Crystal of quinoline-substituted compound

Abstract

The present invention addresses the problem of providing a crystal of a compound having EGFR inhibitory ability or a salt thereof, the crystal having favorable storage stability, low hygroscopicity, low chargeability, or at least one characteristic of excellent pharmacokinetics. 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 which has a peak at a predetermined angle as a diffraction angle (2θ±0.2º) in a powder X-ray diffraction spectrum.

Description

Crystal of quinoline-substituted compound

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

[0002] EGFR (Epidermal Growth Factor Receptor) is a receptor-type tyrosine kinase. In normal tissues, it binds to epidermal growth factor (EGF), a ligand, to exert its physiological function and contributes to proliferation, apoptosis inhibition, etc. 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, kidney 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, occupying the top positions among 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. 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]

[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 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 what crystalline form compound (1) obtained by this method may have. Furthermore, there is no specific disclosure of what crystalline forms compound (1) or its salts may form, or what physical properties those crystalline forms may have.

[0009] International Public Brochure WO2015 / 025936 International Public Brochure WO2024 / 248083

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

[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 crystals of compounds or salts thereof that have EGFR inhibitory activity and exhibit good properties such as storage stability, low hygroscopicity, low electrostatic charge, or excellent pharmacokinetics (hereinafter sometimes referred to as PK). This disclosure aims to provide a compound (1) having one or more properties such as storage stability, low hygroscopicity, low electrostatic charge, or excellent pharmacokinetics. This disclosure also aims to provide crystals of compound (1) that are useful as pharmaceuticals or pharmaceutical raw materials. Furthermore, this disclosure aims to provide a method for producing crystals of compound (1).

[0013] The present inventors conducted diligent research and obtained crystals of salts of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, or cocrystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, which have good properties in terms of storage stability, low hygroscopicity, low electrostatic charge, or excellent pharmacokinetics.

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

[65] : [1] Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°. [2] The crystal according to [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 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9° at diffraction angles (2θ ± 0.2°). [3] The crystal according to [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 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9° at diffraction angles (2θ ± 0.2°). [4] Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having a powder X-ray diffraction spectrum substantially identical to that measured by CuKα characteristic X-rays shown in Figure 1. [5] The crystal according to any one of [1] to [4], wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. [6] The crystal according to any one of [1] to [5], wherein the crystal purity is 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], wherein the chemical purity is 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more).[8] A method for producing Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, according to any one of [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 with succinic acid in a solvent comprising at least one selected from the group consisting of a lower alcohol and an aprotic polar solvent. [9] A pharmaceutical composition containing the crystal according to any one of [1] to [7].

[10] A pharmaceutical composition containing the crystal according to any one of [1] to [7] and a pharmaceutically acceptable carrier.

[11] An antitumor agent containing the crystal according to any one of [1] to [7].

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

[13] Use of the crystal described in any of [1] to [7] for the manufacture of an antitumor agent for oral administration.

[14] Form II crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9° in a powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

[15] The crystal according to

[14] , 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 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°.

[16] The crystal according to

[14] or

[15] , 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 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°.

[17] Form II crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, 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 3.

[18] A crystal according to any one of

[14] to

[17] , wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C.

[19] A crystal according to any one of

[14] to

[18] , wherein the crystal purity is 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).

[20] A crystal according to any one of

[14] to

[19] , wherein the chemical purity is 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more).

[21] A method for producing Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, according to any one of

[14] to

[20] , 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 with succinic acid in a solvent comprising at least one selected from the group consisting of lower alcohols, aprotic polar solvents, and water.

[22] A pharmaceutical composition containing the crystal according to any one of

[14] to

[20] .

[23] A pharmaceutical composition containing the crystal according to any one of

[14] to

[20] and a pharmaceutically acceptable carrier.

[24] An antitumor agent containing the crystal according to any one of

[14] to

[20] .

[25] A method for treating a tumor, comprising orally administering an effective amount of the crystal described in any of

[14] to

[20] to a subject in need of such treatment.

[26] Use of the crystals described in any of

[14] to

[20] for the manufacture of an antitumor agent for oral administration.

[27] The crystals described in [27-1] or [27-2] below: [27-1] Form III crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9° and 27.4° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays. [27-2] Form III crystals (0.5 hydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

[28] The crystal according to

[27] , 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 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°.

[29] The crystal according to

[27] or

[28] , 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 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°.

[30] Crystals described in [30-1] or [30-2] below: [30-1] Form III crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, 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 5. [30-2] Form III crystals (0.5 hydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, 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 5.

[31] The crystal according to any one of

[27] to

[30] , wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 218°C.

[32] The crystal according to any one of

[27] to

[31] , wherein the crystal purity is 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).

[33] The crystal according to any one of

[27] to

[32] , wherein the chemical purity is 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more).

[34] Crystals as described in [34-1] or [34-2] below: [34-1] A method for producing Form III crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, as described in any of

[27] to

[33] , 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 with succinic acid in a solvent containing water.[34-2] A method for producing Form III crystals (0.5 hydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, according to any one of [27-1] to [33-1], 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 with succinic acid.

[35] A pharmaceutical composition containing the crystals according to any one of

[27] to

[33] .

[36] A pharmaceutical composition containing the crystals according to any one of

[27] to

[33] and a pharmaceutically acceptable carrier.

[37] An antitumor agent containing the crystals according to any one of

[27] to

[33] .

[38] A method for treating a tumor, comprising orally administering an effective amount of the crystal described in any of

[27] to

[33] to a subject in need thereof.

[39] Use of the crystal described in any of

[27] to

[33] for the manufacture of an antitumor agent for oral administration.

[40] Form I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6° and 22.2°.

[41] The crystal according to

[40] , 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 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

[42] The crystal according to

[40] or

[41] , 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 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

[43] Form I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, 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 7.

[44] The crystal according to any one of

[40] to

[43] , wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 208°C.

[45] The crystal according to any one of

[40] to

[44] , wherein the crystal purity is 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).

[46] The crystal according to any one of

[40] to

[45] , wherein the chemical purity is 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more).

[47] A method for producing Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, according to any one of

[40] to

[46] , 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 with adipic acid, according to any one of

[40] to

[46] .

[48] A pharmaceutical composition containing the crystal according to any one of

[40] to

[46] .

[49] A pharmaceutical composition containing the crystal according to any one of

[40] to

[46] and a pharmaceutically acceptable carrier.

[50] An antitumor agent containing the crystal according to any one of

[40] to

[46] .

[51] A method for treating a tumor, comprising orally administering an effective amount of the crystal described in any of

[40] to

[46] to a subject in need of such treatment.

[52] Use of the crystals described in any of

[40] to

[46] for the manufacture of an antitumor agent for oral administration.

[53] Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9° and 27.6° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

[54] The crystal according to

[53] , 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 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°.

[55] The crystal according to

[53] or

[54] , 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 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°.

[56] Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, 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 9.

[57] The crystal according to any one of

[53] to

[56] , wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 53°C.

[58] The crystal according to any one of

[53] to

[57] , wherein the crystal purity is 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).

[59] The crystal according to any one of

[53] to

[58] , wherein the chemical purity is 90% or more (preferably 95% or more, more preferably 97% or more, and even more preferably 98% or more).

[60] A method for producing Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, according to any one of

[53] to

[58] , 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 with phosphoric acid, according to any one of

[53] to

[58] .

[61] A pharmaceutical composition containing the crystals according to any one of

[53] to

[59] .

[62] A pharmaceutical composition containing the crystals according to any one of

[53] to

[59] and a pharmaceutically acceptable carrier.

[63] An antitumor agent containing the crystals according to any one of

[53] to

[59] .

[64] A method for treating a tumor, comprising orally administering an effective amount of the crystal described in any of

[53] to

[59] to a subject in need thereof.

[65] Use of the crystal described in any of

[53] to

[59] for manufacturing an antitumor agent for oral administration.

[0015] According to one aspect of the present invention, crystals of a compound or salt thereof having EGFR inhibitory activity are provided, which exhibit good properties such as storage stability, low hygroscopicity, low electrostatic charge, or excellent pharmacokinetics.

[0016] The powder X-ray diffraction spectrum of the Form I crystal of compound (1) with succinic acid obtained in Example 1 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with succinic acid obtained in Example 1 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form II crystal of compound (1) with succinic acid obtained in Example 2 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form II crystals of compound (1) with succinic acid obtained in Example 2 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 Form III crystals of compound (1) with succinic acid obtained in Example 3 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form III crystals of compound (1) with succinic acid obtained in Example 3 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 Form I crystal of compound (1) with adipic acid obtained in Example 4 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with adipic acid obtained in Example 4 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form I crystal (dihydrate) of compound (1) with phosphoric acid obtained in Example 5 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal (dihydrate) of compound (1) obtained in Example 5 with phosphoric acid 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 Form I crystal of compound (1) with citric acid obtained in Example 6 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with citric acid obtained in Example 6 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form I crystal of compound (1) with fumaric acid obtained in Example 7 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with fumaric acid obtained in Example 7 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 Form II crystal of compound (1) with fumaric acid obtained in Example 8 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form II crystal of compound (1) with fumaric acid obtained in Example 8 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 Form III crystal of compound (1) with fumaric acid obtained in Example 9 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form III crystal of compound (1) with fumaric acid obtained in Example 9 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with fumaric acid obtained in Example 10 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric (TG-DTA) simultaneous measurement of Form IV crystals of compound (1) with fumaric acid obtained in Example 10 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 Form I crystals of compound (1) with benzoic acid obtained in Example 11 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)).The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with benzoic acid obtained in Example 11 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 Form I crystal of compound (1) with maleic acid obtained in Example 12 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form I crystal of compound (1) with maleic acid obtained in Example 12 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 Form II crystal of compound (1) with maleic acid obtained in Example 13 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form II crystal of compound (1) with maleic acid obtained in Example 13 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form III crystal of compound (1) with maleic acid obtained in Example 14 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form III crystal of compound (1) with maleic acid obtained in Example 14 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 Form IV crystal of compound (1) with maleic acid obtained in Example 15 is shown (the vertical axis represents intensity (counts), and the horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form IV crystal of compound (1) with maleic acid obtained in Example 15 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 results of the dynamic water absorption / desorption (DVS) test of the Form I crystal of compound (1) with succinic acid in Test Example 2 are shown. The results of the dynamic water absorption / desorption (DVS) test of Form II crystals of compound (1) of Test Example 2 with succinic acid are shown.The results of the dynamic water absorption and desorption (DVS) tests of Form III crystals of compound (1) in Test Example 2 with succinic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals of compound (1) in Test Example 2 with adipic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals (dihydrate) of compound (1) in Test Example 2 with phosphoric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals of compound (1) in Test Example 2 with citric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals of compound (1) in Test Example 2 with fumaric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form II crystals of compound (1) in Test Example 2 with fumaric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form III crystals of compound (1) in Test Example 2 with fumaric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form IV crystals of compound (1) in Test Example 2 with fumaric acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals of compound (1) in Test Example 2 with benzoic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form I crystals of compound (1) in Test Example 2 with maleic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form II crystals of compound (1) in Test Example 2 with maleic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form III crystals of compound (1) in Test Example 2 with maleic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of Form IV crystals of compound (1) in Test Example 2 with maleic acid are shown. The results of the dynamic water absorption and desorption (DVS) tests of amorphous compound (1) in Test Example 2 are shown. The powder X-ray diffraction spectrum of the Form III crystal of compound (1) with phosphoric acid obtained in Example 16 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)). The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form III crystal of compound (1) with phosphoric acid obtained in Example 16 are shown (left vertical axis represents weight (%) in the TG curve, right vertical axis represents heat flux (μV) in the DTA curve, horizontal axis represents temperature (°C)). The powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with phosphoric acid obtained in Example 17 is shown (vertical axis represents intensity (counts), horizontal axis represents diffraction angle (2θ)).The results of the differential thermal-thermogravimetric analysis (TG-DTA) of the Form IV crystal of compound (1) with phosphoric acid obtained in Example 17 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 results of the dynamic water absorption and desorption (DVS) test of the Form III crystal of compound (1) with phosphoric acid in Test Example 2 are shown. The results of the dynamic water absorption and desorption (DVS) test of the Form IV crystal of compound (1) with phosphoric acid in Test Example 2 are shown.

[0017] The present invention relates to a crystal 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) and an acid. Specifically, this invention relates to the crystals of compound (1) with an acid (i.e., crystals or cocrystals of compound (1) and its salt). In this specification, the terms succinate Form I crystals, succinate Form II crystals, adipic acid Form I crystals, 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 and / or molecules are arranged in a regular repeating structure, and are different from amorphous solids (non-crystalline materials) that do not have a repeating structure. Whether a solid is crystalline or amorphous can be determined by 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 and / or molecules within 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 somewhat 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 some variations in peak position and / or 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 simply referred to, it means (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide, and is used to include both "crystalline" and "amorphous" forms. In this specification, when "crystals of compound (1)" is referred to, it means crystals of the free form of compound (1). In this specification, crystals in which molecules other than 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-dihydropyrimide[5,4-b]indolidine-8-yl)acrylamide, and are not limited to a single crystalline form such as type I, but may include multiple free 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. It should be noted that by performing single-crystal X-ray structural analysis using known methods, it is possible to distinguish whether the crystals of compound (1) with an acid are salt crystals or cocrystals with an acid. 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. 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 adipic acid, it indicates either a crystal of the adipicate 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 adipic acid.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 phosphoric acid, it indicates either a crystal of the phosphate 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 phosphoric acid. 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 citrate, it indicates either a crystal of the citrate 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 citrate. 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 fumaric acid, it indicates either a crystal of the fumarate 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 fumaric acid.If it is a crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with benzoic acid, it indicates either a crystal of the benzoate of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide or a cocrystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with benzoic acid. 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 maleic acid, it indicates either a crystal of the maleate 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 maleic acid. 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 hippuric acid, it indicates either a crystal of hippurate 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 hippuric 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, glutaric acid, adipic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid (mesylic acid), p-toluenesulfonic acid (p-tosylic acid), glutamic acid, and benzoic acid.

[0024] In this specification, when the term "equivalent" is used, it refers to the molar equivalent. In the crystals of compound (1) with an acid (the crystals of its salt or cocrystals), the equivalent amount of acid to compound (1) can be analyzed, for example, by NMR and / or ion chromatography. In this specification, the crystals may be either hydrates or anhydrous forms. Furthermore, if it is a hydrate, any hydrate is acceptable, and it is not limited to any particular hydrate. For example, 0.3 hydrate, 0.5 hydrate, monohydrate, 1.5 hydrate, dihydrate, etc., can be given. The number of water molecules in the hydrate can be measured by known methods, such as single-crystal X-ray diffraction or differential thermal analysis.

[0025] Labeled forms of compound (1) or its salts, i.e., compounds obtained by substituting one or more atoms of compound (1) or a salt of compound (1) with radioactive or non-radioactive isotopes, are also included in the present invention.

[0026] The crystals may include crystals of compound (1) with an acid, and may be single crystals or polymorphic mixtures including crystals of other compounds (1) with acids. In this specification, crystal purity refers to the proportion of a particular crystal polymorphism contained in a crystal from the viewpoint of crystal polymorphism. Specifically, the crystal purity may be 40% by weight or more (i.e., 40% by weight or more are single crystals). A crystal purity of 50% by weight or more (i.e., 50% by weight or more are single crystals) is preferable, a crystal purity of 75% by weight or more (i.e., 75% by weight or more are single crystals) is more preferable, a crystal purity of 90% by weight or more (i.e., 90% by weight or more are single crystals) is even more preferable, a crystal purity of 95% by weight or more (i.e., 95% by weight or more are single crystals) is even more preferable, a crystal purity of 97% by weight or more (i.e., 97% by weight or more are single crystals) is even more preferable, and a crystal purity of 98% by weight or more (i.e., 98% by weight or more are single crystals) is particularly preferable. Furthermore, according to one aspect of the present invention, the crystal purity may be 40% or more (i.e., 40% or more are single crystals). It is preferable that the crystal purity is 50% or more (i.e., 50% or more are single crystals), more preferably 75% or more (i.e., 75% or more are single crystals), more preferably 90% or more (i.e., 90% or more are single crystals), even more preferably 95% or more (i.e., 95% or more are single crystals), even more preferably 97% or more (i.e., 97% or more are single crystals), and particularly preferably 98% or more (i.e., 98% or more are single crystals). This crystal 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 the crystals of compound (1) with acid, it refers to the purity of the crystals of compound (1) with acid measured by HPLC. The higher the chemical purity, the more impurities (related substances, etc.) are contained in the crystals. For example, 100% chemical purity means that when the chemical purity is measured by HPLC, the impurity content is 0%. 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) with acid is preferably 90% or higher, more preferably 95% or higher, even more preferably 97% or higher, and even more preferably 98% or higher. 99% or higher is particularly preferred. Furthermore, according to one aspect of the present invention, the chemical purity of the crystals of compound (1) with acid is preferably 90% by weight or higher, more preferably 95% by weight or higher, even more preferably 97% by weight or higher, even more preferably 98% by weight or higher, and even more preferably 99% by weight or higher.

[0028] In this specification, optical purity refers to the purity measured by a polarimeter, and when referring to the optical purity of the crystal of compound (1) with the acid, it refers to the purity of the crystal of compound (1) with the acid 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 errors 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, and it includes diffraction angles from "7.8° to 8.2°". Furthermore, this value can be obtained 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 approximately 25°C. In this specification, "approximately" refers to a value within ±10%, preferably ±5%, and more preferably ±3%.

[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, 1-propanol, 2-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] A non-protic polar organic solvent is a solvent that does 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 (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 "around" used in this context means ±5.0°C.

[0039] In one embodiment of the present invention, the inventors relate to the crystallization of compound (1) with an acid. The inventors have found that crystallization of compound (1) with an acid, for example, a salt crystal of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, or a cocrystal of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, and hippuric acid, has properties advantageous for pharmaceutical manufacturing or as a pharmaceutical, such as storage stability, low hygroscopicity, low electrostatic charge, or excellent pharmacokinetics. Furthermore, the present inventors have found that crystals of compound (1) with an acid, for example, salt crystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, or cocrystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, exhibit excellent solubility.

[0040] In this specification, the storage stability of the crystals can be evaluated, for example, by the solid stability test shown in Test Example 1 below. The crystals of compound (1) with acid in one embodiment of the invention have a change in chemical purity of preferably ±2.0% or less, more preferably ±1.0% or less, even more preferably ±0.5% or less, and even more preferably ±0.3% after storage under the conditions described in Test Example 1 for 4 weeks, 12 weeks, or 24 weeks. Furthermore, there is no change in crystal shape when measured by XRD after storage, and there is no obvious 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. In one embodiment of the invention, when the crystals of compound (1) with an acid are anhydrous, the weight increase rate when evaluated under the conditions described in Test Example 2 is preferably less than 5%, more preferably less than 3%, even more preferably less than 2%, and even more preferably less than 1%. When the crystals of compound (1) with an acid are hydrates, it is sufficient that they are stable as hydrates, and the weight increase rate from the relative humidity at which they become hydrates is preferably less than 5%, more preferably less than 3%, even more preferably less than 2%, and even more preferably less than 1%. For example, in the case of crystals of compound (1) and phosphoric acid, an increase in weight is observed at a relative humidity of approximately 20%, but since the weight increase rate thereafter is less than 2%, it can be understood that they are stable as hydrates.

[0042] In this specification, the chargeability of a crystal can be evaluated by the chargeability evaluation test shown in Test Example 3 below. In one embodiment of the invention, when evaluated under the conditions of Test Example 3, the fewer crystals of compound (1) with the acid detected, the lower the chargeability can be determined. By comparing various types of crystals and amorphous materials under the same conditions, the relative chargeability can be evaluated.

[0043] In this specification, excellent pharmacokinetics can be evaluated by administering the crystal to dogs and measuring pharmacokinetic parameters. If the area under the blood concentration-time curve (AUC, area under the concentration-time curve) of the crystal of compound (1) with an acid is larger than the AUC of the free form type I crystal of compound (1), it can be determined that it has excellent pharmacokinetics. Preferably, when the AUC of the free form type I crystal of compound (1) is set to 1, the AUC of the crystal of compound (1) with an acid is greater than 1.25, more preferably the AUC of the crystal of compound (1) with an acid is 1.5 or more, and even more preferably the AUC of the crystal of compound (1) with an acid is 1.8 or more. In addition to the AUC, if the maximum blood concentration (Cmax) of the crystal of compound (1) with an acid is larger than the Cmax of the free form type I crystal of compound (1), it can be determined that it has excellent pharmacokinetics. Preferably, when the Cmax of the free form type I crystal of compound (1) is set to 1, the Cmax of the crystal of compound (1) with an acid is greater than 1.25, more preferably the Cmax of the crystal of compound (1) with an acid is 1.5 or more, and even more preferably the Cmax of the crystal of compound (1) with an acid is 1.8 or more. Either the AUC or the Cmax may be improved, and more preferably both the AUC and the Cmax may be improved.

[0044] One embodiment of the present invention provides an antitumor agent containing the crystal of compound (1) with an acid (that is, a salt crystal or a cocrystal) described above. Further, one embodiment of the present invention provides a method for treating a tumor, which includes administering an effective amount of the crystal of compound (1) with an acid (that is, a salt crystal or a cocrystal) described above to a subject who needs it. One embodiment of the present invention provides the use of the crystal of compound (1) with an acid (that is, a salt crystal or a cocrystal) for manufacturing an antitumor agent. Furthermore, one embodiment of the present invention provides the crystal of compound (1) with an acid (that is, a salt crystal or a cocrystal) for use in treating a tumor. One embodiment of the present invention provides a method for producing the crystal of compound (1) with an acid (that is, a salt crystal or a cocrystal) described above.

[0045] The crystal of compound (1) with an acid in one embodiment of the present invention, that is, the crystal of the salt of compound (1) with succinic acid (Form I, Form II, Form III), adipic acid (Form I), phosphoric acid (Form I, Form III, Form IV), citric acid (Form I), fumaric acid (Form I, Form II, Form III, Form IV), benzoic acid (Form I) or maleic acid (Form I, Form II, Form III, Form IV), or the co-crystal of compound (1) with succinic acid (Form I, Form II, Form III), adipic acid (Form I), phosphoric acid (Form I, Form III, Form IV), citric acid (Form I), fumaric acid (Form I, Form II, Form III, Form IV), benzoic acid (Form I) or maleic acid (Form I, Form II, Form III, Form IV) has one or more advantageous properties such as storage stability, low hygroscopicity, low chargeability, solubility or excellent pharmacokinetics compared to other crystals such as the free form type I crystal of compound (1) or the amorphous form of compound (1) in pharmaceutical production or as a pharmaceutical product.

[0046] (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 disclosed in Patent Document 1 as a compound having an excellent EGFR inhibitory action. Compound (1) used in the present invention is not particularly limited, and for example, those produced by the production methods described in Patent Document 1 or 2 and known production methods can be used. It is possible to produce a crystal form using compound (1).

[0047] Production method of free form type 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))

[0048] Free form type I crystals of compound (1) can be produced by dissolution crystallization and other known crystal production methods. Although not limited to these methods, the method for producing free form type I crystals of compound (1) using dissolution crystallization will be described in detail below.

[0049] Dissolution Crystallization Method In the present invention, the dissolution crystallization method involves dissolving a 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, and drying the crystals obtained after filtration to produce crystals. In this method, seed crystals can also be added as needed. 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. 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 in a stable state without decomposition in the solution. Examples include a mixed solvent of lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.) and water, or a mixed solvent of aprotic polar solvents (acetonitrile, DMF, DMA, NMP, DMSO, etc.) and water. These solvents can be used in any combination in any proportion, provided that compound (1) is dissolved. 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 most preferably 1:1. When ethanol and water are used as a mixture, they can be used in a ratio of 4:1 to 0.25:1. Preferably, it 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, most preferably 0.67:1 to 0.5:1, and most preferably 0.5:1. When 2-propanol and water are used as a mixture, they 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, more preferably 1:1 to 0.25:1. Even more preferably, it 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, it 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. 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), the amount of solvent that can be used is 0.005 to 0.080 mL. Preferably, the volume 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 when dissolving compound (1) can be adjusted as appropriate, but for example, it can be 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, 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 for example, it can be 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. These solvents can be used individually or in combination of two or more.When producing crystals by the dissolution crystallization method, the crystals can also be produced by adding the desired crystals as seed crystals to the solvent described above. In either crystal production method, it is necessary to maintain compound (1) in a saturated or supersaturated state in 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) in order to produce crystals.

[0050] Free-form type I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) According to one embodiment of the present invention, a free-form type I crystal of compound (1) is provided. The free-form type I crystal of compound (1) in one embodiment obtained by the dissolution crystallization method described above may have characteristic peaks in the powder X-ray diffraction spectrum, for example, at 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°.

[0051] In one embodiment of the present invention, the free type I crystal of compound (1) has an endothermic peak (peak top value) of 239 to 249°C, or in other words, around 244°C, as determined by differential thermal-thermogravimetric analysis (TG-DTA).

[0052] Form 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 succinic acid According to one embodiment of the present invention, Form I crystals of compound (1) with succinic acid are provided. Form I crystals of compound (1) with succinic acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 1 or a powder X-ray diffraction spectrum substantially identical thereto.

[0053] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°.

[0054] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with succinic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with succinic acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°. In another embodiment of the present invention, the Form I crystal of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above-mentioned diffraction angles (2θ±0.2°) as selected from the above. In yet another embodiment, it may have one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0055] In one embodiment, the Form I crystal of compound (1) with succinic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 216 to 226°C, or in other words, around 221°C. In another embodiment, the Form I crystal of compound (1) with succinic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 2.

[0056] In one embodiment of the present invention, the Form I crystal of compound (1) with succinic acid may be a salt or cocrystal of compound (1) and succinic acid. The ratio of compound (1) to succinic acid is not particularly limited, but preferably the equivalent ratio of compound (1) to succinic acid is 1:0.5 to 10, more preferably 1:0.75 to 5, even more preferably 1:1 to 3, and particularly preferably 1:1 to 1.5.

[0057] In one embodiment of the present invention, the Form I crystal of compound (1) with succinic acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with succinic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. The Form I crystal of compound (1) with succinic acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. The Form I crystal of compound (1) with succinic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C. In another embodiment of the present invention, the Form I crystal of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 221°C.

[0058] Method for producing Form 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 succinic acid

[0059] Form I crystals of compound (1) with succinic acid can be produced, for example, from free form 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)) as described above. Although not limited to this production method, the method for producing Form I crystals of compound (1) with succinic acid will be described in detail below.

[0060] Form I crystals of compound (1) with succinic acid in embodiments of the present invention can be produced, for example, by adding succinic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of succinic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. The amount of succinic acid is not particularly limited, but preferably 1.5 to 10 mol can be used per 1 mol of compound (1). More preferably 1.5 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1.5 to 3 mol can be used per 1 mol of compound (1), particularly preferably 2 to 3 mol can be used per 1 mol of compound (1), and most preferably 3 mol per 1 mol of compound (1). 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. Furthermore, any solvent that can return to a suspension state after stirring for several minutes to several hours, even if temporarily dissolved, can be used. Examples include lower alcohols (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.), and aprotic polar solvents (acetonitrile, etc.). Among these, lower alcohols and aprotic polar solvents 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 is, for example, a solvent obtained by mixing ethanol with 1-propanol or 2-propanol in a 1:1 ratio. Preferably, the solvent is acetone alone, tetrahydrofuran alone, 1-propanol alone, or 2-propanol alone.For every 1 mg of compound (1), the amount of solvent can be 0.001 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL. The temperature of the solvent can be adjusted as appropriate, but for example, it can be 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. To precipitate crystals, after stirring at the above temperature, a cooling operation may be performed. The temperature for the cooling operation 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 for example, it can be 1 to 72 hours. Preferably, it is 1 to 72 hours, more preferably 1 to 48 hours, even more preferably 1 to 24 hours, and most preferably 3 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. These solvents can be used individually or in combination of two or more.

[0061] Form II 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 succinic acid According to one embodiment of the present invention, Form II crystals of compound (1) with succinic acid are provided. Form II crystals of compound (1) with succinic acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 3 or a powder X-ray diffraction spectrum substantially identical thereto.

[0062] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°.

[0063] Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with succinic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°. In preferred embodiments of the present invention, Form II crystals of compound (1) with succinic acid have, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°. In other embodiments of the present invention, Form II crystals of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above-mentioned diffraction angles (2θ±0.2°) as selected from the above. In yet another embodiment, there may be one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0064] In one embodiment, the Form II crystal of compound (1) with succinic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 216 to 226°C, or in other words, around 221°C. In another embodiment, the Form II crystal of compound (1) with succinic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 4.

[0065] In one embodiment of the present invention, the Form II crystal of compound (1) with succinic acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with succinic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 221°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with succinic acid 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 221°C. The Form II crystal of compound (1) with succinic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 221°C. In another embodiment of the present invention, the Form II crystal of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 221°C.

[0066] In one embodiment of the present invention, the Form II crystal of compound (1) with succinic acid may be a salt or cocrystal of compound (1) and succinic acid. The ratio of compound (1) to succinic acid is not particularly limited, but preferably the equivalent ratio of compound (1):succinic acid is 1:0.5 to 10, more preferably 1:0.75 to 3, even more preferably 1:1 to 1.5, and particularly preferably 1:1. The ratio of compound (1) to succinic acid may change depending on the solvent used. When methanol is used as the solvent, the equivalent ratio of compound (1):succinic acid is preferably 1:3.

[0067] Method for producing Form II 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 succinic acid

[0068] Form II crystals of compound (1) with succinic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. Although not limited to this production method, the method for producing Form II crystals of compound (1) with succinic acid will be described in detail below.

[0069] Form II crystals of compound (1) with succinic acid in embodiments of the present invention can be produced, for example, by adding succinic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of succinic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. The amount of succinic acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). Particularly preferably 1 mol can be used per 1 mol of compound (1). When methanol is used as the solvent, using 2 to 3 mol per 1 mol of compound (1) can accelerate crystallization compared to other solvents. 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. Furthermore, any solvent that can return to a suspension state after stirring for several minutes to several hours, even if temporarily dissolved, can be used. Examples include lower alcohols (methanol, ethanol, 1-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, THF, 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 includes, for example, a solvent mixed with 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, methanol alone, or a mixed solvent of ethanol and water in a 1:1 ratio. For 1 mg of compound (1), the amount of solvent can be 0.001 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL. The temperature of the solvent can be adjusted as appropriate, but for example, it can be 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 crystals, after stirring at the above temperature, a cooling operation may be performed. The temperature for the cooling operation 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 for example, it can be 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. These solvents can be used individually or in combination of two or more.

[0070] Form III crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with succinic acid According to one embodiment of the present invention, Form III crystal of compound (1) with succinic acid is provided. Form III crystal of compound (1) with succinic acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 5 or a powder X-ray diffraction spectrum substantially identical thereto.

[0071] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°.

[0072] Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with succinic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with succinic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with succinic acid has, in the powder X-ray diffraction spectrum, 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 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°. In another embodiment of the present invention, the Form III crystal of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above peaks at diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0073] In one embodiment, the Form III crystal of compound (1) with succinic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 213 to 223°C, or in other words, around 218°C. In another embodiment, the Form III crystal of compound (1) with succinic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 6.

[0074] In one embodiment of the present invention, the Form III crystal of compound (1) with succinic acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 218°C. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with succinic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above with diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 218°C. The Form III crystal of compound (1) with succinic acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 218°C. The Form III crystal of compound (1) with succinic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 218°C, preferably a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 218°C, more preferably a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 218°C, and even more preferably a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 218°C. In another embodiment of the present invention, the Form III crystal of compound (1) with succinic acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 218°C.

[0075] In one embodiment of the present invention, the Form III crystal of compound (1) with succinic acid may be a salt or cocrystal of compound (1) and succinic acid. The ratio of compound (1) to succinic acid is not particularly limited, but preferably the equivalent ratio of compound (1) to succinic acid is 1:0.5 to 10, more preferably 1:0.75 to 3, and even more preferably 1:1. The Form III crystal of compound (1) with succinic acid may also be a hydrate. Preferably it is a 0.05 to 3 hydrate, more preferably a 0.1 to 1 hydrate, and even more preferably a 0.5 hydrate.

[0076] Method for producing Form III 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 succinic acid

[0077] Form III crystals of compound (1) with succinic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. Although not limited to this production method, the method for producing Form III crystals of compound (1) with succinic acid will be described in detail below.

[0078] Form III crystals of compound (1) with succinic acid in embodiments of the present invention can be produced, for example, by adding succinic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of succinic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. The amount of succinic acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). The solvent can be 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. Any solvent that can be temporarily dissolved but then resuspended after stirring for several minutes to several hours can be used. Examples include water, or a mixed solvent of water and an organic solvent. Water alone, or water combined with one or more organic solvents in any proportion, can also be used. For example, a solvent mixed with methanol and water in a 1:9 ratio, or with ethanol and water in a 1:9 ratio. Preferably, the solvent is water alone. For 1 mg of compound (1), the amount of solvent used can be 0.001 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL. The temperature of the solvent can be adjusted as appropriate, but for example, it can be set to 40 to 60°C. Preferably, it is 45 to 55°C, more preferably 47.5 to 52.5°C, and even more preferably 50°C. To precipitate crystals, after stirring at the above temperature, a cooling operation can be performed. The temperature for the cooling operation can be, for example, 10 to 40°C. The temperature 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.Preferably, the incubation period is 4 to 60 hours, more preferably 8 to 48 hours, even more preferably 12 to 36 hours, and most preferably 22 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. These solvents can be used individually or in combination of two or more.

[0079] Form I crystal of compound (1) with adipic acid According to one embodiment of the present invention, Form I crystal of compound (1) with adipic acid is provided. Form I crystal of compound (1) with adipic acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 7 or a powder X-ray diffraction spectrum substantially identical thereto.

[0080] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with adipic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

[0081] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with adipic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with adipic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with adipic acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°. In another embodiment of the present invention, the Form I crystal of compound (1) with adipic acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above-listed diffraction angles (2θ±0.2°) as peaks. In yet another embodiment, there may be one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0082] In one embodiment, the Form I crystal of compound (1) with adipic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 203 to 213°C, or in other words, around 208°C. In another embodiment, the Form I crystal of compound (1) with adipic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 8.

[0083] In one embodiment of the present invention, the Form I crystal of compound (1) with adipic acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with adipic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above have diffraction angles (2θ ± 0.2°), and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with adipic acid 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 208°C. The Form I crystal of compound (1) with adipic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C, preferably a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C, more preferably a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C, and even more preferably a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 208°C. In another embodiment of the present invention, the Form I crystal of compound (1) with adipic acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 208°C.

[0084] In one embodiment of the present invention, the Form I crystal of compound (1) with adipic acid may be a salt or cocrystal of compound (1) and adipic acid. The ratio of compound (1) to adipic acid is not particularly limited, but preferably the equivalent ratio of compound (1):adipic acid is 1:0.5 to 10, more preferably 1:0.75 to 3, even more preferably 1:1 to 2, and particularly preferably 1:1.

[0085] Method for producing Form 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 adipic acid

[0086] Form I crystals of compound (1) with adipic acid can be produced, for example, from free form 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)) as described above. Although not limited to this production method, the method for producing Form I crystals of compound (1) with adipic acid will be described in detail below.

[0087] Form I crystals of compound (1) with adipic acid in embodiments of the present invention can be produced, for example, by adding adipic acid and a solvent to a container containing free form I crystals of compound (1), stirring in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of adipic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. The amount of adipic acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). The solvent can be 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. Furthermore, any solvent that can be temporarily dissolved but then resuspended after stirring for several minutes to several hours 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 combination of two or more in any proportion. Examples of mixed solvents include methanol and water in a 1:1 ratio, ethanol and water in a 1:1 ratio, and ethanol and diisopropyl ether in a 1:1 ratio. Preferably, the solvent is methanol alone, ethanol alone, 1-propanol alone, tetrahydrofuran alone, water, or a mixed solvent of ethanol and water in a 1:1 ratio.For every 1 mg of compound (1), the amount of solvent used can be 0.001 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.022 mL. The solvent temperature can be adjusted as appropriate, but for example, it can be 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. To precipitate crystals, after stirring at the above temperature, a cooling operation can also be performed. The temperature for the cooling operation 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 for example, it can be 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. These solvents can be used individually or in combination of two or more.

[0088] Form I crystal of compound (1) with phosphoric acid According to one aspect of the present invention, Form I crystal of compound (1) with phosphoric acid is provided. Form I crystal of compound (1) with phosphoric acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 9 or a powder X-ray diffraction spectrum substantially identical thereto.

[0089] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°.

[0090] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with phosphoric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°. In another embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above-mentioned diffraction angles (2θ±0.2°) as selected from the above. In yet another embodiment, it may have one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0091] In one embodiment, the Form I crystal of compound (1) with phosphoric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 48 to 58°C, or in other words, around 53°C. In another embodiment, the Form I crystal of compound (1) with phosphoric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 10.

[0092] In one embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 53°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 53°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid 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 53°C. The Form I crystal of compound (1) with phosphoric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 53°C, preferably a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 53°C, more preferably a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 53°C, and even more preferably a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 53°C. In another embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 53°C.

[0093] In one embodiment of the present invention, the Form I crystal of compound (1) with phosphoric acid may be a salt or cocrystal of compound (1) and phosphoric acid. The ratio of compound (1) to phosphoric acid is not particularly limited, but preferably the equivalent ratio of compound (1) to phosphoric acid is 1:0.5 to 5, more preferably 1:0.6 to 3, even more preferably 1:0.7 to 1.5, and particularly preferably 1:0.8 to 1.2. The Form I crystal of compound (1) with phosphoric acid may also be a hydrate. Preferably it is a 1 to 5-hydrate, more preferably a 1 to 3-hydrate, and even more preferably a dihydrate. By drying the Form I crystal of compound (1) with phosphoric acid under reduced pressure at about 70°C, the water evaporates and it changes into a Form II crystal (anhydrous) of compound (1) with phosphoric acid. When the Form II crystal of compound (1) with phosphoric acid is stored at a relative humidity of 20% or higher, it changes into a Form I crystal of compound (1) with phosphoric acid.

[0094] In one embodiment of the present invention, Form I crystals of compound (1) with phosphoric acid are dried under reduced pressure at approximately 70°C, causing the water to evaporate and transforming them into Form II crystals (anhydrous) of compound (1) with phosphoric acid. These transformed crystals (Form II crystals of compound (1) with phosphoric acid) are further dried at 150°C, transforming them into Form VI crystals of compound (1) with phosphoric acid. By cooling the Form VI crystals of compound (1) with phosphoric acid, they revert back to Form II crystals of compound (1) with phosphoric acid. Finally, they revert back to Form I crystals of compound (1) with phosphoric acid.

[0095] Method for producing Form 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 phosphoric acid

[0096] Form I crystals of compound (1) with phosphoric acid can be produced, for example, from free form 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)) as described above. Although not limited to this production method, the method for producing Form I crystals of compound (1) with phosphoric acid will be described in detail below.

[0097] Furthermore, Form I crystals of compound (1) with phosphoric acid can also be produced, for example, from the amorphous or anisole solvate of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl) acrylamide (compound (1)) mentioned above.

[0098] Form I crystals of compound (1) with phosphoric acid in embodiments of the present invention can be produced, for example, by adding phosphoric acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. The crystals obtained after filtering may be a solvate. Crystals can be obtained by appropriately adjusting parameters such as the amount of phosphoric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. The amount of phosphoric acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). The solvent can be 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. Any solvent that can be temporarily dissolved but then resuspended after stirring for several minutes to several hours can be used. For example, lower alcohols (ethanol) can be used. Among these, ethanol is preferred. In addition to ethanol, other solvents can be used in any proportion. For example, acetone can be used as a solvent that can be combined with ethanol. Preferably, the solvent is ethanol alone or a mixed solvent of ethanol and acetone. For 1 mg of compound (1), the amount of solvent used can be 0.001 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL. The temperature of the solvent can be adjusted as appropriate, but for example, it can be set to 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 crystals, after stirring at the above temperature, a cooling operation can be performed. The temperature during the cooling operation can be, for example, 10 to 40°C.The temperature 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. 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, etc., 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. These solvents can be used alone or in combination of two or more.

[0099] Form III crystal of compound (1) with phosphoric acid According to one aspect of the present invention, Form III crystal of compound (1) with phosphoric acid is provided. Form I crystal of compound (1) with phosphoric acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 47 or a powder X-ray diffraction spectrum substantially identical thereto.

[0100] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°.

[0101] Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with phosphoric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°. In preferred embodiments of the present invention, the Form III crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably all seven, diffraction angles (2θ±0.2°) selected from 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°. In further embodiments, there may be one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0102] In one embodiment, the Form III crystal of compound (1) with phosphoric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 66 to 76°C, or in other words, around 71°C. In another embodiment, the Form III crystal of compound (1) with phosphoric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 48.

[0103] In one embodiment of the present invention, the Form III crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 71°C. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with phosphoric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 71°C. The Form III crystal of compound (1) with phosphoric acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 71°C. The Form III crystal of compound (1) with phosphoric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 71°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 71°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 71°C, and even more preferably a crystal having all seven peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 71°C.

[0104] In one embodiment of the present invention, the Form III crystal of compound (1) with phosphoric acid may be a salt or cocrystal of compound (1) and phosphoric acid. The ratio of compound (1) to phosphoric acid is not particularly limited, but preferably the equivalent ratio of compound (1) to phosphoric acid is 1:0.5 to 5, more preferably 1:0.6 to 3, even more preferably 1:0.7 to 1.5, and particularly preferably 1:0.8 to 1.2. The Form III crystal of compound (1) with phosphoric acid changes to the Form IV crystal of compound (1) with phosphoric acid described later by storage at 50°C. Furthermore, by storing this Form IV crystal of compound (1) with phosphoric acid at 70 to 80°C, it becomes a Form V crystal of compound (1) with phosphoric acid, and even if the Form V crystal of compound (1) with phosphoric acid is cooled, it does not change to a Form IV crystal of compound (1) with phosphoric acid, but remains a Form V crystal of compound (1) with phosphoric acid. However, when the Form V crystals of compound (1) with phosphoric acid are subjected to humidification and drying treatment, some of them change into Form IV crystals of compound (1) with phosphoric acid.

[0105] Method for producing Form III 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 phosphoric acid

[0106] Form III crystals of compound (1) with phosphoric acid can be produced, for example, from the free form I crystal or amorphous form of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) as described above. Although not limited to this production method, the method for producing Form III crystals of compound (1) with phosphoric acid will be described in detail below.

[0107] Form III crystals of compound (1) with phosphoric acid in embodiments of the present invention can be obtained, for example, by adding phosphoric acid and a solvent to a container containing free form I crystals or amorphous compound (1), dissolving them at a high temperature, and then cooling. After filtration, the obtained crystals can be dried to produce the crystals. Here, "high temperature" refers to, for example, about 50 to 80°C. "Cooling" refers to returning from a high temperature to around room temperature. Crystals can be obtained by appropriately adjusting parameters such as the amount of phosphoric acid, the type of solvent, the temperature (temperature when compound (1) is dissolved and the temperature when the crystals precipitate), and the cooling time. The amount of phosphoric acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). Any solvent can be used that allows (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide to dissolve at high temperature during the stirring step and precipitate at room temperature. Examples include water alone or a combination of water and an organic solvent. Examples of organic solvents include acetonitrile and acetone. Preferably, a mixed solvent of water and acetonitrile, or a mixed solvent of water and acetone, and more preferably, a mixed solvent of water and acetonitrile. Any ratio of water to organic solvent can be used. For example, a mixture of water and acetonitrile in a ratio of 1:1 to 1:9 (volume ratio) can be used. Preferably, the ratio of water to acetonitrile is 1:4 to 1:9 (volume ratio). Acetone can also be used instead of acetonitrile. For 1 mg of compound (1), the amount of solvent can be 0.005 to 0.1 mL. Preferably, the amount is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL.The solvent temperature can be adjusted as appropriate, as long as it is the temperature at which (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide dissolves, for example, 50 to 80°C. The solvent temperature is preferably 50 to 70°C, and more preferably 50 to 60°C. When heating, the boiling point of the solvent used must not be exceeded. After dissolving (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, crystals can be precipitated by lowering the solvent temperature. The solvent temperature at this time is not particularly limited as long as crystals precipitate, but can be, for example, 5°C to 30°C. The solvent temperature for crystal precipitation is preferably 15 to 30°C, and more preferably room temperature. The cooling time can be adjusted as appropriate, but can be, for example, 1 to 72 hours. Preferably, the incubation period is 1 to 48 hours, more preferably 1 to 12 hours, even more preferably 1 to 6 hours, and most preferably 3 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 acetone and acetonitrile. These solvents can be used individually or in combination of two or more.

[0108] Form IV crystals of compound (1) with phosphoric acid According to one aspect of the present invention, Form IV crystals of compound (1) with phosphoric acid are provided. Form IV crystals of compound (1) with phosphoric acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 49 or a powder X-ray diffraction spectrum substantially identical thereto.

[0109] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°.

[0110] Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with phosphoric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with phosphoric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, 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 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°. In another embodiment of the present invention, the Form IV crystal of compound (1) with phosphoric acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above peaks at diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0111] In one embodiment, the Form IV crystal of compound (1) with phosphoric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 62 to 72°C, or in other words, around 67°C. In another embodiment, the Form IV crystal of compound (1) with phosphoric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 50.

[0112] In one embodiment of the present invention, the Form IV crystal of compound (1) with phosphoric acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 67°C. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with phosphoric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 67°C. The Form IV crystal of compound (1) with phosphoric acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 67°C. The Form IV crystal of compound (1) with phosphoric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 67°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 67°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 67°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 67°C. In another embodiment of the present invention, the Form IV crystal of compound (1) with phosphoric acid may have, in the powder X-ray diffraction spectrum, peaks at eight or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 67°C.

[0113] The Form IV crystal of compound (1) with phosphoric acid in one embodiment of the present invention may be a salt or cocrystal of compound (1) and phosphoric acid. The ratio of compound (1) to phosphoric acid is not particularly limited, but preferably the equivalent ratio of compound (1) to phosphoric acid is 1:0.5 to 5, more preferably 1:0.6 to 3, even more preferably 1:0.7 to 1.5, and particularly preferably 1:0.8 to 1.2.

[0114] Method for producing Form IV 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 phosphoric acid

[0115] Form IV crystals of compound (1) with phosphoric acid can be produced, for example, from the free form I crystal or amorphous form of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) as described above. Although not limited to this production method, the method for producing Form IV crystals of compound (1) with phosphoric acid will be described in detail below.

[0116] Form IV crystals of compound (1) with phosphoric acid in embodiments of the present invention can be obtained, for example, by adding phosphoric acid and a solvent to a container containing free form I crystals or amorphous compound (1), dissolving them at a high temperature, and then cooling. After filtration, the obtained crystals can be dried to produce the crystals. Here, "high temperature" refers to approximately 50 to 80°C. "Cooling" refers to returning from a high temperature to approximately room temperature. Crystals can be obtained by appropriately adjusting parameters such as the amount of phosphoric acid, the type of solvent, the temperature (temperature when compound (1) is dissolved and the temperature when the crystals precipitate), and the cooling time. The amount of phosphoric acid is not particularly limited, but preferably 1 to 10 mol can be used per 1 mol of compound (1). More preferably 1 to 5 mol can be used per 1 mol of compound (1). Even more preferably 1 to 3 mol can be used per 1 mol of compound (1). Any solvent can be used that allows (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide to dissolve at high temperature during the stirring step and precipitate at room temperature. Examples include water alone or a combination of water and an organic solvent. An example of an organic solvent is 2-propanol. Preferably, a mixed solvent of water and 2-propanol is used. Any ratio of water to organic solvent can be used. For example, a mixture of water and 2-propanol in a ratio of 1:1 to 1:9 can be used. Preferably, the ratio of water to 2-propanol is 1:4 to 1:9. For 1 mg of compound (1), the amount of solvent can be 0.005 to 0.1 mL. Preferably, it is 0.005 to 0.04 mL, more preferably 0.01 to 0.03 mL, and even more preferably 0.02 mL. The solvent temperature can be adjusted as appropriate, as long as it is the temperature at which (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide dissolves, for example, at 50 to 80°C. The solvent temperature is preferably 50 to 70°C, and more preferably 50 to 60°C.When heating, the boiling point of the solvent used must not be exceeded. After dissolving (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide, crystals can be precipitated by lowering the temperature of the solvent. The solvent temperature at this time is not particularly limited as long as crystals precipitate, but for example, precipitation can be achieved at 5°C to 30°C. The temperature for crystal precipitation is preferably 15 to 30°C, and more preferably room temperature. The cooling time can be adjusted as appropriate, but for example, it can be done for 1 to 72 hours. Preferably, it is 1 to 48 hours, more preferably 1 to 12 hours, even more preferably 1 to 6 hours, and most preferably 3 hours. The precipitated crystals can be isolated and purified from the crystal suspension, etc., by known separation and purification means such as filtration, washing with water or an organic solvent, or vacuum drying. An example of an organic solvent used for washing is 2-propanol.

[0117] Form I crystals of compound (1) with citric acid According to one embodiment of the present invention, Form I crystals of compound (1) with citric acid are provided. Form I crystals of compound (1) with citric acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 11 or a powder X-ray diffraction spectrum substantially identical thereto.

[0118] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with citric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7°, and 26.6°.

[0119] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with citric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7°, and 26.6°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with citric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7°, and 26.6°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with citric acid has, in the powder X-ray diffraction spectrum, 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 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7°, and 26.6°. In another embodiment of the present invention, the Form I crystal of compound (1) with citric acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above peaks at diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0120] In one embodiment, the Form I crystal of compound (1) with citric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 152 to 162°C, or in other words, around 157°C. In another embodiment, the Form I crystal of compound (1) with citric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 12.

[0121] In one embodiment of the present invention, the Form I crystal of compound (1) with citric acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7°, and 26.6°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 157°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with citric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 157°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with citric acid 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 157°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with citric acid is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 157°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 157°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 157°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 157°C. In another embodiment of the present invention, the Form I crystal of compound (1) with citric acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 157°C.

[0122] In one embodiment of the present invention, the Form I crystal of compound (1) with citric acid may be a salt or cocrystal of compound (1) and citric acid.

[0123] Form I crystals of compound (1) with citric acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form I crystals of compound (1) with citric acid can be produced by the following method.

[0124] Form I crystals of compound (1) with citric acid in embodiments of the present invention can be produced, for example, by adding citric acid and a solvent to a container containing free form I crystals of compound (1), stirring the suspended mixture for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of citric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 1 to 3 mol of citric acid can be used per 1 mol of compound (1). For example, water can be used as the type of solvent. The temperature of the solvent during stirring can be, for example, room temperature, preferably 25°C. The stirring time can be, for example, 2 hours or more, preferably 3 hours or more, and more preferably 6 hours. There is no particular upper limit set for the stirring time.

[0125] Form I crystal of compound (1) with fumaric acid According to one aspect of the present invention, Form I crystal of compound (1) with fumaric acid is provided. Form I crystal of compound (1) with fumaric acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 13 or a powder X-ray diffraction spectrum substantially identical thereto.

[0126] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8°, and 27.1°.

[0127] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8°, and 27.1°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with fumaric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8°, and 27.1°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8°, and 27.1°. In another embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, eight or all of the above-listed diffraction angles (2θ±0.2°) as peaks. In yet another embodiment, it may have one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0128] In one embodiment, the Form I crystal of compound (1) with fumaric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 157 to 167°C, or in other words, around 162°C. In another embodiment, the Form I crystal of compound (1) with fumaric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 14.

[0129] In one embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8°, and 27.1°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 157°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above with diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 162°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid 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 162°C. The Form I crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 162°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 162°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 162°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 162°C. In another embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, peaks at eight or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 162°C.

[0130] In one embodiment of the present invention, the Form I crystal of compound (1) with fumaric acid may be a salt or cocrystal of compound (1) and fumaric acid.

[0131] Form I crystals of compound (1) with fumaric acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form I crystals of compound (1) with fumaric acid can be produced by the following method.

[0132] Form I crystals of compound (1) with fumaric acid in embodiments of the present invention can be produced, for example, by adding fumaric acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of fumaric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 2 to 3 mol of fumaric acid can be used per 1 mol of compound (1). For example, methanol can be used as the solvent. The temperature of the solvent during stirring can be, for example, 25 to 50°C. The stirring time can be, for example, 2 hours or more. Preferably, 3 hours or more. There is no particular upper limit set for the stirring time.

[0133] Form II 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 fumaric acid According to one aspect of the present invention, Form II crystals of compound (1) with fumaric acid are provided. Form II crystals of compound (1) with fumaric acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 15 or a powder X-ray diffraction spectrum substantially identical thereto.

[0134] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5°, and 25.7°.

[0135] Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5°, and 25.7°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with fumaric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5°, and 25.7°. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, 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 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5°, and 25.7°. In another embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, eight or all of the above-listed peaks at diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0136] In one embodiment, the Form II crystal of compound (1) with fumaric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 173 to 183°C, or in other words, around 178°C. In another embodiment, the Form II crystal of compound (1) with fumaric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 16.

[0137] In one embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5°, and 25.7°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 178°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above with diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 178°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid 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 178°C. The Form II crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 178°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 178°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 178°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 178°C. In another embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, peaks at eight or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 178°C.

[0138] In one embodiment of the present invention, the Form II crystal of compound (1) with fumaric acid may be a salt or cocrystal of compound (1) and fumaric acid.

[0139] Form II crystals of compound (1) with fumaric acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form II crystals of compound (1) with fumaric acid can be produced by the following method.

[0140] Form II crystals of compound (1) with fumaric acid in embodiments of the present invention can be produced, for example, by adding fumaric acid and a solvent to a container containing free form I crystals of compound (1), stirring the suspended mixture for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of fumaric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 3 mol of fumaric acid can be used for 1 mol of compound (1). For example, ethanol, 1-propanol, and 2-propanol can be used as the type of solvent. The temperature of the solvent during stirring can be, for example, 25 to 50°C. The stirring time can be, for example, 2 hours or more. Preferably, it is 3 hours or more, and more preferably 6 hours. There is no particular upper limit set for the stirring time.

[0141] Form III crystal of compound (1) with fumaric acid According to one aspect of the present invention, Form III crystal of compound (1) with fumaric acid is provided. Form III crystal of compound (1) with fumaric acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 17 or a powder X-ray diffraction spectrum substantially identical thereto.

[0142] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°.

[0143] Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form III crystal of compound (1) with fumaric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°. In another embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid may have peaks in the powder X-ray diffraction spectrum at all of the above-selected diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0144] In one embodiment, the Form III crystal of compound (1) with fumaric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 64 to 74°C, or in other words, around 69°C. In another embodiment, the Form III crystal of compound (1) with fumaric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 18.

[0145] In one embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from the diffraction angles (2θ ± 0.2°) of 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 69°C. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above with diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 69°C. The Form III crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 69°C. The Form III crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 69°C, preferably a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 69°C, more preferably a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 69°C, and even more preferably a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 69°C. In another embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid may have peaks in the powder X-ray diffraction spectrum at all of the diffraction angles (2θ ± 0.2°) selected from the above, and may have an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 69°C.

[0146] In one embodiment of the present invention, the Form III crystal of compound (1) with fumaric acid may be a salt or cocrystal of compound (1) and fumaric acid.

[0147] Form III crystals of compound (1) with fumaric acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form III crystals of compound (1) with fumaric acid can be produced by the following method.

[0148] Form III crystals of compound (1) with fumaric acid in embodiments of the present invention can be produced, for example, by adding fumaric acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of fumaric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 3 mol of fumaric acid can be used for 1 mol of compound (1). For example, a mixed solvent of water and acetonitrile can be used as the type of solvent. Preferably, a mixed solvent of water and acetonitrile in a ratio of 3:1 is used. The temperature of the solvent during stirring can be, for example, 50°C. The stirring time can be, for example, 1.5 hours or more. Preferably, it is 2 hours or more, and more preferably 3 hours. There is no particular upper limit set for the stirring time.

[0149] Form IV crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with fumaric acid According to one aspect of the present invention, Form IV crystal of compound (1) with fumaric acid is provided. Form IV crystal of compound (1) with fumaric acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 19 or a powder X-ray diffraction spectrum substantially identical thereto.

[0150] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°.

[0151] Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with fumaric acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with fumaric acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, 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 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°. In another embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, eight or all of the above-listed peaks at diffraction angles (2θ±0.2°). In yet another embodiment, there may be one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0152] In one embodiment, the Form IV crystal of compound (1) with fumaric acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 172 to 182°C, or in other words, around 177°C. In another embodiment, the Form IV crystal of compound (1) with fumaric acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 20.

[0153] In one embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from the diffraction angles (2θ ± 0.2°) of 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 177°C. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2°) have two or more peaks selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 177°C. The Form IV crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 177°C. The Form IV crystal of compound (1) with fumaric acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 177°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 177°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 177°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 177°C. In another embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid may have, in the powder X-ray diffraction spectrum, peaks at eight or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 177°C.

[0154] In one embodiment of the present invention, the Form IV crystal of compound (1) with fumaric acid may be a salt or cocrystal of compound (1) and fumaric acid.

[0155] Method for producing Form IV 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 fumaric acid

[0156] Form IV crystals of compound (1) with fumaric acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form IV crystals of compound (1) with fumaric acid can be produced by the following method.

[0157] Form IV crystals of compound (1) with fumaric acid in embodiments of the present invention can be produced, for example, by adding fumaric acid and a solvent to a container containing free form I crystals of compound (1), stirring the suspended mixture for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of fumaric acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 1 to 2 mol of fumaric acid can be used per 1 mol of compound (1). For example, 1-propanol can be used as the solvent. For example, the temperature of the solvent during stirring can be 50°C. For example, the stirring time can be 6 hours or more. Preferably, it is 8 hours or more, and more preferably 10 hours. There is no particular upper limit set for the stirring time.

[0158] Form I crystals of compound (1) with benzoic acid According to one embodiment of the present invention, Form I crystals of compound (1) with benzoic acid are provided. Form I crystals of compound (1) with benzoic acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 21 or a powder X-ray diffraction spectrum substantially identical thereto.

[0159] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with benzoic acid in one embodiment of the present invention include, for example, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2°, and 27.9°.

[0160] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with benzoic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2°, and 27.9°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with benzoic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2°, and 27.9°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid has, in the powder X-ray diffraction spectrum, four or more, preferably five or more, more preferably six or more, and even more preferably seven or more, diffraction angles (2θ±0.2°) selected from 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2°, and 27.9°. In another embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid may have, in the powder X-ray diffraction spectrum, eight or all of the diffraction angles (2θ±0.2°) selected from the above. In yet another embodiment, it may have one or more additional peaks at the diffraction angles (2θ±0.2°) described in the other embodiments.

[0161] In one embodiment, the Form I crystal of compound (1) with benzoic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 95 to 105°C, or in other words, around 100°C. In another embodiment, the Form I crystal of compound (1) with benzoic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 22.

[0162] In one embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from the diffraction angles (2θ ± 0.2°) of 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2°, and 27.9°, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2°) have two or more peaks selected from the above, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid 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 100°C. The Form I crystal of compound (1) with benzoic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C, preferably a crystal having five or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C, more preferably a crystal having six or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C, and even more preferably a crystal having seven or more peaks and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 100°C. In another embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid may have, in the powder X-ray diffraction spectrum, peaks at eight or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 100°C.

[0163] In one embodiment of the present invention, the Form I crystal of compound (1) with benzoic acid may be a salt or cocrystal of compound (1) and benzoic acid.

[0164] Method for producing Form 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 benzoic acid

[0165] Form I crystals of compound (1) with benzoic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form I crystals of compound (1) with benzoic acid can be produced by the following method.

[0166] Form I crystals of compound (1) with benzoic acid in embodiments of the present invention can be produced, for example, by adding benzoic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of benzoic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 3 mol of benzoic acid can be used per 1 mol of compound (1). For example, water can be used as the solvent. For example, the temperature of the solvent during stirring can be 50°C. For example, the stirring time can be 24 hours or more. Preferably, it is 36 hours or more. There is no particular upper limit set for the stirring time.

[0167] Form I crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with maleic acid According to one embodiment of the present invention, Form I crystal of compound (1) with maleic acid is provided. The Form I crystal of compound (1) with maleic acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 23 or a powder X-ray diffraction spectrum substantially identical thereto.

[0168] Here, characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with maleic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 12.2°, 14.3°, 18.2°, and 22.4°.

[0169] Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with maleic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 12.2°, 14.3°, 18.2°, and 22.4°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form I crystal of compound (1) with maleic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 12.2°, 14.3°, 18.2°, and 22.4°. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with maleic acid may have peaks in the powder X-ray diffraction spectrum at all diffraction angles (2θ ± 0.2°) selected from 12.2°, 14.3°, 18.2°, and 22.4°. In further embodiments, there may be one or more additional peaks at diffraction angles (2θ ± 0.2°) described in the other embodiments.

[0170] In one embodiment, the Form I crystal of compound (1) with maleic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 148 to 158°C, or in other words, around 153°C. In another embodiment, the Form I crystal of compound (1) with maleic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 24.

[0171] In one embodiment of the present invention, the Form I crystal of compound (1) with maleic acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 12.2°, 14.3°, 18.2°, and 22.4°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 100°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 153°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angle (2θ ± 0.2°) has peaks at three or more locations selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 153°C. In a preferred embodiment of the present invention, the Form I crystal of compound (1) with maleic acid may have peaks in the powder X-ray diffraction spectrum at all locations selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 153°C.

[0172] In one embodiment of the present invention, the Form I crystal of compound (1) with maleic acid may be a salt or cocrystal of compound (1) and maleic acid. The ratio of compound (1) to maleic acid is not particularly limited, but preferably the equivalent ratio of compound (1) to maleic acid is 1:1 to 10, more preferably 1:1 to 5, and even more preferably 1:1 to 3.

[0173] Method for producing Form 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 maleic acid

[0174] Form I crystals of compound (1) with maleic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form I crystals of compound (1) with maleic acid can be produced by the following method.

[0175] Form I crystals of compound (1) with maleic acid in embodiments of the present invention can be produced, for example, by adding maleic acid and a solvent to a container containing free form I crystals of compound (1), stirring the suspended mixture for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of maleic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 1 mol of maleic acid can be used for 1 mol of compound (1). As for the type of solvent, for example, acetone, tetrahydrofuran, or a mixture thereof can be used. The temperature of the solvent during stirring can be, for example, 25 to 50°C. The stirring time can be, for example, 24 hours or more. Preferably, it is 36 hours or more. There is no particular upper limit set for the stirring time.

[0176] Form II 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 maleic acid According to one embodiment of the present invention, Form II crystals of compound (1) with maleic acid are provided. Form II crystals of compound (1) with maleic acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 25 or a powder X-ray diffraction spectrum substantially identical thereto.

[0177] Here, characteristic peaks in the powder X-ray diffraction spectrum of Form II crystals of compound (1) with maleic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 13.9°, 17.1°, 20.5°, and 25.6°.

[0178] Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with maleic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 13.9°, 17.1°, 20.5°, and 25.6°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form II crystal of compound (1) with maleic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 13.9°, 17.1°, 20.5°, and 25.6°. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with maleic acid may have peaks in the powder X-ray diffraction spectrum at all diffraction angles (2θ ± 0.2°) selected from 13.9°, 17.1°, 20.5°, and 25.6°. In further embodiments, there may be one or more additional peaks at the diffraction angles (2θ ± 0.2°) described in the other embodiments.

[0179] In one embodiment, the Form II crystal of compound (1) with maleic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 145 to 155°C, or in other words, around 150°C. In another embodiment, the Form II crystal of compound (1) with maleic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 26.

[0180] In one embodiment of the present invention, the Form II crystal of compound (1) with maleic acid has, in the powder X-ray diffraction spectrum, one or more peaks with diffraction angles (2θ ± 0.2°) selected from 13.9°, 17.1°, 20.5°, and 25.6°, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 150°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks with diffraction angles (2θ ± 0.2°) selected from the above, and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 150°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angle (2θ ± 0.2°) has peaks at three or more locations selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 150°C. In a preferred embodiment of the present invention, the Form II crystal of compound (1) with maleic acid may have peaks in the powder X-ray diffraction spectrum at all locations selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 150°C.

[0181] In one embodiment of the present invention, the Form II crystal of compound (1) with maleic acid may be a salt or cocrystal of compound (1) and maleic acid. The ratio of compound (1) to maleic acid is not particularly limited, but preferably the equivalent ratio of compound (1) to maleic acid is 1:1 to 10, more preferably 1:1 to 5, and even more preferably 1:1 to 3.

[0182] Method for producing Form II 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 maleic acid

[0183] Form II crystals of compound (1) with maleic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form II crystals of compound (1) with maleic acid can be produced by the following method.

[0184] Form II crystals of compound (1) with maleic acid in embodiments of the present invention can be produced, for example, by adding maleic acid and a solvent to a container containing free form I crystals of compound (1), stirring the suspended mixture for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of maleic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 1 mol of maleic acid can be used for 1 mol of compound (1). For example, ethanol can be used as the type of solvent. The temperature of the solvent during stirring can be, for example, 25 to 50°C. The stirring time can be, for example, 24 hours or more. Preferably, it is 36 hours or more. There is no particular upper limit set for the stirring time.

[0185] Form III crystal of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with maleic acid According to one aspect of the present invention, Form III crystal of compound (1) with maleic acid is provided. Form III crystal of compound (1) with maleic acid in one embodiment of the present invention has the powder X-ray diffraction spectrum shown in Figure 27 or a powder X-ray diffraction spectrum substantially identical thereto.

[0186] Here, characteristic peaks in the powder X-ray diffraction spectrum of Form III crystals of compound (1) with maleic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9°, and 26.8°.

[0187] Characteristic peaks in the powder X-ray diffraction spectrum of Form III crystals of compound (1) with maleic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9°, and 26.8°. Characteristic peaks in the powder X-ray diffraction spectrum of Form III crystals of compound (1) with maleic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9°, and 26.8°. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with maleic acid has, in the powder X-ray diffraction spectrum, 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 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9°, and 26.8°. In another embodiment of the present invention, the Form III crystal of compound (1) with maleic acid may have, in the powder X-ray diffraction spectrum, eight, nine, or all of the above peaks at diffraction angles (2θ±0.2°). In yet another embodiment, it may have one or more additional peaks at diffraction angles (2θ±0.2°) as described in the other embodiments.

[0188] In one embodiment, the Form III crystal of compound (1) with maleic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 160 to 170°C, or in other words, around 165°C. In another embodiment, the Form III crystal of compound (1) with maleic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 28.

[0189] In one embodiment of the present invention, the Form III crystal of compound (1) with maleic acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from diffraction angles (2θ ± 0.2°) of 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9°, and 26.8°, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C. In a preferred embodiment of the present invention, the Form III crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angles (2θ ± 0.2°) have two or more peaks selected from the above, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C. The Form III crystal of compound (1) with maleic acid in a preferred embodiment of the present invention is a crystal in which the powder X-ray diffraction spectrum has three or more peaks selected from the above at diffraction angles (2θ ± 0.2°), and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 165°C. The Form III crystal of compound (1) with maleic acid in a preferred embodiment of the present invention is a crystal having four or more peaks selected from the above in the powder X-ray diffraction spectrum with diffraction angles (2θ ± 0.2°), and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C, preferably a crystal having five or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C, more preferably a crystal having six or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C, and even more preferably a crystal having seven or more peaks and having an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 165°C. In another embodiment of the present invention, the Form III crystal of compound (1) with maleic acid may have, in the powder X-ray diffraction spectrum, peaks at eight, nine, or all of the above-selected diffraction angles (2θ ± 0.2°), and an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement at around 165°C.

[0190] In one embodiment of the present invention, the Form III crystal of compound (1) with maleic acid may be a salt or cocrystal of compound (1) and maleic acid.

[0191] Method for producing Form III 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 maleic acid

[0192] Form III crystals of compound (1) with maleic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form III crystals of compound (1) with maleic acid can be produced by the following method.

[0193] Form III crystals of compound (1) with maleic acid in embodiments of the present invention can be produced, for example, by adding maleic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of maleic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 1 mol of maleic acid can be used for 1 mol of compound (1). For example, water can be used as the type of solvent. For example, the temperature of the solvent during stirring can be 25 to 50°C. For example, the stirring time can be 24 hours or more. Preferably, it is 36 hours or more. There is no particular upper limit set for the stirring time.

[0194] Form IV 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 maleic acid According to one embodiment of the present invention, Form IV crystals of compound (1) with maleic acid are provided. Form IV crystals of compound (1) with maleic acid in one embodiment of the present invention have the powder X-ray diffraction spectrum shown in Figure 29 or a powder X-ray diffraction spectrum substantially identical thereto.

[0195] Here, characteristic peaks in the powder X-ray diffraction spectrum of Form IV crystals of compound (1) with maleic acid in one embodiment of the present invention include, for example, one or more selected from diffraction angles (2θ ± 0.2°) of 12.0°, 14.8°, 15.4°, 19.9°, and 26.0°.

[0196] Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with maleic acid in one embodiment of the present invention include, for example, two or more peaks selected from diffraction angles (2θ ± 0.2°) of 12.0°, 14.8°, 15.4°, 19.9°, and 26.0°. Characteristic peaks in the powder X-ray diffraction spectrum of the Form IV crystal of compound (1) with maleic acid include, for example, three or more peaks selected from diffraction angles (2θ ± 0.2°) of 12.0°, 14.8°, 15.4°, 19.9°, and 26.0°. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid has peaks in the powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of four or more, preferably all of the above. In further embodiments, there may be one or more additional peaks in the diffraction angles (2θ ± 0.2°) described in the embodiments other than those described above.

[0197] In one embodiment, the Form IV crystal of compound (1) with maleic acid has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric analysis at 164 to 174°C, or in other words, around 169°C. In another embodiment, the Form IV crystal of compound (1) with maleic acid has the differential thermal-thermogravimetric analysis (TG-DTA) curve shown in Figure 30.

[0198] In one embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid has, in the powder X-ray diffraction spectrum, one or more peaks selected from the diffraction angles (2θ ± 0.2°) of 12.0°, 14.8°, 15.4°, 19.9°, and 26.0°, and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 169°C. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, two or more peaks selected from the above with diffraction angles (2θ ± 0.2°), and has an endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement around 169°C. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid 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 169°C. In a preferred embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid is a crystal in which, in the powder X-ray diffraction spectrum, the diffraction angle (2θ ± 0.2°) has four or more peaks selected from the above, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 169°C, preferably having five peaks, and the endothermic peak (peak top value) determined by differential thermal-thermogravimetric simultaneous measurement is around 169°C.

[0199] In one embodiment of the present invention, the Form IV crystal of compound (1) with maleic acid may be a salt or cocrystal of compound (1) and maleic acid.

[0200] Method for producing Form IV 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 maleic acid

[0201] Form IV crystals of compound (1) with maleic acid can be produced, for example, from free form I crystals of the (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) described above. For example, Form IV crystals of compound (1) with maleic acid can be produced by the following method.

[0202] Form IV crystals of compound (1) with maleic acid in embodiments of the present invention can be produced, for example, by adding maleic acid and a solvent to a container containing free form I crystals of compound (1), stirring the mixture in a suspension state for several hours to several days, filtering, and then drying the resulting crystals. Crystals can be obtained by appropriately adjusting parameters such as the amount of maleic acid, the type of solvent, the temperature of the solvent during stirring, and the stirring time. For example, 3 mol of maleic acid can be used per 1 mol of compound (1). For example, methanol can be used as the type of solvent. The temperature of the solvent during stirring can be, for example, room temperature, preferably 25°C. The stirring time can be, for example, 24 hours or more, preferably 36 hours or more. There is no particular upper limit set for the stirring time.

[0203] (Activity and Uses) In one embodiment of the present invention, the salt crystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, or the cocrystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, have excellent EGFR inhibitory activity and are useful as antitumor agents. They also have excellent selectivity for EGFR and have the advantage of fewer side effects from other kinases. The types of malignant tumors targeted are not particularly limited, but examples include epithelial cancers (e.g., respiratory system cancers, digestive 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, crystals of salts of compound (1) of the present invention with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, or cocrystals of compound (1) with succinic acid, adipic acid, phosphoric acid, citric acid, fumaric acid, benzoic acid, maleic acid, or hippuric acid, have excellent inhibitory activity against mutant EGFRs. Examples of such mutant EGFRs include drug-resistant mutant EGFRs and highly sensitive mutant EGFRs. Therefore, crystals of the compound of the present invention or its salts are useful as antitumor agents against the aforementioned malignant tumors having mutant EGFRs.

[0204] 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.

[0205] 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 biological or medical response in a subject, such as a decrease or inhibition of enzyme activity and / 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.

[0206] 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.

[0207] One embodiment of the present invention provides an orally administered antitumor agent comprising crystals of the above-described compound (1) with an acid. Another embodiment of the present invention provides a method for treating a tumor, comprising orally administering an effective amount of the above-described compound (1) with an acid crystal to a subject in need of such treatment. Another embodiment of the present invention provides the use of the above-described compound (1) with an acid crystal for producing an orally administered antitumor agent. Another embodiment of the present invention provides the above-described compound (1) with an acid crystal for use in the treatment of a tumor by orally administration.

[0208] One embodiment of the present invention provides a pharmaceutical composition comprising the above-described compound (1) with an acid crystal. The pharmaceutical composition of one embodiment of the present invention comprises the above-described compound (1) with an acid crystal and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides the use of the above-described compound (1) with an acid crystal for the production of a pharmaceutical composition. Another embodiment of the present invention provides the above-described compound (1) with an acid crystal for use as a pharmaceutical.

[0209] 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.

[0210] Excipients include starches, sugars, polysaccharides, and inorganic compounds. 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. Polysaccharides can also be listed as sugars. Examples include cellulose and dextran, and more specifically, crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Examples of inorganic compounds include silicic acids, such as light anhydrous silicic acid and calcium silicate. Examples of binders include hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, syrup 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, cyclodextrin, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants, such as sorbitan fatty acid esters like polysorbate 80, sucrose fatty acid esters, and sodium lauryl sulfate. Suspensioning 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 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.

[0211] When preparing oral preparations, excipients, and optionally binders, disintegrants, lubricants, colorants, flavorings, and odor-masking agents, etc., are added to the crystals of compound (1) with an acid, 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 crystals of compound (1) with an acid, and then subcutaneous, intramuscular, and intravenous injectable preparations can be manufactured by conventional methods.

[0212] The amount of compound (1) crystals with acid 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.

[0213] Furthermore, the daily dose of the crystalline compound (1) with acid 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 a typical adult (weighing 50 kg), the daily dose should be approximately 1 to 1000 mg, preferably 1 to 400 mg, of the free form of compound (1).

[0214] 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.

[0215] In the following examples of compounds, percentages (%) indicate weight percentages unless otherwise specified. In these examples, "approximately" indicates a range of ±10%.

[0216] Powder X-ray diffraction measurement: Powder X-ray diffraction was measured after lightly grinding an appropriate amount of the test material in an agate mortar as needed, and then measuring according to one of the following test conditions.

[0217] Equipment: PAN-LYTICAL EMPYREAN (Method A) Reflection method (focusing method) Target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scanning range: 2θ = 5.0 to 40.0° Step: 2θ = 0.0131° Average time / step: 8.670 s Scan speed: 0.0015° / s Divergence slit: 1° Scattering slit: 2.0 mm Receiving slit: 8.0 mm

[0218] Equipment: PAN-LYTICAL EMPYREAN (Method B) Transmission method target: Cu X-ray tube current: 40 mA X-ray tube voltage: 45 kV Scanning range: 2θ = 2.0 to 40.0° Step: 2θ = 0.0066° Average time / step: 8.670 s Scan speed: 0.0008° / s Divergence slit: 1 / 2° Scattering slit: 2.0 mm Receiving slit: None

[0219] The handling of the equipment, including data processing, followed the methods and procedures specified for each instrument. HighScore Ver. 4.1 from PANical was used for analysis, and peak heights were calculated using the default analysis conditions. 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.

[0220] Differential thermal-thermogravimetric (TG-DTA) measurement was performed on approximately 5 mg of the test substance according to the following test conditions: Apparatus: TG / DTA7200 manufactured by Hitachi High-Tech Science Corporation Sample container: Aluminum Heating rate: Heating from 25 to 290°C at 10°C / min Atmosphere gas: Air (200 mL / min) Control substance: Empty pan The handling of the apparatus, including data processing, was carried out according to the methods and procedures instructed for each apparatus.

[0221] Production Example 1: Production of Free-Form 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) 1.00 g of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (Compound (1)) synthesized by the method described in Patent Document 1 was mixed with 15 mL of 75% ethanol water and stirred at 55°C for 1 hour. The insoluble material was filtered off and washed with 0.6 mL of 75% ethanol water. Next, 16.6 mL of water was added and stirred at 55°C for 2 hours, then cooled to 25°C and stirred for 20 hours. The solid was filtered and washed with 36% ethanol water (10 mL), then dried under reduced pressure at 50°C for 5 hours to obtain the crystals (free form type I crystals) (825 mg, yield 83%, chemical purity 99.6%).

[0222] The powder X-ray diffraction spectrum (Method A) of the free-form type I crystal obtained by the above method was obtained using the procedure described above. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum included 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 are shown in Table 1 below. The differential thermal-thermogravimetric curve of the crystal obtained in Production Example 1 was obtained using the procedure described above. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 244°C.

[0223] Example 1 Form 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)) synthesized by the method described in Example 1 for the production of Form 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)) were prepared by adding 4.465 g of succinic acid and 100 mL of acetone to the free form I crystals (5.00 g) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) and succinic acid. The mixture was stirred at 50°C for 3 hours, and the solid was collected by filtration. The mixture was dried under reduced pressure (-0.1 MPa or less) at 50°C for 17.5 hours to obtain 6.64 g of the crystals.

[0224] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with succinic acid was obtained using the above procedure 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°): 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4° and 28.9°. Other peaks are as shown in Table 2 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method 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 221°C.

[0225] Example 2 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Free form I crystals (5.00 g) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Example 1 for Form II crystal production with succinic acid were mixed with 1.488 g of succinic acid and 100 mL of methanol. The mixture was stirred at room temperature for 24 hours, and then stirred at 50°C for 4 hours. Subsequently, an additional 2.976 g of succinic acid was added, and the mixture was stirred at 50°C for 18.5 hours. The solid was filtered and dried under reduced pressure (-0.1 MPa or less) at 50°C for 24 hours to obtain 4.04 g of the crystals.

[0226] The powder X-ray diffraction spectrum (Method A) of the Form II crystal of compound (1) obtained by the above method with succinic acid was obtained using the above procedure 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°): 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°. Other peaks are as shown in Table 3 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 4. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 221°C.

[0227] Example 3 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Free form I crystal (5.00 g) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Example 1 for Form III crystal production with succinic acid. 4.465 g of succinic acid and 100 mL of ultrapure water were added, and the mixture was stirred at 55°C for 22 hours. The solid was then filtered off and dried under reduced pressure (-0.1 MPa or less) at 50°C for 15.5 hours to obtain 6.00 g of the crystal.

[0228] The powder X-ray diffraction spectrum (Method A) of the Form III crystal of compound (1) obtained by the above method with succinic acid was obtained using the above procedure and is shown in Figure 5. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°. Other peaks are as shown in Table 4 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 6. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 218°C.

[0229] Example 4 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Free form I crystal (5.00 g) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Example 1 for Form I crystal production with adipic acid, 1.841 g of adipic acid and 110 mL of methanol were added, and the mixture was stirred at room temperature for 23.5 hours. The solid was then filtered off and dried under reduced pressure (-0.1 MPa or less) at 50°C for 24 hours to obtain 5.24 g of the crystal.

[0230] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with adipic acid was obtained using the above procedure and is shown in Figure 7. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6° and 22.2° Other peaks are as shown in Table 5 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 8. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 208°C.

[0231] Example 5 Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with phosphoric acid 5.00 g of free form I crystals (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Production Example 1 were mixed with 0.86 mL of 85% phosphoric acid aqueous solution and 100 mL of 99.5% ethanol. The mixture was stirred at room temperature for 20 hours, and the solid was filtered off. The mixture was then dried under reduced pressure (-0.1 MPa or less) at 50°C for 15.5 hours to obtain 5.63 g of the crystals (mass after returning to room temperature).

[0232] The powder X-ray diffraction spectrum (Method A) of the Form I crystal (dihydrate) of compound (1) with phosphoric acid obtained by the above method was obtained using the above procedure and is shown in Figure 9. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°. Other peaks are as shown in Table 6 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 10. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 53°C.

[0233] Example 6 Form 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)) synthesized by the method described in Example 1 for the production of Form 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)) were prepared by adding 726.5 mg of citric acid and 10 mL of ultrapure water to the free form I crystals (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)). The mixture was stirred at 50°C for 6 hours, and the solid was collected by filtration. The mixture was then dried under reduced pressure at room temperature for 61 hours to obtain 323 mg of the crystals.

[0234] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with citric acid was obtained using the above procedure and is shown in Figure 11. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 6.3°, 7.9°, 11.7°, 12.3°, 12.9°, 14.3°, 15.0°, 17.0°, 22.7° and 26.6°. Other peaks are as shown in Table 7 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 12. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 157°C.

[0235] Example 7 Form 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)) synthesized by the method described in Example 1 for the production of Form 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)) were prepared by adding 438.9 mg of fumaric acid and 10 mL of methanol to the free form I crystals (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)). The mixture was stirred at 50°C for 2 hours, and the solid was collected by filtration. The mixture was then dried under reduced pressure (-0.1 MPa or less) at room temperature for 65 hours to obtain 503 mg of the crystals. To wash away excess fumaric acid, 5 mL of methanol was added, and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered and dried under reduced pressure (-0.1 MPa or less) at 50°C for 12.5 hours to obtain 362 mg of the crystals.

[0236] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with fumaric acid was obtained using the above procedure and is shown in Figure 13. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ±0.2°): 5.9°, 9.4°, 11.6°, 12.7°, 14.2°, 17.4°, 18.5°, 25.8° and 27.1°. Other peaks are as shown in Table 8 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 14. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 162°C.

[0237] Example 8 Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Example 1 for the production of Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) were prepared by adding 438.9 mg of fumaric acid and 10 mL of 99.5% ethanol to the free form type I crystals (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)). The mixture was stirred at room temperature for 6 hours, and the solid was collected by filtration. The mixture was then dried under reduced pressure (-0.1 MPa or less) at room temperature for 61 hours to obtain 554 mg of the crystals.

[0238] The powder X-ray diffraction spectrum (Method A) of the Form II crystal of compound (1) obtained by the above method with fumaric acid was obtained using the above procedure and is shown in Figure 15. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 5.7°, 6.7°, 9.0°, 11.2°, 14.1°, 15.1°, 16.8°, 18.5° and 25.7°. Other peaks are as shown in Table 9 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 16. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 178°C.

[0239] Example 9 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) free form I crystals synthesized by the method described in Example 1 for Form III crystal production of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with fumaric acid were mixed with 500 mg of free form I crystals, 438.9 mg of fumaric acid, 7.5 mL of ultrapure water and 2.5 mL of acetonitrile were added, and the mixture was stirred at 50°C for 3 hours. The solid was then filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 65 hours to obtain 595 mg of the crystals.

[0240] The powder X-ray diffraction spectrum (Method A) of the Form III crystal of compound (1) obtained by the above method with fumaric acid was obtained using the above procedure and is shown in Figure 17. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 5.6°, 8.7°, 9.4°, 11.0°, 16.5°, 17.2°, 25.0°, and 25.6°. Other peaks are as shown in Table 10 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 18. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 69°C.

[0241] Example 10 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) was synthesized by the method described in Example 1 for Form IV crystal production with fumaric acid. 500 mg of free form 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)) were added to 146.3 mg of fumaric acid and 10 mL of 1-propanol. The mixture was stirred at 50°C for 11 hours, and the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 12 hours to obtain 368 mg of the crystals. To this, fumaric acid was saturated in 1-propanol, filtered, and 5 mL of the saturated fumaric acid solution obtained by filtration was added. After stirring at room temperature for 30 minutes, the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at 50°C for 19 hours to obtain 176 mg of the crystals.

[0242] The powder X-ray diffraction spectrum (Method A) of the Form IV crystal of compound (1) obtained by the above method with fumaric acid was obtained using the above procedure and is shown in Figure 19. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 5.9°, 9.5°, 11.7°, 12.7°, 17.5°, 19.6°, 23.0°, 25.7°, and 27.0°. Other peaks are as shown in Table 11 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 20. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 177°C.

[0243] Example 11 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Free form I crystals (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Example 1 for the production of Form 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)) were added to 461.6 mg of benzoic acid and 10 mL of ultrapure water. The mixture was stirred at 50°C for 65.5 hours, and the solid was filtered off. The mixture was then dried under reduced pressure (-0.1 MPa or less) at room temperature for 25 hours to obtain 773 mg of the crystals. To wash away excess benzoic acid, 5 mL of heptane was added, and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered and dried under reduced pressure (-0.1 MPa or less) at 50°C for 12.5 hours to obtain 700 mg of the crystals. Furthermore, 20 mL of heptane was added, and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered and dried under reduced pressure (-0.1 MPa or less) at 50°C for 19 hours to obtain 590 mg of the crystals.

[0244] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with benzoic acid was obtained using the above procedure and is shown in Figure 21. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 5.9°, 6.4°, 10.1°, 11.6°, 12.8°, 14.4°, 18.8°, 27.2° and 27.9°. Other peaks are as shown in Table 12 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 22. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at around 100°C.

[0245] Example 12 Form 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)) synthesized by the method described in Example 1 for Form I crystal production of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) were added to 500 mg of free form 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)) by the method described in Example 1. 146.3 mg of maleic acid and 10 mL of acetone were added, and the mixture was stirred at 50°C for 66.5 hours. The solid was then filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 25 hours to obtain 491 mg of the crystals. To remove residual solvent, the mixture was dried under reduced pressure (-0.1 MPa or less) at 50°C for 14.5 hours to obtain 458 mg of the crystals.

[0246] The powder X-ray diffraction spectrum (Method A) of the Form I crystal of compound (1) obtained by the above method with maleic acid was obtained using the above procedure and is shown in Figure 23. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 12.2°, 14.3°, 18.2°, and 22.4°. Other peaks are as shown in Table 13 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 24. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 153°C.

[0247] Example 13 Form II crystal production of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with maleic acid 500 mg of free form 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)) synthesized by the method described in Example 1, was added to 146.3 mg of maleic acid and 10 mL of 99.5% ethanol. The mixture was stirred at 50°C for 67 hours, and the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 25 hours to obtain 383 mg of the crystals. To remove residual solvent, the crystals were dried under reduced pressure (-0.1 MPa or less) at 50°C for 14.5 hours, yielding 349 mg of the crystals.

[0248] The powder X-ray diffraction spectrum (Method A) of Form II crystals of compound (1) obtained by the above method with maleic acid was obtained using the above procedure and is shown in Figure 25. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 13.9°, 17.1°, 20.5°, and 25.6°. Other peaks are as shown in Table 14 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 26. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at around 150°C.

[0249] Example 14 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) Free form I crystals synthesized by the method described in Example 1 for Form III crystal production of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with maleic acid 500 mg was added to 146.3 mg of maleic acid and 10 mL of ultrapure water, stirred at 50°C for 63 hours, and the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 25 hours to obtain 423 mg of the crystals.

[0250] The powder X-ray diffraction spectrum (Method A) of the Form III crystal of compound (1) obtained by the above method with maleic acid was obtained using the above procedure and is shown in Figure 27. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 7.1°, 14.1°, 14.4°, 16.6°, 17.6°, 18.4°, 19.4°, 20.4°, 25.9° and 26.8°. Other peaks are as shown in Table 15 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 28. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 165°C.

[0251] Example 15 (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) was synthesized by the method described in Example 1 for Form IV crystal production of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) with maleic acid. 500 mg of free form 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)) were added to 438.9 mg of maleic acid and 10 mL of methanol. The mixture was stirred at room temperature for 62 hours, and the solid was filtered off. The mixture was dried under reduced pressure (-0.1 MPa or less) at room temperature for 25 hours to obtain 471 mg of the crystals. To remove the residual solvent, the mixture was dried under reduced pressure (-0.1 MPa or less) at 50°C for 14.5 hours to obtain 448 mg of the crystals.

[0252] The powder X-ray diffraction spectrum (Method A) of the Form IV crystal of compound (1) obtained by the above method with maleic acid was obtained using the above procedure and is shown in Figure 29. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 12.0°, 14.8°, 15.4°, 19.9°, and 26.0°. Other peaks are as shown in Table 16 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 30. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 169°C.

[0253] Example 16 Form III 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 phosphoric acid Amorphous (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Reference Example 1 was added to 86 μL of 85% aqueous phosphoric acid solution and 10 mL of acetonitrile / water mixture (8:2 (volume ratio)), dissolved at 60°C, and then cooled to room temperature. After stirring for 3 hours, the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 21 hours to obtain 277 mg of the crystals.

[0254] The powder X-ray diffraction spectrum (Method B) of the Form III crystal of compound (1) obtained by the above method with phosphoric acid was obtained using the above procedure and is shown in Figure 47. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 6.1°, 12.2°, 12.7°, 14.8°, 15.7°, 16.4°, and 18.4°. Other peaks are as shown in Table 17 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 48. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 71°C.

[0255] Example 17 Form IV 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 phosphoric acid Amorphous (500 mg) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) synthesized by the method described in Reference Example 1 was added to 86 μL of 85% aqueous phosphoric acid solution and 10 mL of 2-propanol / water mixture (8:2), dissolved at 50°C, and then cooled to room temperature. After stirring for 3 hours, the solid was filtered off and dried under reduced pressure (-0.1 MPa or less) at room temperature for 21 hours to obtain 220 mg of the crystals.

[0256] The powder X-ray diffraction spectrum (Method B) of the Form IV crystal of compound (1) obtained by the above method with phosphoric acid was obtained using the above procedure and is shown in Figure 49. The characteristic diffraction angles observed in the powder X-ray diffraction spectrum include the following peaks: Characteristic diffraction angles (2θ ± 0.2°): 6.1°, 12.2°, 12.7°, 14.8°, 15.8°, 16.5°, 17.2°, 17.8°, and 18.3°. Other peaks are as shown in Table 18 below. The differential thermal-thermogravimetric curve of the crystal obtained by the above method was obtained using the procedure described above and is shown in Figure 50. An endothermic peak (peak top value) was observed in the differential thermal-thermogravimetric curve at approximately 67°C.

[0257] Reference Example 1: Preparation of Amorphous Compound (1) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide (compound (1)) 20 g of free type I crystals of compound (1) were dissolved in methanol (20 mL) and chloroform (100 mL). After dissolving compound (1), the solution was dried under reduced pressure at 40°C using an evaporator and a water bath to obtain amorphous compound (1). The obtained amorphous compound (1) was a foamy mass, so the mass was crushed using an agate mortar and pestle to obtain 17.4 g of powder. The amorphous nature of the powder was confirmed by XRD measurement.

[0258] Test Example 1: Solid Stability Test The effect of temperature was confirmed using the crystalline form of compound (1) obtained in Examples 1-17 with acid, and the amorphous form of compound (1) obtained in Reference Example 1. The evaluation was carried out according to the following procedure. The appearance was also visually confirmed before and after storage. Storage conditions: 40°C (closed system) (HIFLEX (ETAC high-temperature storage machine)) Storage period: 4 weeks (4W), 12 weeks (12W), 24 weeks (24W) Storage amount: Approximately 25 mg Storage container: Glass bottle

[0259] The results are shown in Table 19 below.

[0260] Changes in the amount of related substances (the amount of substances detected other than compound (1)) were analyzed by HPLC using the following method. As a sample for analysis, each sample was weighed, and an acetonitrile-water mixture (1:1 v / v) was added to it to a concentration of 0.5 mg / mL to dissolve the active pharmaceutical ingredient. 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 handling of the instruments, including data processing, followed the methods and procedures instructed for each instrument. Instrument: Shimadzu Prominence-i LC-2030C 3D Column: GL Sciences InertSustain C8 (4.6 × 150 mm, 3 μm) UV detection: 275 nm Column temperature: 40°C Flow rate: 1.0 mL / min Sample cooler: 5°C Sample concentration: 0.5 mg / mL Mobile phase A: 10 mM potassium dihydrogen phosphate buffer (pH 6.5) Mobile phase B: Acetonitrile gradient is shown in Table 20.

[0261] As a result, the crystals of compound (1) with acid showed almost no change in the chemical purity of the crystals, almost no increase in related substances, and no change in crystal shape or color, indicating that they are stable crystals. In particular, Form I crystals of compound (1) with succinic acid, Form II crystals of compound (1) with succinic acid, Form III crystals of compound (1) with succinic acid, Form I crystals of compound (1) with adipic acid, and Form I crystals (dihydrate) of compound (1) with phosphoric acid showed almost no decomposition after storage (24W), and no visible changes in color, etc., indicating stability. At 12W after storage, it was visually confirmed that the Form I crystals of compound (1) with maleic acid, Form II crystals of compound (1) with maleic acid, and Form IV crystals of compound (1) with maleic acid had changed to a slightly brownish color. At 24W after storage, the Form I crystals of compound (1) with citric acid and the amorphous form of compound (1) were slightly reddish. At 4W, the Form III crystals of compound (1) with phosphoric acid and the Form IV crystals of compound (1) with phosphoric acid were visually confirmed to be slightly reddish.

[0262] Test Example 2 Dynamic Moisture Adsorption / Desorption (DVS) Test A moisture adsorption / desorption test was performed using the crystals of compound (1) obtained in Examples 1 to 17 with acid and the amorphous material obtained in Reference Example 1. The moisture adsorption / desorption test was measured under the following conditions. Approximately 10 mg of the sample was filled into a dedicated quartz holder, and the weight of the sample at each humidity level was continuously measured and recorded under the following conditions. The handling of the equipment, including data processing, followed the methods and procedures instructed for each device. Equipment: VTI SA+ (manufactured by T.A. Instruments) Drying temperature: 60°C Heating rate: 5°C / min Drying equilibrium: Confirm 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: Confirm 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 range obtained in these tests are shown in Figures 31 to 46, 51 and 52.

[0263] As shown in Figures 31-46, 51, and 52, the Form I crystals of compound (1) with benzoic acid, Form II crystals of compound (1) with maleic acid, and Form III crystals of compound (1) with maleic acid showed a weight increase of less than 5%. Furthermore, the Form I crystals of compound (1) with succinic acid, Form II crystals of compound (1) with succinic acid, Form III crystals of compound (1) with succinic acid, Form I crystals of compound (1) with adipic acid, and Form I crystals (dihydrate) of compound (1) with phosphoric acid showed a weight increase of 2% or less.

[0264] Based on the above results, Form I crystals of compound (1) with succinic acid, Form II crystals of compound (1) with succinic acid, Form III crystals of compound (1) with succinic acid, Form I crystals of compound (1) with adipic acid, and Form I crystals (dihydrate) of compound (1) with phosphoric acid exhibit extremely low hygroscopicity, and can be said to be superior in terms of stable quality for industrial production of pharmaceuticals as a candidate compound for drug development.

[0265] Test Example 3: Electrostatic Evaluation Test. An electrostatic evaluation test was conducted using the free form type I crystals of compound (1) obtained in Manufacturing Example 1 and Examples 1-5, the crystals of compound (1) with acid, and the amorphous form prepared as Reference Example 1. The electrostatic evaluation test was performed according to the following conditions: A 9 mL glass vial was filled with the powder sample. A micro-spatula (stainless steel) was inserted into the glass vial containing the sample to near the bottom and stirred slowly for 30 seconds. Then, the micro-spatula was slowly withdrawn from the vial, and the powder that easily fell off due to vibration was removed by lightly tapping it twice with another micro-spatula. This micro-spatula was placed in a 50 mL glass vial, and 40 mL of acetonitrile / water (1:1) was added to dissolve the active pharmaceutical ingredient adhering to the micro-spatula. 5 μL of this solution was accurately measured and analyzed by HPLC. The amount of powder adhering to the micro-spatula was calculated by multiplying the concentration by the amount of solvent (40 mL). For salt samples, the amount of salt attached (mg) was calculated considering the molecular weight of the acid contained in the salt. HPLC measurement method (quantitative test) The crystals of compound (1) with the acid and the amorphous form of compound (1) in the sample solution were measured by HPLC analysis. The handling of the instruments, including data processing, followed the methods and procedures instructed for each instrument. Instrument: Shimadzu Prominence-i LC-2030C 3D Column: GL Sciences InertSustain C18HP (4.6 × 150 mm, 3 μm) UV detection: 275 nm Column temperature: 40°C Flow rate: 1.0 mL / min Sample cooler: 5°C Mobile phase A: 0.1% phosphoric acid aqueous solution Mobile phase B: Acetonitrile gradient are shown in Table 21.

[0266] The results are shown in Table 22 below.

[0267] Compared to the amorphous form, the other forms exhibited less adhesion to the microspatula due to their electrostatic properties. Based on these results, the crystals of compound (1) with acid exhibit lower electrostatic properties than the amorphous form, suggesting superiority in the industrial production of stable-quality pharmaceuticals as a candidate compound for drug development.

[0268] Test Example 4: Form I crystals (dihydrate) of compound (1) with phosphate, prepared in Example 5 of the PK test using dogs, and free form I crystals of compound (1) were orally administered to dogs according to the following procedure. Blood samples were taken from the dogs at different time points, and the blood concentration of compound (1) was measured. The free form I crystals of compound (1) were prepared according to a method described in known literature.

[0269] <Absorption Test Conditions> Animals Used: Beagle dogs (Kitayama Labes, 6 males) Dietary Conditions: Fasting for 20 hours from the day before, feeding after the test. Dosage: 100 mg / body (amount of compound (1)) Dosage Samples: 133.8 mg of Form I crystals (dihydrate) of compound (1) with phosphate prepared in Example 5, filled into 5 mL gelatin capsules (Size: #12, Torpac), and 100 mg of free form I crystals of compound (1), filled into 5 mL gelatin capsules (Size: #12, Torpac). Dosage Method: Oral administration using a tube with 50 mL of water. Low gastric pH model Pretreatment: 30 minutes before administration of the sample, atropine sulfate intravenous injection 0.02 mg / 0.04 mL / kg and pentagastrin intramuscular injection 0.01 mg / 0.1 mL / kg were administered intramuscularly, followed by two intramuscular administrations of pentagastrin intramuscular injection 0.01 mg / 0.1 mL / kg at 45-minute intervals. Neutral gastric pH model Pretreatment: 30 minutes before administration, atropine sulfate intravenous injection 0.02 mg / 0.04 mL / kg and omeprazole intravenous injection 1 mg / 0.25 mL / kg were administered intravenously, and 60 minutes after administration, omeprazole intravenous injection 1 mg / 0.25 mL / kg was administered intravenously. Blood samples were collected from each animal 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after oral administration of each sample. The blood concentration of compound (1) was measured using LC / MS / MS, and the AUC (area under the blood concentration-time curve calculated using the trapezoidal method from 0 to 8 hours after administration), Cmax (peak blood concentration), and Tmax (time to reach peak blood concentration) were calculated.

[0270] The results are shown in Table 23 below.

[0271] Test Example 5 Single Crystal Analysis of Form I Crystals (Dihydrate) of Compound (1) with Phosphoric Acid 5 g of compound (1) was dissolved by adding 10 mL of DMSO and 140 mL of methanol and stirring at 70°C. Methanol was removed by distillation under reduced pressure using an evaporator. 1.6 g of 85% phosphoric acid solution and 10 mL of ethanol were added to this solution. 5 mL of this solution was measured out and 5 mL of ethanol was added. 1 mL of this solution was measured out and 1 mL of acetone was added, and it was allowed to stand for 6 days. The precipitate was filtered to recover the solid, and it was dried under reduced pressure at 70°C overnight. The sample (Form I crystals of compound (1) and phosphoric acid) was obtained by allowing this dried product to absorb moisture. The measurement results below clearly showed that the crystals were dihydrate.

[0272] Measurements were taken using the following equipment and conditions: Measurement device: Rigaku XtaLABPRO Synergy-Custom MM007DW X-ray source: CuKα rays (λ = 1.54184 Å) Measurement temperature: -173°C The crystal data is shown below. Measured crystal size: 0.11 × 0.04 × 0.03 mm

[0273] Test Example 6: Investigation of Manufacturing Characteristics of Form I Crystals (Dihydrate) of Compound (1) with Phosphate To evaluate the tablet properties of Form I crystals (dihydrate) of Compound (1) with Phosphate, 792 g of the mixed powder of the formulation shown in Table 24 below was prepared. Using a rotary tablet press VELAG (manufactured by Kikusui Seisakusho) with a single punch of Φ9 mm and R13 mm, the tablet was continuously compressed for 50 minutes at 40 revolutions per minute and a pressure of 9-11 kN, yielding 2000 tablets with a mass of approximately 330 mg each. No problematic phenomena were observed during manufacturing.

[0274] 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. Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has three or more peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°.

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 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°.

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 8.1°, 15.1°, 18.6°, 19.6°, 20.2°, 21.4°, 22.2°, 23.1°, 25.4°, and 28.9°.

4. Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, 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 221°C.

6. The crystal according to any one of claims 1 to 5, wherein the crystal purity is 50% by weight or more.

7. The crystal according to any one of claims 1 to 6, wherein the chemical purity is 90% or higher.

8. A method for producing Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, 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 with succinic acid in a solvent containing at least one selected from the group consisting of lower alcohols and aprotic polar solvents.

9. A pharmaceutical composition containing the crystal described in any one of claims 1 to 7.

10. Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

11. The crystal according to claim 10, 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 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°.

12. The crystal according to claim 10 or 11, 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 7.1°, 8.4°, 11.3°, 14.0°, 16.6°, 20.6°, 21.5°, 23.9°, 25.6°, and 27.9°.

13. Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having a powder X-ray diffraction spectrum substantially identical to that measured by CuKα characteristic X-rays shown in Figure 3.

14. The crystal according to any one of claims 10 to 13, wherein the endothermic peak determined by simultaneous differential thermal-thermogravimetric measurement is around 221°C.

15. The crystal according to any one of claims 10 to 14, wherein the crystal purity is 50% by weight or more.

16. The crystal according to any one of claims 10 to 15, wherein the chemical purity is 90% or higher.

17. A method for producing Form II crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, according to any one of claims 10 to 16, 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 with succinic acid in a solvent containing at least one selected from the group consisting of lower alcohols, aprotic polar solvents, and water.

18. A pharmaceutical composition containing the crystal described in any one of claims 10 to 16.

19. Form III crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having three or more peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

20. The crystal according to claim 19, 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 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°.

21. The crystal according to claim 19 or 20, 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 7.0°, 7.8°, 8.8°, 13.9°, 15.4°, 21.0°, 21.8°, 25.2°, 25.9°, and 27.4°.

22. Form III crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, having a powder X-ray diffraction spectrum substantially identical to that measured by CuKα characteristic X-rays shown in Figure 5.

23. The crystal according to any one of claims 19 to 22, wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 218°C.

24. The crystal according to any one of claims 19 to 23, wherein the crystal purity is 50% by weight or more.

25. The crystal according to any one of claims 19 to 24, wherein the chemical purity is 90% or higher.

26. A method for producing Form III crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with succinic acid, according to any one of claims 19 to 25, 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 with succinic acid according to any one of claims 19 to 25.

27. A pharmaceutical composition containing the crystal described in any one of claims 19 to 25.

28. Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, wherein the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays has three or more peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

29. The crystal according to claim 28, 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 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

30. The crystal according to claim 28 or 29, 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 5.4°, 6.1°, 11.1°, 12.1°, 13.4°, 14.5°, 17.1°, 18.1°, 21.6°, and 22.2°.

31. Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, 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 7.

32. The crystal according to any one of claims 28 to 31, wherein the endothermic peak determined by differential thermal-thermogravimetric simultaneous measurement is around 208°C.

33. The crystal according to any one of claims 28 to 32, wherein the crystal purity is 50% by weight or more.

34. The crystal according to any one of claims 28 to 33, wherein the chemical purity is 90% or higher.

35. A method for producing Form I crystals of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, according to any one of claims 19 to 25, 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 with adipic acid, wherein (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with adipic acid, as described in any one of claims 19 to 25.

36. A pharmaceutical composition containing the crystal described in any one of claims 28 to 34.

37. Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, having three or more peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6° in the powder X-ray diffraction spectrum measured by CuKα characteristic X-rays.

38. The crystal according to claim 37, 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 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°.

39. The crystal according to claim 37 or 38, 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 7.4°, 10.9°, 15.2°, 17.4°, 20.1°, 21.3°, 23.5°, 24.2°, 24.9°, and 27.6°.

40. Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, having a powder X-ray diffraction spectrum substantially identical to that measured by CuKα characteristic X-rays shown in Figure 9.

41. The crystal according to any one of claims 37 to 40, wherein the endothermic peak determined by simultaneous differential thermal-thermogravimetric measurement is around 53°C.

42. The crystal according to any one of claims 37 to 41, wherein the crystal purity is 50% by weight or more.

43. A crystal according to any one of claims 37 to 42, wherein the chemical purity is 90% or higher.

44. A method for producing Form I crystals (dihydrate) of (S)-N-(4-amino-6-methyl-5-(quinoline-3-yl)-8,9-dihydropyrimido[5,4-b]indolidine-8-yl)acrylamide with phosphoric acid, according to any one of claims 37 to 43, 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 with phosphoric acid according to any one of claims 37 to 43.

45. A pharmaceutical composition containing the crystal described in any one of claims 37 to 43.

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