WO2018099451A1 - 化合物的晶型 - Google Patents

化合物的晶型 Download PDF

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WO2018099451A1
WO2018099451A1 PCT/CN2017/114194 CN2017114194W WO2018099451A1 WO 2018099451 A1 WO2018099451 A1 WO 2018099451A1 CN 2017114194 W CN2017114194 W CN 2017114194W WO 2018099451 A1 WO2018099451 A1 WO 2018099451A1
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Prior art keywords
cancer
degrees
compound
formula
solvent
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PCT/CN2017/114194
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English (en)
French (fr)
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吴振平
李文姬
储玉平
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和记黄埔医药（上海）有限公司
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Priority to CN201780074441.8A priority Critical patent/CN110023318A/zh
Publication of WO2018099451A1 publication Critical patent/WO2018099451A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • 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
    • 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

Definitions

  • the present invention belongs to the field of pharmacy and provides the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro
  • epidermal growth factor (EGF)
  • EGFR epidermal growth factor receptor
  • Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer.
  • compounds that inhibit EGFR overexpression and/or overactivation are candidates for treating tumors.
  • Patent CN102906086A discloses the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , 4-b]pyrrole-5(1H)-carboxamide and a process for the preparation thereof.
  • the invention provides (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrole Form I crystal of [3,4-b]pyrrole-5(1H)-carboxamide, Form I of the compound of formula A.
  • Form I of the compound of formula A provided by the present invention has good crystallinity, non-hygroscopicity and stability characteristics, and has acceptable oral bioavailability.
  • the invention provides a process for the preparation of Form I of a compound of formula A which is reproducible and easy to handle.
  • the invention provides a pharmaceutical composition comprising an effective amount of Form I of a compound of Formula A, and the balance of at least one pharmaceutically acceptable carrier.
  • the invention also provides a method of treating cancer that has an effect on inhibiting epidermal growth factor receptor overexpression and/or overactivity.
  • the method comprises administering to a subject in need thereof an effective amount of Form I of a compound of Formula A.
  • the invention also provides the use of Form I of a compound of formula A for the manufacture of a medicament for the treatment of a cancer, such as lung cancer, head and neck cancer, which has an effect on inhibiting the overexpression and/or overactivity of the epidermal growth factor receptor, Colorectal cancer, pharyngeal cancer, epidermoid carcinoma and pancreatic cancer.
  • a cancer such as lung cancer, head and neck cancer
  • Figure 1 shows a powder X-ray diffraction pattern of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the diffraction angle 2 ⁇ and the vertical axis (Y-axis) being the diffraction intensity.
  • Figure 2 shows a differential scanning calorimetry diagram of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the temperature and the vertical axis (Y-axis) being the heat flow.
  • Figure 3 is a graph showing the thermogravimetric analysis of Form I of the compound of Formula A, with the horizontal axis (X-axis) being the temperature and the vertical axis (Y-axis) being the weight percent.
  • crystalline form of the invention refers to crystalline form I of the compound of formula A.
  • compound of formula A or "(3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-" Methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide refers to a compound having the chemical structure of formula A below (also Can be called compound A):
  • C1-6 alkyl alcohol refers to a fully saturated linear or branched alkyl alcohol having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples thereof include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, n-hexanol, and the like.
  • halogenated alkane having less than three carbon atoms means a fully saturated hydrocarbon having 1 or 2 carbon atoms which is substituted by one or more halogen atoms selected from F, Cl, Br or I. Examples thereof include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like.
  • solution refers to a mixture of one or more solutes in one or several solvents for a particular use.
  • solution is meant a homogeneous mixture, and a multi-phase mixture, such as a beater or other suspension mixture containing insolubles.
  • organic solvent refers broadly to any suitable organic solvent for a particular use herein.
  • solvent means any suitable organic solvent which can partially or completely dissolve the solute under suitable conditions, such as a suitable amount, a suitable temperature, such as room temperature or elevated temperature.
  • anti-solvent solvent refers to any suitable organic solvent in which the solubility of the material is less than the solubility in the dissolved solvent.
  • an "effective amount" of a compound of formula A and a crystalline form of a compound of formula A which refers to a dose administered to a patient
  • the amount of the drug in this amount, can effectively alleviate and improve a certain cancer that inhibits the overexpression and/or excessive activity of the epidermal growth factor receptor, and the individual can be a human or an animal.
  • the cancer in which the inhibition of epidermal growth factor receptor overexpression and/or excessive activity is inhibited may be, but not limited to, lung cancer, head and neck cancer, colorectal cancer, pharyngeal cancer, epidermoid carcinoma, and pancreatic cancer.
  • the "effective amount” will vary depending on the compound, the condition being treated, the severity of the condition being treated, the age and associated condition of the individual, the route and form of administration, the judgment of the attending physician or the veterinary practitioner, and the like. .
  • mammals means both mammalian and non-mammal.
  • Mammal means any member of the mammalian class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and pigs; domestic animals such as rabbits , dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs; Examples of non-mammals include, but are not limited to, birds and the like.
  • the term "individual” does not mean a particular age or gender.
  • the present invention provides the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 , a new crystalline form of 4-b]pyrrole-5(1H)-carboxamide.
  • the crystalline form I of the present invention has the characteristics of good crystallinity, non-hygroscopicity and stability, and has acceptable oral bioavailability, and is suitable for preparation of an oral pharmaceutical preparation.
  • the reproducibility of the crystalline form I of the present invention is good, and reproducible amplification can be carried out to produce the crystalline form I; and it is stable in a common preparation, thereby facilitating the production of a preparation and use in the treatment of a disease.
  • the crystal form I of the present invention has high purity; less solvent residue, which meets the requirements for the quality of the drug substance, such as the requirement of ICH Q3A.
  • the crystalline form of the invention can be carried out by one or several solid state analytical methods Identification.
  • the crystalline form of the present invention can be carried out by one or more methods such as powder X-ray diffraction, single crystal lattice parameters, Fourier infrared spectroscopy, differential scanning calorimetry data, and/or thermogravimetric curves. Identification. And if the result of the discrimination analysis of one of the methods is consistent with the crystal form of the present invention, it does not mean that the identification result of any of the other methods is inconsistent with the crystal form of the present invention.
  • the new crystal form can be identified by powder X-ray diffraction spectroscopy.
  • the peak intensities and/or peak conditions of powder X-ray diffraction may vary depending on experimental conditions, such as different diffraction test conditions and/or orientation preferences.
  • the measured 2 ⁇ value will have an error of about ⁇ 0.2 2 ⁇ .
  • the relative intensity value of the peak is more dependent on the properties of the sample than the position of the peak, such as the size of the crystal in the sample, the orientation of the crystal, and the purity of the material being analyzed, thus the peaks thus displayed.
  • a strength deviation of about ⁇ 20% or more is possible.
  • those skilled in the art can obtain sufficient information for discriminating the crystal form I from the XRPD data provided in this patent.
  • the present invention provides Form I of the compound of Formula A.
  • Form I of the compound of Formula A can be identified by X-ray powder diffraction.
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 10.1 degrees, 12.2 degrees, 13.1 degrees, 16.2 degrees, and the measured 2 ⁇ values are An error of about ⁇ 0.2 2 ⁇ .
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 22.6. Degree, 25.4 degrees, the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • powder X-ray diffraction characteristic diffraction of Form I of a compound of Formula A The angles (2 ⁇ ) are 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 17.3 degrees, 18.1 degrees, 20.5 degrees, 22.6 degrees, 23.1 degrees, At 25.4 degrees and 26.6 degrees, the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.8 degrees, 16.2 degrees, 17.3 degrees, 18.1 degrees, 18.8 degrees, 20.5 degrees, 21.1 degrees, 22.6 degrees, 23.1 degrees, 24.1 degrees, 25.4 degrees, 26.6 degrees, 27.2 degrees, and the measured 2 ⁇ values have about ⁇ 0.2 2 ⁇ . error.
  • the powder X-ray diffraction characteristic diffraction angle (2 ⁇ ) of Form I of the compound of Formula A is 5.4 degrees, 6.5 degrees, 8.0 degrees, 10.1 degrees, 10.8 degrees, 12.0 degrees, 12.2 degrees, 13.1 degrees, 14.4, 14.8, 16.2, 17.3, 18.1, 18.8, 20.5, 21.1, 22.6, 23.1, 24.1, 25.4, 26.6, 27.2, 29.9, 30.7.
  • the measured 2 ⁇ value has an error of about ⁇ 0.2 2 ⁇ .
  • Form I of the compound of Formula A has a diffraction pattern as shown in FIG. Those skilled in the art can obtain sufficient information for identifying Form I of the compound of Formula A from the XRPD data provided in this patent, despite experimental error, instrumental error, and orientation preference.
  • Form I of the compound of Formula A can be identified by differential scanning calorimetry. In some embodiments, Form I of the compound of Formula A has a differential scanning calorimetry curve as shown in FIG. In the DSC spectrum, the endothermic peak of Form I of the compound of Formula A is between about 259.4 and 261.7 °C.
  • Form I of the compound of Formula A can be identified by thermogravimetric analysis.
  • Form I of the compound of Formula A has a thermogravimetric analysis curve as shown in Figure 3, which shows that Form I is an anhydride or a pure crystal.
  • the compound of formula A has a Form I weight content of at least 99%, At least 95%, at least 90%, or as low as 80%. Still alternatively, the crystalline form I compound has a Form I weight content of at least 70%, or at least 60%. Further or more, the compound of formula A has a Form I weight content of at least 50%.
  • This patent relates to a process for the preparation of Form I of a compound of formula A, comprising:
  • the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1- Methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide is preferably a solid, such as a single crystal form, such as Form I, or two or more crystal forms. mixture.
  • the compound (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1 -Methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide is not completely dissolved in the suspension system, i.e., some of the compounds are present in solid form.
  • the water-miscible organic solvent accounts for a volume of the mixed solvent.
  • the score is less than about 95%.
  • the water miscible organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylacetamide, and acetonitrile.
  • the selected water-miscible organic solvent is ethanol, the volume percentage of ethanol is not less than about 10%.
  • the water miscible organic solvent and water are mixed in a suitable ratio.
  • the volume ratio of water-miscible organic solvent to water is from about 9:1 to about 1:9, or about 1:1, such as ethanol/water (volume ratio is from about 9:1 to about 1:9) ).
  • the suspension in the step (2), may be heated while stirring, and the heating temperature should be no higher than the boiling point of the solvent system, for example, about 40 degrees, about 60 degrees, and about 80 degrees.
  • the heating can promote the conversion of the solid in the suspension system to Form I of the compound of Formula A.
  • the suspension in the step (2), may be stirred for a period of 20 to 100 hours, such as at least 24 hours, at least 48 hours, at least 60 hours, and at least 72 hours.
  • This patent relates to another method of preparing Form I of a compound of Formula A, comprising:
  • the dissolving solvent is selected from the group consisting of N,N-dimethylformamide or N,N- Dimethylacetamide.
  • the reverse dissolution solvent is selected from the group consisting of acetonitrile.
  • the volume ratio of the dissolving solvent to the anti-solvent solvent is from about 1:10 to about 5:1, such as 0.3/1.
  • compositions and methods of treatment are provided.
  • Form I of the compound of formula A can be used in the treatment of diseases such as cancer.
  • the cancer includes, but is not limited to, lung cancer, head and neck cancer, colon cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and sarcoma, such as Soft tissue sarcoma, as well as leukemia.
  • compositions of formula A comprising administering an active pharmaceutical ingredient formed from a compound of formula A, or a pharmaceutically acceptable salt thereof, or Form I of the inventive compound of formula A.
  • such a method of treatment is directed to at least one method of inhibiting epidermal growth factor receptor overexpression and/or overactivation, such as cancer.
  • an effective amount of a pharmaceutical composition of the invention is administered to an individual in need thereof, the pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and Form I of the compound of Formula A.
  • the amount of the at least one active pharmaceutical ingredient selected from the compound of the formula A and/or a pharmaceutically acceptable salt thereof, or the crystalline form I of the compound of the formula A to achieve the desired physiological effect depends on various factors, for example, the purpose of use, The mode of administration, as well as the clinical condition of the patient.
  • the daily dose may be, for example For example, ranging from 0.01 mg to 3 g per day (eg, from 0.05 mg to 2 g per day, or even from 100 mg to 1 g per day).
  • Unit dosage formulations which can be administered orally include, for example, tablets or capsules.
  • Form I of the compound of Formula A can be administered in the form of the compound itself, but usually they are used in the form of a pharmaceutical composition in combination with one or more pharmaceutically acceptable carriers or excipients. .
  • a representative carrier or excipient should be compatible with the other ingredients of the composition and will not compromise the health of the patient.
  • the carrier or excipient may be either solid or liquid, or both, in combination with Form I of the compound of Formula A, in a pharmaceutical composition or unit dosage form (eg, tablet, capsule), which may contain 0.05% by weight. Up to 95% of the compound of formula A.
  • the pharmaceutical compositions described in the present invention can be prepared by known pharmaceutical preparation methods, for example, by mixing with a pharmaceutically acceptable carrier and/or adjuvants and diluents, and the like.
  • representative carriers or adjuvants include, but are not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, disintegrants such as starch, croscarmellose sodium. , complex silicates and high molecular weight polyethylene glycols, granulating binders (such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic), and lubricants (such as magnesium stearate, glycerin and talc).
  • microcrystalline cellulose lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine
  • disintegrants such as starch, croscarmellose sodium.
  • complex silicates and high molecular weight polyethylene glycols such as polyvinylpyrrolidone, sucrose, gelatin, gum arabic
  • lubricants such as magnesium stearate, glycerin and talc
  • Form I of the compound of Formula A can be combined with at least one component, such as a carrier and/or adjuvant and/or diluent, which can be selected from sweeteners, flavoring agents. , colorants, dyes and emulsifiers.
  • a carrier and/or adjuvant and/or diluent which can be selected from sweeteners, flavoring agents. , colorants, dyes and emulsifiers.
  • Form I of the compound of Formula A does not undergo conversion when formulated with one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents.
  • Form I of the compound of Formula A may be converted, when formulated in one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents, in whole or in part converted to a One or more crystalline forms, including conversion to a non-solid form.
  • Exemplary carriers and/or adjuvants and/or diluents include, but are not limited to, water, Ethanol, propylene glycol, glycerin, and mixtures thereof.
  • Form I of the present invention can be dissolved when formulated into a pharmaceutical composition. Thus, in these "dissolved” examples, Form I is no longer present in crystalline form in the pharmaceutical composition.
  • Form I of the compound of Formula A is administered in a suitable formulation.
  • compositions described herein may be those which are suitable for oral and oral (e.g. sublingual) administration, and the appropriate mode of administration may depend on the condition of each case and the severity of the treatment. It also depends on the nature of the particular form of Form I of the compound of Formula A used in the preparation of a pharmaceutical composition.
  • the pharmaceutical compositions described herein may also be in the form of a coated dosage form and a coated sustained release dosage form. Acidic and anti-gastric dosage forms are also possible. Suitable anti-gastric coating materials include cellulose acetate phthalate, polyvinyl acetate phthalic acid, cellulose hydroxypropyl methyl phthalate, anionic polymers of methacrylic acid, methyl methacrylate .
  • Suitable pharmaceutical compositions for oral administration from Form I of the compound of formula A may also be in unit dosage form, for example, capsules, cachets and tablets, including suckable tablets, each consisting of At least one active pharmaceutical ingredient of the invention is prepared quantitatively; the formulation may also be selected from powders, granules, solutions, suspensions in water or non-aqueous liquids, oil-in-water and water-in-oil emulsions. These compositions may also be prepared as described above by any suitable pharmaceutical formulation, for example, including the following steps: Form I of the compound of Formula A, and carriers and/or adjuvants and/or diluents (optional) One or more of the added ingredients are combined). These compositions are generally prepared by uniformly and homogeneously mixing Form I of the compound of Formula A with a liquid or a finely divided solid carrier, the product of which may be shaped.
  • compositions of the invention may be administered topically or systemically.
  • compositions suitable for oral (including sublingual) administration can be made into a formable tablet comprising Form I of the compound of Formula A and a flavoring agent.
  • Flavoring agents are typically selected from the group consisting of sucrose, gum arabic, tragacanth, and the like.
  • compositions of the present invention may also be those which can be administered parenterally, such as inhalation sprays, or implantable reservoirs.
  • Solid carriers for use therein include, for example, starch, lactose, microcrystalline cellulose, aluminosilicates, and any suitable ingredients.
  • Liquid carriers include, for example, water for injection, polyvinyl alcohol, nonionic surfactants, and corn oil, as well as any suitable ingredients.
  • Other commonly used pharmaceutical formulation excipients include coloring agents, preservatives, flavoring agents, and antioxidants such as vitamin E, vitamin A, BHT, and BHA.
  • Form I of the compound of formula A according to the invention may also be administered intraperitoneally.
  • Solutions and suspensions of the compounds can be prepared by dissolving or suspending these compounds in water containing the surfactant.
  • Dispersed suspensions may be prepared from glycerol, polyethylene glycol (PEG) or mixtures thereof with a suitable oil.
  • Preservative ingredients can be added to these formulations to prevent the growth of microorganisms during use.
  • Injectable formulations include non-toxic aqueous solutions or suspensions and non-toxic powders. In all of these cases, these dosage forms must be non-toxic, easily transferable from the syringe, stable under the conditions of manufacture and storage, and free from contamination and microbial infections.
  • the carrier can be a solvent or dispersing agent, including water, alcohol, and some suitable oils.
  • Form I of the compound of formula A can also be used in combination with one or more other active ingredients (e.g., in a synergistic treatment).
  • the active ingredients may be separate compositions for simultaneous administration by the same or different routes of administration in therapy or separately (eg, sequentially administered in any order) at different times, or they may be the same
  • the pharmaceutical compositions are administered together.
  • Form I of a compound of Formula A can be administered concurrently with one or more other active ingredients known to have therapeutic effects, such as for treatment of inhibition of epidermal growth factor receptor overexpression and/or overactivity.
  • Affected diseases such as cancer.
  • anti-tumor method May refer to any method for the treatment of cancer.
  • anti-tumor methods include, but are not limited to, radiotherapy, immunotherapy, chemotherapy for DNA damage, and chemotherapy for disrupting cell replication.
  • topoisomerase I inhibitors eg, irinotecan, topotecan, camptothecin, and analogs or metabolites thereof
  • Topoisomerase II inhibitors eg, etoposide, teniposide, daunorubicin
  • alkylating agents eg, melphalan, chlorambucil, busulfan, thiotepa, Cyclophosphamide, carmustine, lomustine, semustine, streptozotocin, dacarbazine, methotrexate, mitomycin, cyclophosphamide
  • DNA intercalators eg, cis Platinum, oxaliplatin and carboplatin; DNA intercalators and free radical generators such as bleomycin; and nucleoside analogues (eg 5-fluorouracil, capecitabine, gemcitabine, fludarabine, Cytara
  • Chemotherapy drugs that disrupt cell replication including but not limited to: paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, related analogs; thalidomide and related analogs (eg, CC-5013 and CC-) 4047); protein tyrosine kinase inhibitors (eg, imatinib mesylate, furazolinib, and gefitinib); protease inhibitors (eg, bortezomib); inhibitors of NF- ⁇ B, Kinase inhibitors including I ⁇ B; antibodies that bind to overexpressed proteins in cancer, which can downregulate cell replication (eg, rituximab, cetuximab, bevacizumab, etc.); other known in cancer An inhibitor of a protein or enzyme that is up-regulated or over-expressed or activated, which can down-regulate cell replication by inhibiting these proteins or enzymes.
  • the methods described herein are not limited to the order of administration, and one or more additional active ingredients may be administered either simultaneously or after administration or administration.
  • the starting material of the compound of formula A used in the examples was prepared according to CN102906086A.
  • Differential scanning calorimetry analysis is measured by a DSC 7 from Perkin Elmer (purge gas: nitrogen, flow rate: 50mL min -1, temperature rise rate: 5-10 °C / min, measuring range: 25 °C ⁇ 200 °C) measured sample
  • the measurement used a rolled aluminum pan and temperature correction using indium.
  • Thermogravimetric analysis was determined by Perkin Elmer's TGA7 (purge gas: nitrogen, flow rate: 50 mL min-1, temperature increase rate: 10 ° C/min).
  • Solvent condition result Solvent usage (volume/mass ratio) Methanol 50 ° C / 3 days Crystal form I 10 times Ethanol 50 ° C / 3 days Crystal form I 10 times Isopropanol 50 ° C / 3 days Crystal form I 10 times Tetrahydrofuran 50 ° C / 3 days Crystal form I 10 times Dichloromethane 50 ° C / 3 days Crystal form I 10 times acetone 50 ° C / 3 days Crystal form I 10 times Butanone 50 ° C / 3 days Crystal form I 10 times Acetonitrile 50 ° C / 3 days Crystal form I 10 times Toluene 50 ° C / 3 days Crystal form I 10 times Ethanol/water (9:1, V/V) Room temperature / 66 hours Crystal form I 30 times
  • Determination method The test sample of the formula I of the compound of the formula A prepared by the above examples was weighed and placed in a petri dish, and the opening was placed in a sealed clean container at a temperature of 60 ° C, 25 ° C and relative humidity, respectively. After being placed for 92 days at 92.5% ⁇ 5% and illuminance at 4500lx ⁇ 500lx, sampling, the purity of the sample (using HPLC analysis) and the crystal form (using X-ray powder diffraction analysis) were investigated, and the results were compared. The results are shown in Table 3.
  • Determination method Weigh two samples of the crystal form I prepared by the foregoing examples, placed in two Petri dishes, respectively, and the exposed openings were placed in a sealed clean container having a relative humidity of 92.5% and 75%, room temperature. After 10 days under the test, the sample weight was weighed and placed for 10 days, and the moisture absorption weight percentage and crystal form (using X-ray powder diffraction analysis) of the sample were calculated in comparison with the sample weight before the start of the test. The results are shown in Table 4.
  • Form I is placed under high humidity conditions for 10 days, and the moisture absorption gain is only 0.01%.
  • Form I is non-hygroscopic. During the placement process, the crystal form does not change. Form I is stable.
  • a compound of formula A prepared by the foregoing examples, which is Form I, has a purity of 98.5%.
  • HS 15 polyethylene glycol stearate
  • Preparation of intravenous administration solution of compound of formula A warm water heating HS 15, after the fluidity became better, take 22.5 mL, add 22.5 mL of physiological saline, vortex and mix it evenly, and prepare a mixture solution of Solutol and physiological saline (volume ratio 1:1) for use.
  • the crystalline form I of the compound of formula A was weighed 108.47 mg, 1.06 mL of DMSO was added, 90 ⁇ L of 12 M HCl was added, and vortexed to obtain a yellow clear transparent solution.
  • HS 15 and saline mixed solution (volume ratio of 1:1) 42.6mL, vortex 1min, ultrasound for 2min, add physiological saline to 212.8mL, for intravenous injection.
  • the final intravenous preparation is 10% Physiological saline solution of HS 15, 0.5% DMSO and 0.04% 12 M HCl.
  • Formulation for Oral Administration of Compound A of Formula A According to the body weight of the animal and the dose to be administered, an appropriate amount of the compound I of the formula A is weighed and filled into a capsule for human (CAPSUGEL, Lot#: 12832590), a dog Give a capsule.
  • 6 beagle dogs, half male and half female. Dosing was administered in 4 experimental cycles, self-control.
  • the first, second and third cycles are oral administration of 1.0, 2.5 and 7.5 mg/kg for single administration (the above-mentioned formulated oral administration preparation), and the fourth period is intravenous administration of 1.0 mg/kg for single administration (the above preparation) Intravenous preparation).
  • the cleaning period during the week is one week. Animals were fasted overnight before dosing and fed 30 min before dosing. Before each dose was administered, blank blood was taken. After intravenous administration, 1 ml of blood was taken through the forelimb vein at 5 min, 15 min, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours.
  • the method of precipitating protein by acetonitrile was carried out by adding 150 ⁇ l of an internal standard acetonitrile solution to 50 ⁇ l of the plasma sample to be shaken for 2 min, centrifuging at 14,000 rpm for 10 min, then taking 150 ⁇ l of the supernatant, diluting twice with 150 ⁇ l of ultrapure water, and taking 10 ⁇ L of the injection analysis.
  • the drug concentration of the compound of formula A in the biological sample was determined by LC-MS/MS analysis.
  • the instrument is an API4000 triple quadrupole mass spectrometer from Applied Biosystem of the United States and a 1200 series liquid chromatography system from Agilent, Germany.
  • the column was a CAPCELL PAK C 18 column (MG, 50 x 2.0 mm, 5 ⁇ m).
  • ESI electrospray ionization source
  • Kinetica 4.0 American Thermo-Fisher pharmacokinetic software was used for data analysis and pharmacokinetic parameters were calculated using the non-compartment model statistical moment method. C max and T max is found.
  • the average exposure (AUC 0- ⁇ ) in vivo was 714 h ⁇ ng/mL; the terminal phase half-life (t 1/2 ) was 4.12 hours.
  • the average exposure (AUC 0- ⁇ ) in vivo was 228, 1126 and 5424 h ⁇ ng/mL, respectively; the terminal phase half-life after oral administration was 3.22 and 4.20, respectively. And 7.71 hours.
  • the half-life of oral doses of 1 and 2.5 mg/kg was about 4 hours.
  • the blood concentration of the 7.5 mg/kg dose group was slower than that of the 1 and 2.5 mg/kg dose groups. The blood concentration was still 24 hours after administration. More than 50 ng/mL.
  • the oral absolute bioavailability calculated by the mean of the in vivo plasma exposure (AUC 0- ⁇ ) obtained by oral and intravenous injection of the same dose (1 mg/kg) was 30.6 ⁇ 15.0%.
  • Form I Compound I Form I has acceptable oral bioavailability and is suitable for the preparation of oral pharmaceutical preparations.

Abstract

本发明属于药学领域，提供了化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型、其药物组合物，及其制备方法和应用。

Description

化合物的晶型 技术领域
本发明属于药学领域，提供了化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的新晶型、其药物组合物，及其制备方法和应用。
背景技术
表皮生长因子(EGF)与表皮生长因子受体(EGFR)结合能激活酪氨酸激酶活性，从而引发导致细胞增殖的反应。EGFR的过量表达和/或过度活化可导致失控的细胞分裂，失控的细胞分裂可以是癌症的诱因。因此，能抑制EGFR过量表达和/或过度活化的化合物是治疗肿瘤的候选物。
本发明相关化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺，其化学结构见式A，具有有效抑制EGFR过量表达和/或过度活化的作用。因此，可用于与EGFR的过量表达和/或过度活化相关疾病的治疗，例如癌症的治疗。
Figure PCTCN2017114194-appb-000001
在发现一种化合物的晶型之前，很难预知(1)特定的化合物是否存在晶体形式；(2)如何制得未知的晶型；(3)晶型的性质会是怎样的，例如稳定性、生物利用度等。
由于固体的特性取决于结构和化合物本身的性质，因此，化合物的不同固体形式经常表现出不同的物理和化学性质。化学性质的差异可以通过多种分析技术手段来测定、分析和比较，而这些差异最终可以用来区分这些存在的不同固体形态。物理性质的差异，例如溶解度和生物利用度，在描述药物化合物的固体形态时也很重要。同样地，在药物化合物，例如式A化合物的开发中，药物化合物的新晶体和无定型形态也很重要。
专利CN102906086A揭示了化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺及其制备方法。
发明内容
概述
经过大量探索研究，我们发现式A化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺)可以存在结晶型态。我们对式A化合物进行了大量研究，确定并制备得到符合药用需求的结晶型态。基于这些研究，本发明提供了式A化合物的晶型I。
一方面，本发明提供了(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的I型晶体，即式A化合物的晶型I。
本发明提供的式A化合物的晶型I具有结晶性好、无吸湿性和稳定的特性，而且具有可接受的口服生物利用度。
另一方面，本发明提供了式A化合物的晶型I的制备方法，这些制备方法是可重复的，并且易于操作。
又一方面，本发明提供了药物组合物，所述的药物组合物含有有效量的式A化合物的晶型I，以及余量的至少一种药学上可接受的载体。
本发明还提供了一种治疗对抑制表皮生长因子受体过量表达和/或过度活性有影响的癌症的方法。该方法包括向有需要的个体施用有效量的式A化合物的晶型I。
本发明还提供了式A化合物的晶型I用于制备药物的用途，所述药物用于治疗对抑制表皮生长因子受体过量表达和/或过度活性有影响的癌症，如肺癌、头颈癌、结直肠癌、咽癌、表皮样癌和胰腺癌。
附图说明
图1表示式A化合物的晶型I的粉末X-射线衍射图，横轴(X-轴)是衍射角度2θ，纵轴(Y-轴)是衍射强度。
图2表示式A化合物的晶型I的差示扫描量热图，横轴(X-轴)是温度，纵轴(Y-轴)是热流。
图3表示式A化合物的晶型I的热重分析图，横轴(X-轴)是温度，纵轴(Y-轴)是重量百分数。
定义
除非另有说明，否则本申请(包括说明书和权利要求书)中所用的下列简称或术语具有下文所给出的定义。必需注意到的是，本说明书和所附权利要求书中所用的单数形式也包括复数形式，除非上下文清楚显示并非如此。
本文所使用的“本发明的晶型”指式A化合物晶体形式晶型I。
本文所使用的“式A化合物”或“(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7- 甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺”是指具有如下式A化学结构的化合物(也可称为化合物A)：
Figure PCTCN2017114194-appb-000002
本文所使用的“C1-6烷基醇”是指具有1、2、3、4、5或6个碳原子的完全饱和的直链或支链烷基醇。其实例包括但不限于甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、正戊醇、异戊醇、正己醇等。
本文所使用的“少于三个碳原子的卤代烷烃”是指具有1或2个碳原子的完全饱和的烃，其被一个或多个选自F、Cl、Br或I的卤素原子取代。其实例包括二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷等。
本文所使用的“约”是指偏离具体给定的数值至多±10％。
本文所使用的“溶液”指某种用途的一种或几种溶质在一种或几种溶剂中的混合物。溶液意指包括均相混合物，和多相混合物，如打浆液或其他含有不溶物的混悬混合物。
本文所使用的“有机溶剂”泛指用于文中某种用途的任何恰当的有机溶剂。
本文所使用的“溶解溶剂”指在适当条件下，如适当的量，适当的温度，如室温或升温等，任何可以部分或全部溶解溶质的恰当有机溶剂。
本文所使用的“反溶解溶剂”指任何恰当的有机溶剂，物质在其中的溶解度小于在溶解溶剂中的溶解度。
式A化合物以及式A化合物的晶型的“有效量”，指给患者服用的一 个药物数量，在此数量下能有效的减轻、改善某种对抑制表皮生长因子受体过量表达和/或过度活性有影响的癌症，服用个体可以是人，也可以是动物等受试者，其中对抑制表皮生长因子受体过量表达和/或过度活性有影响的癌症可以是，但不限于肺癌、头颈癌、结直肠癌、咽癌、表皮样癌和胰腺癌等。“有效量”将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医从业者的判断等多种因素而变化。
本文所使用的“个体”意指哺乳动物和非哺乳动物。哺乳动物意指哺乳动物类的任何成员，包括但不限于人；非人灵长类动物如黑猩猩和其它猿类和猴类；农场动物如牛、马、绵羊、山羊和猪；家养动物如兔、犬和猫；实验室动物，包括啮齿动物，如大鼠、小鼠和豚鼠；等。非哺乳动物的实例包括但不限于鸟类等。术语“个体”并不表示特定的年龄或性别。
发明详述
本发明提供了化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的新晶型。
本发明的晶型I具有结晶性好、无吸湿性和稳定性好的特性，而且具有可接受的口服生物利用度，适合制备口服药物制剂。本发明的晶型I的重现性好，可以实现重复性放大生产晶型I；而且其在普通制剂中稳定，因而方便制剂生产和治疗疾病时使用。另外，本发明的晶型I纯度高；溶剂残留少，符合原料药质量要求，例如ICH Q3A的要求。
本领域技术人员可以基于药典中公开的测试方法、其变通方法或本领域的常规方法对本发明晶型的以上优势进行验证。
如本文所述，本发明的晶型可以通过一种或几种固态分析的方法进行 鉴定。例如，本发明的晶型可以通过一种或多种方法，如粉末X-射线衍射、单晶的晶格参数、傅里叶红外光谱、差示扫描量热分析数据和/或热重曲线进行鉴定。并且如果其中一种方法的鉴别分析结果与本发明的晶型一致，并不表示其他任何一种方法的鉴定结果是与本发明的晶型不一致。
如本文所述，新晶型可以通过粉末X-射线衍射谱进行鉴定。然而，本领域技术人员知道，粉末X-射线衍射的峰强度和/或者峰情况可能会因为实验条件的不同而不同，如不同的衍射测试条件和/或者取向优先等。同时由于不同仪器的精确度不同，测得的2θ值会有约±0.2 2θ的误差。然而，已知的是峰的相对强度值比峰的位置更依赖于所测定样品的某些性质，例如样品中晶体的尺寸、结晶的取向作用和被分析的材料的纯度，因此所显示的峰强度偏差在约±20％或更大范围是可能出现的。但是，尽管存在试验误差、仪器误差和取向优先等，本领域技术人员还是可以从本专利提供的XRPD数据获取足够的鉴别晶型I的信息。
晶型I
本发明提供了式A化合物的晶型I。
在一些实施方案中，式A化合物的晶型I可以通过X-射线粉末衍射进行鉴别。在一些实施方案中，式A化合物的晶型I的粉末X-射线衍射特征衍射角(2θ)是5.4度、6.5度、10.1度、12.2度、13.1度、16.2度，测得的2θ值有约±0.2 2θ的误差。
在一些实施方案中，晶型I的粉末X-射线衍射特征衍射角(2θ)是5.4度、6.5度、8.0度、10.1度、10.8度、12.2度、13.1度、14.8度、16.2度、22.6度、25.4度，测得的2θ值有约±0.2 2θ的误差。
在一些实施方案中，式A化合物的晶型I的粉末X-射线衍射特征衍射 角(2θ)是5.4度、6.5度、8.0度、10.1度、10.8度、12.0度、12.2度、13.1度、14.8度、16.2度、17.3度、18.1度、20.5度、22.6度、23.1度、25.4度、26.6度，测得的2θ值有约±0.2 2θ的误差。
在一些实施方案中，式A化合物的晶型I的粉末X-射线衍射特征衍射角(2θ)是5.4度、6.5度、8.0度、10.1度、10.8度、12.0度、12.2度、13.1度、14.8度、16.2度、17.3度、18.1度、18.8度、20.5度、21.1度、22.6度、23.1度、24.1度、25.4度、26.6度、27.2度，测得的2θ值有约±0.2 2θ的误差。
在一些实施方案中，式A化合物的晶型I的粉末X-射线衍射特征衍射角(2θ)是5.4度、6.5度、8.0度、10.1度、10.8度、12.0度、12.2度、13.1度、14.4度、14.8度、16.2度、17.3度、18.1度、18.8度、20.5度、21.1度、22.6度、23.1度、24.1度、25.4度、26.6度、27.2度、29.9度、30.7度。测得的2θ值有约±0.2 2θ的误差。
在一些实施方案中，式A化合物的晶型I具有如图1所示的衍射谱图。尽管存在试验误差、仪器误差和取向优先等，本领域技术人员还是可以从本专利提供的XRPD数据获取足够的鉴别式A化合物的晶型I的信息。
在一些实施方案中，式A化合物的晶型I可用差示扫描量热分析进行鉴定。在一些实施方案中，式A化合物的晶型I具有如图2所示的差示扫描量热分析曲线。在DSC谱图中，式A化合物的晶型I的吸热峰在约259.4-261.7℃。
在一些实施方案中，式A化合物的晶型I可用热重分析进行鉴定。在一些实施方案中，式A化合物的晶型I具有如图3所示的热重分析曲线，其显示该晶型I是无水物或纯晶。
在一些实施方案中，例如式A化合物的晶型I重量含量至少达到99％， 至少95％，至少90％，或更低至80％。又或者，式A化合物的晶型I重量含量至少达到70％，或至少60％。或更进一步，式A化合物的晶型I重量含量至少达到50％。
晶型I的制备方法
方法A
本专利涉及式A化合物的晶型I的制备方法，包括:
(1)将化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺混悬于适量的一种溶剂或几种溶剂的混合溶剂中；其中，所述溶剂选自溶解溶剂(例如N,N-二甲基乙酰胺、C1-6烷基醇、四氢呋喃、少于三个碳原子的卤代烷烃、丙酮、丁酮、乙腈和甲苯)、或者水互溶性有机溶剂和水组成的混合溶剂；
(2)搅拌步骤(1)得到的混悬液；
(3)分离得到(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型I固体；
(4)干燥步骤(3)所得固体。
在一些实施方案中，所述步骤(1)所用化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺优选是固体，例如一种单一晶型，例如晶型I，也可以是两种或更多种晶型的混合物。
在一些实施方案中，所述步骤(1)中，化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺在混悬体系中未被完全溶解，即其中部分化合物是以固体形式存在的。
在一些实施方案中，所述水互溶性有机溶剂占所述混合溶剂的体积百 分数小于约95％。
在一些实施方案中，所述水互溶性有机溶剂选自丙酮、甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基乙酰胺和乙腈。当所选水互溶性有机溶剂为乙醇时，乙醇所占体积百分比不少于约10％。
在一些实施方案中，所述水互溶性有机溶剂和水以适当比例混合。在一些实施方案中，水互溶性有机溶剂和水的体积比为约9:1到约1:9、或约1:1，例如乙醇/水(体积比为约9:1到约1:9)。
在一些实施方案中，所述步骤(2)中，搅拌混悬液的同时可以进行加热，加热温度应不高于溶剂体系沸点，例如约40度、约60度和约80度。所述加热可以促进混悬体系中固体转变成式A化合物的晶型I。
在一些实施方案中，所述步骤(2)中，搅拌混悬液的时间可以为20-100小时，例如至少24小时，至少48小时，至少60小时，至少72小时。
方法B
本专利涉及式A化合物的晶型I的另一种制备方法，包括：
(1)将化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺混合于至少一种溶解溶剂中，然后加热混合物得第1种溶液；
(2)向所述第1溶液中加入至少一种反溶解溶剂，得到第2溶液；
(3)将所述第2溶液自然冷却至室温；然后
(4)分离得到(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型I固体；
(5)干燥步骤(4)所得固体。
在一些实施方案中，其中，所述溶解溶剂选自N,N-二甲基甲酰胺或N,N- 二甲基乙酰胺。
在一些实施方案中，所述反溶解溶剂选自乙腈。
在一些实施方案中，所述溶解溶剂和反溶解溶剂的体积比是从约1：10到约5:1，例如0.3/1。
涉及式A化合物的晶型的上述制备方法的各个实施方案中的特征可以任意进行相互组合，这些相互组合得到的各个方案包括在本发明的范围内，就如同在本文中具体地且逐一地列出这些相互组合得到的方案一样。
药物组合物和治疗方法
式A化合物的晶型I可用于治疗的疾病，如癌症。所述癌症包括但不限于，肺癌，头颈癌，大肠癌，胰腺癌，结肠癌，乳腺癌，卵巢癌，前列腺癌，胃癌，肾癌，肝癌，脑癌，食道癌，骨癌和肉瘤，如软组织肉瘤，以及白血病。
本文提供了治疗对抑制表皮生长因子受体过量表达和/或过度活化有影响的癌症的方法，包括施用由式A化合物形成的活性药物成分，或者是其药学上可接受的盐，或者是本发明的式A化合物的晶型I。
在一些实施方案中，这种治疗方法至少针对一种对抑制表皮生长因子受体过量表达和/或过度活化有影响的疾病的方法，如癌症。其中，向有需要的个体施用有效量的本发明的药物组合物进行治疗，所述药物组合物中包含至少一种药学可接受载体，以及式A化合物的晶型I。
选自式A化合物和/或其药学上可接受的盐、或式A化合物的晶型I的至少一种活性药物成分达到预期生理作用的给药量取决于多种因素，例如，使用目的，给药方式，以及病人的临床状况。每天的剂量可能是，例 如，范围从0.01mg到3g每天(如从0.05mg到2g每天，甚至从100mg到1g每天)。可口服给药的单位剂量制剂包括，例如片剂或胶囊。
为达到以上提到的治疗目的，式A化合物的晶型I可以以化合物本身的形式给药，但是通常它们都以与一种或多种可药用载体或辅料组成药物组合物的形式来使用。
代表性的载体或辅料应该是与组合物中其它成分相容的，并且不会危害患者的健康。载体或辅料可以是固体或液体，或是两者都有，它们与式A化合物的晶型I组成药物组合物或单位剂型(例如，片剂、胶囊剂)，它可含以重量计0.05％到95％的式A化合物。本发明中所述的药物组合物可由已知的药物制备方法制得，例如方法中包括与药学上可接受的载体和/或辅料及稀释剂的混合等。
在一些实例中，代表性的载体或辅料包括但不限于：微晶纤维素，乳糖，柠檬酸钠，碳酸钙，磷酸氢钙，甘氨酸，崩解剂如淀粉，交联羧甲基纤维素钠，复合硅酸盐及高分子量的聚乙二醇，造粒粘合剂(如聚乙烯吡咯烷酮，蔗糖，明胶，阿拉伯胶)，和润滑剂(例如硬脂酸镁，甘油和滑石粉)。
在一些实例中，式A化合物的晶型I可与至少一种组分组合起来，所述组分例如是载体和/或辅料和/或稀释剂，其可以选自甜味剂、矫味剂、着色剂、染料和乳化剂。
在一些实例中，式A化合物的晶型I不会在与一种或多种药学上可接受的载体和/或辅料和/或稀释剂制成制剂时发生转化。在另一些实例中，式A化合物的晶型I在与一种或多种药学上可接受的载体和/或辅料和/或稀释剂制成制剂时可能会转化，其全部或部分地转化成一种或多种晶型，包括转化成非固态形式。示例性的载体和/或辅料和/或稀释剂包括但不限于：水、 乙醇、丙二醇、甘油和它们的混合物。在一些实例中，本发明的晶型I在制成药物组合物时可以被溶解。因此，在这些“溶解”的实例中，晶型I在药物组合物中已不再以晶型存在。
在一些实例中，式A化合物的晶型I被制成合适的制剂形式给药。
本发明所描述的药物组合物可以是那些适用于口服和经口(如舌下)的给药方式的剂型，而合适的给药方式可能取决于每个病例的病情以及治疗情况的严重性，也取决于式A化合物的晶型I在制备药物组合物中使用的具体形式的性质。本发明所描述的药物组合物也可以是包衣剂型及包衣缓释剂型。酸性的及抗胃液的剂型也是可能的。适用的抗胃液的包衣物质包括邻苯二甲酸乙酸纤维素、聚乙酸乙烯酯邻苯二甲酸、羟丙甲基邻苯二甲酸纤维素、甲基丙烯酸的阴离子聚合物、甲基丙烯酸甲酯。
由式A化合物的晶型I来制成用于口服的合适的药物组合物也可能是单位剂型的形式，例如，胶囊，扁囊和片剂，包括可吮吸的片剂，每一种都由至少一种本发明所述的活性药物成分定量地制得；其制剂形式也可以选自粉末，颗粒，溶液，在水或非水液体的混悬剂，水包油和油包水的乳剂。这些组合物也可如上文所述由任何适用的药物制剂的制备方法制得，例如，这些方法包括以下步骤：将式A化合物的晶型I以及载体和/或辅料和/或稀释剂(可由一个或更多的添加成分组成)混合起来。这些组合物通常可由式A化合物的晶型I和液体或经精细分割的固体载体均匀地、均相地混合制备而成，其产品是可以做成一定形状的。
本发明所述的组合物可以是局部地或全身地给药。
可适用于口服(包括舌下)给药的药物组合物可以制成可吮吸的片剂，其包含式A化合物的晶型I与矫味剂。矫味剂通常选自蔗糖、阿拉伯树胶、黄蓍胶等。
本发明所述的药物组合物也可以是指那些可以胃肠外给药的形式，例如吸入喷雾剂，或植入性的储槽。其中使用的固体载体物例如包括淀粉、乳糖、微晶纤维素、铝硅酸盐，以及任何适用的成分。液体载体例如包括注射用水、聚乙烯醇、非离子表面活性剂剂和玉米油，以及任何适用的成分。另一些通常用于药物制剂辅料包括着色剂、防腐剂、矫味剂和抗氧化剂，例如维生素E、维生素A、BHT和BHA。
本发明所述的式A化合物的晶型I也可以通过腹膜内给药。所述化合物的溶液剂和混悬剂可通过把这些化合物溶解或悬浮于含表面活性剂的水中来制备。分散的混悬剂可用甘油、聚乙二醇(PEG)或它们与适用的油的混合物制备而得。在这些制剂中可以加入防腐成分以阻止在使用中微生物的生长。
可注射的剂型包括无毒的水溶液剂或混悬剂以及无毒的粉末。所有这些情况，这些剂型必须是无毒的、可轻易从注射器中转移的，在生产及仓储条件下是稳定的，同时也是免于被污染及微生物感染的。载体可以是溶剂或分散剂，包括水、醇以及一些适用的油类。
式A化合物的晶型I也可以与一种或更多其它活性成分组合使用(例如在协同治疗中)。当被组合使用时，活性成分可以是分开的组合物，用于在治疗中通过相同或不同的施用途径同时施用或者在不同时间分别(例如以任何次序相继施用)施用，或者它们也可以在同一药物组合物中一起施用。
在一些实例中，式A化合物的晶型I可以和一种或多种已知有治疗作用的其它活性成分同时施用，如用于治疗对抑制表皮生长因子受体过量表达和/或过度活性有影响的疾病，例如癌症。
这里所说的“组合使用”是用来定义式A化合物的晶型I与一种或多种其它活性成分的联用，如在抗肿瘤方法中联用。此处，“抗肿瘤方法” 可指任何以治疗癌症为目的的方法。抗肿瘤方法的实例包括但不限于：放疗法、免疫法、致DNA损伤的化疗法、破坏细胞复制的化疗法。
致DNA损伤的化疗药物有很多，包括但不限于以下所述，例如，拓扑异构酶I抑制剂(例如，伊立替康、拓扑替康、喜树碱及其类似物或代谢产物与阿霉素)；拓扑异构酶II抑制剂(例如，依托泊苷、替尼泊苷、柔红霉素)；烷化剂(例如，马法兰、苯丁酸氮芥、白消安、塞替派、环磷酰胺、卡莫司汀、洛莫司汀、司莫司汀、链脲菌素、达卡巴嗪、甲氨蝶呤、丝裂霉素、环磷酰胺)；DNA嵌入剂(例如，顺铂、奥沙利铂和卡铂)；DNA嵌入剂及自由基发生器如博来霉素；和核苷类似物(如5-氟脲嘧啶、卡培他滨、吉西他滨、氟达拉滨、阿糖胞苷、巯基嘌呤、硫鸟嘌呤、喷司他丁、羟基脲)。
破坏细胞复制的化疗药物，包括但不限于：紫杉醇、多西紫杉醇和相关类似物；长春新碱、长春碱、有关类似物；沙利度胺和相关类似物(例如，CC-5013和CC-4047)；蛋白酪氨酸激酶抑制剂(例如，甲磺酸伊马替尼、呋喹替尼和吉非替尼)；蛋白酶抑制剂(例如，硼替佐米)；NF-κB的抑制剂，包括IκB的激酶抑制剂；与癌症中过度表达蛋白质结合的抗体，其可以下调细胞复制(例如，利妥昔单抗，西妥昔单抗，贝伐单抗等)；其他已知的在癌症中上调的或过度表达的或激活的蛋白质或酶的抑制剂，其通过抑制这些蛋白质或酶，可以下调细胞复制。
因此，本文所述的方法不限于给药的顺序，可以同时给药或给药之前或之后给予一种或多种的其他活性成分。
以下为非限制性的实例。
实验部分
实施例中所用的式A化合物原料根据CN102906086A制备得到。
本发明所用的所有试剂(除了中间体)均为商业市场购得。所有化合物的名称(除了试剂)由软件ChemBioDraw Ultra 12.0产生。
除另有注明外，粉末X射线衍射光谱是通过德国Bruker D8ADVANCE(靶：Cu，电压：40kV，电流：40mA，扫描速度：4度/分钟，步长：0.02度，测定范围：3-45度)测定。
差示扫描量热分析测定是通过Perkin Elmer公司的DSC7(吹扫气体：氮气，流速：50mL min-1，升温速度：5-10℃/分钟，测定范围：25℃→200℃)测定，样品测量使用了轧孔铝盘，使用铟进行温度校正。
热重分析通过Perkin Elmer公司的TGA7(吹扫气体：氮气，流速：50mL min-1，升温速度：10℃/分钟)测定。
实施例1 式A化合物的晶型I的制备
将适量式A化合物混悬于10倍(体积/质量比)量的乙醇/水(9:1，V/V)的混合溶剂中，于室温搅拌60小时，过滤，得固体样品。所得粉末样品为式A化合物的晶型I，其粉末X-射线衍射图谱如图1所示，其中的主要数据如下表1所示。从中择出的峰有以下值：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和27.2，每个不同的角度误差±0.2度(2θ)，其中特征峰为5.4、6.5、8.0、10.1、10.8、12.2、13.1、14.8、16.2、22.6和25.4。DSC测试结果如图2所示，显示晶型I的熔点范围为约259.4-261.7℃。
表1
Figure PCTCN2017114194-appb-000003
Figure PCTCN2017114194-appb-000004
实施例2 式A化合物的晶型I的制备
将适量式A化合物分别混悬于表2所列的各种溶剂中，于表中所列条件下搅拌一定时间。分别过滤，得各固体样品。经检测，所得各样品的X射线粉末衍射谱与实施例1中所得式A化合物的晶型I样品一致。
表2
溶剂 条件 结果 溶剂用量(体积/质量比)
甲醇 50℃/3天 晶型I 10倍
乙醇 50℃/3天 晶型I 10倍
异丙醇 50℃/3天 晶型I 10倍
四氢呋喃 50℃/3天 晶型I 10倍
二氯甲烷 50℃/3天 晶型I 10倍
丙酮 50℃/3天 晶型I 10倍
丁酮 50℃/3天 晶型I 10倍
乙腈 50℃/3天 晶型I 10倍
甲苯 50℃/3天 晶型I 10倍
乙醇/水(9:1，V/V) 室温/66小时 晶型I 30倍
乙醇/水(9:1，V/V) 40℃/66小时 晶型I 30倍
乙醇/水(9:1，V/V) 60℃/66小时 晶型I 30倍
乙醇/水(9:1，V/V) 80℃/66小时 晶型I 30倍
乙醇/水(1:9，V/V) 室温/66小时 晶型I 30倍
乙醇/水(1:9，V/V) 40℃/66小时 晶型I 30倍
乙醇/水(1:9，V/V) 60℃/66小时 晶型I 30倍
乙醇/水(1:9，V/V) 80℃/66小时 晶型I 30倍
实施例3 式A化合物的晶型I的制备
将式A化合物0.4克与N,N-二甲基乙酰胺24毫升(60倍，体积/质量比)混合，加热至60℃溶解；向其中加入乙腈80毫升，析出大量沉淀，过滤，得固体样品。经检测，所得样品的X射线粉末衍射谱与实施例1中所得式A化合物的晶型I样品一致。
实施例4 晶型I在高温、高湿、光照条件下的稳定性：
测定方法：称取由前述实施例制备得到的式A化合物晶型I的供试品置于培养皿中，开口裸露放置于密封洁净容器中，分别在温度为60℃，25℃且相对湿度均为92.5％±5％，以及照度为4500lx±500lx的条件下放置10天，取样，对样品的纯度(采用HPLC分析)和晶型(采用X射线粉末衍射分析)进行考察，并比较考察结果，结果见表3。
表3晶型I的影响因素实验结果(10天)
Figure PCTCN2017114194-appb-000005
结论：表中数据说明，晶型I在高温、高湿和光照条件下放置10天，其化学纯度和晶型均没有发生改变，表明晶型I是稳定的。
实施例5 晶型I的吸湿性
测定方法：称取由前述实施例制备得到的晶型I的供试品两份，置于两个培养皿中，分别开口裸露放置于相对湿度为92.5％和75％的密封洁净容器中，室温下放置10天，取样，称量放置10天后的样品重量，并与开始试验前样品重量比较，计算样品的吸湿增重百分数和晶型(采用X射线粉末衍射分析)，结果见表4。
表4
相对湿度(％) 92.5％RH,25℃ 75％RH,40℃
放置5天增重(％) 0.01％ 0％
放置10天增重(％) 0.01％ 0.01％
放置10天晶型 I I
结论：表中数据说明，晶型I在高湿条件下放置10天，吸湿增重只有0.01％，晶型I是无吸湿性的，在放置过程中，晶型没有发生改变，晶型I是稳定的。
实施例6 晶型I在犬体内的药代动力学研究
1.实验动物
比格犬6条，雌雄各半，相同周龄，购自北京玛斯生物技术有限公司。
2.实验材料
由前述实施例制备得到的式A化合物，其为晶型I，纯度98.5％。
Figure PCTCN2017114194-appb-000006
HS 15(聚乙二醇硬脂酸酯)购自上海昌为医药辅料技术有限公司(代理商，产地：德国BASF)。
3.药液配制
式A化合物的静注给药溶液的配制：温水加热
Figure PCTCN2017114194-appb-000007
HS 15，待流 动性变好以后，量取22.5mL，加入22.5mL生理盐水，涡旋使其混合均匀，配成Solutol和生理盐水混合溶液(体积比1：1)备用。称量式A化合物晶型I 108.47mg，加入DMSO 1.06mL，加入12M HCl 90μL，涡旋超声，得黄色澄清透明溶液。将该溶液全部转移至250mL广口瓶中，加入
Figure PCTCN2017114194-appb-000008
HS 15和生理盐水混合溶液(体积比为1：1)42.6mL，涡旋1min，超声2min，加入生理盐水定容至212.8mL，用于静脉注射。最终静脉给药制剂为含10％
Figure PCTCN2017114194-appb-000009
HS 15、0.5％DMSO和0.04％12M HCl的生理盐水溶液。
式A化合物晶型I的口服给药制剂：根据动物体重和给药剂量，称取适量的式A化合物晶型I，装入0号人用胶囊中(CAPSUGEL,Lot#:12832590)，一条犬给予一粒胶囊。
4.实验方案
6条比格犬，雌雄各半。按4个实验周期给药，自身对照。其中第一、二、三周期分别为口服1.0、2.5和7.5mg/kg单次给药(上述配制的口服给药制剂)，第四周期为静脉注射1.0mg/kg单次给药(上述配制的静脉注射制剂)。周期间清洗期为一周。给药前，动物禁食过夜，并于给药前30min开始喂食。每个周期给药前，均取空白血。静注给药后，于5min、15min、30min、1小时、2小时、3小时、4小时、6小时、8小时、12小时和24小时经前肢静脉取血1ml。口服给药后，于30min、1小时、1.5小时、2小时、3小时、4小时、5小时、6小时、8小时、12小时和24小时经前肢静脉取血1ml。离心分离血浆，-80℃保存待测。
5.血浆样品预处理
采用乙腈沉淀蛋白的方法：在50μl待测血浆样品中加入150μl含内标的乙腈溶液振荡2min，14000rpm离心10min，然后取上清150μl，用150μl的超纯水稀释一倍，取10μL进样分析。
6.生物样品分析方法
采用LC-MS/MS分析方法，测定生物样品中式A化合物的药物浓度。仪器为美国Applied Biosystem公司的API4000型三重四级杆质谱仪及德国Agilent公司的1200系列液相色谱系统。色谱柱为CAPCELL PAK C18柱(MG,50×2.0mm,5μm)。流动相为含0.1％甲酸的超纯水(A相)和含1％甲酸的乙腈：甲醇(v/v＝1：1)混合溶液(B相)。采用电喷雾电离源(ESI)正离子MRM扫描方式检测。
7.数据处理
采用非房室模型统计矩方法，应用Kinetica 4.0(美国Thermo-Fisher公司)药代动力学软件进行数据分析，计算药代动力学参数。Cmax和Tmax为实测值。
8.结果
犬静脉注射1.0mg/kg式A化合物后，体内的暴露量(AUC0-∞)平均值为714h·ng/mL；末端相半衰期(t1/2)为4.12小时。口服1.0、2.5和7.5mg/kg式A化合物后，体内的暴露量(AUC0-∞)的平均值分别为228、1126和5424h·ng/mL；口服后的末端相半衰期分别为3.22、4.20和7.71小时。口服1和2.5mg/kg两个剂量组的半衰期为4小时左右，7.5mg/kg剂量组相比1和2.5mg/kg剂量组血药浓度下降较为缓慢，给药后24小时血药浓度仍大于50ng/mL。通过口服与静脉注射相同剂量(1mg/kg)下得到的体内血浆暴露量(AUC0-∞)平均值计算得到的口服绝对生物利用度为30.6±15.0％。
因而，式A化合物晶型I具有可接受的口服生物利用度，适合制备口服药物制剂。
应当理解的是，本文所述的实施例和实施方案仅用于解释说明目的，有鉴于此的各种改进或变化会提示给本领域技术人员，它们包括在本申请的主旨和范围以及所附权利要求的范围内。通过引用的方式将本文所引用的所有出版物、专利和专利申请合并入本文并用于所有目的。

Claims (8)

  1. 化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型I。
  2. 权利要求1的晶型I，其特征在于，在粉末X射线衍射图谱中的下述2θ角有特征峰：5.4度、6.5度、10.1度、12.2度、13.1度和16.2度，每个2θ值约有±0.2°的误差。
  3. 权利要求1或2的晶型I，其特征在于，在粉末X射线衍射图谱中的下述2θ角有特征峰：5.4度、6.5度、8.0度、10.1度、10.8度、12.2度、13.1度、14.8度、16.2度、22.6度、25.4度，测得的2θ值有约±0.2 2θ的误差。
  4. 药物组合物，其特征在于，所述药物组合物含有有效量的权利要求1-3中任意一项所述的晶型，以及药学上可接受的载体。
  5. 权利要求1-3中任意一项所述的晶型在制备药物中的用途，所述药物用于治疗与EGFR的过量表达和/或过度活化相关的疾病，例如癌症的治疗，其中所述癌症优选选自：肺癌，头颈癌，大肠癌，胰腺癌，结肠癌，乳腺癌，卵巢癌，前列腺癌，胃癌，肾癌，肝癌，脑癌，食道癌，骨癌和肉瘤，如软组织肉瘤，以及白血病。
  6. 治疗与EGFR的过量表达和/或过度活化相关的疾病、例如癌症的方法，该方法包括向有需要的个体施用有效量的权利要求1-3中任意一项所述的晶型，其中所述癌症优选选自：肺癌，头颈癌，大肠癌，胰腺癌，结肠癌，乳腺癌，卵巢癌，前列腺癌，胃癌，肾癌，肝癌，脑癌，食道癌，骨癌和肉瘤，如软组织肉瘤，以及白血病。
  7. 制备权利要求1-3中任意一项的晶型I的方法，其包括：
    (1)将化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6- 基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺混悬于适量的一种溶剂或几种溶剂的混合溶剂中；其中，所述溶剂选自溶解溶剂(例如N,N-二甲基乙酰胺、C1-6烷基醇、四氢呋喃、少于三个碳原子的卤代烷烃、丙酮、丁酮、乙腈和甲苯)、或者水互溶性有机溶剂(例如丙酮、甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基乙酰胺和乙腈)和水组成的混合溶剂；
    (2)搅拌步骤(1)得到的混悬液；
    (3)分离得到(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型I固体；
    (4)干燥步骤(3)所得固体。
  8. 制备权利要求1-3中任意一项的晶型I的方法，其包括：
    (1)将化合物(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺混合于至少一种溶解溶剂(例如N,N-二甲基甲酰胺或N,N-二甲基乙酰胺)中，然后加热混合物得第1种溶液；
    (2)向所述第1溶液中加入至少一种反溶解溶剂(例如乙腈)，得到第2溶液；
    (3)将所述第2溶液自然冷却至室温；然后
    (4)分离得到(3aR,6aR)-N-(4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基)-1-甲基-六氢吡咯并[3,4-b]吡咯-5(1H)-甲酰胺的晶型I固体；
    (5)干燥步骤(4)所得固体。
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