TW201833112A - Crystalline form of a compound - Google Patents

Abstract

The present invention relates to the field of pharmacy and provides a crystalline form of the compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin -6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, a pharmaceutical composition thereof, and preparation processes and use thereof.

Description

 Crystal form of the compound  

The present invention belongs to the field of pharmacy and provides the compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl- A new crystalline form of hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide, a pharmaceutical composition thereof, and a process for the preparation thereof and use thereof.

Binding of epidermal growth factor (EGF) to the epidermal growth factor receptor (EGFR) initiates tyrosine kinase activity, which triggers a response that leads to cell proliferation. Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer. Thus, compounds that inhibit EGFR overexpression and/or overactivation are candidates for treating tumors.

Related Compounds of the Invention (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[ 3,4- b ]pyrrol-5(1 H )-carbenamide, whose chemical structure is shown in formula A, has an effect of effectively inhibiting EGFR overexpression and/or excessive activation. Therefore, it can be used for the treatment of diseases associated with overexpression and/or overactivation of EGFR, such as the treatment of cancer.

Before the crystal form of a compound is found, it is difficult to predict (1) whether a particular compound is in the form of a crystal; (2) how to make an unknown crystal form; (3) what the nature of the crystal form will be, such as stability, Bioavailability, etc.

Since the properties of a solid depend on the nature of the structure and the compound itself, different solid forms of the compound often exhibit different physical and chemical properties. Chemical differences can be determined, analyzed, and compared by a variety of analytical techniques that can ultimately be used to distinguish between the different solid forms present. Differences in physical properties, such as solubility and bioavailability, are also important in describing the solid form of a pharmaceutical compound. Likewise, in the development of pharmaceutical compounds, such as compounds of formula A, new crystals and amorphous forms of the drug compounds are also important.

Patent CN102906086A discloses the compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrole [3,4- b ]pyrrole-5(1 H )-formamide and a process for the preparation thereof.

Overview

After extensive exploration, we found a compound of formula A (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl - Hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-carbenamide) may exist in a crystalline form. We have conducted extensive research on compounds of formula A to determine and prepare crystalline forms that meet pharmaceutical requirements. Based on these studies, the present invention provides Form I of the compound of Formula A.

In one aspect, the invention provides (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydro Form I crystal of pyrrolo[3,4- b ]pyrrole-5( 1H )-formamide, 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.

In another aspect, the invention provides a process for the preparation of Form I of a compound of formula A which is reproducible and easy to handle.

In still another aspect, 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.

definition

Unless otherwise stated, the following abbreviations or terms used in the present application (including the specification and claims) have the definitions given below. It must be noted that the singular forms used in the specification and the claims

As used herein, "crystalline form of the invention" refers to crystalline form I of the compound of formula A.

As used herein, "compound of formula A" or "(3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-yl The hexa-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide refers to a compound having the chemical structure of the following formula A (also referred to as Compound A):

As used herein, " _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.

As used herein, "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.

As used herein, "about" refers to deviations from a given given value by up to ±10%.

As used herein, "solution" refers to a mixture of one or more solutes in one or several solvents for a particular use. By solution is meant a homogeneous mixture, and a multi-phase mixture, such as a beater or other suspension mixture containing insolubles.

As used herein, "organic solvent" refers broadly to any suitable organic solvent for a particular use herein.

As used herein, "dissolving 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.

As used herein, "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.

The "effective amount" of the compound of formula A and the crystalline form of the compound of formula A refers to the amount of a drug administered to a patient, in which amount is effective to alleviate and ameliorate some of the overexpression and/or overexpression of the epidermal growth factor receptor. The cancer in which the activity is affected may be a human or a subject such as an animal, and the cancer which inhibits the overexpression and/or excessive activity of the epidermal growth factor receptor may be, but is not limited to, lung cancer, head and neck cancer, and knot. Rectal cancer, pharyngeal cancer, epidermal 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.

As used herein, "individual" 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.

Fig. 1 shows a powder X-ray diffraction pattern of Form I of the compound of Formula A, wherein the horizontal axis (X-axis) is the diffraction angle 2θ, and the vertical axis (Y-axis) is the diffraction intensity.

Figure 2 is a graph showing the differential scanning calorimetry 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 flux.

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.

Detailed description of the invention

The present invention provides the compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrole A new crystalline form of [3,4- b ]pyrrole-5(1 H )-formamide.

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. Further, 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.

One skilled in the art can verify the above advantages of the crystalline form of the present invention based on the test methods disclosed in the Pharmacopoeia, variations thereof, or conventional methods in the art.

As described herein, the crystalline forms of the invention can be identified by one or several solid state analytical methods. For example, the crystalline form of the present invention can be identified 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. . 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.

As described herein, the new crystal form can be identified by powder X-ray diffraction spectroscopy. However, it is known to those skilled in the art that 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. At the same time, due to the different precision of different instruments, the measured 2θ value will have an error of about ±0.2 2θ. However, it is known that 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. However, in spite of experimental error, instrument error and orientation priority, etc., those skilled in the art can obtain sufficient information for discriminating the crystal form I from the XRPD data provided in this patent.

Crystal form I

The present invention provides Form I of the compound of Formula A.

In some embodiments, Form I of the compound of Formula A can be identified by X-ray powder diffraction. In some embodiments, the powder X-ray diffraction characteristic diffraction angle (2θ) 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 2θ values are An error of about ±0.2 2θ.

In some embodiments, the powder X-ray diffraction characteristic diffraction angle (2θ) 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 2θ value has an error of about ± 0.2 2θ.

In some embodiments, the powder X-ray diffraction characteristic diffraction angle (2θ) 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, 20.5 degrees, 22.6 degrees, 23.1 degrees, 25.4 degrees, 26.6 degrees, the measured 2θ value has an error of about ± 0.2 2θ.

In some embodiments, the powder X-ray diffraction characteristic diffraction angle (2θ) 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 2θ values have about ± 0.2 2θ. error.

In some embodiments, the powder X-ray diffraction characteristic diffraction angle (2θ) 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 2θ value has an error of about ±0.2 2θ.

In some embodiments, Form I of the compound of Formula A has a diffraction pattern as shown in Figure 1. Those skilled in the art can obtain sufficient information for identifying the crystal form I of the compound of formula A from the XRPD data provided in this patent, despite the existence of test errors, instrumental errors, and orientation preferences.

In some embodiments, 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 Figure 2. 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.

In some embodiments, Form I of the compound of Formula A can be identified by thermogravimetric analysis. In some embodiments, 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.

In some embodiments, for example, the compound of formula A has a Form I weight content of at least 99%, at least 95%, at least 90%, or even less than 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%.

Method for preparing crystal form I

Method A

This patent relates to a process for the preparation of Form I of a compound of formula A, which comprises: (1) the compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazole Benzo-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-carboxamide is suspended in a suitable solvent or a mixed solvent of several solvents; Wherein the solvent is selected from the group consisting of a dissolution solvent (for example, N,N -dimethylacetamide, C _1-6 alkyl alcohol, tetrahydrofuran, halogenated alkane having less than three carbon atoms, acetone, methyl ethyl ketone, acetonitrile and toluene) , or a mixed solvent of a water-miscible organic solvent and water; (2) stirring the suspension obtained in the step (1); (3) separating (3a R , 6a R )- N - (4-(3- Crystal form of ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-carboxamide I solid; (4) drying the solid obtained in step (3).

In some embodiments, the compound (3a R , 6a R ) -N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)- used in the step (1) 1-Methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide is preferably a solid, such as a single crystal form, such as Form I, or two or more a mixture of crystal forms.

In some embodiments, in step (1), the compound (3a R , 6a R ) -N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl) 1-Methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide is not completely dissolved in the suspension system, i.e., some of the compounds are present in solid form.

In some embodiments, the water miscible organic solvent comprises less than about 95% by volume of the mixed solvent.

In some embodiments, the water miscible organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, N,N -dimethylacetamide, and acetonitrile. When the selected water-miscible organic solvent is ethanol, the volume percentage of ethanol is not less than about 10%.

In some embodiments, the water miscible organic solvent and water are mixed in a suitable ratio. In some embodiments, 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) ).

In some embodiments, in the step (2), the suspension 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.

In some embodiments, in the step (2), the suspension 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.

Method B

This patent relates to another process for the preparation of Form I of the compound of formula A, which comprises: (1) the compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxy The quinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide is mixed in at least one solvent, and then the mixture is heated to obtain the first a solution; (2) adding at least one anti-dissolving solvent to the first solution to obtain a second solution; (3) naturally cooling the second solution to room temperature; and then separating (4) to obtain (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole- Form 5 solid of 5( 1H )-carbamide; (5) solid obtained by drying step (4).

In some embodiments, wherein the dissolving solvent is selected from the group consisting of N,N -dimethylformamide or N,N -dimethylacetamide.

In some embodiments, the reverse dissolution solvent is selected from the group consisting of acetonitrile.

In some embodiments, 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.

The features of the various embodiments of the above-described preparation methods relating to the crystalline form of the compound of formula A may be arbitrarily combined with each other, and the various schemes obtained by combining these are included in the scope of the present invention, as specifically and individually listed herein. The same is true for the combination of these.

Pharmaceutical compositions and methods of treatment

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.

Provided herein are methods of treating cancer that have an effect on inhibiting overexpression and/or overactivation of epidermal growth factor receptor, 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.

In some embodiments, 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. Therein, 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 its pharmaceutically acceptable salt, or the crystalline form I of the compound of the formula A, which achieves the desired physiological effect depends on various factors, for example, for the purpose of administration, administration The way, as well as the clinical condition of the patient. The daily dose may be, for example, ranging from 0.01 mg to 3 g per day (e.g., 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.

For the therapeutic purposes mentioned above, 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.

In some examples, 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, crosslinked carboxymethyl fibers. Sodium, complex citrate and high molecular weight polyethylene glycol, granulation binders (eg polyvinylpyrrolidone, sucrose, gelatin, gum arabic), and lubricants (eg magnesium stearate, glycerin and talc) .

In some examples, 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 the group consisting of sweeteners, flavoring agents, coloring agents. Agents, dyes and emulsifiers.

In some examples, 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. In other instances, Form I of the compound of Formula A may be converted when formulated with one or more pharmaceutically acceptable carriers and/or adjuvants and/or diluents, which are converted in whole or in part into one or A variety of crystal 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. In some examples, 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.

In some instances, Form I of the compound of Formula A is administered in a suitable formulation.

The pharmaceutical 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 being at least An active pharmaceutical ingredient according to 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.

The compositions of the invention may be administered topically or systemically.

Pharmaceutical 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.

The pharmaceutical 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, aluminosilicate, 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 the compound in a surfactant-containing water. 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). When used in combination, 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 also be The same pharmaceutical composition is administered together.

In some embodiments, Form I of a compound of Formula A can be administered concurrently with one or more other active ingredients known to have a therapeutic effect, such as for treating an effect of inhibiting overexpression and/or overactivity of the epidermal growth factor receptor. A disease, such as cancer.

As used herein, "combination" is used to define the combination of Form I of a compound of Formula A with one or more other active ingredients, such as in combination with an anti-tumor method. Here, "anti-tumor method" may refer to any method for the purpose of treating cancer. Examples of anti-tumor methods include, but are not limited to, radiotherapy, immunotherapy, chemotherapy for DNA damage, and chemotherapy for disrupting cell replication.

There are many chemotherapeutic drugs that cause DNA damage, including but not limited to, for example, 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 intercalating agents (eg , cisplatin, oxaliplatin and carboplatin); DNA intercalators and free radical generators such as bleomycin; and nucleoside analogues (eg 5-fluorouracil, capecitabine, gemcitabine, fludarabi) Bin, cytarabine, guanidinium, thioguanine, pentastatin, hydroxyurea).

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, furitinib and gefitinib); protease inhibitors (eg, bortezomib); inhibitors of NF-κB, Kinase inhibitors including IκB; antibodies that bind to overexpressed proteins in cancer, which can downregulate cell replication (eg, rituximab, cetuximab, bevacizumab, etc.); others are known An inhibitor of a protein or enzyme that is upregulated or overexpressed or activated in cancer, which can downregulate cell replication by inhibiting these proteins or enzymes.

Thus, 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 following are non-limiting examples.

Experimental part

The starting material of the compound of formula A used in the examples was prepared according to CN102906086A.

All reagents (except intermediates) used in the present invention are commercially available. The names of all compounds (except reagents) were generated by the software ChemBioDraw Ultra 12.0.

Powder X-ray diffraction spectra were obtained by German Bruker D8 ADVANCE (target: Cu, voltage: 40 kV, current: 40 mA, scanning speed: 4 degrees/min, step size: 0.02 degrees, measurement range: 3, unless otherwise noted). -45 degrees) measurement.

Differential scanning calorimetry was determined by Perkin Elmer's DSC7 (purge gas: nitrogen, flow rate: 50 mL min ^-1 , temperature increase rate: 5-10 ° C / min, measurement range: 25 ° C → 200 ° C). The sample was measured using a rolled aluminum pan and temperature corrected 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).

Example 1 Preparation of Form I of the Compound of Formula A

An appropriate amount of the compound of the formula A was suspended in a mixed solvent of 10 times (volume/mass ratio) of ethanol/water (9:1, V/V), stirred at room temperature for 60 hours, and filtered to obtain a solid sample. The obtained powder sample was Form I of the compound of Formula A, and its powder X-ray diffraction pattern is shown in Fig. 1, and the main data thereof are shown in Table 1 below. The peaks selected therefrom have the following values: 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 is ± 0.2 degrees (2θ), with characteristic peaks of 5.4, 6.5, 8.0, 10.1, 10.8, 12.2, 13.1, 14.8, 16.2, 22.6, and 25.4. The DSC test results, as shown in Figure 2, show that Form I has a melting point in the range of about 259.4-261.7 °C.

Example 2 Preparation of Form I of the Compound of Formula A

Appropriate amounts of the compound of formula A were separately suspended in the various solvents listed in Table 2 and stirred for a certain period of time under the conditions listed in the table. Filtered separately to obtain each solid sample. The X-ray powder diffraction spectrum of each of the obtained samples was examined to be in agreement with the crystal form I sample of the compound of the formula A obtained in Example 1.

Example 3 Preparation of Form I of the Compound of Formula A

0.4 g of the compound of the formula A was mixed with N,N -dimethylacetamide 24 ml (60 times, volume/quality ratio), and heated to dissolve at 60 ° C; 80 ml of acetonitrile was added thereto, and a large amount of precipitate was precipitated and filtered to obtain Solid sample. The X-ray powder diffraction spectrum of the obtained sample was examined to be in agreement with the crystal form I sample of the compound of the formula A obtained in Example 1. I. Example 4 Stability of Form I under high temperature, high humidity, and light conditions:

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.

Conclusion: The data in the table indicate that the crystal form I was kept under high temperature, high humidity and light for 10 days, and its chemical purity and crystal form did not change, indicating that Form I was stable.

Example 5 Hygroscopicity of Form I

Determination method: Weigh two samples of the crystal form I prepared by the foregoing examples, placed in two Petri dishes, respectively, and exposed to a sealed clean container having a relative humidity of 92.5% and 75%, respectively. After standing for 10 days under temperature, sample, weigh the sample weight after 10 days of storage, and compare the weight of the sample with the weight of the sample before the start of the test, calculate the moisture absorption weight percentage and crystal form (using X-ray powder diffraction analysis), the results are shown in the table. 4.

Conclusion: The data in the table indicate that Form I is placed under high humidity for 10 days, and the moisture absorption gain is only 0.01%. Form I is non-hygroscopic. During the placement, the crystal form does not change. I is stable.

Example 6 Pharmacokinetics of Form I in Dogs

Experimental animal

Beagle 6, male and female, same week, purchased from Beijing Max Biotechnology Co., Ltd.

2. Experimental materials

A compound of formula A prepared by the foregoing examples, which is Form I, has a purity of 98.5%.

Solutol ^® HS 15 (polyethylene glycol stearate) were purchased from Shanghai Ltd. Chang pharmaceutical materials (agents, Origin: Germany BASF).

3. Preparation of liquid medicine

Preparation of intravenous injection solution of compound of formula A: warm water heating Solutol ^® HS 15. After the fluidity is good, take 22.5mL, add 22.5mL of normal saline, vortex and mix it evenly, and prepare it into Solutol and physiology. The brine mixed solution (volume ratio 1:1) was used. The crystalline form I of the compound of formula A was weighed 108.47 mg, 1.06 mL of DMSO was added, 90 μL of 12 M HCl was added, and vortexed to obtain a yellow clear transparent solution. Transfer the solution to a 250mL jar, add 42.6mL of Solutol ^® HS 15 and saline solution (1:1 by volume), vortex for 1min, sonicate for 2min, add physiological saline to 212.8mL, use Intravenous injection. The final intravenous formulation was a physiological saline solution containing 10% Solutol ^® 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.

4. Experimental protocol

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. After oral administration, 1 ml of blood was taken through the forelimb vein at 30 min, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, and 24 hours. The plasma was separated by centrifugation and stored at -80oC for testing.

5. Plasma sample pretreatment

The method of protein precipitation using acetonitrile: Add 150 μ l in 50 μ l test plasma samples containing the internal standard solution was shaken in acetonitrile 2min, centrifuged 14000rpm 10min, and then the supernatant was 150 μ l, was diluted with ultrapure water in a 150 μ l times, L analysis sample taken 10 μ.

6. Biological sample analysis method

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 chromatographic column was a CAPCELL PAK C ₁₈ column (MG, 50 臎譃臎 2.0 mm, 5 麱 m). The mobile phase was a mixture of ultrapure water (A phase) containing 0.1% formic acid and acetonitrile: methanol (v/v = 1:1) containing 1% formic acid (phase B). It was detected by electrospray ionization source (ESI) positive ion MRM scanning.

7. Data processing

Kinetica 4.0 (American Thermo-Fisher) pharmacokinetic software was used to analyze the pharmacokinetic parameters using the non-compartment model statistical moment method. C _max and T _max are measured values.

8. Results

After intravenous injection of 1.0 mg/kg of compound A in dogs, the average exposure (AUC _0-∞ ) in the body was 714 h. Ng/mL; terminal phase half-life (t _1/2 ) was 4.12 hours. After oral administration of 1.0, 2.5 and 7.5 mg/kg of compound A, the average exposure (AUC _0-∞ ) in vivo was 228, 1126 and 5424 h, respectively. Ng/mL; the terminal phase half-lives after oral administration were 3.22, 4.20 and 7.71 hours, respectively. 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%.

Thus, Form I Compound I Form I has acceptable oral bioavailability and is suitable for the preparation of oral pharmaceutical preparations.

It should be understood that the embodiments and the embodiments described herein are for illustrative purposes only, and that various modifications and changes may be made to those skilled in the art, which are included in the spirit and scope of the application and the appended claims Within the scope of the request. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety in their entirety herein

Claims (8)

A compound (3a R , 6a R )- N -(4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3, Form I of 4- b ]pyrrole-5(1 H )-formamide.  The crystal form I as described in claim 1, wherein the following 2θ angles in the powder X-ray diffraction pattern have characteristic peaks: 5.4 degrees, 6.5 degrees, 10.1 degrees, 12.2 degrees, 13.1 degrees, and 16.2 degrees, Each 2θ value has an error of about ±0.2o.    The crystal form I as described in claim 1 or 2, wherein the following 2θ angles in the powder X-ray diffraction pattern have characteristic peaks: 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 degrees, 25.4 degrees, the measured 2θ value has an error of about ± 0.22θ.    A pharmaceutical composition comprising an effective amount of the crystalline form of any one of claims 1 to 3, and a pharmaceutically acceptable carrier.    Use of a crystalline form according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of a disease associated with overexpression and/or overactivation of EGFR, such as the treatment of cancer, wherein The cancer is preferably selected from the group consisting of: lung cancer, head and neck cancer, colon cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and sarcoma, such as soft tissue. Sarcoma, as well as leukemia.    A method of treating a disease, such as cancer, associated with overexpression and/or overactivation of EGFR, the method comprising administering to an individual in need thereof an effective amount of a crystal according to any one of claims 1 to 3. Type, wherein the cancer is selected from the group consisting of: lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and sarcoma, soft tissue Sarcoma, as well as leukemia.   A process for the preparation of Form I of any one of claims 1 to 3, which comprises: (1) the compound (3a R , 6a R ) -N -(4-(3-ethynylanilino) -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrol-5(1 H )-carboxamide is suspended in an appropriate amount of a solvent or a mixed solvent of several solvents; wherein the solvent is selected from the group consisting of a solvent (for example, N,N -dimethylacetamide, C _1-6 alkyl alcohol, tetrahydrofuran, halogenated alkane having less than three carbon atoms, acetone , butanone, acetonitrile and toluene), or a mixed solvent of a water-miscible organic solvent (such as acetone, methanol, ethanol, isopropanol, tetrahydrofuran, N,N -dimethylacetamide and acetonitrile) and water; 2) stirring in step (1) to give the suspension; (3) to obtain (3a R, 6a R) - N - (4- (3- ethynylphenylamino) -7-methoxy-quinazolin -6 a crystalline form I solid of 1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-carboxamide; (4) a solid obtained by drying step (3). A process for the preparation of Form I of any one of claims 1 to 3, which comprises: (1) the compound (3a R , 6a R ) -N -(4-(3-ethynylanilino) -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-formamide is mixed in at least one solvent (for example N,N -dimethylformamide or N,N -dimethylacetamide), then heating the mixture to obtain a first solution; (2) adding at least one anti-dissolving solvent to the first solution ( For example, acetonitrile), to obtain a second solution; (3) to naturally cool the second solution to room temperature; and then (4) to obtain (3a R , 6a R )- N -(4-(3-ethynylphenyl) a crystalline form I solid of -7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4- b ]pyrrole-5(1 H )-carboxamide; 5) Drying the solid obtained in the step (4).