Crystal of quinoline-substituted compound

Abstract

The present invention addresses the problem of providing a crystal of a compound having EGFR inhibition ability or a salt thereof, said crystal being excellent in the characteristic of stability (heat, purity) and / or low hygroscopicity. One aspect of the present invention provides a crystal form of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide that has a peak at a prescribed angle as the diffraction angle (2θ±0.2°) in a powder X-ray diffraction spectrum.

Description

Crystals of substituted quinoline compounds

[0001] The present invention relates to crystals of quinoline-substituted compounds and a method for crystallizing the same.

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor tyrosine kinase that exerts physiological functions in normal tissues by binding to its ligand, epidermal growth factor (EGF), and contributes to proliferation and apoptosis inhibition in epithelial tissues (Non-Patent Document 1).

[0003] EGFR is also an oncogene, and amplification of the EGFR gene and high protein expression and mutations are known to be involved in various types of cancer, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, and brain tumors (Non-Patent Document 2). In Japan and Western countries, approximately 170 to 360 people per 100,000 population die from cancer each year, making it a leading cause of death (Non-Patent Document 3). In particular, the number of deaths from lung cancer reaches approximately 1.4 million per year worldwide, and non-small cell lung cancer accounts for more than 80% of lung cancer cases, so the development of effective treatments is desired (Non-Patent Document 4).

[0004] Patent Document 1 describes a compound represented by the following formula (I) as an antitumor agent having EGFR inhibitory activity.

[0005]

[0006] This quinoline-substituted compound is (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (hereinafter, in this specification, (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide may also be referred to as “compound (1)”).

[0007] Generally, when a compound is used as an active ingredient in a pharmaceutical, chemical and physical stability of the compound is required to maintain stable quality. Therefore, it is desirable for the resulting compound to have a stable crystalline form. However, even the same molecule may have polymorphic forms, which have different molecular arrangements within the crystal. It is known that different crystalline forms result in different peaks obtained in powder X-ray diffraction (XRD) measurements, and furthermore, each crystalline form is known to have different physical properties such as solubility, stability, and hygroscopicity. In pharmaceutical development, it is necessary to find the optimal crystal from the perspectives of quality, manufacturing, etc.

[0008] Patent Document 1 discloses that compound (1) can be obtained by adding a solution of diisopropylethylamine and acrylic acid chloride in acetonitrile to a solution of a mixture of (S)-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizine-4,8-diamine and (S)-6-methylene-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine in acetonitrile and water, stirring the mixture, and, after the reaction, extracting the mixture with water, saturated sodium bicarbonate, and ethyl acetate, followed by drying and purification. However, there is no disclosure regarding the crystalline form of compound (1) obtained by this method. Furthermore, there is no specific disclosure regarding the crystalline form that compound (1) or a salt thereof may form, or the physical properties of such crystalline form.

[0009] International Publication No. WO2015 / 025936

[0010] Nature Rev. Cancer, vol. 6, pp. 803-811 (2006); J. Clin. Oncol., vol. 19, 32s-40s (2001); Ministry of Internal Affairs and Communications, Statistics Bureau Homepage / Statistical Data / World Statistics; "World Statistics 2022" Chapter 14: National Life and Social Security 14-1 Mortality Rates by Cause of Death; Lung Cancer, vol. 69, pp. 1-12 (2010).

[0011] When a compound is used as an active ingredient of a pharmaceutical, it is desirable for the compound to have a stable crystalline form in order to maintain stable quality and / or facilitate storage and management. Furthermore, it is preferable for the crystalline form of the compound to have low hygroscopicity, etc. However, it is difficult to predict whether a specific compound or its salt will form crystals and which crystalline form will have excellent physical properties such as stability.

[0012] In light of the above-mentioned circumstances, there is a need for crystals of a compound or a salt thereof having EGFR inhibitory activity, which crystals have good properties in one or more of thermal stability, storage stability, and / or low hygroscopicity. The present disclosure aims to provide compound (1) having one or more properties such as thermal stability, storage stability, and / or low hygroscopicity. The present disclosure also aims to provide crystals of compound (1) that are useful as pharmaceuticals or active pharmaceutical ingredients. Furthermore, the present disclosure aims to provide a method for producing crystals of compound (1).

[0013] As a result of extensive research, the present inventors have obtained a crystalline form of the free form of compound (1) that has excellent properties in terms of thermal stability, storage stability, and / or low hygroscopicity.

[0014] That is, the present invention provides, for example, the following [1] to

[16] : [1] A type I crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, which has peaks at three or more diffraction angles (2θ±0.2°) selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured with CuKα characteristic X-rays. [2] A type I crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, which has peaks at five or more diffraction angles (2θ±0.2°) selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured using CuKα characteristic X-rays. [3] A type I crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, having peaks at seven or more diffraction angles (2θ±0.2°) selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured with CuKα characteristic X-rays. [4] A type I crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum measured with CuKα characteristic X-rays shown in FIG. [5] The crystal according to any one of [1] to [4], which has an endothermic peak (peak top value) determined by simultaneous differential thermal and thermogravimetric analysis at around 244° C. [6] The crystal according to any one of [1] to [5], which has a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, and even more preferably 95% by weight or more).[7] The crystal according to any one of [1] to [6], having a chemical purity of 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more). [8] A pharmaceutical composition comprising the crystal according to any one of [1] to [7]. [9] A pharmaceutical composition comprising the crystal according to any one of [1] to [7] and a pharmaceutically acceptable carrier.

[10] An antitumor agent comprising the crystal according to any one of [1] to [7].

[11] A method for producing type I crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide according to any one of [1] to [7], comprising a step of stirring (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide in a solvent (in one solvent or in a mixed solvent of two or more solvents) containing at least one selected from the group consisting of lower alcohols, aprotic polar solvents, and water.

[12] A method for producing type I crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide according to any one of [1] to [7], comprising a step of dissolving and crystallizing (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide in a mixed solvent of a lower alcohol and water, or a mixed solvent of an aprotic polar solvent and water.

[13] (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide is dissolved in a mixed solvent of ethanol and water (ethanol:water=4:1 to 0.25:1, preferably 3:1 to 0.25:1, more preferably 2:1 to 0.25:1, even more preferably 1.5:1 to 0.5:1, still more preferably 1:1 to 0.5:1, particularly preferably 0.67:1 to 0.5:1, and most preferably 0.5:1), or acetonitrile and water. (acetonitrile:water=3:1 to 0.15:1, preferably 1.5:1 to 0.15:1, more preferably 1:1 to 0.15:1, even more preferably 0.67:1 to 0.33:1, still more preferably 0.5:1 to 0.33:1, and particularly preferably 0.5:1).

[14] A method for producing type I crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide according to

[12] or

[13] , wherein the chemical purity of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide is 90% or more (preferably 95% or more, more preferably 97% or more, even more preferably 98% or more, and still more preferably 99% or more).

[15] A method for treating a tumor, comprising orally administering an effective amount of the crystal according to any of [1] to [7] to a subject in need thereof.

[16] Use of the crystal according to any of [1] to [7] for producing an antitumor agent for oral administration.

[0015] According to one aspect of the present invention, there is provided a crystal of a compound having EGFR inhibitory activity or a salt thereof, which has excellent properties such as thermal stability, storage stability and / or low hygroscopicity.

[0016] 1 shows the powder X-ray diffraction spectrum of the I-type crystal of compound (1) obtained in Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of the I-type crystal of compound (1) obtained in Example 1 are shown (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the I-type crystal of compound (1) obtained in Example 2 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The powder X-ray diffraction spectrum of the solvated crystal type b of compound (1) obtained in Comparative Example 1 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). 1 shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of the solvated crystal type b of compound (1) obtained in Comparative Example 1 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). This figure shows the powder X-ray diffraction spectrum of amorphous compound (1) obtained in Reference Example 1 (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). This figure shows the results of simultaneous differential thermal analysis-thermogravimetry (TG-DTA) of amorphous compound (1) obtained in Reference Example 1 (the left vertical axis represents weight (%) in the TG curve, the right vertical axis represents heat flux (μV) in the DTA curve, and the horizontal axis represents temperature (°C)). This figure shows the results of a dynamic moisture adsorption-desorption (DVS) test of type I crystal of compound (1) in Test Example 2. This figure shows the results of a dynamic moisture adsorption-desorption (DVS) test of the solvated crystal type b of compound (1) in Test Example 2. 1 shows the results of a dynamic moisture sorption / desorption (DVS) test of amorphous compound (1) in Test Example 2.

[0017] The present invention relates to a crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide represented by the following formula (I): Specifically, the present invention relates to a crystal of compound (1) (i.e., type I crystal of compound (1)). In this specification, the terms type I, solvated crystal type b, etc. are convenient names for distinguishing between crystalline forms, and the crystals according to the present invention are not limited to these names.

[0018] A crystal is a solid in which atoms and molecules are arranged in a regular repeating structure, and is different from an amorphous (non-crystalline) solid that does not have a repeating structure. Crystal or amorphous solids can be investigated by methods such as powder X-ray diffraction measurement (XRD measurement), differential scanning calorimetry (DSC measurement), simultaneous thermogravimetry-differential thermal analysis (TG-DTA), and single crystal analysis. Crystal polymorphs refer to the same molecule but with different atomic or molecular arrangements in the crystal, and it is known that the peaks obtained in XRD measurement differ between crystal polymorphs. It is also known that solubility, oral absorbability, and / or stability differ between crystal polymorphs.

[0019] In this specification, the terms "crystal" and "amorphous" are used in their usual sense, and the fact that a material is crystalline can be confirmed by X-ray diffraction spectroscopy.

[0020] Due to the nature of the data, when determining the identity of a crystal, the diffraction angle and overall pattern of a powder X-ray diffraction pattern are important. The relative intensities of a powder X-ray diffraction pattern may vary somewhat depending on the direction of crystal growth, particle size, measurement conditions, maintenance status of the measurement equipment, and the method of preparing the measurement sample, and therefore should not be interpreted strictly. In this specification, the phrase "a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in the figure" refers to a powder X-ray diffraction spectrum that a person skilled in the art would recognize as identical, taking into account slight variations in peak position and intensity relative to the powder X-ray diffraction spectrum shown in the figure. For example, the numerical values ​​of the diffraction angle (2θ) may have a measurement error of approximately ±0.2°.

[0021] In this specification, the term "compound (1)" simply refers to (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, and is used in the sense of including both "crystal" and "amorphous." In this specification, the term "crystal of compound (1)" refers to a crystal of the free form of compound (1). In this specification, a crystal in which molecules other than compound (1) that constitute the crystal (other molecules that constitute a salt or co-crystal) are not specified refers to a crystal of the free form of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, and is not limited to a single crystalline form such as Form I, but may include multiple free form crystals.

[0022] In this specification, a crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (compound (1)) with an acid refers to a crystal of a salt or a co-crystal with an acid. A salt crystal is a crystal in which compound (1) and an acid molecule are bound by an ionic bond, and a co-crystal is a crystal in which compound (1) and an acid molecule are bound by a non-ionic interaction. In the present invention, a crystal of compound (1) with an acid may be a crystal of a salt or a co-crystal, and includes both meanings. For example, a crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide with succinic acid means a crystal of the succinate salt of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide or a co-crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide with succinic acid.

[0023] Generally, pharmaceutically acceptable acid salts include many salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, ascorbic acid, isoascorbic acid, mandelic acid, fumaric acid, aspartic acid, maleic acid, lactic acid, malic acid, hippuric acid, glutarate, adipate, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid (mesylic acid), p-toluenesulfonic acid (p-tosylic acid), and glutamic acid.

[0024] As used herein, the crystals may be either hydrated or anhydrous.

[0025] The present invention also encompasses labeled forms of compound (1) or salts thereof, i.e., compound (1) or salts of compound (1), and compounds in which one or more atoms are substituted with a radioactive isotope or a non-radioactive isotope.

[0026] The crystal may be any crystal of compound (1), and may be a single crystal or a polymorphic mixture containing other crystals of compound (1). Specifically, the purity of the crystal may be 40% by weight or more (i.e., 40% by weight or more of single crystals). The purity of the crystal is preferably 50% by weight or more (i.e., 50% by weight or more of single crystals), more preferably 75% by weight or more (i.e., 75% by weight or more of single crystals), more preferably 90% by weight or more (i.e., 90% by weight or more of single crystals), even more preferably 95% by weight or more (i.e., 95% by weight or more of single crystals), even more preferably 98% by weight or more (i.e., 98% by weight or more of single crystals), and particularly preferably 99% by weight or more (i.e., 99% by weight or more of single crystals). This purity can be measured by analysis such as differential scanning calorimetry (DSC measurement).

[0027] In this specification, chemical purity refers to the purity measured by high performance liquid chromatography (HPLC), and when referring to the chemical purity of compound (1), it refers to the purity measured by HPLC of compound (1). In this case, the wavelength of the detector used for purity measurement can be appropriately set. Specifically, the chemical purity of the crystals of compound (1) is preferably 90% or more, more preferably 95% or more, even more preferably 97% or more, and particularly preferably 98% or more.

[0028] In this specification, the optical purity refers to the purity measured by a polarimeter, and the optical purity of compound (1) refers to the purity measured by a polarimeter. In this case, the light source of the device used for purity measurement can be appropriately selected.

[0029] Numerical values ​​obtained from powder X-ray diffraction patterns may have some error depending on the direction of crystal growth, particle size, measurement conditions, etc. Therefore, in this specification, the numerical values ​​of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error of about ±0.2°. In other words, when the term "diffraction angle (2θ±0.2°)" is used in this specification, it means that a measurement error of ±0.2° is allowed for the numerical value of the diffraction angle (2θ). For example, when the diffraction angle (2θ±0.2°) is described as "8.0°," this means that a diffraction angle of up to 8.0°±0.2° is allowed, and includes diffraction angles of "7.8° to 8.2°." Furthermore, this value can be calculated using the Bragg formula (2d sinθ=nλ) and varies depending on the wavelength measured. In other words, it is also possible to convert it to a diffraction angle at a different measurement wavelength by substituting the measurement wavelength into the above formula. For example, the diffraction angles (2θ) at a wavelength λ of 1.54 Å, which is the characteristic X-ray of CuKα, are 8.0° and 10.6°, respectively, and if the values ​​of d and n are unchanged, the diffraction angles (2θ) at 0.75 Å are 3.9° and 5.2°, respectively.

[0030] The compound (1) used in the crystallization method of the present invention can be, for example, a compound produced by the method described in Patent Document 1. For crystallization, the compound (1) can be used either directly after synthesis without being extracted as crystals, or after being extracted as crystals (crude crystals).

[0031] In this specification, "room temperature" generally refers to about 18°C ​​to about 25°C.

[0032] In this specification, the term "lower alcohol" refers to an alcohol having 1 to 5 carbon atoms, which may be linear or branched. Examples include methanol, ethanol, propanol, butanol, and pentanol.

[0033] In this specification, the term "ketone solvent" refers to a solvent having a ketone structure in the molecule, such as acetone and methyl ethyl ketone.

[0034] As used herein, the term "ester solvent" refers to a solvent having an ester structure in the molecule, such as ethyl acetate, isopropyl acetate, and butyl acetate.

[0035] In this specification, the term "saturated hydrocarbon solvent" refers to a solvent made of saturated hydrocarbon, which may be linear or branched. Examples include hexane and heptane.

[0036] As used herein, the term "ether solvent" refers to a solvent having an ether structure in the molecule, such as diethyl ether, ethyl methyl ether, diphenyl ether, ethylene oxide, tetrahydrofuran, 1,4-dioxane, and benzofuran.

[0037] The aprotic polar organic solvent refers to a solvent that does not contain ionizable protons, and examples thereof include acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), chloroform, dichloromethane, and dimethyl sulfoxide (DMSO).

[0038] The endothermic peak in a simultaneous differential thermal analysis-thermogravimetry (TG-DTA) curve usually means ±5.0°C, as the measurement temperature may vary depending on the rate of temperature rise per minute, the chemical purity of the sample, etc. Therefore, when the crystal according to the present invention is measured by TG-DTA, an error of ±5.0°C in the endothermic peak (peak top value) should be taken into account. The term "around" used in this case means ±5.0°C.

[0039] One embodiment of the present invention relates to a type I crystal of compound (1). The present inventors have found that type I crystal of compound (1) has advantageous properties in pharmaceutical production, such as thermal stability, storage stability, low hygroscopicity, and reproducibility.

[0040] In this specification, the thermal stability and storage stability of a crystal can be evaluated, for example, by the solid-state stability test shown in Test Example 1 described below. In one embodiment of the invention, the change in chemical purity of the crystal of compound (1) after storage for 2 weeks or 4 weeks under the conditions described in Test Example 1 is preferably ±1.0% or less, more preferably ±0.5% or less, and even more preferably ±0.1% or less. In addition, there is no change in the crystal form when measured by XRD, and there is no change in the appearance (color tone) after storage.

[0041] In this specification, the hygroscopicity of a crystal can be evaluated by a dynamic moisture sorption / desorption (DVS) test shown in the following Test Example 2. When evaluated under the conditions described in Test Example 2, the crystal of compound (1) in one embodiment of the invention preferably exhibits a weight increase rate of less than 5%, more preferably less than 3%, and even more preferably less than 2%.

[0042] One embodiment of the present invention provides an antitumor agent comprising the above-mentioned crystal of compound (1) (i.e., type I crystal of compound (1)). Another embodiment of the present invention provides a method for treating tumors, comprising administering to a subject in need thereof an effective amount of the above-mentioned crystal of compound (1) (i.e., type I crystal of compound (1)). One embodiment of the present invention provides use of the crystal of compound (1) (i.e., type I crystal of compound (1)) for the manufacture of an antitumor agent. Furthermore, one embodiment of the present invention provides the crystal of compound (1) (i.e., type I crystal of compound (1)) for use in the treatment of tumors. One embodiment of the present invention provides a method for producing the above-mentioned crystal of compound (1) (i.e., type I crystal of compound (1)).

[0043] In one embodiment of the present invention, the type I crystal of compound (1) has advantageous properties in pharmaceutical production, such as excellent thermal stability, storage stability, low hygroscopicity, and reproducibility of preparation, compared to other crystals such as the solvated type b crystal of compound (1).

[0044] (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) Compound (1) is a compound having the following structure, which is disclosed in Patent Document 1 as a compound having excellent EGFR inhibitory activity. The compound (1) used in the present invention is not particularly limited, and for example, a compound produced by the production method described in Patent Document 1 or a known production method can be used. A crystalline form can be produced using compound (1).

[0045] Method for producing type I crystals of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (compound (1))

[0046] Form I crystals of compound (1) can be produced by a slurry method, a dissolution crystallization method, or other known crystal production methods. Although not limited to these production methods, methods for producing Form I crystals of compound (1) using a slurry method and a dissolution crystallization method are described in detail below.

[0047] Slurry Method In the present invention, the slurry method refers to a method for producing crystals by adding a solvent to a container containing compound (1) produced by the production method described in Patent Document 1 or a known production method, stirring the resulting suspension for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the type of solvent, the temperature of the solvent during stirring, and the stirring time. Any solvent can be used as long as it can maintain (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide in a suspended state during the stirring step. Examples of the solvent include lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.), ketone solvents (methyl ethyl ketone, acetone, etc.), ester solvents (ethyl acetate, isopropyl acetate, butyl acetate, etc.), saturated hydrocarbon solvents (hexane, etc.), ether solvents (tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether, etc.), aprotic polar solvents (acetonitrile, chloroform, etc.), aryl halides (chlorobenzene, etc.), and water. Among these, lower alcohols, aprotic polar solvents, water, etc. are preferred. These solvents can be used alone or in combination of two or more in any ratio. Examples of mixed solvents of two or more include a 1:1 mixture of methanol and water, a 1:1 mixture of ethanol and water, and a 1:1 mixture of ethanol and diisopropyl ether. Preferred is a solvent containing only acetonitrile, or a 1:1 mixture of ethanol and water. A solvent amount of 0.001 to 0.03 mL can be used per 1 mg of compound (1). The amount is preferably 0.002 to 0.02 mL, more preferably 0.003 to 0.01 mL, and even more preferably 0.005 mL. The temperature of the solvent can be adjusted appropriately, for example, at 20 to 60°C. The temperature is preferably 25 to 50°C, more preferably 30 to 50°C, even more preferably 40 to 50°C, and most preferably 50°C. In order to precipitate crystals of compound (1), it is preferable to stir the mixture at the aforementioned temperature and then allow it to cool.The temperature for cooling can be, for example, 10 to 40°C. It is preferably 15 to 30°C, more preferably room temperature. The stirring time can be adjusted appropriately, for example, for 1 to 72 hours. It is preferably 4 to 60 hours, more preferably 8 to 48 hours, even more preferably 12 to 36 hours, and most preferably 24 hours. The precipitated crystals can be isolated and purified from the crystal suspension by known separation and purification means, such as filtration, washing with water or an organic solvent, and drying under reduced pressure. Examples of organic solvents used for washing include lower alcohols, acetone, and acetonitrile.

[0048] Dissolution Crystallization Method In the present invention, the dissolution crystallization method is a method for producing crystals by dissolving compound (1) produced by the production method described in Patent Document 1 or a known production method in a solvent, stirring the mixture under heated or cooled conditions for several hours to several days, filtering, and drying the obtained crystals. This method also allows for the addition of seed crystals as needed. This method can produce crystals by appropriately adjusting parameters such as the type of solvent, the temperature of the solvent during stirring, and the stirring time. The solvent is not particularly limited, as long as it dissolves (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide and allows it to exist in a stable state without decomposition or the like in the solution. Examples of suitable solvents include a mixed solvent of a lower alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol) and water, and a mixed solvent of an aprotic polar solvent (e.g., acetonitrile, DMF, DMA, NMP, DMSO) and water. These solvents can be used in any combination as long as compound (1) dissolves. For example, methanol and water can be used in a ratio of 4:1 to 0.5:1. This ratio is preferably 3:1 to 1:1, more preferably 2:1 to 1:1, even more preferably 1.5:1 to 1:1, and particularly preferably 1:1. When ethanol and water are used in combination, they can be used in a ratio of 4:1 to 0.25:1. This ratio is preferably 3:1 to 0.25:1, more preferably 2:1 to 0.25:1, even more preferably 1.5:1 to 0.5:1, even more preferably 1:1 to 0.5:1, particularly preferably 0.67:1 to 0.5:1, and most preferably 0.5:1. When 2-propanol and water are used in combination, they can be used in a ratio of 4:1 to 0.25:1. The ratio is preferably 2:1 to 0.25:1, more preferably 1.5:1 to 0.25:1, even more preferably 1:1 to 0.5:1, still more preferably 0.67:1 to 0.5:1, and particularly preferably 0.5:1. When 1-propanol and water are mixed, they can be used in a ratio of 2:1 to 0.15:1.The ratio is preferably 1.5:1 to 0.15:1, more preferably 1:1 to 0.25:1. It is even more preferably 0.67:1 to 0.33:1, even more preferably 0.5:1 to 0.33:1, and particularly preferably 0.33:1. When acetonitrile and water are mixed, they can be used in a ratio of 3:1 to 0.15:1. It is preferably 1.5:1 to 0.15:1, more preferably 1:1 to 0.15:1, even more preferably 0.67:1 to 0.33:1, even more preferably 0.5:1 to 0.33:1, and particularly preferably 0.5:1. A preferred solvent is a mixed solvent of ethanol and water or a mixed solvent of acetonitrile and water, more preferably a mixed solvent of ethanol and water. The ratio of the mixed solvent is as described above. For 1 mg of compound (1), 0.005 to 0.080 mL of solvent can be used. The volume is preferably 0.015 to 0.060 mL, more preferably 0.025 to 0.045 mL, and even more preferably 0.035 mL. The temperature of the solvent used to dissolve compound (1) can be adjusted as appropriate, but can be, for example, 20 to 80°C. It is preferably 20 to 60°C, more preferably 30 to 60°C, even more preferably 45 to 60°C, and most preferably 55°C. Furthermore, in order to precipitate crystals of compound (1), it is preferable to allow the solution to cool after stirring at the aforementioned temperature. The temperature at which the solution is allowed to cool can be, for example, 10 to 40°C. It is preferably 15 to 30°C, and more preferably room temperature. The stirring time can be adjusted as appropriate, but can be, for example, 1 to 72 hours. It is preferably 5 to 60 hours, more preferably 12 to 48 hours, even more preferably 16 to 24 hours, and most preferably 20 hours. The precipitated crystals can be isolated and purified from the suspension of the crystals by known separation and purification means, such as filtration, washing with water or an organic solvent, drying under reduced pressure, etc. Examples of organic solvents used for washing include lower alcohols, acetone, and acetonitrile. When producing crystals by the dissolution crystallization method, they can also be produced by adding the target crystals as seed crystals to the above-mentioned solvent.In any of the crystal production methods, compound (1) must be maintained in a saturated or supersaturated state with respect to the solvent for a certain period of time (e.g., 1 to 72 hours, preferably 4 to 60 hours, more preferably 8 to 48 hours, and even more preferably 12 to 36 hours) to produce crystals. If the saturated or supersaturated state is maintained for a short period of time (e.g., 30 minutes or less, preferably 1 second to 20 minutes, and more preferably 30 seconds to 15 minutes), crystals cannot be produced and the solution tends to become amorphous, which is undesirable.

[0049] The crystalline purity of the type I crystal of compound (1) produced by the solution crystallization method is 90% by weight or more, preferably 95% by weight or more, more preferably 98% by weight or more, and even more preferably 99% by weight or more.

[0050] The chemical purity of the type I crystal of compound (1) produced by the solution crystallization method is 90% or more, preferably 95% or more, more preferably 97% or more, even more preferably 98% or more, and still more preferably 99%.

[0051] Form I Crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) According to one aspect of the present invention, Form I crystal of Compound (1) is provided. Form I crystal of Compound (1) in one embodiment of the present invention obtained by the above-described slurry method has a powder X-ray diffraction spectrum shown in FIG. 1 or a powder X-ray diffraction spectrum substantially identical thereto.

[0052] Here, in one embodiment of the present invention, characteristic peaks in the powder X-ray diffraction spectrum of type I crystal of compound (1) can include, for example, one or more peaks selected from the diffraction angles (2θ±0.2°) of 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°.

[0053] In one embodiment of the present invention, the type I crystal of compound (1) has, in its powder X-ray diffraction spectrum, diffraction angles (2θ±0.2°) of two or more selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°. In one embodiment of the present invention, the type I crystal of compound (1) has, in its powder X-ray diffraction spectrum, diffraction angles (2θ±0.2°) of three or more selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°. In a preferred embodiment of the present invention, the type I crystal of compound (1) has peaks in its powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°, preferably at least five, more preferably at least six, and even more preferably at least seven. In another embodiment of the present invention, the type I crystal of compound (1) may have peaks in its powder X-ray diffraction spectrum at diffraction angles (2θ±0.2°) selected from the above, or at all eight or all of the above. In yet another embodiment, it may further have peaks at one or more of the diffraction angles (2θ±0.2°) described in the examples other than those described above.

[0054] In one embodiment of the present invention, the type I crystal of compound (1) has an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at 239 to 249° C., in other words, around 244° C. In another embodiment, the type I crystal of compound (1) has a simultaneous differential thermal analysis-thermogravimetry (TG-DTA) curve shown in FIG.

[0055] In one embodiment of the present invention, the type I crystal of compound (1) has, in its powder X-ray diffraction spectrum, a peak at a diffraction angle (2θ±0.2°) selected from 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°, and has an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244° C. In a preferred embodiment of the present invention, the type I crystal of compound (1) has, in its powder X-ray diffraction spectrum, a peak at a diffraction angle (2θ±0.2°) selected from the above, and has an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244° C. In a preferred embodiment of the present invention, the type I crystal of compound (1) is a crystal having, in a powder X-ray diffraction spectrum, peaks at diffraction angles (2θ±0.2°) selected from the above, and having an endothermic peak (peak top value) at around 244°C as determined by simultaneous differential thermal and thermogravimetric analysis. In a preferred embodiment of the present invention, the type I crystal of compound (1) is a crystal having, in a powder X-ray diffraction spectrum, four or more peaks at diffraction angles (2θ±0.2°) selected from those described above, and having an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244°C, preferably five or more peaks, and having an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244°C, more preferably six or more peaks, and having an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244°C, and even more preferably seven or more peaks, and having an endothermic peak (peak top value) determined by simultaneous differential thermal analysis-thermogravimetry at around 244°C. In another embodiment of the present invention, the type I crystal of compound (1) may have peaks at eight or all of the diffraction angles (2θ±0.2°) selected from the above in a powder X-ray diffraction spectrum, and may have an endothermic peak (peak top value) at around 244°C as determined by simultaneous differential thermal and thermogravimetry analysis.

[0056] (Activity and Use) The crystals of compound (1) in one embodiment of the present invention have excellent EGFR inhibitory activity and are useful as antitumor agents. They also have the advantage of having excellent selectivity for EGFR and few side effects from other kinases. The type of malignant tumor to be treated is not particularly limited, and examples include epithelial cancers (e.g., respiratory system cancers, digestive system cancers, reproductive system cancers, and endocrine system cancers), sarcomas, hematopoietic tumors, central nervous system tumors, and peripheral nerve tumors, with epithelial cancers being preferred, and respiratory system cancers being more preferred. The type of organ in which the tumor develops is not particularly limited, and examples thereof include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelioma, etc., preferably head and neck cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, kidney cancer, prostate cancer, and brain tumor, particularly preferably head and neck cancer, lung cancer, and brain tumor, and more preferably lung cancer. Furthermore, crystals of the compound of the present invention or a salt thereof have excellent inhibitory activity against mutant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the crystals of the compound of the present invention or a salt thereof are useful as antitumor agents against the above-mentioned malignant tumors having mutant EGFR.

[0057] The crystals of the present invention may be used for postoperative adjuvant chemotherapy, which is carried out to prevent recurrence after surgical removal of a tumor, or for neoadjuvant chemotherapy, which is carried out before surgical removal of a tumor.

[0058] As used herein, the term "effective amount" of a compound refers to an amount of a compound of the present invention that elicits a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, or slows or delays the progression of a disease (therapeutically effective amount). As used herein, the term "subject" includes mammals and non-mammals. In one embodiment, the subject is a human, and may be a human diagnosed with a need for treatment for a symptom, condition, or disease disclosed herein.

[0059] When using crystals or cocrystals of compound (1) or its salt as a pharmaceutical, various administration forms can be adopted depending on the therapeutic purpose, with or without pulverization of the crystals, and they can be used in dosage forms generally used for pharmaceuticals. Examples of such forms include oral preparations such as tablets, capsules, granules, fine granules, powders, and dry syrups, and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, and injections. Pharmaceutical compositions suitable for these administration forms can be prepared using pharmaceutically acceptable carriers by formulation methods commonly known and commonly used by those skilled in the art.

[0060] One embodiment of the present invention provides an oral antitumor agent comprising the aforementioned type I crystal of compound (1). Another embodiment of the present invention provides a method for treating tumors, comprising orally administering to a subject in need thereof an effective amount of the aforementioned type I crystal of compound (1). Another embodiment of the present invention provides use of the aforementioned type I crystal of compound (1) for the manufacture of an oral antitumor agent. Another embodiment of the present invention provides the aforementioned type I crystal of compound (1) for use in the treatment of tumors by oral administration.

[0061] One embodiment of the present invention provides a pharmaceutical composition comprising the aforementioned type I crystal of compound (1). One embodiment of the present invention provides a pharmaceutical composition comprising the aforementioned type I crystal of compound (1) and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides use of the aforementioned type I crystal of compound (1) for producing a pharmaceutical composition. Another embodiment of the present invention provides the aforementioned type I crystal of compound (1) for use as a pharmaceutical.

[0062] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials. Examples of formulation materials used in solid formulations include excipients, binders, disintegrants, lubricants, and coating agents. Examples of formulation materials used in liquid formulations include solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents. These formulation materials are blended during the preparation of the formulation. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers can also be used as needed.

[0063] Examples of excipients include starches, sugars, polysaccharides, inorganic compounds, and the like. Examples of starches include potato starch, corn starch, rice starch, and partially pregelatinized starch. Examples of sugars include monosaccharides, disaccharides, trisaccharides, and sugar alcohols. Examples include lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Examples of sugars also include polysaccharides. Examples include cellulose and dextran, and more specifically, crystalline cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. Examples of inorganic compounds include silicic acids, such as light anhydrous silicic acid and calcium silicate. Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, candy powder, and hypromellose. Disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch. Lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearyl fumarate. Coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose. Solvents include water, propylene glycol, and physiological saline. Solubilizers include polyethylene glycol, alcohols such as ethanol, cyclodextrins, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants, such as sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid esters, and sodium lauryl sulfate. Suspending agents include carrageenan, crystalline cellulose-carmellose sodium, polyoxyethylene hydrogenated castor oil, gum arabic, and sodium alginate. Examples of isotonic agents include sodium chloride, glycerin, potassium chloride, etc. Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, etc.Examples of soothing agents include procaine hydrochloride and lidocaine. Examples of preservatives include ethyl parahydroxybenzoate, cresol, and benzalkonium chloride. Examples of antioxidants include sodium sulfite, ascorbic acid, and tocopherol. Examples of coloring agents include titanium oxide, ferric oxide, Food Blue No. 1, and copper chlorophyll. Examples of flavoring and odor correcting agents include aspartame, saccharin, sucralose, 1-menthol, and mint flavor. Examples of stabilizers include sodium metabisulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0064] When preparing oral preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, and odorants, etc., are added to the type I crystals of compound (1), and tablets, coated tablets, granules, powders, capsules, etc. can be produced by conventional methods. When preparing injections, pH adjusters, buffers, stabilizers, isotonicity agents, local anesthetics, etc. are added to the type I crystals of compound (1), and subcutaneous, intramuscular, and intravenous injections can be produced by conventional methods.

[0065] The amount of type I crystals of compound (1) to be incorporated into each dosage unit form varies depending on the symptoms of the patient to which it is to be administered or on the dosage form, etc., but in general, it is desirable that the amount per dosage unit form be about 1 to 400 mg in terms of the free form of compound (1) for oral preparations, about 5 to 300 mg for injections, and about 1 to 400 mg for suppositories or external preparations.

[0066] The daily dose of the type I crystal of compound (1) in each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but it is usually about 1 to 1000 mg, preferably 1 to 400 mg, of compound (1) in free form per day for an adult (body weight 50 kg).

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Although the present invention has been fully explained with reference to examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not deviate from the scope of the present invention, they are included in the present invention.

[0068] In the following compound examples, % means weight percent unless otherwise specified.

[0069] Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to one of the following test conditions after lightly crushing an appropriate amount of the test substance in an agate mortar as required.

[0070] Apparatus: PANalytical EMPYREAN (A method) Reflection method (focusing method) Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scan range: 2θ = 5.0 to 40.0° Step: 2θ = 0.0131° Averaging time / step: 8.670 s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Receiving slit: 8.0 mm

[0071] Equipment: PANalytical EMPYREAN (Method B) Transmission method Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scan range: 2θ = 2.0 to 40.0° Step: 2θ = 0.0066° Averaging time / step: 8.670 s Scan speed: 0.0008° / s Divergence slit: 1 / 2° Scattering slit: 2.0 mm Receiving slit: None

[0072] The operation of the equipment, including data processing, followed the methods and procedures specified for each device. Note that the values ​​obtained from various spectra may vary slightly depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, these values ​​should not be interpreted strictly.

[0073] Simultaneous differential thermal analysis and thermogravimetry (TG-DTA measurement) was performed on 4 to 5 mg of test material under the following test conditions: Apparatus: TG / DTA7200 manufactured by Hitachi High-Tech Science Corporation Sample container: made of aluminum Heating rate: 25 to 290°C at 10°C / min Ambient gas: air (200 mL / min) Reference substance: empty pan The equipment was handled, including data processing, in accordance with the methods and procedures specified for each equipment.

[0074] Example 1 Production of Form I Crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) (Slurry Method) Acetonitrile (32 mL) was added to (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1))) (6.40 g) synthesized by the method described in Patent Document 1, and the mixture was stirred at 50° C. for 24 hours. After allowing to cool to room temperature, the mixture was stirred at room temperature for 48 hours. After stirring was completed, the resulting solid was collected by filtration, washed with acetonitrile (6.4 mL), and then dried under reduced pressure at 50° C. for 24 hours to obtain the crystals (4.14 g).

[0075] The powder X-ray diffraction spectrum (Method A) of the Form I crystal obtained by the above method was obtained by the procedure described above and is shown in Figure 1. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks. Characteristic diffraction angles (2θ±0.2°): 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°. Other peaks were as shown in Table 1 below. The differential thermal-thermogravimetric simultaneous measurement curve of the crystals obtained in Example 1 was obtained by the above procedure and is shown in Figure 2. An endothermic peak (peak top value) was observed at around 244°C in the differential thermal-thermogravimetric simultaneous measurement curve.

[0076] Preliminary Test: Investigation of Conditions for Producing Crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1))) A preliminary test was conducted to find an appropriate solvent for producing crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)). The type and mixing ratio of the solvent were varied to investigate the precipitation of crystals and the conditions. The yield in this case was determined by calculation. The results are shown in Table 2 below. The precipitation of crystals was confirmed visually. A solvent was identified through this preliminary test, and Examples 2 and 3 described below were carried out.

[0077]

[0078] Example 2 Preparation of Form I Crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) (Dissolution Crystallization Method) 75% aqueous ethanol (15 mL) was added to (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) (1.00 g) synthesized by the method described in Patent Document 1, and the mixture was stirred at 55° C. for 1 hour. Insoluble matter was then filtered off and washed with 75% aqueous ethanol (0.6 mL). Next, water (16.6 mL) was added, and the mixture was stirred at 55° C. for 2 hours, followed by cooling to 25° C. and stirring for 20 hours. The solid was collected by filtration, washed with 36% aqueous ethanol (10 mL), and then dried under reduced pressure at 50° C. for 5 hours to obtain the crystals (825 mg, yield 83%, chemical purity 99.6%).

[0079] The powder X-ray diffraction spectrum (Method A) of the Form I crystal obtained by the above method was obtained by the procedure described above and is shown in Figure 3. Characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1°.

[0080] Example 3 Preparation of Form I Crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) (Dissolution Crystallization Method) Preparation was carried out in the same manner as in Example 2, except that the solvent ratio of the mixed solvent was changed as shown in the table (ratios listed in Table 3). Even when the ratio of the mixed solution was changed, Form I crystals of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) with high chemical purity (99% or more) could be prepared.

[0081] Comparative Example 1 Preparation of solvated crystal type b of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1)) Type I crystals of Compound (1) (1.5 g) were dissolved in methanol (225 mL), and then the solvent was dried under reduced pressure at 40°C using an evaporator and a hot water bath, yielding 1.012 g of amorphous Compound (1). To 1 g of the amorphous solution, 20 mL of anisole was added, and the mixture was stirred at room temperature for about 28 hours, and then filtered under reduced pressure to recover the solid. This was dried under reduced pressure at room temperature for about 26 hours to yield 856 mg of the title crystals.

[0082] The powder X-ray diffraction spectrum (Method B) of the obtained crystals was obtained by the above procedure and is shown in Figure 4. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum were as follows: Characteristic diffraction angles (2θ±0.2°): 10.9°, 11.8°, 12.8°, 15.3°, 16.1°, 19.6°, and 22.4° The simultaneous differential thermal and thermogravimetric measurement curve of the obtained crystals was obtained by the above procedure and is shown in Figure 5.

[0083] Reference Example 1 Preparation of amorphous (non-crystalline) (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide (Compound (1))) Form I crystals of Compound (1) (500 mg) were dissolved in ethyl acetate (80 mL) / methanol (40 mL) at 40° C., and the solvent was then dried under reduced pressure at 40° C. using an evaporator and a hot water bath to obtain 279.6 mg of amorphous Compound (1).

[0084] The powder X-ray diffraction spectrum (Method B) of the resulting amorphous material was obtained using the procedure described above and is shown in Figure 6. As a result of the measurement, no characteristic diffraction angles were observed. The differential thermal and thermogravimetric simultaneous measurement curve of the resulting amorphous material was obtained using the procedure described above and is shown in Figure 7.

[0085] Test Example 1: Solid Stability Test The effect of temperature was confirmed using the type I crystal, solvated type b crystal, and amorphous form of Compound (1) obtained in Example 1, Comparative Example 1, and Reference Example 1. Evaluation was carried out according to the following procedure. The appearance was visually confirmed before and after storage. Storage conditions: 60°C or 80°C (closed system) (HIFLEX (high-temperature storage device manufactured by ETAC)) Storage period: 2 weeks and 4 weeks Storage amount: Approximately 100 mg Storage container: Glass bottle

[0086] The results are shown in Tables 4 and 5 below.

[0087] The change in the amount of related substances (the amount of substances detected other than compound (1)) was analyzed by HPLC using the following method. For the analytical sample, approximately 1 mg of each sample was weighed as compound (1), dissolved in 10 mL of a 3:1 v / v acetonitrile-water mixture, and 5 μL of this solution was accurately measured and used. HPLC Measurement Method (Stability Test) The amount of related substances in the sample solution was measured by HPLC analysis. The instrumentation, including data processing, was performed according to the method and procedure specified for each instrument. Column: InertSustain C18HP (4.6 × 150 mm, 3 μm) manufactured by GL Sciences; UV detection: 220 nm; Column temperature: 40°C; Flow rate: 1.0 mL / min; Sample cooler: 5°C; Sample concentration: 0.1 mg / mL; Mobile phase A: 0.1% phosphoric acid; Mobile phase B: acetonitrile. The gradient is shown in Table 6.

[0088] As a result, compared with the solvated crystal b-type and amorphous, the type I crystal of compound (1) showed almost no change in the chemical purity of the crystal, hardly any increase in related substances was observed, and no change in the crystal shape or color tone was observed, making it an extremely stable crystal.

[0089] Test Example 2 Dynamic Moisture Sorption / Desorption (DVS) Test A moisture sorption / desorption test was performed using the type I crystal, solvated type b crystal, and amorphous form of Compound (1) obtained in Example 1, Comparative Example 1, and Reference Example 1. The moisture sorption / desorption test was performed under the following conditions. Approximately 10 mg of sample was placed in a dedicated quartz holder, and the weight of the sample at each humidity was continuously measured and recorded under the following conditions. The operation of the device, including data processing, followed the method and procedure specified for each device. Equipment: VTI SA+ (TA Instruments) Drying temperature: 60°C Heating rate: 5°C / min Drying equilibrium: Confirmed that there is no decrease of 0.01 wt% in 5 minutes, within a range not exceeding 300 minutes Measurement temperature: 25°C Humidification equilibrium: Confirmed that there is no increase of 0.01 wt% in 5 minutes, within a range not exceeding 120 minutes Relative humidity program: Increase in 5% RH increments from 5 to 95% RH, and decrease in 5% RH increments from 95 to 5% RH The weight changes within the measurement condition ranges obtained in these tests are shown in Figures 8 to 10.

[0090] As shown in Figures 8 to 10, the type I crystal of compound (1) showed a weight gain of 1.28% at 95% relative humidity (RH) in a moisture adsorption / desorption test. Furthermore, the type I crystal showed almost no weight gain (less than 0.4%) when the humidity was changed up to 75% RH. The solvated crystal type b of compound (1) showed a weight gain of more than 5% under the same conditions, and an almost linear weight increase was observed from the low humidity region. The amorphous form also showed a weight gain of more than 2% at 50% RH, and a weight gain of about 10% at 95% RH.

[0091] From the above results, it can be said that type I crystal of compound (1) has lower hygroscopicity than solvated crystal type b and amorphous, and is therefore superior as a candidate compound for pharmaceutical development from the viewpoint of industrial production of pharmaceuticals with stable quality.

[0092] In addition to Comparative Example 1, metastable crystals and hydrate crystals of compound (1) were obtained and compared with the type I crystals obtained by the method described in Example 1. As a result, it was confirmed that the type I crystals obtained by the method described in Example 1 have superior properties in terms of hygroscopicity, storage stability, etc. compared to the metastable crystals and hydrate crystals (data not shown).

[0093] Although several embodiments of the present invention have been described, these embodiments are presented as examples and are not intended to limit the scope of the invention. These novel embodiments can be embodied in various other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their modifications are included within the scope and spirit of the invention, and are also included in the scope of the invention and its equivalents as defined in the claims.

Claims

1. A type I crystal of (S)—N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide, which has peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured using CuKα characteristic X-rays.

2. The crystal described in claim 1, which has peaks at five or more diffraction angles (2θ±0.2°) selected from the group consisting of 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured using CuKα characteristic X-rays.

3. The crystal described in claim 1 or 2, which has peaks at seven or more diffraction angles (2θ±0.2°) selected from the group consisting of 8.0°, 10.6°, 12.2°, 15.1°, 16.6°, 17.6°, 19.4°, 21.7°, and 26.1° in a powder X-ray diffraction spectrum measured using CuKα characteristic X-rays.

4. A type I crystal of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide having a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum measured using CuKα characteristic X-rays shown in Figure 1.

5. The crystal according to any one of claims 1 to 4, which has an endothermic peak at about 244°C as determined by simultaneous differential thermal and thermogravimetric measurements.

6. The crystal according to any one of claims 1 to 5, having a crystal purity of 95% by weight or more.

7. The crystal according to any one of claims 1 to 6, having a chemical purity of 95% or more.

8. A method for producing type I crystals of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide according to any one of claims 1 to 7, comprising a step of stirring (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide in a solvent containing at least one member selected from the group consisting of lower alcohols, aprotic polar solvents, and water.

9. A method for producing type I crystals of (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide according to any one of claims 1 to 7, comprising a step of dissolving and crystallizing (S)-N-(4-amino-6-methyl-5-(quinolin-3-yl)-8,9-dihydropyrimido[5,4-b]indolizin-8-yl)acrylamide in a mixed solvent of a lower alcohol and water, or a mixed solvent of an aprotic polar solvent and water.

10. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 7.