Crystals of quinoline-substituted compounds

Abstract

The present invention provides crystals of a compound or salt thereof that has EGFR inhibitory activity, exhibiting good stability (thermal, purity) and / or low hygroscopicity. [Solution] According to one aspect of the present invention, a crystalline form of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide is provided, in which the diffraction angle (2θ±0.2°) has a peak at a predetermined angle in the powder X-ray diffraction spectrum.

Description

Technical Field

[0001] The present invention relates to a crystal of a quinoline-substituted compound and a method for crystallizing the same, etc.

Background Art

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor-type tyrosine kinase. In normal tissues, it binds to the ligand Epidermal Growth Factor (EGF) to exert its physiological function and contributes to proliferation and apoptosis inhibition in epithelial tissues (Non-Patent Document 1).

[0003] EGFR is also one of the oncogenes, and amplification of the EGFR gene, high expression of the protein, and mutations are known in various cancer types, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer, brain tumors, etc. (Non-Patent Document 2). In Japan and Western countries, about 170 to 360 people per 100,000 population die of cancer every year and occupy the top positions in the causes of death (Non-Patent Document 3). Among them, the number of deaths due to lung cancer reaches about 1.4 million annually worldwide, and since non-small cell lung cancer accounts for more than 80% of lung cancer, the development of effective treatment methods is desired (Non-Patent Document 4).

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

[0005]

Chemical formula

[0006] This quinoline-substituted compound is (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide (hereinafter, in this specification, (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide is also referred to as "compound (1)").

[0007] Generally, when compounds are used as active ingredients in pharmaceuticals, chemical and physical stability of the compound is necessary to maintain stable quality. Therefore, it is desirable for the resulting compound to be in a stable crystalline form. However, even with the same molecule, crystals can have polymorphs with different molecular arrangements. It is known that different crystalline forms result in different peaks obtained by 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, finding the optimal crystal from the perspectives of quality and manufacturing is essential.

[0008] Patent Document 1 describes that compound (1) can be obtained by adding an acetonitrile and water solution of a mixture of (S)-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indridine-4,8-diamine and (S)-6-methylene-5-(quinoline-3-yl)-6,7,8,9-tetrahydropyrimide[5,4-b]indridine-4,8-diamine, adding an acetonitrile solution of diisopropylethylamine and acrylate chloride, stirring, and after the reaction, extracting with water, saturated sodium bicarbonate, and ethyl acetate, followed by drying and purification. However, there is no description of the crystalline form of compound (1) obtained by this method. Furthermore, there is no specific disclosure of what crystalline forms compound (1) or its salts may form, or what physical properties those crystalline forms possess. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Open Brochure WO2015 / 025936 [Non-patent literature]

[0010] [Non-Patent Document 1] Nature Rev.Cancer,vol.6,pp803-811(2006) [Non-Patent Document 2] J.Clin.Oncol.,vol.19,32s-40s(2001) [Non-Patent Document 3] Ministry of Internal Affairs and Communications, Statistics Bureau website / Statistical Data / World Statistics "World Statistics 2022" Chapter 14 National Life and Social Security 14-1 Mortality Rate by Cause of Death [Non-Patent Document 4] Lung Cancer,vol.69,pp1-12(2010) [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] When compounds are used as active ingredients in pharmaceuticals, it is desirable for them to be in a stable crystalline form in order to maintain stable quality and / or to facilitate storage 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 particular compound or its salt will form crystals, and which crystalline form will have superior physical properties such as stability.

[0012] Given the circumstances described above, there is a need for crystalline compounds or salts thereof that have EGFR inhibitory activity and exhibit good properties such as thermal stability, storage stability, and / or low hygroscopicity. This disclosure aims to provide a compound (1) having one or more properties such as thermal stability, storage stability, and / or low hygroscopicity. This disclosure also aims to provide crystalline compounds (1) that are useful as pharmaceuticals or pharmaceutical raw materials. Furthermore, this disclosure aims to provide a method for producing crystalline compounds (1). [Means for solving the problem]

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

[0014] In other words, the present invention provides, for example, the following [1] to

[16] . [1] A type I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, having three or more peaks 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° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays. [2] A type I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, having five or more peaks with 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 the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays. [3] A type I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, having seven or more peaks with 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 the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays. [4] Type I crystals 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 by CuKα characteristic X-rays shown in FIG. 1. [5] Crystals according to any one of [1] to [4], having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244 °C. [6] Crystals according to any one of [1] to [5], having a crystal purity of 50% by weight or more (preferably 75% by weight or more, more preferably 80% by weight or more, still more preferably 95% by weight or more). [7] Crystals 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, still more preferably 98% or more). [8] A pharmaceutical composition containing crystals according to any one of [1] to [7]. [9] A pharmaceutical composition comprising crystals according to any one of [1] to [7] and a pharmaceutically acceptable carrier.

[10] An antitumor agent containing crystals 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 containing at least one selected from the group consisting of lower alcohols, aprotic polar solvents, and water (in one solvent or in a mixed solvent of two or more).

[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 the 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] 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] , comprising the 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 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, still 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 a mixed solvent of 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, still more preferably 0.67:1 to 0.33:1, still more preferably 0.5:1 to 0.33:1, particularly preferably 0.5:1).

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

[12] or

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

[15] A method for treating a tumor, comprising orally administering an effective amount of any of the crystals described in [1] to [7] to a subject in need of such treatment.

[16] Use of any of the crystals described in [1] to [7] for the manufacture of an antitumor agent for oral administration. [Effects of the Invention]

[0015] According to one aspect of the present invention, crystals of a compound or salt thereof having EGFR inhibitory activity are provided, which have good properties such as thermal stability, storage stability and / or low hygroscopicity. [Brief explanation of the drawing]

[0016] [Figure 1] The powder X-ray diffraction spectrum of the type I crystal of compound (1) obtained in Example 1 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). [Figure 2] The results of differential thermal-thermogravimetric (TG-DTA) measurements of the type I 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)). [Figure 3] The powder X-ray diffraction spectrum of the type I crystal of compound (1) obtained in Example 2 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). [Figure 4]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)). [Figure 5] The results of differential thermal-thermogravimetric analysis (TG-DTA) of the solvated crystal type b of compound (1) obtained in Comparative 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)). [Figure 6] The amorphous powder X-ray diffraction spectrum of compound (1) obtained in Reference Example 1 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents the diffraction angle (2θ)). [Figure 7] The results of the differential thermal-thermogravimetric (TG-DTA) analysis of the amorphous compound (1) obtained in Reference 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)). [Figure 8] The results of the dynamic water absorption / desorption (DVS) test of the type I crystal of compound (1) in Test Example 2 are shown. [Figure 9] The results of the dynamic water absorption / desorption (DVS) test of the solvated crystal type b of compound (1) in Test Example 2 are shown. [Figure 10] The results of the dynamic water absorption / desorption (DVS) test of the amorphous compound (1) in Test Example 2 are shown. [Modes for carrying out the invention]

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

[0018] Crystals are solids in which atoms or molecules are arranged in a regular, repeating structure, and they differ from amorphous (non-crystalline) solids that do not have such repeating structures. Crystalline or amorphous solids can be investigated using methods such as powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric-differential thermal analysis (TG-DTA), and single-crystal analysis. Crystalline polymorphisms refer to the same molecule but with different arrangements of atoms or molecules in the crystal, and it is known that the peaks obtained by XRD measurement differ among crystalline polymorphs. Furthermore, it is known that solubility, oral absorption, and / or stability differ among each crystalline polymorph.

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

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

[0021] In this specification, when "compound (1)" is mentioned simply, it means (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, and is used to include both "crystalline" and "amorphous" forms. In this specification, "crystals of compound (1)" refers to crystals of the free form of compound (1). In this specification, crystals in which molecules other than the compound (1) constituting the crystal (salt or other molecules constituting the cocrystal) are not specified mean crystals of the free form of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, and are not limited to a single crystal form such as type I, but may include multiple free form crystals.

[0022] In this specification, the crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with an acid refer to either salt crystals or cocrystals with an acid. Salt crystals are crystals in which compound (1) and acid molecules are bonded by ionic bonds, while cocrystals are crystals in which compound (1) and acid molecules are bonded by nonionic interactions. In the present invention, the crystals of compound (1) with an acid may be either salt crystals or cocrystals, and encompass both meanings. For example, if it is a crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide with succinic acid, it means either a crystal of the succinate salt of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide or a cocrystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide with succinic acid.

[0023] Generally, pharmaceutically acceptable acid salts include numerous 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, aspartate, maleic acid, lactic acid, malic acid, hippuric acid, glutarate, adipine, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid (mesylic acid), p-toluenesulfonic acid (p-tosylic acid), and glutamic acid.

[0024] In this specification, the crystals may be either hydrates or anhydrous forms.

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

[0026] The crystals may contain crystals of compound (1), and may be single crystals or polymorphic mixtures containing crystals of other compounds (1). Specifically, the purity of the crystals may be 40% by weight or more (i.e., 40% by weight or more are single crystals). Preferably, the purity of the crystals is 50% by weight or more (i.e., 50% by weight or more are single crystals), more preferably 75% by weight or more (i.e., 75% by weight or more are single crystals), more preferably 90% by weight or more (i.e., 90% by weight or more are single crystals), even more preferably 95% by weight or more (i.e., 95% by weight or more are single crystals), even more preferably 98% by weight or more (i.e., 98% by weight or more are single crystals), and particularly preferably 99% by weight or more (i.e., 99% by weight or more are 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 of compound (1) measured by HPLC. In this case, the wavelength of the detector used for purity measurement can be set as appropriate. Specifically, the chemical purity of the crystals of compound (1) is preferably 90% or higher, more preferably 95% or higher, even more preferably 97% or higher, and particularly preferably 98% or higher.

[0028] In this specification, optical purity refers to the purity measured by a polarimeter, and when the optical purity of compound (1) is mentioned, it refers to the purity of compound (1) measured by a polarimeter. In this case, the light source of the apparatus used for purity measurement can be selected as appropriate.

[0029] The 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 value of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error of approximately ±0.2°. That is, when "diffraction angle (2θ±0.2°)" is written in this specification, it means that a measurement error of ±0.2° is acceptable for the numerical value of the diffraction angle (2θ). For example, if "8.0°" is written for the diffraction angle (2θ±0.2°), it means that a diffraction angle of up to 8.0°±0.2° is acceptable, encompassing diffraction angles from "7.8° to 8.2°". Furthermore, this value can be calculated using the Bragg formula (2d sinθ=nλ), and it changes depending on the wavelength being measured. That is, it is possible to convert it to the diffraction angle at a different measurement wavelength by substituting the measurement wavelength into the above formula. For example, if the diffraction angles (2θ) for the characteristic X-rays of CuKα at a wavelength λ of 1.54 Å are 8.0° and 10.6° respectively, and the values ​​of d and n remain constant, then the diffraction angles (2θ) at 0.75 Å are 3.9° and 5.2° respectively.

[0030] Examples of the compound (1) used in the crystallization method of the present invention include those produced by the method described in Patent Document 1. For crystallization, it is possible to use compound (1) without extracting it as crystals after synthesis, or to use compound (1) that has been extracted as crystals (crude crystals).

[0031] In this specification, "room temperature" typically refers to a temperature between approximately 18°C ​​and 25°C.

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

[0033] In this specification, "ketone solvent" means a solvent having a ketone structure within its molecule. Examples include acetone and methyl ethyl ketone.

[0034] In this specification, "ester solvent" means a solvent having an ester structure within its molecule. Examples include ethyl acetate, isopropyl acetate, and butyl acetate.

[0035] In this specification, "saturated hydrocarbon solvent" means a solvent consisting of saturated hydrocarbons, which may have straight or branched chains. Examples include hexane and heptane.

[0036] In this specification, "ether-based solvent" means a solvent having an ether structure within its molecule. Examples include diethyl ether, ethyl methyl ether, diphenyl ether, ethylene oxide, tetrahydrofuran, 1,4-dioxane, and benzofuran.

[0037] Aprotic polar organic solvents are solvents that do not contain protons that can be ionized. Examples include acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), chloroform, dichloromethane, and dimethyl sulfoxide (DMSO).

[0038] In differential thermal-thermogravimetric analysis (TG-DTA) curves, the endothermic peak can vary depending on the measurement temperature, such as the rate of temperature increase per minute and the chemical purity of the sample, and typically represents an error of ±5.0°C. Therefore, when performing TG-DTA measurements on the crystal according to the present invention, an error of ±5.0°C in the endothermic peak (peak top value) should be considered. The term "approximately" used in this context means ±5.0°C.

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

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

[0041] In this specification, the hygroscopicity of the crystals can be evaluated by the dynamic moisture absorption / desorption (DVS) test shown in Test Example 2 below. When evaluated under the conditions described in Test Example 2, the crystals of compound (1) in one embodiment of the invention have a weight increase of preferably 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 crystals of compound (1) described above (i.e., type I crystals of compound (1)). Another embodiment of the present invention provides a method for treating a tumor, comprising administering an effective amount of crystals of compound (1) described above (i.e., type I crystals of compound (1)) to a subject in need thereof. Another embodiment of the present invention provides the use of crystals of compound (1) (i.e., type I crystals of compound (1)) for producing an antitumor agent. Furthermore, another embodiment of the present invention provides crystals of compound (1) (i.e., type I crystals of compound (1)) for use in treating a tumor. Another embodiment of the present invention provides a method for producing crystals of compound (1) described above (i.e., type I crystals of compound (1)).

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

[0044] (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Compound (1) is a compound having the following structure, disclosed in Patent Document 1 as a compound with excellent EGFR inhibitory activity. [ka] The compound (1) used in the present invention is not particularly limited, but for example, a compound produced by the manufacturing method described in Patent Document 1 and a known manufacturing method can be used. It is possible to produce a crystalline form using compound (1).

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

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

[0047] Slurry method In the present invention, the slurry method is a method of producing crystals by adding a solvent to a container containing a compound (1) produced by the manufacturing method described in Patent Document 1 or by a known manufacturing method, stirring the mixture in a suspension state for several hours to several days, filtering it, 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 that can maintain the suspension state of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide during the stirring step can be used. Examples 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, and water are preferred. These solvents can be used individually or in any combination of two or more in any proportion. A mixed solvent of two or more types of solvents is, for example, a solvent obtained by mixing methanol and water in a 1:1 ratio, ethanol and water in a 1:1 ratio, or ethanol and diisopropyl ether in a 1:1 ratio. Preferably, the solvent is acetonitrile alone, or a mixed solvent of ethanol and water in a 1:1 ratio. For 1 mg of compound (1), the amount of solvent that can be used is 0.001 to 0.03 mL. Preferably, it is 0.002 to 0.02 mL, more preferably 0.003 to 0.01 mL, and even more preferably 0.005 mL. The solvent temperature can be adjusted as appropriate, but can be set to, for example, 20 to 60°C. Preferably, it is 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 the crystals of compound (1), it is preferable to stir at the above temperature and then allow it to cool. The cooling temperature can be, for example, 10 to 40°C. Preferably, it is 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. Preferably, it is 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 methods such as filtration, washing with water or an organic solvent, or vacuum drying. Examples of organic solvents used for washing include lower alcohols, acetone, and acetonitrile.

[0048] Solution crystallization method In the present invention, the dissolution crystallization method involves dissolving compound (1), produced by the manufacturing method described in Patent Document 1 or by a known manufacturing method, in a solvent, stirring under heating or cooling conditions for several hours to several days, filtering, and then drying the resulting crystals to produce crystals. In this method, seed crystals can also be added as needed. This method allows you to obtain 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 can dissolve (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide and remain stable in the solution without decomposition. Examples include a mixed solvent of lower alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.) and water, or a mixed solvent of aprotic polar solvent (acetonitrile, DMF, DMA, NMP, DMSO, etc.) and water. These solvents can be used in any combination in any proportion as long as compound (1) dissolves in them. For example, methanol and water can be used in a ratio of 4:1 to 0.5:1. Preferably, it is 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 using a mixture of ethanol and water, it can be used in a ratio of 4:1 to 0.25:1. Preferably, the ratio is 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 using a mixture of 2-propanol and water, it can be used in a ratio of 4:1 to 0.25:1. Preferably, the ratio is 2:1 to 0.25:1, more preferably 1.5:1 to 0.25:1, even more preferably 1:1 to 0.5:1, even more preferably 0.67:1 to 0.5:1, and particularly preferably 0.5:1. When using a mixture of 1-propanol and water, it can be used in a ratio of 2:1 to 0.15:1. Preferably, the ratio is 1.5:1 to 0.15:1, and more preferably 1:1 to 0.25:1. More preferably, the ratio is 0.67:1 to 0.33:1, even more preferably 0.5:1 to 0.33:1, and particularly preferably 0.33:1. When using a mixture of acetonitrile and water, it can be used in a ratio of 3:1 to 0.15:1.Preferably, the ratio is 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. The preferred solvent is a mixed solvent of ethanol and water or a mixed solvent of acetonitrile and water, and more preferably a mixed solvent of ethanol and water. The ratio of the mixed solvent is as described above. For every 1 mg of compound (1), the amount of solvent can be 0.005 to 0.080 mL. Preferably, it is 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 set to, for example, 20 to 80°C. Preferably, it is 20 to 60°C, more preferably 30 to 60°C, even more preferably 45 to 60°C, and most preferably 55°C. In order to precipitate the crystals of compound (1), it is preferable to allow it to cool after stirring at the above temperature. The cooling temperature can be set to, for example, 10 to 40°C. Preferably, it is 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. Preferably, it is 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 crystal suspension by known separation and purification methods such as filtration, washing with water or an organic solvent, or vacuum drying. Examples of organic solvents used for washing include lower alcohols, acetone, and acetonitrile. When producing crystals using the dissolution crystallization method, the crystals can also be produced by adding the desired crystals as seed crystals to the solvent mentioned above. In all crystal production methods, the formation of crystals requires maintaining compound (1) in a saturated or supersaturated state with respect to the solvent for a certain period of time (for example, 1 to 72 hours, preferably 4 to 60 hours, more preferably 8 to 48 hours, and even more preferably 12 to 36 hours). If the period during which saturation or supersaturation is maintained is short (for example, 30 minutes or less, preferably 1 to 20 minutes, more preferably 30 to 15 minutes), crystals cannot be formed and the mixture tends to become amorphous, which is undesirable.

[0049] The crystal purity of the type I crystals of compound (1) produced by the dissolution crystallization method is 90% by weight or more. Preferably it is 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 crystals of compound (1) produced by the dissolution crystallization method is 90% or higher. Preferably it is 95% or higher, more preferably 97% or higher, even more preferably 98% or higher, and even more preferably 99%.

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

[0052] Here, characteristic peaks in the powder X-ray diffraction spectrum of the type I crystal of compound (1) in one embodiment of the present invention include, for example, one or more selected from 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) may have two 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 its powder X-ray diffraction spectrum. In one embodiment of the present invention, the type I crystal of compound (1) may have 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 its powder X-ray diffraction spectrum. In a preferred embodiment of the present invention, the type I crystal of compound (1) has four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, peaks 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° in the powder X-ray diffraction spectrum. In another embodiment of the present invention, the type I crystal of compound (1) may have eight or all of the above peaks at diffraction angles (2θ±0.2°) selected from the above in the powder X-ray diffraction spectrum. In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0054] In one embodiment, the type I crystal of compound (1) has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 239-249°C, or in other words, around 244°C. In another embodiment, the type I crystal of compound (1) has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 2.

[0055] In one embodiment of the present invention, the type I crystal of compound (1) has one or more peaks in the powder X-ray diffraction spectrum with 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°, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C. In a preferred embodiment of the present invention, the type I crystal of compound (1) is a crystal in which the powder X-ray diffraction spectrum has two or more peaks with diffraction angles (2θ±0.2°) selected from the above, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C. In a preferred embodiment of the present invention, the type I crystal of compound (1) is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angle (2θ ± 0.2°) has three or more peaks selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 244°C. In a preferred embodiment of the present invention, the type I crystal of compound (1) is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with a diffraction angle (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C. Preferably, it is a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C. More preferably, it is a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C. Even more preferably, it is a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement 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 above-selected diffraction angles (2θ±0.2°) in the powder X-ray diffraction spectrum, and may have an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 244°C.

[0056] (Activity and Uses) The crystals of compound (1) in one embodiment of the present invention have excellent EGFR inhibitory activity and are useful as an antitumor agent. They also have excellent selectivity for EGFR and have the advantage of fewer side effects caused by other kinases. The types of malignant tumors targeted are not particularly limited, but examples include epithelial cancers (e.g., respiratory system cancers, gastrointestinal system cancers, reproductive system cancers, endocrine system cancers, etc.), sarcomas, hematopoietic malignancies, central nervous system tumors, peripheral nerve tumors, etc., and are preferably epithelial cancers, and more preferably respiratory system cancers. Furthermore, there are no particular restrictions on the type of organ in which the tumor originates, but examples include head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder and 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, hematological 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 even more preferably lung cancer. Furthermore, the compounds of the present invention or crystals of their salts exhibit excellent inhibitory activity against mutant EGFR. Examples of such mutant EGFR include drug-resistant mutant EGFR and highly sensitive mutant EGFR. Therefore, the compounds of the present invention or crystals of their salts are useful as antitumor agents against the aforementioned malignant tumors that have mutant EGFR.

[0057] The crystals of the present invention may be used in adjuvant chemotherapy administered after surgical removal of a tumor to prevent recurrence, or they may be used in adjuvant chemotherapy administered prior to surgical removal of a tumor.

[0058] In this specification, the term "effective amount" of a compound refers to the amount of the compound of the present invention (therapeutic effective amount) that causes a target biological or medical response, such as a decrease or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of a condition, or slowing or delaying the progression of a disease. In this specification, the term “subject” includes mammals and non-mammals. In one embodiment, the subject may be a human being diagnosed as requiring treatment for one of the symptoms, conditions, or diseases disclosed herein.

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

[0060] One embodiment of the present invention provides an orally administered antitumor agent comprising type I crystals of compound (1) described above. Another embodiment of the present invention provides a method for treating a tumor, comprising orally administering an effective amount of type I crystals of compound (1) described above to a subject in need of such treatment. Another embodiment of the present invention provides the use of type I crystals of compound (1) described above for producing an orally administered antitumor agent. Another embodiment of the present invention provides type I crystals of compound (1) described above for use in the treatment of a tumor by orally administration.

[0061] One embodiment of the present invention provides a pharmaceutical composition comprising type I crystals of compound (1) described above. The pharmaceutical composition of one embodiment of the present invention comprises type I crystals of compound (1) described above and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides the use of type I crystals of compound (1) described above for the manufacture of a pharmaceutical composition. Another embodiment of the present invention provides type I crystals of compound (1) described above 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 coatings, while examples of formulation materials used in liquid formulations include solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics. These formulation materials are then blended during the manufacturing of the formulation. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers may be used as needed.

[0063] Excipients include starches, sugars, polysaccharides, and inorganic compounds. Examples of starches include potato starch, corn starch, rice starch, and partially pregelatinized starch. Sugars include monosaccharides, disaccharides, trisaccharides, and sugar alcohols. Examples include lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Polysaccharides can also be listed as sugars. Examples include cellulose and dextran, and more specifically, crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Inorganic compounds include silicic acids, such as light anhydrous silicic acid and calcium silicate. Examples of binders include hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, syrup powder, and hypromellose. Examples of disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch. Examples of lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearyl fumarate. Examples of coating agents include ethylcellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose. Examples of solvents include water, propylene glycol, and physiological saline. Examples of solubilizers include polyethylene glycol, alcohols such as ethanol, cyclodextrin, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants. Examples include sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid esters, and sodium lauryl sulfate. Examples of suspending agents include carrageenan, crystalline cellulose / carmellose sodium, polyoxyethylene hydrogenated castor oil, acacia gum, and sodium alginate. Examples of isotonic agents include sodium chloride, glycerin, and potassium chloride. Examples of pH adjusters and buffering agents include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate. Examples of pain relievers 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 dioxide, ferric oxide, food coloring blue No. 1, and copper chlorophyll. Examples of flavoring and odor-masking agents include aspartame, saccharin, sucralose, l-menthol, and mint flavor. Examples of stabilizers include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0064] When preparing oral preparations, excipients, and optionally binders, disintegrants, lubricants, colorants, flavorings, and odor-masking agents, etc., are added to the type I crystals of compound (1), and then tablets, coated tablets, granules, powders, capsules, etc., can be manufactured by conventional methods. When preparing injectable preparations, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc., are added to the type I crystals of compound (1), and subcutaneous, intramuscular, and intravenous injectable preparations can be manufactured by conventional methods.

[0065] The amount of type I crystals of compound (1) to be included in each dosage unit is not constant, depending on the symptoms of the patient to whom it is administered, or the dosage form, etc. However, generally, it is desirable that the amount per dosage unit be approximately 1 to 400 mg of compound (1) in free form for oral preparations, approximately 5 to 300 mg for injectable preparations, and approximately 1 to 400 mg for suppositories or topical preparations.

[0066] Furthermore, the daily dose of type I crystals of compound (1) for each dosage form of the drug varies depending on the patient's symptoms, weight, age, sex, etc., and cannot be determined in general terms. However, for an adult (weighing 50 kg), the daily dose should be approximately 1 to 1000 mg, preferably 1 to 400 mg, of compound (1) in free form. [Examples]

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited in any way thereto. Although the present invention has been sufficiently described by the examples, it will be understood that various modifications and / or modifications are possible for those skilled in the art. Accordingly, such modifications and / or modifications are included in the present invention as long as they do not depart from the scope of the present invention.

[0068] In the following examples of compounds, percentages indicate weight percentages unless otherwise specified.

[0069] Powder X-ray diffraction measurement Powder X-ray diffraction was performed by lightly grinding an appropriate amount of the test material in an agate mortar as needed, and then measuring it according to one of the following test conditions.

[0070] Equipment: PANalytical EMPYREAN (Method A) Reflection method (concentration method) Target: Cu X-ray tube current: 40mA X-ray tube voltage: 45kV Scanning range: 2θ = 5.0~40.0° Step: 2θ = 0.0131° Average time / step: 8.670s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Light-receiving slit: 8.0mm

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

[0072] The handling of the equipment, including data processing, followed the methods and procedures specified for each instrument. Note that the numerical 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] Differential thermal-thermogravimetric analysis (TG-DTA measurement) was performed on 4-5 mg of the test substance according to the following test conditions. Equipment:TG / DTA7200 Manufactured by Hitachi High-Tech Science Corporation Sample container: Made of aluminum Heating rate: Heats up from 25 to 290°C at a rate of 10°C / minute. Atmospheric gas: Air (200 mL / min) Control material: Empty bread The handling of equipment, including data processing devices, followed the methods and procedures specified for each device.

[0074] Example 1: Preparation of type I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) (Slurry method) (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) (6.40 g), synthesized by the method described in Patent Document 1, was mixed with acetonitrile (32 mL) and stirred at 50°C for 24 hours. After cooling to room temperature, the mixture was stirred at room temperature for 48 hours. After stirring, the resulting solid was filtered, washed with acetonitrile (6.4 mL), and 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 type I crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 1. The 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. [Table 1] The differential thermal-thermogravimetric curve of the crystal obtained in Example 1 was obtained using the procedure described above and is shown in Figure 2. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 244°C.

[0076] Preliminary study: Investigation of crystal production conditions for (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) A preliminary study was conducted to find a suitable solvent for producing crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)). The type of solvent and mixing ratio were varied, and the crystal precipitation and conditions were investigated. The yield was calculated. The results are shown in Table 2 below. Crystal precipitation was confirmed visually. Based on this preliminary test, we identified a suitable solvent and carried out Examples 2 and 3 described below.

[0077] [Table 2]

[0078] Example 2: Preparation of type I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) (Dissolution crystallization method) (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) (1.00 g), synthesized by the method described in Patent Document 1, was mixed with 75% ethanol water (15 mL) and stirred at 55°C for 1 hour. The insoluble matter was filtered off and washed with 75% ethanol water (0.6 mL). Next, water (16.6 mL) was added and stirred at 55°C for 2 hours, then cooled to 25°C and stirred for 20 hours. The solid was filtered off and washed with 36% ethanol water (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 Type I crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 3. The 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 type I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) (Dissolution crystallization method) The preparation was carried out in the same manner as described in Example 2, except that the solvent ratio of the mixed solvent was changed as shown in the table (the ratios listed in Table 3). Even when the ratio of the mixed solution was changed, type I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with high chemical purity (99% or more) could be produced. [Table 3]

[0081] Comparative Example 1: Preparation of solvated crystal type b of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) After dissolving 1.5 g of type I crystals of compound (1) in methanol (225 mL), the solvent was dried under reduced pressure at 40°C using an evaporator and a water bath to obtain 1.012 g of amorphous compound (1). 1 g of amorphous material was mixed with 20 mL of anisole, stirred at room temperature for approximately 28 hours, and then filtered under reduced pressure to collect the solid. This was then dried under reduced pressure at room temperature for approximately 26 hours to obtain 856 mg of the indicated crystals.

[0082] The powder X-ray diffraction spectrum (Method B) of the obtained crystal was obtained using the procedure described above 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 differential thermal-thermogravimetric curve of the obtained crystal was obtained using the procedure described above and is shown in Figure 5.

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

[0084] The obtained amorphous powder X-ray diffraction spectrum (Method B) was acquired using the procedure described above and is shown in Figure 6. No characteristic diffraction angles were observed in the measurement results. The differential thermal-thermogravimetric curve of the obtained 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 investigated using type I crystals, solvated type b crystals, and amorphous compounds of compound (1) obtained in Example 1, Comparative Example 1, and Reference Example 1. The evaluation was carried out according to the following procedure. In addition, the appearance was visually confirmed before and after storage. Storage conditions: 60°C or 80°C (closed system) (HIFLEX (ETAC high-temperature storage machine)) Storage period: 2 weeks and 4 weeks Storage amount: approx. 100mg Storage container: glass jar

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

[0087] Changes in the amount of related substances (the amount of substances detected other than compound (1)) were analyzed by HPLC using the following method. For the analysis, approximately 1 mg of each sample was weighed as compound (1), dissolved in 10 mL of acetonitrile-water mixture (3:1 v / v), and 5 μL of this solution was accurately measured and used as the sample. HPLC measurement method (stability test) The amount of related substances in the sample solution was measured by HPLC analysis. The handling of the instruments, including data processing, followed the methods and procedures specified for each instrument. Column: Manufactured by GL Sciences InertSustain C18HP (4.6×150mm, 3μm) UV detection: 220nm Column temperature: 40℃ Flow rate: 1.0mL / min Sample cooler: 5℃ Sample concentration: 0.1 mg / mL Mobile phase A: 0.1% phosphate Mobile phase B: Acetonitrile The gradient is shown in Table 6. [Table 6]

[0088] As a result, the type I crystals of compound (1) showed almost no change in chemical purity compared to the solvated type b crystals and amorphous crystals, and there was almost no increase in related substances. Furthermore, no changes were observed in crystal shape or color, indicating that they are extremely stable crystals.

[0089] Test Example 2: Dynamic Moisture Absorption / Desorption (DVS) Test Water adsorption and desorption tests were performed using the type I crystals, solvated type b crystals, and amorphous form of compound (1) obtained in Example 1, Comparative Example 1, and Reference Example 1. The moisture absorption and desorption test was performed according to the following conditions. Approximately 10 mg of the sample was placed in a dedicated quartz holder, and its weight at various humidity levels was continuously measured and recorded under the following conditions. The handling of the equipment, including data processing, followed the methods and procedures specified for each instrument. Equipment: VTI SA+ (manufactured by T.A. Instruments) Drying temperature: 60℃ Heating rate: 5°C / min Drying equilibrium: Ensure that there is no decrease of 0.01 wt% in 5 minutes, within a range not exceeding 300 minutes. Measurement temperature: 25℃ Humidification equilibrium: Ensure that the humidity does not increase by 0.01 wt% in 5 minutes, within a range not exceeding 120 minutes. Relative humidity program: Increases humidity by 5% RH increments from 5% to 95% RH, and decreases it by 5% RH increments from 95% to 5% RH. The weight changes within the measurement condition range obtained in these tests are shown in Figures 8 to 10.

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

[0091] Based on the above results, the type I crystal of compound (1) has lower hygroscopicity compared to the solvated type b crystal and amorphous form, and can be said to be superior in terms of stable quality for industrial production of pharmaceuticals as a candidate compound for drug development.

[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 with the metastable crystals and hydrate crystals described above (data not shown).

[0093] While several embodiments of the present invention have been described, these embodiments are presented as examples only and are not intended to limit the scope of the invention. These novel embodiments can be carried out in a variety of other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their variations are included in the scope and spirit of the invention, as well as in the claims of the invention and its equivalents.

Claims

1. A type I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, having three or more peaks selected from the group consisting of 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° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

2. The crystal according to claim 1, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has five or more peaks selected from the group consisting of 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°.

3. The crystal according to claim 1 or 2, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has seven or more peaks selected from the group consisting of 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°.

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

5. The crystal according to any one of claims 1 to 4, wherein the endothermic peak determined by simultaneous differential thermal-thermogravimetric measurement is around 244°C.

6. A crystal according to any one of claims 1 to 5, wherein the crystal purity is 95% by weight or more.

7. A crystal according to any one of claims 1 to 6, wherein the chemical purity is 95% or higher.

8. A method for producing type I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide according to any one of claims 1 to 7, comprising the step of stirring (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide in a solvent containing at least one 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-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide according to any one of claims 1 to 7, comprising the step of dissolving and crystallizing (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-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 containing the crystals described in any one of claims 1 to 7.

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