To reach above-mentioned therapeutic purposes, the crystal form I of formula A compound can be administered in the form of compound itself, but usually they all with formed with one or more pharmaceutical acceptable carrier or auxiliary material come in the form of pharmaceutical composition using.
Representative carrier or auxiliary material should be compatible with ingredients other in composition, and will not endanger the health of patient.Carrier or auxiliary material can be solid or liquid, or both have, the crystal form I composition pharmaceutical composition or unit dosage forms (for example, tablet, capsule) of they and formula A compound, it can contain by weight 0.05% to 95% formula A compound.Heretofore described pharmaceutical composition can be made by known process for preparing medicine, such as include and pharmaceutically acceptable carrier and/or the mixing of auxiliary material and diluent etc. in method.
In some instances, representative carrier or auxiliary material include but is not limited to: microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium monohydrogen phosphate, glycine, disintegrating agent such as starch, croscarmellose sodium, the polyethylene glycol of composition silicate and high molecular weight, Granulating Bonding Agent (such as polyvinylpyrrolidone, sucrose, gelatin, Arabic gum) and lubricant (such as magnesium stearate, glycerol and talcum powder).
In some instances, the crystal form I of formula A compound can combine at least one component, and the component is, for example, carrier and/or auxiliary material and/or diluent, can be selected from sweetener, corrigent, colorant, dyestuff and emulsifier.
In some instances, the crystal form I of formula A compound will not be converted when preparation is made with one or more pharmaceutically acceptable carriers and/or auxiliary material and/or diluent.In other examples, the crystal form I of formula A compound may be converted when preparation is made with one or more pharmaceutically acceptable carriers and/or auxiliary material and/or diluent, entirely or partly be converted to one or more crystal forms, including be converted to non-solid form.Illustrative carrier and/or auxiliary material and/or diluent include but is not limited to: water,
Ethyl alcohol, propylene glycol, glycerol and their mixture.In some instances, crystal form I of the invention can be dissolved when pharmaceutical composition is made.Therefore, in the example of these " dissolutions ", crystal form I no longer exists with crystal form in pharmaceutical composition.
In some instances, the crystal form I of formula A compound is made into suitable dosage form administration.
Pharmaceutical composition described in the invention can be the dosage form for the administration mode that those are suitable for oral and oral (such as sublingual), and suitable administration mode is likely to be dependent on the state of an illness of each case and the seriousness for the treatment of condition, also depends on the property of crystal form I concrete form used in preparation pharmaceutical composition of formula A compound.Pharmaceutical composition described in the invention is also possible to coated dosage form and coated slow release dosage form.The dosage form of acid and anti-gastric juice is also possible.The coating substance of applicable anti-gastric juice includes cellulose acetate phthalate, polyvinyl acetate phthalic acid, hydroxypropyl phthalate, cellulose, the anionic polymer of methacrylic acid, methyl methacrylate.
The form that the suitable pharmaceutical composition for taking orally is also likely to be unit dosage forms is made of the crystal form I of formula A compound, for example, capsule, sachet and tablet, including the tablet that can be sucked, each is all quantitatively made by least one active pharmaceutical ingredient of the present invention；Its dosage form can also be selected from powder, granule, solution, in water or the suspension of on-aqueous liquid, the emulsion of oil-in-water and Water-In-Oil.These compositions can also be made by the preparation method of any applicable pharmaceutical preparation as described above, for example, these methods are the following steps are included: the crystal form I of formula A compound and carrier and/or auxiliary material and/or diluent (can be made of one or more adding ingredients) are mixed.These compositions usually can equably, homogeneously be mixed with by the crystal form I and liquid of formula A compound or the solid carrier through fine segmentation, and product can be made certain shapes.
Composition of the present invention, which can be, locally or to be capapie administered.
The tablet that can be sucked can be made by being applicable to take orally the pharmaceutical composition being administered (including sublingual), and it includes the crystal form I of formula A compound and corrigents.Corrigent is generally selected from sucrose, gum arabic, bassora gum etc..
Pharmaceutical composition of the present invention may also mean that those can be in the form of parenteral, such as the storage tank of nebulizer or implantable.Solid carrier object used in it is for example including starch, lactose, microcrystalline cellulose, aluminosilicate and any applicable ingredient.Liquid-carrier is for example including water for injection, polyvinyl alcohol, nonionic surfactant agent and corn oil and any applicable ingredient.Other include colorant, preservative, corrigent and antioxidant, such as vitamin E, vitamin A, BHT and BHA commonly used in pharmaceutical preparation auxiliary material.
The crystal form I of formula A compound of the present invention can also pass through Intraperitoneal medication.The solution and suspension of the compound can be prepared by the way that these compounds are dissolved or are suspended in the water containing surfactant.The suspension of dispersion can with glycerol, polyethylene glycol (PEG) or they and be applicable in oil mixture be prepared.Anti-corrosion composition can be added in these formulations to prevent the growth of microorganism in use.
The dosage form of injectable includes nontoxic aqueous pharmaceutical or suspension and nontoxic powder.All these situations, these dosage forms must be it is nontoxic, can be shifted from syringe easily, be stable under the conditions of production and storage, while being also to protect against contaminated and microorganism infection.Carrier can be solvent or dispersing agent, including water, alcohol and some applicable oils.
The crystal form I of formula A compound can also use (such as in synergistic treatment) with one or more of other active ingredient combinations.When be combined use when, active constituent can be separated composition, for in the treatment by identical or different administration method be administered simultaneously perhaps different time difference (such as sequentially in any order apply) application or they can also apply together in the same pharmaceutical composition.
In some instances, the crystal form I of formula A compound can be administered simultaneously with one or more known medicative other active constituents, such as treating on inhibiting EGF-R ELISA overexpression and/or the influential disease of overactivity, such as cancer.
" being applied in combination " mentioned here is the combination of the crystal form I and one or more other active constituents for definition A compound, is such as combined in anti-tumor method.Herein, " anti-tumor method "
It can refer to any method for the purpose for the treatment of cancer.The example of anti-tumor method includes but is not limited to: radiotherapy, immunization, the amic therapy method for causing DNA damage, the amic therapy method for destroying cellular replication.
Causing the chemotherapeutics of DNA damage has very much, including but not limited to as described below, for example, topoisomerase I inhibitor (for example, Irinotecan, topotecan, camptothecine and the like or metabolite and adriamycin)；Topoisomerase II inhibitors (for example, Etoposide, Teniposide, daunorubicin)；Alkylating agent (for example, melphalan, Chlorambucil, busulfan, phosphinothioylidynetrisaziridine, cyclophosphamide, Carmustine, lomustine, Semustine, streptozotocin, Dacarbazine, methotrexate (MTX), mitomycin, cyclophosphamide)；DNA intercalator (for example, cis-platinum, oxaliplatin and carboplatin)；DNA intercalator and free-radical generator such as bleomycin；With nucleoside analog (such as 5-fluor-uracil, capecitabine, gemcitabine, fludarabine, cytarabine, purinethol, thioguanine, Pentostatin, hydroxycarbamide).
The chemotherapeutics of cellular replication is destroyed, including but not limited to: the pure and mild related analogs of taxol, Taxotere；Vincristine, vincaleukoblastinum, related analog；Thalidomide and related analogs (for example, CC-5013 and CC-4047)；Protein tyrosine kinase inhibitor (for example, imatinib mesylate, furan quinoline are for Buddhist nun and Gefitinib)；Protease inhibitors (for example, bortezomib)；The inhibitor of NF- κ B, the kinase inhibitor including I κ B；Antibody in conjunction with overexpression protein in cancer, can lower cellular replication (for example, Rituximab, Cetuximab, bevacizumab etc.)；The inhibitor of other known raising in cancer or overexpression or activation protein or enzyme can lower cellular replication by inhibiting these protein or enzyme.
Therefore, method described herein is not limited to the sequence of administration, can be administered simultaneously or give before or after being administered one or more other active components.
The following are unrestricted examples.
Experimental section
Formula A raw materials of compound used in embodiment is prepared according to CN102906086A.
All reagents (in addition to intermediate) are that commercial market is bought used in the present invention.The title (in addition to reagent) of all compounds is generated by software ChemBioDraw Ultra 12.0.
Outer except as otherwise indicating, powder x-ray diffraction spectrum is measured by German Bruker D8ADVANCE (target: Cu, voltage: 40kV, electric current: 40mA, scanning speed: 4 degrees/min, step-length: 0.02 degree, measurement range: 3-45 degree).
Differential scanning calorimetric analysis measurement is the DSC7 (purge gas: nitrogen, flow velocity: 50mL min by Perkin Elmer company-1, heating rate: 5-10 DEG C/min, measurement range: 25 DEG C → 200 DEG C) measurement, sample measurement, which has used, rolls hole aluminium dish, carries out temperature correction using indium.
Thermogravimetric analysis is measured by the TGA7 (purge gas: nitrogen, flow velocity: 50mL min-1, heating rate: 10 DEG C/min) of Perkin Elmer company.
The preparation of the crystal form I of 1 formula A compound of embodiment
Appropriate formula A compound is suspended in the in the mixed solvent of the ethanol/water (9:1, V/V) of 10 times (volume/mass ratio) amount, is stirred at room temperature 60 hours, filters, obtains solid sample.Gained powder sample is the crystal form I of formula A compound, and powder x-ray diffraction map is as shown in Figure 1, key data therein is as shown in table 1 below.There is following values at the peak therefrom selected out: 5.4,6.5,8.0,10.1,10.8,12.0,12.2,13.1,14.8,16.2,17.3,18.1,18.8,20.5,21.1,22.6,23.1,24.1,25.4,26.6 and 27.2, each different angular error ± 0.2 degree (2 θ), wherein characteristic peak is 5.4,6.5,8.0,10.1,10.8,12.2,13.1,14.8,16.2,22.6 and 25.4.Test results are shown in figure 2 by DSC, and the melting range of display crystal form I is about 259.4-261.7 DEG C.
Table 1
The preparation of the crystal form I of 2 formula A compound of embodiment
Appropriate formula A compound is suspended in respectively in various solvents listed by table 2, stirs certain time under the conditions of listed in table.It filters respectively, obtains each solid sample.Through detecting, the X-ray powder diffraction spectrum of gained each sample is consistent with the gained crystal form I sample of formula A compound in embodiment 1.
Table 2
| Solvent | Condition | As a result | Solvent usage (volume/mass ratio) |
| Methanol | 50 DEG C/3 days | Crystal form I | 10 times |
| Ethyl alcohol | 50 DEG C/3 days | Crystal form I | 10 times |
| Isopropanol | 50 DEG C/3 days | Crystal form I | 10 times |
| Tetrahydrofuran | 50 DEG C/3 days | Crystal form I | 10 times |
| Methylene chloride | 50 DEG C/3 days | Crystal form I | 10 times |
| Acetone | 50 DEG C/3 days | Crystal form I | 10 times |
| Butanone | 50 DEG C/3 days | Crystal form I | 10 times |
| Acetonitrile | 50 DEG C/3 days | Crystal form I | 10 times |
| Toluene | 50 DEG C/3 days | Crystal form I | 10 times |
| Ethanol/water (9:1, V/V) | Room temperature/66 hour | Crystal form I | 30 times |
| Ethanol/water (9:1, V/V) | 40 DEG C/66 hours | Crystal form I | 30 times |
| Ethanol/water (9:1, V/V) | 60 DEG C/66 hours | Crystal form I | 30 times |
| Ethanol/water (9:1, V/V) | 80 DEG C/66 hours | Crystal form I | 30 times |
| Ethanol/water (1:9, V/V) | Room temperature/66 hour | Crystal form I | 30 times |
| Ethanol/water (1:9, V/V) | 40 DEG C/66 hours | Crystal form I | 30 times |
| Ethanol/water (1:9, V/V) | 60 DEG C/66 hours | Crystal form I | 30 times |
| Ethanol/water (1:9, V/V) | 80 DEG C/66 hours | Crystal form I | 30 times |
The preparation of the crystal form I of 3 formula A compound of embodiment
0.4 gram of formula A compound is mixed with (60 times, volume/mass ratio) of 24 milliliters of n,N-dimethylacetamide, is heated to 60 DEG C of dissolutions；80 milliliters of acetonitrile are added thereto, a large amount of precipitatings are precipitated, filtering obtains solid sample.Through detecting, the X-ray powder diffraction spectrum of gained sample is consistent with the gained crystal form I sample of formula A compound in embodiment 1.
Stability of the 4 crystal form I of embodiment under high temperature, high humidity, illumination condition:
Measuring method: the test sample for weighing the formula A compound crystal form I being prepared by previous embodiment is placed in culture dish, be open exposed be placed in sealing clean container, it is respectively 60 DEG C in temperature, 25 DEG C and relative humidity are 92.5% ± 5%, and illumination is sampled, is investigated to the purity (being analyzed using HPLC) and crystal form (using X-ray powder diffraction analysis) of sample to place 10 days under conditions of 4500lx ± 500lx, and compare investigation as a result, the results are shown in Table 3.
The influence factor experimental result (10 days) of 3 crystal form I of table
Conclusion: data illustrate in table, and crystal form I is placed 10 days under high temperature, high humidity and illumination condition, and no change has taken place for chemical purity and crystal form, show that crystal form I is stable.
The hygroscopicity of 5 crystal form I of embodiment
Measuring method: two parts of test sample of the crystal form I being prepared by previous embodiment are weighed, it is placed in two culture dishes, it is open in the exposed sealing clean container for being placed in relative humidity and being 92.5% and 75% respectively, it places 10 days at room temperature, sampling weighs the example weight after placing 10 days, and compared with starting to test preceding example weight, the moisture absorption weight gain percentage and crystal form (being analyzed using X-ray powder diffraction) for calculating sample, the results are shown in Table 4.
Table 4
| Relative humidity (%) | 92.5%RH, 25 DEG C | 75%RH, 40 DEG C |
| Place weight gain (%) in 5 days | 0.01% | 0% |
| Place weight gain (%) in 10 days | 0.01% | 0.01% |
| Place 10 days crystal forms | I | I |
Conclusion: data illustrate in table, and crystal form I is placed 10 days under conditions of high humidity, and moisture absorption weight gain only 0.01%, crystal form I is no hygroscopicity, and in placement process, no change has taken place for crystal form, and crystal form I is stable.
6 crystal form I of embodiment is in the intracorporal pharmacokinetic of dog
1. experimental animal
Beasle dog 6, half male and half female, identical week old is purchased from Beijing Marshall Biotechnology Co., Ltd.
2. experimental material
The formula A compound being prepared by previous embodiment is crystal form I, purity 98.5%.
HS 15 (polyethylene glycol stearate) is medical auxiliary materials Technology Co., Ltd. (agent, the place of production: German BASF) purchased from upper Hydron.
3. drug solution preparing
The preparation of the Bolos intravenous administration solution of formula A compound: warm water heatingHS 15, wait flow
After dynamic property improves, 22.5mL is measured, 22.5mL physiological saline is added, vortex is uniformly mixed it, is made into Solutol and physiological saline mixed solution (volume ratio 1:1) is spare.DMSO 1.06mL is added in weighing type A compound crystal form I 108.47mg, and 90 μ L of 12M HCl is added, and be vortexed ultrasound, obtains yellow clear transparent solutions.The solution is fully transferred in 250mL wide-mouth bottle, is addedHS 15 and physiological saline mixed solution (volume ratio 1:1) 42.6mL, vortex 1min, ultrasonic 2min are added physiological saline and are settled to 212.8mL, for being injected intravenously.Final intravenous administration formulation is containing 10%The normal saline solution of HS 15,0.5%DMSO and 0.04%12M HCl.
The oral administration preparation of formula A compound crystal form I: according to the weight of animals and dosage, suitable formula A compound crystal form I is weighed, is fitted into No. 0 people's capsule (CAPSUGEL, Lot#:12832590), a dog gives a capsule.
4. experimental program
6 beasle dogs, half male and half female.It is administered by 4 experimental periods, own control.Wherein the first, second and third period was respectively oral 1.0,2.5 and 7.5mg/kg single-dose (oral administration preparation of above-mentioned preparation), and the period 4 is intravenous injection 1.0mg/kg single-dose (intravenous formulations of above-mentioned preparation).It is one week that the phase is cleaned during week.Before administration, animal overnight fasting, and 30min starts feeding before being administered.Before each cycle administration, blank blood is taken.After Bolos intravenous administration, in 5min, 15min, 30min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours through forelimb venous blood sampling 1ml.After oral administration, in 30min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours and 24 hours through forelimb venous blood sampling 1ml.Centrifugal separation plasma, -80 DEG C of preservations are to be measured.
5. plasma sample pre-processes
Using the method for acetonitrile precipitation albumen: acetonitrile solution oscillation 2min, 14000rpm the centrifugation 10min of 150 μ l containing the internal standards being added in 50 μ l test plasma samples, then takes 150 μ l of supernatant, dilutes one times with the ultrapure water of 150 μ l, taking 10 μ L, sample introduction is analyzed.
6. biological sample analysis method
Using LC-MS/MS analysis method, the drug concentration of biological sample compound of formula A is measured.Instrument is the triple level four bars mass spectrographs of API4000 type of U.S. Applied Biosystem company and 1200 series liquid chromatograph systems of Agilent company, Germany.Chromatographic column is CAPCELL PAK C18Column (MG, 50 × 2.0mm, 5 μm).Mobile phase is the ultrapure water (A phase) containing 0.1% formic acid and the acetonitrile containing 1% formic acid: methanol (v/v=1:1) mixed solution (B phase).It is detected using electrospray ionisation source (ESI) cation MRM scanning mode.
7. data processing
Moment Methods are counted using non-compartment model, data analysis is carried out using (Thermo-Fisher company, the U.S.) the pharmacokinetics software of Kinetica 4.0, calculates pharmacokinetic parameter.CmaxAnd TmaxFor measured value.
8. result
After dog is injected intravenously 1.0mg/kg formula A compound, intracorporal exposed amount (AUC0-∞) average value be 714hng/mL；End phase half-life period (t1/2) it is 4.12 hours.After oral 1.0,2.5 and 7.5mg/kg formula A compound, intracorporal exposed amount (AUC0-∞) average value be respectively 228,1126 and 5424hng/mL；End phase half-life period after oral is respectively 3.22,4.20 and 7.71 hours.The half-life period of oral 1 and 2.5mg/kg, two dosage groups is 4 hours or so, and 7.5mg/kg dosage group is more slow compared to the decline of 1 and 2.5mg/kg dosage group blood concentration, and 24 hours blood concentrations are still greater than 50ng/mL after administration.Pass through the internal plasma exposure amount (AUC obtained under oral and intravenous injection same dose (1mg/kg)0-∞) the obtained oral absolute bioavailability of mean value calculation is 30.6 ± 15.0%.
Thus, formula A compound crystal form I has acceptable oral administration biaavailability, is suitble to prepare oral drug preparation.
It should be understood that embodiment as described herein and embodiment are only used for illustrating purpose, various improvement or variation in view of this can be prompted to those skilled in the art, they include in the spirit and scope and scope of the appended claims of the application.By reference by all publications, patents and patent applications cited herein be merged into herein and for all purposes.
Claims (8)
- Compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form I.
- The crystal form I of claim 1, which is characterized in that there is characteristic peak at the angle following 2 θ in x-ray diffractogram of powder spectrum: 5.4 degree, 6.5 degree, 10.1 degree, 12.2 degree, 13.1 degree and 16.2 degree, there are about ± 0.2 ° of errors for each 2 θ value.
- The crystal form I of claims 1 or 2, it is characterized in that, there is characteristic peak at the angle following 2 θ in x-ray diffractogram of powder spectrum: 5.4 degree, 6.5 degree, 8.0 degree, 10.1 degree, 10.8 degree, 12.2 degree, 13.1 degree, 14.8 degree, 16.2 degree, 22.6 degree, 25.4 degree, the 2 θ values measured have the error of about ± 0.2 2 θ.
- Pharmaceutical composition, which is characterized in that described pharmaceutical composition contains crystal form and pharmaceutically acceptable carrier described in any one of a effective amount of claim 1-3.
- The purposes of crystal form in medicine preparation described in any one of claim 1-3, the drug is for treating disease relevant to the overexpression of EGFR and/or overactivity, such as the treatment of cancer, wherein the cancer is preferably selected from: lung cancer, head and neck cancer, colorectal cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, gastric cancer, kidney, liver cancer, the cancer of the brain, cancer of the esophagus, osteocarcinoma and sarcoma, such as soft tissue sarcoma and leukaemia.
- Disease relevant to the overexpression of EGFR and/or overactivity, the method for such as cancer are treated, this method includes applying crystal form described in any one of a effective amount of claim 1-3 to individual in need, wherein the cancer is preferably selected from: lung cancer, head and neck cancer, colorectal cancer, cancer of pancreas, colon cancer, breast cancer, oophoroma, prostate cancer, gastric cancer, kidney, liver cancer, the cancer of the brain, cancer of the esophagus, osteocarcinoma and sarcoma, such as soft tissue sarcoma and leukaemia.
- The method for preparing the crystal form I of any one of claim 1-3 comprising:(1) by compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- Base) simultaneously [3,4-b] pyrroles -5 (1H)-formamide is suspended in the in the mixed solvent of a kind of suitable solvent or several solvents to -1- methyl-hexahydropyrrolo；Wherein, the solvent is selected from dissolution solvent (such as n,N-dimethylacetamide, C1-6Alkylol, tetrahydrofuran, the halogenated alkane less than three carbon atoms, acetone, butanone, acetonitrile and toluene) or water-miscible organic solvent (such as acetone, methanol, ethyl alcohol, isopropanol, tetrahydrofuran, DMAC N,N' dimethyl acetamide and acetonitrile) and water composition mixed solvent；(2) suspension that whipping step (1) obtains；(3) isolated (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form I solid；(4) drying steps (3) obtained solid.
- The method for preparing the crystal form I of any one of claim 1-3 comprising:(1) by compound (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide is mixed at least one dissolution solvent (such as N, dinethylformamide or N, N- dimethyl acetamide) in, it then heats mixture and obtains the 1st kind of solution；(2) at least one anti-dissolution solvent (such as acetonitrile) is added in the 1st solution of Xiang Suoshu, obtains the 2nd solution；(3) by the 2nd solution cooled to room temperature；Then(4) isolated (3aR, 6aR)-N- (4- (3- ethynylanilino) -7- methoxyquinazoline hydrochloride -6- base) -1- methyl-hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-formamide crystal form I solid；(5) drying steps (4) obtained solid.
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| PCT/CN2017/114194 WO2018099451A1 (en) | 2016-12-01 | 2017-12-01 | Crystal form of compound |
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| WO2012000182A1 (en) * | 2010-06-30 | 2012-01-05 | Hutchison Medipharma Limited | Quinazoline compounds |
| CN102311438A (en) * | 2010-06-30 | 2012-01-11 | 和记黄埔医药（上海）有限公司 | Quinazoline compound |
| CN102906086A (en) * | 2010-06-30 | 2013-01-30 | 和记黄埔医药（上海）有限公司 | Quinazoline compounds |
-
2017
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| WO2012000182A1 (en) * | 2010-06-30 | 2012-01-05 | Hutchison Medipharma Limited | Quinazoline compounds |
| CN102311438A (en) * | 2010-06-30 | 2012-01-11 | 和记黄埔医药（上海）有限公司 | Quinazoline compound |
| CN102906086A (en) * | 2010-06-30 | 2013-01-30 | 和记黄埔医药（上海）有限公司 | Quinazoline compounds |
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| WO2021073494A1 (en) * | 2019-10-14 | 2021-04-22 | Hutchison Medipharma Limited | The salts of a compound and the crystalline forms thereof |
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