New crystal of (2R)-n-benzyl-1-[5-(2-fluoropropane-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, and method for producing same

Abstract

The present invention provides a C-form crystal and a D-form crystal of (2R)-N-benzyl-1-[5-(2-fluoropropane-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide characterized by at least one physicochemical property selected from a specific diffraction peak in a powder X-ray diffraction spectrum and a specific endothermic peak in differential scanning calorimetry, a pharmaceutical composition containing the crystals, a method for producing the crystals, a medical kit comprising the crystals and / or the pharmaceutical composition, and a pharmaceutical application of the crystals and the pharmaceutical composition.

Description

Novel crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide and method for producing the same

[0001] The present invention relates to novel crystalline polymorphs of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, pharmaceutical compositions containing the same as an active ingredient, methods for preparing them, medical kits containing one or more of the crystalline polymorphs and / or pharmaceutical compositions, and medical uses of the crystals and pharmaceutical compositions, as well as methods of treatment. One aspect of the present invention relates to type C and type D crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, which have inhibitory activity against kynurenine aminotransferase-2 (hereinafter sometimes referred to as KAT2) and are useful as a preventive or therapeutic agent for cognitive impairment, neurodegenerative disease, or schizophrenia, and which have excellent stability. This application also relates to pharmaceutical compositions containing the same as an active ingredient, as well as methods for producing the same. This application claims priority based on Japanese Patent Application No. 2024-118891, filed July 24, 2024, the contents of which are incorporated herein by reference.

[0002] N-methyl-D-aspartate receptors (hereinafter sometimes referred to as NMDAR) and nicotinic acetylcholine receptors (hereinafter sometimes referred to as nAChR) are known to be involved in several cognitive functions. Animal studies have shown that activation of NMDAR or nAChR improves several psychiatric disorders, including schizophrenia, dementia, depression, and stress vulnerability (see Non-Patent Document 1 for NMDAR and Non-Patent Documents 2 and 3 for nAChR).

[0003] Kynurenic acid (hereinafter sometimes referred to as KYNA) is an endogenous tryptophan metabolite produced in the brain via the kynurenine pathway. Tryptophan is metabolized by indoleamine 2,3-dioxygenase (IDO) and other enzymes to produce kynurenine, which is then metabolized to produce KYNA. The enzymes that catalyze the reaction of kynurenine to KYNA are called kynurenine aminotransferases (KATs), and four types (KAT1, KAT2, KAT3, and KAT4) are known to exist. These are kynurenine aminotransferases 1, 2, 3, and 4. Of these, KAT2 plays a major role in KYNA production in the brain, and it is known that KYNA concentrations in the hippocampus of KAT2 knockout mice are significantly reduced compared to wild-type mice (see Non-Patent Document 4).

[0004] KYNA is known to be an antagonist of NMDAR and nicotinic acetylcholine α7 receptor (hereinafter, sometimes referred to as α7nAChR), and is therefore thought to be involved in regulating presynaptic activity of GABAergic neurons and glutamate neurons in the brain primarily via α7nAChR, and in regulating postsynaptic activity of glutamate neurons via NMDAR (see Non-Patent Documents 5, 6, and 7).

[0005] Therefore, KAT2 inhibitors are expected to be useful in the treatment of central nervous system disorders such as schizophrenia, attention-deficit / hyperactivity disorder, Alzheimer's disease, and major depression through activation of NMDAR and / or nAChR due to a decrease in the concentration of KYNA in the brain. The following, for example, have been reported as literature describing the association between KAT2 and / or KYNA and dementia, depression, or stress vulnerability.

[0006] Studies in mammals have confirmed that increased KYNA concentrations in the brain cause impairment of cognitive functions such as contextual learning and working memory, and the possibility that increased KYNA concentrations may be involved in cognitive dysfunction such as schizophrenia has been discussed (see Non-Patent Documents 8 to 10).

[0007] R. Schwarcz et al. have shown that local injection of KYNA into the brain of rodents suppresses the release of dopamine, acetylcholine, or glutamate in that area, and have proposed that reducing the production of KYNA in the brain may improve cognitive function in schizophrenia (for dopamine, see Non-Patent Document 11; for acetylcholine, see Non-Patent Document 12; for glutamate, see Non-Patent Document 13).

[0008] It has been reported that KYNA concentrations in the cerebrospinal fluid of patients with schizophrenia and bipolar disorder are significantly higher than those of healthy volunteers and patients without psychiatric disorders, supporting the involvement of KYNA in the pathophysiology of schizophrenia and bipolar disorder (see Non-Patent Document 14 for schizophrenia and Non-Patent Document 15 for bipolar disorder).

[0009] It has been reported that administration of a KAT2 inhibitor dose-dependently reduces the KYNA concentration in brain dialysates, and that KAT2 inhibitors are active in an anhedonia model (chronic mild stress), a model of depression, and that KAT2 inhibitors may be suitable for cognitive function and negative symptoms of schizophrenia (see Non-Patent Document 16).

[0010] It has been reported that BTBR mice, a type of mouse with autism spectrum disorder, have higher KYNA concentrations in the medial prefrontal cortex compared to C57Bl / 6J mice (see Non-Patent Document 17).

[0011] It is known that KYNA concentrations are significantly higher in the putamen and caudate nucleus of postmortem brains of Alzheimer's disease patients compared to non-demented controls. It has been reported that NMDAR inhibition by KYNA may be the cause of memory impairment, learning, and cognitive function in Alzheimer's disease patients (see Non-Patent Document 18).

[0012] It has been reported that patients with ischemic cerebrovascular disease (cerebral infarction) have a higher kynurenine / tryptophan ratio, which indicates a decline in cognitive function, suggesting that inflammatory responses characterized by increased IDO activity are associated with vascular dementia (see Non-Patent Document 19).

[0013] It has been reported that the concentration of kynurenic acid in the frontal cortex of postmortem brain samples from subgroups of HIV-1 (human immunodeficiency virus type 1) infected patients, such as those with HIV encephalopathy, is significantly increased compared to control groups. It has also been suggested that reducing kynurenic acid production may be useful as an anti-dementia drug (see Non-Patent Document 20).

[0014] For example, the following compounds have been reported as compounds having KAT2 inhibitory activity.

[0015] R. Schwarcz et al. have disclosed that novel kynurenine derivatives having KAT2 inhibitory activity are effective in treating cognitive impairment and perinatal brain damage associated with brain aging (see Patent Document 1).

[0016] MM Claffey et al. and AB Dounay et al. have disclosed that compounds represented by the following formula are KAT2 inhibitors and are useful for treating cognitive deficits associated with schizophrenia and other neurodegenerative and / or neurological disorders (see Patent Documents 2 to 4).

[0017]

[0018] (The symbols in the formula have the same meanings as those described in Patent Documents 2 to 4.)

[0019] The present applicant has also discovered a compound of the following formula (IA):

[0020]

[0021] (wherein each symbol has the same meaning as in Patent Document 5) has KAT2 inhibitory activity and is useful for the treatment or prevention of various diseases in which KAT2 is involved (e.g., schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive dysfunction, dementia, depression, stress vulnerability), particularly for the treatment or prevention of schizophrenia (see Patent Document 5). Furthermore, as an example of a compound of formula (IA), (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide is also disclosed. However, Patent Document 5 does not describe or suggest the existence of multiple crystalline polymorphs of the compound.

[0022] International Publication No. WO 1995 / 004714 International Publication No. WO 2010 / 146488 International Publication No. WO 2012 / 073143 International Publication No. WO 2013 / 186666 International Publication No. WO 2015 / 163339

[0023] R. G. M. Morris et al., Philosophical transactions of the Royal Society of London, 1990, Vol.329, pp. 187-204.E. X. Albuquerque et al., Physiological Reviews, 2009, Vol.89, pp. 73-120.D. S. McGehee, Trends in Neurosciences, 2002, Vol.25, pp. 171-172.M. C. Potter et al., Neuropsychopharmacology, 2010, Vol.35, pp. 1734-174.R. Schwarcz et al., Nature Reviews Neuroscience, 2012, Vol.13, pp. 465-477.M. Alkondon et al., The Journal of Neuroscience, 2004, Vol.24, pp. 4635-4648.G. Henderson et al., Journal of Physiology, 1990, Vol.430, pp. 189-212.A. C. Chess et al., Behavioural Brain Research, 2006, Vol.170, pp. 326-332.A. C. Chess et al., Schizophrenia Bulletin, 2007, Vol.33, pp. 797-804.A. C. Chess et al., Behavioural Brain Research, 2009, Vol.201, pp. 325-331.A. Rassoulpour et al., Journal of Neurochemistry, 2005, Vol.93, pp. 762-765.A. Zmarowski et al., European Journal of Neuroscience, 2009, Vol.29, pp. 529-538.H.-Q. Wu et al., Journal of Molecular Neuroscience, 2010, Vol.40, pp. 204-210.KR Linderholm et al., Schizophrenia Bulletin, 2012, Vol.38, pp. 426-432.SK Olssona et al., Bipolar Disorders, 2012, Vol.14, pp.719-726.B. Campbell et al., Advancing Drug Discovery for Schizophrenia, March 9-11, 2011, The New York Academy of Sciences (Final Program, pp. 17-18)SM McTighe et al., PLoS ONE, 2013, Vol.8, e62189.H. Baran et al., Journal of Neural Transmission, 1999, Vol.106, pp. 165-181.AB Gold et al., Journal of Neuroinflammation, 2011, Vol.8, p.17.H. Baran et al., International Journal of Tryptophan Research, 2012, Vol.5, pp. 49-64.

[0024] An object of the present invention is to provide a novel crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide having excellent stability, and a medicine containing the same as an active ingredient.

[0025] As a result of intensive studies to solve the above problems, the present inventors have identified 12 types of crystal polymorphs (including solvates) that exist as crystalline (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, namely, A-type crystals, B-type crystals, C-type crystals, D-type crystals, E-type crystals, F-type crystals, G-type crystals, H-type crystals, I-type crystals, J-type crystals, K-type crystals, and L-type crystals, and have found that, in particular, C-type crystals and D-type crystals are excellent in stability, with C-type crystals being the most stable.

[0026] That is, the present invention provides a crystalline form of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide. One embodiment of the present invention is, for example, as follows. [1] Form C crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, [2] The crystal according to [1] above, which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, and about 13.7° in powder X-ray diffraction, [3] The crystal according to [1] above, which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, about 13.4°, about 13.7°, and about 15.7° in powder X-ray diffraction, [4] The crystal according to the above-mentioned [1], which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, about 13.4°, about 13.7°, about 15.7°, about 16.4° and about 18.3° in powder X-ray diffraction; [5] The crystal according to the above-mentioned [1], which has diffraction peaks at diffraction angles (2θ) of 6.7±0.2°, 8.1±0.2°, 15.7±0.2°, 21.5±0.2°, 21.8±0.2°, 25.5±0.2° and 27.3±0.2° in powder X-ray diffraction; [6] The crystal according to the above-mentioned [5], which further has a diffraction peak at a diffraction angle (2θ) of 13.7±0.2°; [7] The crystal according to the above-mentioned [5] or [6], which further has a diffraction peak at a diffraction angle (2θ) of 16.4±0.2°; [8] In the powder X-ray diffraction spectrum, the following table:

[0027]

[0028] [9] The crystal according to the above [1], which has a diffraction peak represented by diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown in Figure 3;

[10] The crystal according to any one of the above [1] to [9], which shows an extrapolated onset temperature of about 172°C in differential scanning calorimetry (DSC);

[11] The crystal according to any one of the above [1] to

[10] , which shows an endothermic peak enthalpy of about 83.9 mJ / mg in differential scanning calorimetry (DSC);

[12] Form D crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide;

[13] The crystal according to the above-mentioned

[12] , which has diffraction peaks at diffraction angles (2θ) of about 7.6°, about 9.1°, and about 13.0° in powder X-ray diffraction;

[14] The crystal according to the above-mentioned

[12] , which has diffraction peaks at diffraction angles (2θ) of about 5.5°, about 7.6°, about 9.1°, about 13.0°, and about 15.9° in powder X-ray diffraction;

[15] The crystal according to the above-mentioned

[12] , which has diffraction peaks at diffraction angles (2θ) of about 5.5°, about 7.6°, about 9.1°, about 13.0°, about 15.9°, about 17.8°, and about 19.6° in powder X-ray diffraction;

[16] The crystal according to the above

[12] , which has diffraction peaks at diffraction angles (2θ) of 7.6±0.2°, 9.1±0.2°, 13.0±0.2°, 17.8±0.2°, 19.6±0.2° and 21.9±0.2° in powder X-ray diffraction;

[17] The crystal according to the above

[16] , which further has a diffraction peak at diffraction angle (2θ) of 15.9±0.2°;

[18] The crystal according to the above

[16] or

[17] , which further has a diffraction peak at diffraction angle (2θ) of 28.9±0.2°;

[19] The crystal according to the above

[16] or

[17] , which further has a diffraction peak at diffraction angle (2θ) of 28.9±0.2° in powder X-ray diffraction spectrum, which has the following characteristics:

[0029]

[0030]

[20] The crystal according to the above

[12] , which has a powder X-ray diffraction pattern substantially as shown in FIG. 4;

[21] The crystal according to any one of the above

[12] to

[20] , which shows an extrapolated onset temperature of about 158°C in differential scanning calorimetry (DSC);

[22] The crystal according to any one of the above

[12] to

[21] , which shows an endothermic peak enthalpy of about 72.1 mJ / mg in differential scanning calorimetry (DSC);

[23] Type B crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide;

[24] The crystal according to the above-mentioned

[23] , which has diffraction peaks at diffraction angles (2θ) of about 5.2°, about 5.9° and about 7.4° in powder X-ray diffraction;

[25] The crystal according to the above-mentioned

[23] , which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 5.2°, about 5.9°, about 7.4° and about 22.2° in powder X-ray diffraction;

[26] The crystal according to the above-mentioned

[23] , which has diffraction peaks at diffraction angles (2θ) of 4.5±0.2°, 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 8.3±0.2° and 22.2±0.2° in powder X-ray diffraction;

[27] The crystal according to the above-mentioned

[26] , which further has a diffraction peak at diffraction angle (2θ) of 23.1±0.2°;

[28] The crystal according to the above

[26] or

[27] , further having a diffraction peak at a diffraction angle (2θ) of 19.7±0.2°;

[29] In the powder X-ray diffraction spectrum,

[0031]

[0032]

[30] The crystal according to the above-mentioned

[23] , which has a diffraction peak represented by diffraction angles Pos. [°2Th.] (2θ) and relative intensities according to the above-mentioned formula (I),

[31] The crystal according to any one of the above-mentioned [1] to

[30] , which shows a powder X-ray diffraction pattern substantially as shown in FIG. 2,

[31] The crystal according to any one of the above-mentioned [1] to

[30] , which has a crystalline purity of 70% or more,

[32] A pharmaceutical composition comprising the crystal according to any one of the above-mentioned [1] to

[31] , and a pharmaceutically acceptable carrier,

[33] The pharmaceutical composition according to the above-mentioned

[32] , which is in the form of granules, fine granules, powder, capsules, or tablets,

[34] The pharmaceutical composition according to the above-mentioned

[32] or

[33] , for the prevention and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability,

[35] The pharmaceutical composition according to the above

[32] or

[33] for inhibiting KAT2;

[36] A KAT2 inhibitor comprising the crystal according to any one of the above [1] to

[31] ;

[37] A method for inhibiting KAT2 in a subject, comprising administering to the subject a pharmaceutically effective amount of the crystal according to any one of the above [1] to

[31] ;

[38] A method for preventing and / or treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, comprising administering to the subject a pharmaceutically effective amount of the crystal according to any one of the above [1] to

[31] ;

[39] The method according to the above

[38] , wherein the disease is schizophrenia;

[40] The method according to the above

[38] , wherein the disease is bipolar disorder or attention-deficit / hyperactivity disorder;

[41] The method according to the above-mentioned

[38] , wherein the disease is Alzheimer's disease, major depression, autism, age-related cognitive impairment, or dementia;

[42] A method for inhibiting KAT2, comprising contacting KAT2 with the crystal according to any one of the above-mentioned [1] to

[31] , thereby inhibiting KAT2;

[43] Use of the crystal according to any one of the above-mentioned [1] to

[31] for producing a KAT2 inhibitor;

[44] Use of the crystal according to any one of the above [1] to

[31] for the manufacture of an agent for the prophylaxis and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability;

[45] Use according to the above

[43] or

[44] in combination with at least one other drug effective for the prophylaxis and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability;

[46] (a) the crystal according to any one of the above [1] to

[31] ; and (b) a pharmaceutical composition comprising at least one other drug effective for the prevention and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability;

[47] a combination drug comprising (a) the compound or crystal according to any of the above [1] to

[31] , and (b) at least one other drug effective for the prevention and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability, administered simultaneously, separately, or sequentially;

[48] ​​A method for producing type C crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, comprising: (a) reacting a compound represented by formula (1):

[0033]

[0034] is reacted with D-proline in the presence of a base to obtain a compound represented by formula (2):

[0035]

[0036] (b) amidating the compound of formula (2) by reacting it with benzylamine in the presence of a condensing agent and a base, and then adding acetic acid at 5°C to 15°C, stirring at the same temperature, and crystallizing to obtain type I crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide; (c) dissolving the type I crystals in a mixed solvent of acetonitrile / water at an internal temperature of 40°C to 55°C, followed by cooling to 5°C to 25°C, stirring, and crystallizing the solution to convert the type I crystals into type F crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide; (d) dissolving the F-type crystals in a mixed solvent of ethanol / water at an internal temperature of 30°C to 45°C, followed by cooling to 5°C to 15°C, stirring, and crystallizing to convert them into C-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide;

[49] The production method according to the above

[48] , wherein the condensing agent is propylphosphonic anhydride (T3P);

[50] The production method according to the above

[48] , wherein the crystallization in the step (b) is carried out by adding type I crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide prepared by another method as seed crystals;

[51] The production method according to the above

[48] , wherein the crystallization in the step (c) is carried out by adding type F crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide prepared by another method as seed crystals;

[52] The crystallization in the step (d) is carried out using (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3] the production method according to the above-mentioned

[48] , which is carried out by adding type C crystals of thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide as seed crystals;

[53] A method for producing C-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, comprising adding seed crystals of C-type crystals to a suspension of A-type crystals, D-type crystals, F-type crystals, H-type crystals, J-type crystals, K-type crystals, or L-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, stirring, and crystallizing to obtain C-type crystals;

[54] Form I crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide,

[55] The crystal according to the above-mentioned

[54] , which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, and about 13.1° in powder X-ray diffraction,

[56] The crystal according to the above-mentioned

[54] , which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, about 7.4°, about 10.8°, and about 13.1° in powder X-ray diffraction,

[57] The crystal according to the above

[54] , which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, about 7.4°, about 10.8°, about 13.1°, about 16.2°, and about 18.8° in powder X-ray diffraction;

[58] The crystal according to the above

[54] , which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, about 7.4°, about 10.8°, about 13.1°, about 16.2°, and about 18.8° in powder X-ray diffraction spectrum;

[0037]

[0038]

[59] The crystal according to the above-mentioned

[54] , which has diffraction peaks represented by diffraction angles Pos. [°2Th.] (2θ) and relative intensities according to the above-mentioned formula (1),

[60] The crystal according to any one of the above-mentioned

[54] to

[59] , which shows a powder X-ray diffraction pattern substantially as shown in FIG. 9,

[61] The crystal according to any one of the above-mentioned

[54] to

[59] , which shows a melting point of about 112°C in simultaneous thermogravimetry and differential thermal analysis (TG-DTA),

[62] The crystal according to the above-mentioned

[61] , which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, and about 9.1° in powder X-ray diffraction,

[63] The crystal according to the above-mentioned

[61] , which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, about 9.1°, about 11.2° and about 17.4° in powder X-ray diffraction;

[64] The crystal according to the above-mentioned

[61] , which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, about 9.1°, about 11.2°, about 17.4°, about 17.7° and about 19.0° in powder X-ray diffraction;

[65] The crystal according to the above-mentioned

[61] , which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, about 9.1°, about 11.2°, about 17.4°, about 17.7° and about 19.0° in powder X-ray diffraction spectrum;

[0039]

[0040]

[66] The crystal according to any one of

[61] to

[65] above, which shows a melting point of about 124°C in simultaneous thermogravimetry and differential thermal analysis (TG-DTA),

[67] E-type crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide,

[68] In powder X-ray diffraction spectrum, the crystal has a diffraction peak represented by the following table:

[0041]

[0042]

[69] A method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, comprising administering a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of formula (I) to a subject in need thereof for treating the disease.

[0043]

[0044]

[70] A method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, comprising administering a therapeutically effective amount of the crystal according to any one of [1] to

[31] or

[54] to

[68] above, or a therapeutically effective amount of the pharmaceutical composition according to

[32] or

[33] to a subject in need thereof for treating the disease.

[71] The method according to

[69] or

[70] above, wherein the disease is schizophrenia.

[72] The method according to

[69] or

[70] above, wherein the disease is bipolar disorder or attention-deficit / hyperactivity disorder.

[73] The method according to

[69] or

[70] above, wherein the disease is Alzheimer's disease, major depression, autism, age-associated cognitive impairment, or dementia.

[74] A method for inhibiting KAT2, comprising contacting KAT2 with the crystal according to any one of the above [1] to

[31] or

[54] to

[68] , thereby inhibiting KAT2.

[75] A method for treating cognitive dysfunction, comprising administering a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of formula (I) to a subject in need thereof for treating the cognitive dysfunction.

[0045]

[0046]

[76] A method for treating cognitive dysfunction, comprising administering a therapeutically effective amount of the crystal according to any one of [1] to

[31] or

[54] to

[68] above, or a therapeutically effective amount of the pharmaceutical composition according to

[32] or

[33] to a subject in need thereof for treating the cognitive dysfunction.

[77] The method according to

[75] or

[76] , wherein the subject has been diagnosed with a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[78] The method according to

[77] , wherein the disease is schizophrenia.

[79] The method according to

[77] , wherein the disease is bipolar disorder or attention-deficit / hyperactivity disorder.

[80] The method according to

[77] , wherein the disease is Alzheimer's disease.

[81] The method according to

[77] , wherein the disease is major depression, autism, age-related cognitive impairment, or dementia.

[82] A method for treating cognitive impairment associated with schizophrenia (CIAS), comprising administering a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of formula (I) to a subject in need thereof for treating the cognitive impairment.

[0047]

[0048]

[83] A method for treating cognitive impairment associated with schizophrenia (CIAS), comprising administering to a subject in need thereof a therapeutically effective amount of the crystal according to any of [1] to

[31] or

[54] to

[68] above, or a therapeutically effective amount of the pharmaceutical composition according to

[32] or

[33] , for treating the cognitive impairment.

[84] The method according to any of

[69] to

[83] , wherein the concentration of kynurenic acid (KYNA) in cerebrospinal fluid (CSF) is reduced by at least 40%.

[85] The method according to any of

[69] to

[84] , wherein the treatment enhances glutamate signaling and / or acetylcholine signaling, as measured by an increase in gamma wave amplitude and the ratio of alpha wave amplitude to beta wave amplitude (β / α ratio).

[86] The method according to any of

[69] to

[85] , wherein the treatment increases the concentration of glutamate in the cerebrospinal fluid (CSF) of the subject relative to before treatment.

[87] The method according to any one of

[69] to

[86] , wherein the subject is a human.

[88] The method according to any one of

[69] to

[87] , wherein a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, a therapeutically effective amount of the crystal according to any one of [1] to

[31] or

[54] to

[68] above, or a therapeutically effective amount of the pharmaceutical composition according to

[32] or

[33] is orally administered.

[89] The method according to any one of

[69] to

[88] , wherein the therapeutically effective amount is 0.001 mg / kg / day to 500 mg / kg / day.

[0049] According to the present invention, it is possible to provide stable and novel crystalline polymorphs, namely, type C crystals and type D crystals, of the compound (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (hereinafter referred to as "compound (I)" or may be represented by formula (1)).

[0050]

[0051] Furthermore, according to the present invention, C-type crystals, which are the most stable crystalline form of compound (I), can be obtained with good reproducibility, high purity, and high yield. According to the present invention, C-type crystals and D-type crystals, which are novel and stable crystalline polymorphs of compound (I), can be provided. Furthermore, according to the present invention, C-type crystals, which are the most stable crystalline form of compound (I), can be obtained with good reproducibility, high purity, and high yield, and a practical production method that can be scaled up can be provided. Furthermore, since the C-type crystals of compound (I) of the present invention have excellent KAT2 inhibitory activity, they are useful as pharmaceuticals for the treatment or prevention of various diseases in which KAT2 is involved (e.g., schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive dysfunction, dementia, depression, and stress vulnerability). Thus, the present invention provides novel crystalline polymorphic forms of Compound (I), methods for preparing these polymorphic forms, pharmaceutical compositions comprising one or more novel crystalline polymorphs, medical kits comprising such crystalline polymorphs and / or pharmaceutical compositions, and medical uses of such crystalline polymorphs and pharmaceutical compositions.

[0052] FIG. 1 shows the powder X-ray diffraction pattern of type A crystal of compound (I). FIG. 2 shows the powder X-ray diffraction pattern of type B crystal of compound (I). FIG. 3 shows the powder X-ray diffraction pattern of type C crystal of compound (I). FIG. 4 shows the powder X-ray diffraction pattern of type D crystal of compound (I). FIG. 5 shows the powder X-ray diffraction pattern of type E crystal of compound (I). FIG. 6 shows the powder X-ray diffraction pattern of type F crystal of compound (I) (acetonitrile solvate). FIG. 7 shows the powder X-ray diffraction pattern of type G crystal of compound (I). FIG. 8 shows the powder X-ray diffraction pattern of type H crystal of compound (I). FIG. 9 shows the powder X-ray diffraction pattern of type I crystal of compound (I) (acetic acid solvate). FIG. 10 shows the powder X-ray diffraction pattern of type J crystal of compound (I). FIG. 11 shows the DSC thermal analysis data of type C crystal of compound (I). FIG. 12 shows TG-DTA measurement data for type C crystals of compound (I). FIG. 13 shows DVS data for type C crystals of compound (I). FIG. 14 shows related substance measurement data (HPLC) for type C crystals of compound (I). FIG. 15 shows DSC thermal analysis data for type D crystals of compound (I). FIG. 16 shows TG-DTA measurement data for type D crystals of compound (I). FIG. 17 shows DVS data for type D crystals of compound (I). FIG. 18 shows a powder X-ray diffraction pattern for a mixture of type K crystals and type C crystals of compound (I). FIG. 19 shows a powder X-ray diffraction pattern for a mixture of type L crystals and type C crystals of compound (I). FIG. 20 shows the solubilities of type C crystals and type D crystals of compound (I) in various solvents. Figure 21 shows the change in the KYNA / L-KYN ratio in the brains of marmosets orally administered vehicle alone, 3 mg / kg of Compound (I), and 10 mg / kg of Compound (I) 2 hours before administration of L-KYN (10 mg / kg, iv). Figure 22A shows the change in the amplitude of delta and theta waves in marmosets administered with scopolamine (40 μg / kg). Figure 22B shows the change in the amplitude of delta and theta waves in marmosets administered with scopolamine (40 μg / kg) in combination with 30 mg / kg of Compound (I).

[0053] The present invention will be described in detail below. The compound (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (disclosed as Example 482 in WO 2015 / 163339) (Compound (I)) has the following formula (I):

[0054]

[0055] It is a compound represented by the formula:

[0056] The present invention provides novel crystalline polymorphic forms of Compound (I), methods for preparing these polymorphic forms, pharmaceutical compositions containing one or more novel crystalline polymorphs, medical kits containing such crystalline polymorphs and / or pharmaceutical compositions, and pharmaceutical uses of such crystalline polymorphs and pharmaceutical compositions. For ease of reference, the different crystalline polymorphs described herein (hereinafter sometimes collectively referred to as "the crystals of the present invention") are consistently referred to throughout the application as type A crystals to type L crystals (hereinafter, each crystalline form may be referred to as "type ____ crystals of the present invention" (where "____" indicates any of A to L), respectively), and amorphous forms. The following describes type A crystals to type L crystals of the present invention. The crystals of Compound (I) of the present invention include not only crystalline polymorphs of free Compound (I) but also crystalline polymorphs of solvates of Compound (I).

[0057] The solvate of compound (I) of the present invention is a solvate in which solvent molecules are coordinated to compound (I), and examples thereof include a hydrate, an ethanol solvate, an acetonitrile solvate, a dimethyl sulfoxide solvate, and an acetic acid solvate of compound (I).

[0058] As used herein, "amorphous form" refers to a state of matter that lacks long-range order as in crystals, but has short-range order (non-crystalline), and does not have a discernible pattern by XRPD or other diffraction techniques.

[0059] The crystals obtained are generally analyzed by crystal analysis using X-ray diffraction. Furthermore, methods for determining the crystal form include mechanical and optical methods (e.g., FT-Raman spectroscopy, solid-state NMR spectroscopy, infrared absorption spectroscopy, etc.). Furthermore, thermal analysis of the crystals (differential scanning calorimetry (DSC)) and thermogravimetry-differential thermal analysis (TG-DTA)) can also be performed according to conventional methods.

[0060] The diffraction peak values ​​at the diffraction angle (2θ) of the X-ray powder diffraction (XRPD) data of each crystal described below may have some measurement error depending on the measuring instrument or the measurement conditions. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1, and more preferably ±0.06. The diffraction peak values ​​including the measurement error may be expressed with the word "approximately" added.

[0061] Furthermore, the "relative intensity" in the X-ray powder diffraction (XRPD) data of each crystal described below indicates a numerical value expressed as a percentage relative to the most intense peak.

[0062] Furthermore, the "extrapolated onset temperature" in the thermal analysis of crystals, as defined in JIS K 7121 (Method for measuring transition temperatures of plastics), means the temperature at the intersection of the extrapolated baseline on the low-temperature side toward the high-temperature side in a DSC curve and a tangent drawn at the point where the gradient of the curve on the low-temperature side on the leading edge of the melting peak is maximum.

[0063] The extrapolated onset temperature and melting point measured by thermal analysis of a crystal may have some measurement error depending on the measuring equipment or the measurement conditions. Specifically, the measurement error may be within a range of ±2.0°C. The extrapolated onset temperature and melting point values ​​including the measurement error may be expressed with the word "approximately" added.

[0064] For values ​​other than the above measurement error, the term "about" used herein means an estimate that the true value is within ±5% of the quoted value.

[0065] (Crystals of the Present Invention) 1. Form A Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form A crystal.

[0066] Form A crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated as having Form A crystals.

[0067] (a) It can be produced by adding a miscible antisolvent to compound (I) dissolved in a solvent, thereby causing crystallization. Here, the solvent / antisolvent system is selected from the group consisting of (i) 2-propanol / water, (ii) acetonitrile / toluene, (iii) cyclohexanone / diisopropyl ether, (iv) ethanol / diisopropyl ether, (v) ethanol / heptane, (vi) 2-butanol / diisopropyl ether, (vii) 2-butanol / heptane, (viii) ethyl acetate / diisopropyl ether, (ix) ethyl acetate / heptane, (x) acetone / diisopropyl ether, and (x) acetone / heptane, and among these, ethyl acetate / diisopropyl ether is preferred. (b) Seed crystals of type A crystals may be added during the crystallization in (a) above. (c) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of the Type A crystal of Compound (I): (1) about 10.6°, about 11.9°, and about 13.7°, (2) about 10.6°, about 11.9°, about 13.7°, about 15.7°, about 25.4°, and about 26.0°, (3) about 10.6°, about 11.9°, about 13.7°, about 15.7°, about 18.2°, about 19.2°, about 20.3°, about 25.4°, about 26.0°, and about 27.6°, or (4) those shown in Table 7 below:

[0068]

[0069] (d) When subjected to DSC measurement, the enthalpy of the endothermic peak is about 71.9 J / g, and the extrapolated onset temperature is about 155.7°C. (e) According to TG-DTA measurement, the melting point is about 157°C.

[0070] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 10.6±0.2°, 11.9±0.2°, 13.7±0.2°, 15.7±0.2°, 19.2±0.2°, 25.4±0.2°, and 26.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 20.3±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 27.6±0.2°. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0071] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0072] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 156°C.

[0073] 2. Form B Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form B Crystal.

[0074] Type B crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of Type B crystals.

[0075] (a) They can be produced by adding a miscible antisolvent to Compound (I) dissolved in a solvent, thereby causing crystallization. Here, the solvent / antisolvent system is selected from the group consisting of (i) 2-propanol / water, (ii) tetrahydrofuran / water, and (iii) acetonitrile / water. (b) Type B crystals of Compound (I) can be produced by adding water at 30°C to Type F crystals of Compound (I) dissolved in n-propanol, thereby causing crystallization. (c) Type B crystals of Compound (I) can also be produced by heating an acetonitrile / water suspension of Type I crystals of Compound (I) from 10°C to 35°C over 20 minutes. (d) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of the type B crystal of compound (I): (1) about 5.2°, about 5.9°, and about 7.4°, (2) about 4.5°, about 5.2°, about 5.9°, about 7.4°, and about 22.2°, or (3) those shown in Table 8 below:

[0076]

[0077] (e) According to TG-DTA measurement, the melting point is about 132°C.

[0078] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 4.5±0.2°, 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 8.3±0.2°, and 22.2±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 23.1±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 19.7±0.2°. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 20%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 10%.

[0079] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0080] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 132°C.

[0081] 3. Form C Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), herein referred to as Form C Crystal, which is the most stable crystalline form of Compound (I) at room temperature.

[0082] Form C crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of form C crystals.

[0083] (a) Type C crystals can be produced by adding a miscible antisolvent to compound (I) dissolved in a solvent, causing crystallization. Here, the solvent / antisolvent system is acetone / heptane. Various types and combinations of solvent / antisolvent systems and their mixing ratios were investigated, and only one of 96 conditions yielded type C crystals. However, even with the same solvent / antisolvent combination, type A crystals, type D crystals, and / or type F crystals may crystallize depending on the mixing ratio, resulting in low reproducibility and yield of this production method. (b) Type C crystals of Compound (I) can also be produced by suspending type D crystals of Compound (I) in a solvent selected from the group consisting of (i) dimethyl sulfoxide / water, (ii) methanol / water, (iii) 2-propanol / water, (iv) methanol / toluene, (v) ethanol / heptane, (vi) acetone / heptane, (vii) ethanol / water, (viii) acetone / water, (ix) 1,2-dimethoxyethane / water, (x) ethanol, and (x) acetone, followed by suspension washing at room temperature for a long period (1 month). Seed crystals of type C crystals may be added during suspension washing. (c) Type C crystals of Compound (I) can also be produced by suspending and stirring type F crystals of Compound (I) in ethanol / water at room temperature without adding seed crystals of type C crystals. (d) In order to obtain C-type crystals of compound (I) with good yield, purity, and reproducibility, it is preferable to produce them by the production method described below (hereinafter, sometimes referred to as the "production method of the present invention"). (e) In one embodiment of C-type crystals of compound (I), the following diffraction angles (2θ) were measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) about 6.7°, about 8.1°, and about 13.7°, (2) about 6.7°, about 8.1°, about 13.4°, about 13.7°, and about 15.7°, (3) about 6.7°, about 8.1°, about 13.4°, about 13.7°, about 15.7°, about 16.4°, and about 18.3°, (4) about 6.7°, about 8.1°, about 13.4°, about 13.7°, about 15.7°, about 16.4°, about 18.3°, about 21.5°, about 21.8°, about 23.2°, about 25.5°, about 27.3°, and about 30.3°, or (5) Table 9 below:

[0084]

[0085] (f) In differential scanning calorimetry (DSC), the extrapolated onset temperature is approximately 172°C, and the enthalpy of the endothermic peak is approximately 83.9 J / g. (g) According to TG-DTA measurement, the melting point is approximately 172°C. (h) Even when type C crystals were suspended in various solvents (including good solvent / poor solvent systems) and washed with suspension for a long period (1 month), no transition to other crystalline forms was observed, confirming that they are the most stable crystalline form at room temperature.

[0086] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 6.7±0.2°, 8.1±0.2°, 15.7±0.2°, 21.5±0.2°, 21.8±0.2°, 25.5±0.2°, and 27.3±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 13.7±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 16.4±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 21.2±0.2°. In certain embodiments, the relative intensity of the peaks at said diffraction angles (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0087] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0088] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 172° C. In certain embodiments, the crystalline compound has a differential scanning calorimetry curve substantially identical to that shown in FIG.

[0089] 4. Form D Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), herein referred to as Form D. Form D crystal is a metastable crystalline form of Compound (I).

[0090] Form D crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated as having form D crystals.

[0091] (a) Type D crystals can be produced by adding a miscible antisolvent to Compound (I) dissolved in a solvent and crystallizing it. Here, the solvent / antisolvent system is acetone / heptane. However, even with the same solvent / antisolvent combination, type A crystals and / or type C crystals may crystallize depending on the mixing ratio, so the reproducibility and yield of this production method are low. (b) Type D crystals of Compound (I) can also be produced by suspending type A crystals or type E crystals of Compound (I) together with seed crystals of type D crystals in ethyl acetate at room temperature and suspending and washing them. (c) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of the D-type crystal of Compound (I): (1) about 7.6°, about 9.1°, and about 13.0°, (2) about 5.5°, about 7.6°, about 9.1°, about 13.0°, and about 15.9°, (3) about 5.5°, about 7.6°, about 9.1°, about 13.0°, about 15.9°, about 17.8°, and about 19.6°, (4) about 5.5°, about 7.6°, about 9.1°, about 13.0°, about 15.9°, about 17.8°, about 19.6°, about 20.3°, 21.9°, 23.8°, and 25.3°, or (5) the angles shown in Table 10 below:

[0092]

[0093] (d) In differential scanning calorimetry (DSC), the extrapolated onset temperature is approximately 158°C, and the enthalpy of the endothermic peak is approximately 72.1 J / g. (e) According to TG-DTA measurement, the melting point is 158.1°C to 163.1°C. (f) Type D crystals were obtained by stirring type A crystals or type E crystals together with seed crystals of type D crystals in ethyl acetate at room temperature. Furthermore, as described above, when type D crystals are suspended in a solvent selected from the group consisting of (i) dimethyl sulfoxide / water, (ii) methanol / water, (iii) 2-propanol / water, (iv) methanol / toluene, (v) ethanol / heptane, (vi) acetone / heptane, (vii) ethanol / water, (viii) acetone / water, (ix) 1,2-dimethoxyethane / water, (x) ethanol, and (x) acetone, and then subjected to suspension washing at room temperature for a long period (1 month), they are transformed into type C crystals, and it has been confirmed that type D crystals are a metastable crystal form that is more stable than type A crystals and type E crystals at room temperature and less stable than type C crystals.

[0094] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 7.6±0.2°, 9.1±0.2°, 13.0±0.2°, 17.8±0.2°, 19.6±0.2°, and 21.9±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 15.9±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 28.2±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 25.3±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 5.5±0.2°. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 30%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 20%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 10%.

[0095] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0096] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 158°C.

[0097] 5. Form E Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form E Crystal.

[0098] Form E crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of Form E crystals.

[0099] (a) Type E crystals can be produced by adding a miscible antisolvent to compound (I) dissolved in a solvent, stirring at room temperature, and crystallizing. Here, the solvent / antisolvent system is dimethyl sulfoxide / toluene. Since approximately 0.5 equivalents of dimethyl sulfoxide remained in type E crystals even after drying under reduced pressure, they are presumed to be dimethyl sulfoxide solvates. (b) One embodiment of type E crystals of compound (I) exhibits the following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) approximately 10.0°, approximately 18.3°, and approximately 18.6°; (2) approximately 6.1°, approximately 7.0°, approximately 8.4°, approximately 10.0°, approximately 10.6°, approximately 18.3°, and approximately 18.6°; or (3) Table 11 below:

[0100]

[0101] (c) According to TG-DTA measurement, the melting point is about 124°C.

[0102] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 8.4±0.2°, 10.0±0.2°, 10.6±0.2°, 18.3±0.2°, 18.6±0.2°, 21.0±0.2°, and 22.1±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 7.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 20.2±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 21.5±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 24.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 26.7±0.2°. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 15%.

[0103] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0104] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 124°C.

[0105] 6. Form F Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form F Crystal.

[0106] Form F crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicative of the presence of Form F crystals.

[0107] (a) Type F crystals can be produced by adding acetone to Compound (I) to cause crystallization. (b) Type F crystals of Compound (I) can also be produced by suspending Type G crystals or Type I crystals of Compound (I) in ethanol / water at 30°C and suspending and washing them. (c) Type I crystals of Compound (I) can be crystallized in a water-containing acetonitrile system, and the crystallization solution can be transformed into Type F crystals (acetonitrile solvate) by heating the crystallization solution to 35°C. (d) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of the F-type crystal of Compound (I): (1) about 4.5°, about 8.8°, and about 9.1°, (2) about 4.5°, about 8.8°, about 9.1°, about 11.2°, and about 17.4°, (3) about 4.5°, about 8.8°, about 9.1°, about 11.2°, about 17.4°, about 17.7°, and about 19.0°, (4) about 4.5°, about 8.8°, about 9.1°, about 11.2°, about 17.4°, about 17.7°, about 19.0°, about 20.0°, about 21.2°, and about 24.5°, or (5) the angles shown in Table 12 below:

[0108]

[0109] (e) According to TG-DTA measurement, the melting point is about 124°C.

[0110] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 4.5±0.2°, 8.8±0.2°, 9.1±0.2°, 17.4±0.2°, 21.2±0.2°, and 23.9±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 11.2±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 17.7±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 19.0±0.2°. In certain embodiments, the relative intensities of the peaks at the diffraction angles (2θ) are at least 20%. In certain embodiments, the relative intensities of the peaks at the diffraction angles (2θ) are at least 15%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 10%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 7%.

[0111] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0112] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 124° C. In certain embodiments, Form F crystals are an acetonitrile solvate.

[0113] 7. Form G Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form G crystal.

[0114] Form G crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicative of the presence of form G crystals.

[0115] (a) The G-type crystal can be produced by drying the F-type crystal of Compound (I) under reduced pressure. (b) As one embodiment of the G-type crystal of Compound (I), the following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) about 4.6°, about 5.1°, and about 8.5°, (2) about 4.6°, about 5.1°, about 8.0°, about 8.5°, about 17.6°, and about 18.1°, or (3) Table 13 below:

[0116]

[0117] (c) According to TG-DTA measurement, the melting point is about 119°C.

[0118] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 4.6±0.2°, 5.1±0.2°, 8.0±0.2°, 8.5±0.2°, 17.6±0.2°, and 8.2±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 6.6±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 16.4±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 20.6±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 21.1±0.2°. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 20%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 10%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 7%.

[0119] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0120] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 119°C.

[0121] 8. Form H Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form H Crystal.

[0122] Form H crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of form H crystals.

[0123] (a) Form H crystals can be produced by crystallizing Compound (I) with the addition of tert-butyl methyl ether (TBME). (b) Form H crystals of Compound (I) can also be produced by suspending Form F crystals of Compound (I) in heptane or TBME / heptane and then suspension washing. (c) Form H crystals of Compound (I) can also be produced by suspending Form I crystals of Compound (I) in ethanol / water or N-methyl-2-pyrrolidone / water and then suspension washing. (d) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of the H-type crystal of Compound (I): (1) about 8.5, about 13.4, and about 21.2°, (2) about 8.5, about 13.4, about 15.4, about 15.5, and about 21.2°, (3) about 8.5, about 13.4, about 15.4, about 15.5, about 18.1, about 19.8, about 21.2, about 23.3, about 23.5, and about 26.0°, or (4) those shown in Table 14 below:

[0124]

[0125] (e) In differential scanning calorimetry (DSC), the crystal exhibits an extrapolated onset temperature of approximately 159°C, and the enthalpy of the endothermic peak is approximately 71.0 J / g to 75.7 J / g. (f) In TG-DTA, the melting point is approximately 161°C.

[0126] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 8.5±0.2°, 13.4±0.2°, 15.4±0.2°, 15.5±0.2°, 18.1±0.2°, 21.2±0.2°, and 26.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 19.8±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 23.3±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 23.5±0.2°. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0127] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0128] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 159°C.

[0129] 9. Form I Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), herein referred to as Form I. Form I crystal is obtained as an acetic acid solvate.

[0130] Form I crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of Form I crystals.

[0131] (a) Form I crystals can be produced by adding acetic acid / isopropyl acetate to compound (I) to cause crystallization. (b) Form I crystals of compound (I) are preferably produced by the production method of the present invention described below in order to obtain them in good yield, purity, and reproducibility. (c) The following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å) for one embodiment of Form I crystals of Compound (I): (1) about 5.3°, about 7.0°, and about 13.1°, (2) about 5.3°, about 7.0°, about 7.4°, about 10.8°, and about 13.1°, (3) about 5.3°, about 7.0°, about 7.4°, about 10.8°, about 13.1°, about 16.2°, and about 18.8°, (4) about 5.3°, about 7.0°, about 7.4°, about 10.8°, about 13.1°, about 16.2°, about 18.8°, about 20.0°, about 21.6°, about 22.1°, and about 29.5°, or (5) the angles shown in Table 15 below:

[0132]

[0133] (d) According to TG-DTA measurement, the melting point is about 112°C.

[0134] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 5.3±0.2°, 13.1±0.2°, 16.2±0.2°, 18.8±0.2°, 20.1±0.2°, 21.6±0.2°, and 22.1±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 7.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 29.5±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 10.8±0.2°. In certain embodiments, the relative intensity of the peaks at said diffraction angles (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0135] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0136] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 112°C.

[0137] 10. Form J Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form J Crystal.

[0138] Form J crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicative of the presence of form J crystals.

[0139] (a) Compound (I) can be crystallized with isopropyl acetate to produce type J crystals. (b) Compound (I) can also be crystallized with methyl isobutyl ketone (MIBK) to produce type J crystals. (c) One embodiment of type J crystals of Compound (I) exhibits the following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) about 11.9°, about 15.3°, and about 18.7°; (2) about 9.4°, about 11.9°, about 15.3°, about 18.7°, and about 22.6°; or (3) Table 16 below:

[0140]

[0141] (d) In differential scanning calorimetry (DSC), the extrapolated onset temperature is approximately 179°C, and the enthalpy of the endothermic peak is approximately 69.1 J / g to 70.7 J / g. (e) According to TG-DTA measurement, the melting point is approximately 180°C. (f) When the type A crystal or the type D crystal was heated at 160°C to 175°C and melted, the type J crystal was obtained, confirming that the type J crystal of compound (I) is a high-temperature stable form.

[0142] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 9.4±0.2°, 11.9±0.2°, 15.3±0.2°, 18.7±0.2°, 21.5±0.2°, 22.6±0.2°, and 25.7±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 15.5±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 20.0±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 21.4±0.2°. In certain embodiments, the relative intensity of the peak at said diffraction angle (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0143] In certain embodiments, the powder X-ray diffraction pattern is substantially as shown in FIG.

[0144] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 179°C.

[0145] 11. Form K Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form K Crystal.

[0146] Form K crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of form K crystals.

[0147] (a) By crystallizing type A crystals of compound (I) from ethanol / water, type K crystals can be obtained as a mixture with type C crystals. (b) In one embodiment, type K crystals of compound (I) have the following diffraction angles (2θ) measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) about 6.5°, about 22.9°, and about 25.8°, (2) about 6.5°, about 17.1°, about 17.5°, about 22.9°, about 24.3°, and about 25.8°, or (3) Table 17 below:

[0148]

[0149] (c) According to TG-DTA measurement, the melting point is about 142°C (and about 170°C (C-type crystals)).

[0150] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 6.5±0.2°, 17.5±0.2°, 19.1±0.2°, 20.1±0.2°, 22.9±0.2°, 24.3±0.2°, and 25.8±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 8.1±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 15.6±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 17.9±0.2°. In certain embodiments, the relative intensity of the peaks at said diffraction angles (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0151] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 142°C.

[0152] 12. Form L Crystal In one embodiment, the present invention relates to a polymorph of Compound (I), referred to herein as Form L Crystal.

[0153] Form L crystals may be characterized as having one or more of the following physicochemical properties, although it is noted that a composition need not necessarily exhibit all of these properties to be indicated by the presence of form L crystals.

[0154] (a) The L-type crystal of compound (I) can be obtained as a mixture with the C-type crystal by heating and drying a mixed crystal of the K-type crystal and the C-type crystal. (b) As one embodiment of the L-type crystal of compound (I) (mixture with the C-type crystal), the following diffraction angles (2θ) were measured by powder X-ray diffraction (CuKα, λ=1.5418 Å): (1) about 15.1°, about 17.6°, and about 22.5°, (2) about 7.5°, about 12.1°, about 15.1°, about 17.6°, and about 22.5°, or (3) Table 18 below:

[0155]

[0156] (c) According to TG-DTA measurement, the melting point is about 143°C (and about 170°C (C-type crystals)).

[0157] In one aspect, the present invention provides crystalline Compound (I) exhibiting a powder X-ray diffraction pattern having diffraction peaks at the following diffraction angles (2θ): 6.7±0.2°, 7.5±0.2°, 13.5±0.2°, 15.1±0.2°, 17.6±0.2°, 20.3±0.2°, and 22.5±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 16.6±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 21.1±0.2°. In certain embodiments, the powder X-ray diffraction pattern further has a diffraction peak at the following diffraction angle (2θ): 24.2±0.2°. In certain embodiments, the relative intensity of the peaks at said diffraction angles (2θ) is at least 35%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 25%. In certain embodiments, the relative intensity of the peak at the diffraction angle (2θ) is at least 15%.

[0158] In certain embodiments, the crystalline compound has a melting point onset as determined by differential scanning calorimetry of about 143°C.

[0159] 13. Additional Characterization of Crystal Form The crystals of compound (I) of the present invention may be any of type A crystals, type B crystals, type C crystals, type D crystals, type E crystals, type F crystals, type G crystals, type H crystals, type I crystals, type J crystals, type K crystals, and type L crystals, or may be mixed crystals containing type C crystals and / or type D crystals. When compound (I) is used in pharmaceuticals, etc., type C crystals or type D crystals of compound (I) are preferred in terms of being stable crystals, and type C crystals of compound (I) are more preferred in terms of being the most stable crystals.

[0160] In the present invention, "crystal purity" means the ratio (purity) of a specific crystalline form of Compound (I) to the total amount of crystals of Compound (I). The purity of the crystals of the present invention can be determined by known methods such as powder X-ray diffraction measurement and thermal analysis. The purity of the crystals or mixed crystals of the present invention does not necessarily have to be 100% pure, but is 70% or more, preferably 80% or more, more preferably 90% or more, even more preferably 95% or more, and most preferably 98% or more. A purity within this range is preferable in terms of ensuring quality as a pharmaceutical product.

[0161] Compound (I) of the present invention may contain one or more isotopes (e.g., ３ H. ２ H. １４ C. ３５ For example, any one or more of the groups in compound (I) may be labeled with S. １ H ２ Deuterium-converted derivatives converted to H(D) are also encompassed in the compounds of the present invention.

[0162] (Acetic Acid Solvate of (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide) Another aspect of the present invention provides an acetic acid solvate of (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide. In certain embodiments, the molar ratio of acetic acid to (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide is about 1: 1. In certain embodiments, the molar ratio of acetic acid to (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide is at least 1: 1. In certain embodiments, the solvate is crystalline.

[0163] (Acetonitrile solvate of (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide) Another aspect of the present invention provides an acetonitrile solvate of (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide. In certain embodiments, the molar ratio of acetonitrile to (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide is about 1: 1. In certain embodiments, the molar ratio of acetonitrile to (2R)-N-benzyl-1-[5-(2-fluoropropan-2yl)-7oxo-6,7dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide is at least 1: 1. In certain embodiments, the solvate is crystalline.

[0164] (Method for producing the crystal of the present invention) Examples of methods for producing each crystalline form of the present invention include, but are not limited to, a production method comprising a step of stirring compound (I) obtained by the method described in Example 482 of WO 2015 / 163339 according to the production method of each of the above-mentioned crystalline forms, a step of dissolving compound (I) in a solvent and then crystallizing it, a step of concentrating a solution of compound (I) and crystallizing it, and / or a step of solidifying compound (I) from a molten state, as well as a production method in which seed crystals of each crystalline form are added to these methods. In particular, the following production method (hereinafter also referred to as the "production method of the present invention") is particularly preferred because it is the most stable crystalline form at room temperature, and therefore can produce type C crystals suitable as a drug substance for compound (I) with high yield, high purity, and good reproducibility, and can also be scaled up.

[0165] That is, the production method of the present invention comprises: (a) reacting a compound represented by formula (1):

[0166]

[0167] is reacted with D-proline in the presence of a base to obtain a compound represented by formula (2):

[0168]

[0169] (b) amidating the compound of formula (2) by reacting it with benzylamine in the presence of a condensing agent and a base, and then adding acetic acid at 5°C to 15°C, stirring at the same temperature, and crystallizing to obtain type I crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (compound (I)); (c) dissolving the type I crystals in a mixed solvent of acetonitrile / water at an internal temperature of 40°C to 55°C, followed by cooling to 5°C to 25°C, stirring, and crystallizing, thereby converting them into type F crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (compound (I)); and (d) dissolving the F-type crystals in an ethanol / water mixed solvent at an internal temperature of 30°C to 45°C, followed by cooling to 5°C to 15°C, stirring, and crystallization to convert them into C-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (Compound (I)). Each step is described in detail below.

[0170] (Step (a)) Step (a) can be carried out in a solvent that does not affect the reaction, in the presence of a base. The reaction solvent is not particularly limited, but examples thereof include amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; and mixtures thereof, with N-methylpyrrolidone being preferred. The base is not particularly limited, but examples thereof include organic bases such as triethylamine, pyridine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), with DBU being preferred. The amount of base used is 1 to 5 moles, preferably 2 to 4 moles, per mole of the compound of formula (1). The reaction temperature is 20°C to 50°C.

[0171] (Step (b)) Step (b) is a step in which compound (I) is converted to compound (I) by reacting with benzylamine in the presence of a condensing agent and a base in a solvent that does not affect the reaction, and then acetic acid is added, followed by stirring and crystallization to obtain type I crystals of compound (I). The reaction solvent is not particularly limited, but examples thereof include amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; ethers such as diethyl ether, tetrahydrofuran, and dioxane; nitriles such as acetonitrile; and mixtures thereof, with acetonitrile being preferred. The condensing agent may be any condensing agent that is commonly used in the amidation reaction of a carboxylic acid with an amine, and examples thereof include 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (WSC hydrochloride), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino.morpholino.carbenium hexafluorophosphate (COMU), ethyl (hydroxyimino)cyanoacetate (Oxyma), O-(benzoto O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (propylphosphonic anhydride; T3P), and the like are exemplified, with T3P being preferred.The condensing agent can also be used together with conventional additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine. The amount of the condensing agent used is typically 1 to 5 moles, preferably 1.2 to 2 moles, per mole of the compound of formula (2). The base is not particularly limited, but examples include organic bases such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and pyridine, with N,N-diisopropylethylamine being particularly preferred. The amount of the base used is 1 to 5 moles, preferably 2 to 4 moles, per mole of the compound of formula (2). The amount of acetic acid added is 0.3 to 1.5, preferably 0.5 to 1, per 1 volume of the reaction solution. The crystallization (crystallization) temperature of the type I crystal of compound (I) is 0° C. to 20° C., preferably 5° C. to 15° C. During the crystallization of the type I crystal of compound (I) in step (b), a seed crystal of type I crystal separately prepared may be added.

[0172] (Step (c)) Step (c) is a step of converting the type I crystals of compound (I) obtained in step (b) into type F crystals of compound (I) by dissolving them in an acetonitrile / water mixed solvent at an internal temperature of 40°C to 55°C, cooling to 5°C to 25°C (target temperature: about 10°C), stirring, and crystallizing. The acetonitrile / water mixed solvent has a volume ratio of acetonitrile:water of usually 5:1 to 2:1, preferably 4:1 to 3:1. During the transformation of compound (I) into type F crystals in step (c), separately prepared seed crystals of type F crystals may be added.

[0173] (Step (d)) Step (d) is a step of converting the F-type crystals of compound (I) obtained in step (c) into C-type crystals of compound (I) by dissolving them in an ethanol / water mixed solvent at an internal temperature of 30°C to 45°C (target 40°C to 45°C), cooling to 5°C to 15°C (target 5°C to 10°C), stirring, and crystallizing them. The ethanol / water mixed solvent has a volume ratio of ethanol:water of usually 1:5 to 1:2, preferably 1:3. During the transformation of compound (I) into C-type crystals in step (d), separately prepared seed crystals of C-type crystals may be added.

[0174] The production method of the present invention is characterized in that impurities can be easily removed by going through the type I crystal of compound (I), and as a result, type C crystal can be obtained in high yield and with high purity and with good reproducibility.

[0175] The type C crystals obtained in step (d) can be crushed in a power mill to obtain the drug substance of compound (I).

[0176] In the present invention, it is possible to obtain mixed crystals containing C-type crystals and crystals of other forms in any ratio, and for example, they can be prepared by mixing pure C-type crystals and crystals of other forms obtained by the above-mentioned production method to a desired ratio.

[0177] (Pharmaceutical Composition of the Present Invention) In a pharmaceutical composition containing the crystal of the present invention as an active ingredient (hereinafter also referred to as "pharmaceutical composition of the present invention"), the content ratio of the C-type crystals and other forms of crystals as the pharmaceutically active ingredient, Compound (I), is not particularly limited, but for example, a pharmaceutical composition produced using a drug substance containing about 75% or more of the C-type crystals of the present invention is preferred. Also, a pharmaceutical composition produced using a drug substance containing about 85% or more of the C-type crystals is more preferred, and a pharmaceutical composition produced using a drug substance containing about 98% or more of the C-type crystals is most preferred.

[0178] In another embodiment of the pharmaceutical composition of the present invention, when the crystal of the present invention is used as a medicine, the crystal of the present invention (e.g., type C crystal or type D crystal) itself may be administered alone, but it is preferable to prepare a pharmaceutical composition containing the crystal as an active ingredient using a pharmaceutically acceptable carrier and administer the same. The composition of the pharmaceutical composition is determined by the solubility, chemical properties, administration route, administration schedule, etc. of the crystal. Examples of "pharmaceutical compositions" include mixtures of one or more pharmaceutically active ingredients, including at least the crystal of the present invention, with one or more pharmaceutically acceptable carriers, such as oral preparations such as tablets, capsules, granules, fine granules, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations. Oral preparations such as granules, fine granules, powders, capsules, and tablets are preferred. Therefore, one embodiment of the present invention is a pharmaceutical composition comprising the crystalline Compound (I) described herein and one or more pharmaceutically acceptable carriers.

[0179] The pharmaceutical composition of the present invention is produced by appropriately mixing a suitable amount of the crystal of Compound (I) of the present invention with at least one or more pharmaceutically acceptable carriers, etc., according to a method known per se in the technical field of pharmaceutical formulation. The content of the compound or crystal of the present invention in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the total composition, preferably 0.1 to 70% by weight.

[0180] The "pharmaceutically acceptable carrier" includes various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid formulations, or solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, and fragrances may be used as needed. The above formulations can be prepared according to conventional methods.

[0181] Since the crystals of the present invention have excellent KAT2 inhibitory activity, the pharmaceutical composition of the present invention is useful for the treatment or prevention of diseases or symptoms (e.g., dementia, depression, stress vulnerability) whose pathology is expected to be improved by inhibiting KAT2, i.e., inhibiting KAT2 enzyme activity. Specific examples of such diseases or symptoms include schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive dysfunction, dementia, depression, stress vulnerability, etc. The pharmaceutical composition of the present invention is particularly suitable for the treatment or prevention of schizophrenia, attention-deficit / hyperactivity disorder, Alzheimer's disease, or major depression, and is particularly useful for the treatment or prevention of schizophrenia.

[0182] The dosage of the pharmaceutical composition of the present invention is determined taking into consideration age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, type of concomitant medication, and the severity of the patient's current medical condition, as well as other factors. The daily dosage of the crystals of the present invention varies depending on the patient's condition and body weight, type of compound, and administration route, but for example, in the case of oral administration, it is typically about 0.001 mg / kg / day to 500 mg / kg / day, preferably 0.01 mg / kg / day to 50 mg / kg / day or 0.01 mg / kg / day to 10 mg / kg / day. In some embodiments, the daily dosage ranges from 0.1 mg / kg / day to 50 mg / kg / day. In other embodiments, the daily dosage ranges from 0.1 mg / kg / day to 10 mg / kg / day. These amounts can be administered once or in divided doses.

[0183] As used herein, the term "pharmaceutically effective amount" refers to a dose of an active ingredient sufficient to achieve therapeutic objectives such as curing a disease, improving the pathology of a disease (e.g., improving or alleviating one or more symptoms of a disease), and inhibiting the progression (of the severity) of a disease, and is also referred to as a "therapeutically effective amount" when used for treatment. The "amount" in "therapeutically effective amount" can be replaced with the above-mentioned "dosage."

[0184] As used herein, "prevention" includes preventing the onset of a disease, delaying the onset of a disease, and preventing the development of a pathological condition.

[0185] As used herein, "treatment" includes curing a disease, ameliorating the pathological condition of a disease (e.g., improving or alleviating one or more symptoms), and inhibiting the progression (of the severity) of a disease. "Amelioration" is a concept encompassed by "treatment."

[0186] As used herein, the term "subject" refers to a subject to which a pharmaceutical (pharmaceutical composition) containing an effective amount of an active ingredient is administered to prevent and / or treat (or improve) a disease or the pathology of a disease. The "subject" includes humans and non-human animals (particularly mammals (e.g., mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.)).

[0187] Therapeutic Methods of the Invention Another aspect of the present invention provides a method of treating a KAT2-associated disease, the method comprising administering to a subject in need thereof a pharmaceutically effective amount (therapeutically effective amount) of crystalline Compound (I) or a pharmaceutical composition described herein to treat the disease.

[0188] Another aspect of the present invention provides a method of treating a KAT2-associated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein) to treat the disease. Note that throughout this specification, the terms "comprising" and "consisting" are used interchangeably.

[0189] Another aspect of the present invention provides a method of treating dementia, the method comprising administering a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form described herein or in a pharmaceutical composition described herein) to a subject in need thereof to treat the disease. In one embodiment, the cognitive impairment is associated with (and the patient has been diagnosed with) a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0190] In one embodiment, the disease is schizophrenia.

[0191] In one embodiment, the disease is bipolar disorder.

[0192] In one embodiment, the disease is attention-deficit / hyperactivity disorder.

[0193] In one embodiment, the disease is Alzheimer's disease.

[0194] In one embodiment, the disorder is major depression.

[0195] In one embodiment, the disease is autism.

[0196] In one embodiment, the disease is vascular dementia.

[0197] In one embodiment, the disease is HIV encephalopathy.

[0198] In one embodiment, the disease is age-related cognitive impairment.

[0199] In one embodiment, the disease is dementia.

[0200] In one embodiment, the disorder is depression.

[0201] In one embodiment, the condition is stress vulnerability.

[0202] Another aspect of the present invention provides a method of treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability, comprising administering to a subject in need thereof a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, for example, in a crystalline form described herein or in a pharmaceutical composition described herein) to treat the disease.

[0203] Another aspect of the present invention provides a method of treating cognitive impairment associated with schizophrenia (CIAS), comprising administering to a subject in need thereof a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein) to treat the disease.

[0204] In one embodiment, the treatment reduces the concentration of kynurenic acid (KYNA) in the subject's cerebrospinal fluid (CSF) by at least 40%. In one embodiment, the treatment enhances glutamate signaling and / or acetylcholine signaling, as measured by an increase in gamma wave amplitude and the ratio of alpha wave amplitude to beta wave amplitude (beta / alpha ratio). In one embodiment, the treatment increases the concentration of glutamate in the subject's CSF relative to pre-treatment.

[0205] Another aspect of the present invention provides a method for treating cognitive impairment, comprising administering to a subject in need thereof a pharmaceutically effective amount (therapeutically effective amount) of a crystal of Compound (I) as described herein, or a pharmaceutically effective amount of a pharmaceutical composition as described herein, to treat the disease.

[0206] In one embodiment, the cognitive impairment is associated with (i.e., the patient has been diagnosed with) a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0207] In one embodiment, the disease is schizophrenia.

[0208] In one embodiment, the disease is bipolar disorder.

[0209] In one embodiment, the disease is attention-deficit / hyperactivity disorder.

[0210] In one embodiment, the disease is Alzheimer's disease.

[0211] In one embodiment, the disorder is major depression.

[0212] In one embodiment, the disease is autism.

[0213] In one embodiment, the disease is vascular dementia.

[0214] In one embodiment, the disease is HIV encephalopathy.

[0215] In one embodiment, the disease is age-related cognitive impairment.

[0216] In one embodiment, the disease is dementia.

[0217] In one embodiment, the disorder is depression.

[0218] In one embodiment, the condition is stress vulnerability.

[0219] Another aspect of the present invention provides a method of treating cognitive impairment associated with schizophrenia (CIAS), comprising administering to a subject in need thereof a pharmaceutically effective amount (therapeutically effective amount) of a crystal of Compound (I) as described herein, or a pharmaceutically effective amount of a pharmaceutical composition as described herein, to treat the disease.

[0220] In one embodiment, the treatment reduces the concentration of kynurenic acid (KYNA) in the cerebrospinal fluid (CSF) by at least 40%. In one embodiment, the treatment enhances glutamate signaling and / or acetylcholine signaling, as measured by an increase in gamma wave amplitude and the ratio of alpha wave amplitude to beta wave amplitude (beta / alpha ratio). In one embodiment, the treatment increases the concentration of glutamate in the subject's CSF relative to pre-treatment.

[0221] Another aspect of the present invention provides a method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, the method comprising administering a pharmaceutically effective amount (therapeutically effective amount) of the crystalline Compound (I) described herein or the pharmaceutical composition described herein to a subject in need thereof to treat the disease.

[0222] In certain embodiments, the disease is schizophrenia.

[0223] In certain embodiments, the disease is bipolar disorder.

[0224] In certain embodiments, the disease is attention-deficit / hyperactivity disorder.

[0225] In certain embodiments, the disease is Alzheimer's disease.

[0226] In certain embodiments, the disorder is major depression.

[0227] In certain embodiments, the disease is autism.

[0228] In certain embodiments, the disease is vascular dementia.

[0229] In certain embodiments, the disease is HIV encephalopathy.

[0230] In certain embodiments, the disease is age-related cognitive impairment.

[0231] In certain embodiments, the disease is dementia.

[0232] In certain embodiments, the disease is depression.

[0233] In certain embodiments, the condition is stress vulnerability.

[0234] Yet another aspect of the present invention provides a method of inhibiting KAT2 (including inhibiting KAT2 enzymatic activity), the method comprising contacting KAT2 with crystalline Compound (I) described herein, thereby inhibiting KAT2.

[0235] In certain embodiments, the subject is a human.

[0236] In certain embodiments, the subject is an adult human or a pediatric human.

[0237] Yet another aspect of the present invention provides (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d ]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form described herein or a pharmaceutical composition described herein, or which may be amorphous) for use in a method of treating a KAT2-related disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d ]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form described herein or a pharmaceutical composition described herein, or which may be amorphous) to treat the disorder.

[0238] In one embodiment, the KAT2-related disease is a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0239] Yet another aspect of the present invention provides (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d ]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form described herein or in a pharmaceutical composition described herein) for use in a method for treating cognitive impairment, the method comprising administering to a subject in need thereof a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d ]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form described herein or in a pharmaceutical composition described herein) to treat the disease.

[0240] In one embodiment, the cognitive impairment is associated with (i.e., the patient has been diagnosed with) a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0241] In one embodiment, the disease is schizophrenia.

[0242] In one embodiment, the disease is bipolar disorder.

[0243] In one embodiment, the disease is attention-deficit / hyperactivity disorder.

[0244] In one embodiment, the disease is Alzheimer's disease.

[0245] In one embodiment, the disorder is major depression.

[0246] In one embodiment, the disease is autism.

[0247] In one embodiment, the disease is vascular dementia.

[0248] In one embodiment, the disease is HIV encephalopathy.

[0249] In one embodiment, the disease is age-related cognitive impairment.

[0250] In one embodiment, the disease is dementia.

[0251] In one embodiment, the disorder is depression.

[0252] In one embodiment, the condition is stress vulnerability.

[0253] Yet another aspect of the present invention relates to a compound comprising (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., a compound selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability) for use in a method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability. and (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein, which may be amorphous) to a subject in need thereof to treat the disease.

[0254] Yet another aspect of the present invention provides (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form described herein or a pharmaceutical composition described herein, or which may be amorphous) for use in a method of treating cognitive impairment associated with schizophrenia (CIAS), the method comprising administering to a subject in need thereof a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form described herein or a pharmaceutical composition described herein, or which may be amorphous) to treat the disease.

[0255] In one embodiment, the treatment reduces the concentration of kynurenic acid (KYNA) in the cerebrospinal fluid (CSF) by at least 40%. In one embodiment, the treatment enhances glutamate signaling and / or acetylcholine signaling, as measured by an increase in gamma wave amplitude and the ratio of alpha wave amplitude to beta wave amplitude (beta / alpha ratio). In one embodiment, the treatment increases the concentration of glutamate in the subject's CSF relative to pre-treatment.

[0256] In certain embodiments, the subject is a human.

[0257] In certain embodiments, the subject is an adult human or a pediatric human.

[0258] Yet another aspect of the present invention provides the use of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein) in the manufacture of a medicament for treating a KAT2-associated disorder in a subject in need thereof.

[0259] In one embodiment, the KAT2-related disease is selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0260] Yet another aspect of the present invention provides the use of a pharmaceutically effective dose (therapeutically effective dose) of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (which may be amorphous, e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein) in the manufacture of a medicament for treating a cognitive disorder in a subject in need thereof.

[0261] In one embodiment, the cognitive impairment is associated with (i.e., the patient has been diagnosed with) a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

[0262] In one embodiment, the disease is schizophrenia.

[0263] In one embodiment, the disease is bipolar disorder.

[0264] In one embodiment, the disease is attention-deficit / hyperactivity disorder.

[0265] In one embodiment, the disease is Alzheimer's disease.

[0266] In one embodiment, the disorder is major depression.

[0267] In one embodiment, the disease is autism.

[0268] In one embodiment, the disease is vascular dementia.

[0269] In one embodiment, the disease is HIV encephalopathy.

[0270] In one embodiment, the disease is age-related cognitive impairment.

[0271] In one embodiment, the disease is dementia.

[0272] In one embodiment, the disorder is depression.

[0273] In one embodiment, the condition is stress vulnerability.

[0274] Yet another aspect of the present invention provides the use of a pharmaceutically effective dose (therapeutically effective dose) of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (e.g., in a crystalline form as described herein or in a pharmaceutical composition as described herein, or optionally amorphous) in the manufacture of a medicament for treating cognitive impairment associated with schizophrenia (CIAS) in a subject in need thereof.

[0275] In one embodiment, the medicament reduces the concentration of kynurenic acid (KYNA) in the cerebrospinal fluid (CSF) by at least 40%.

[0276] In another embodiment, the medicament enhances glutamate signaling and / or acetylcholine signaling. Enhancement of these signaling pathways is measured by an increase in the amplitude of gamma waves (gamma power, an EEG biomarker suggestive of glutamatergic signaling) and the ratio of alpha to beta wave amplitudes (beta / alpha ratio, an EEG biomarker suggestive of cholinergic signaling). Increased gamma power and improved beta / alpha ratio reflect specific aspects of cognitive improvement in a subject.

[0277] In another embodiment, the medicament increases glutamate levels in the CSF of the subject compared to glutamate levels in the CSF before treatment.

[0278] In certain embodiments, the subject is a human.

[0279] In certain embodiments, the subject is an adult human or a pediatric human.

[0280] (Combination Therapy of the Present Invention) The compound (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide (including the crystalline form of the present invention, but which may also be amorphous) can be administered in combination with other drugs (concomitant drugs) as long as the efficacy of the compound is not impaired. The concomitant drugs are not particularly limited, and for example, one or more known drugs conventionally used in the treatment of the above-mentioned "diseases or symptoms for which improvement in pathology is expected by inhibition of KAT2" (hereinafter also referred to as "concomitant drugs of the present invention") can be suitably used.

[0281] Specifically, the concomitant drug of the present invention is not particularly limited as long as it is a drug useful for the prevention and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive dysfunction, dementia, depression, and stress vulnerability.

[0282] When a concomitant drug is used, the administration timing is not limited, and they may be administered to the subject simultaneously or at staggered times. Staggered administration may involve administering the pharmaceutical composition of the present invention first and the concomitant drug later, or the concomitant drug first and the pharmaceutical composition of the present invention later. The respective administration methods may be the same or different. Furthermore, the crystal of the present invention (crystalline Compound (I)) and the concomitant drug may be administered in combination as a single formulation (pharmaceutical composition).

[0283] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The mixing ratio of the crystal of the present invention (crystalline Compound (I)) to the concomitant drug can be appropriately selected depending on the subject of administration (subject's age, body weight, general health condition, sex, severity of disease, etc.), administration route, type of disease, type of concomitant drug, etc.

[0284] The mass ratio of the crystal of the present invention (crystalline Compound (I)) to the concomitant drug is not particularly limited.

[0285] Furthermore, concomitant drugs that complement and / or enhance the therapeutic effect of compound (I) also include those that have not been discovered so far but will be discovered in the future, based on the above-mentioned mechanism.

[0286] (Medical Kit of the Present Invention) The pharmaceutical composition of the present invention may be provided in the form of a kit together with instructions for administration and the like. The drugs contained in the kit are supplied in a container made of a material that maintains the activity of the components of the pharmaceutical composition effectively for a long period of time, does not adsorb to the inside of the container, and does not alter the components. For example, a sealed glass ampoule may contain a buffer or the like sealed in the presence of a neutral, non-reactive gas such as nitrogen gas. The kit may also include instructions for use. The instructions for use of the kit may be printed on paper or stored on an electromagnetically readable medium such as a CD-ROM or DVD-ROM and provided to the user.

[0287] An example of a method for producing Compound (I) and its crystals of the present invention will be described below, but these test examples, examples, and formulation examples are merely illustrative and do not limit the present invention. All reagents and solvents used were of commercial quality and were used without further purification. Powder X-ray diffraction analysis was performed using a powder X-ray diffractometer (X'Pert Pro, manufactured by Spectris Inc.). Differential scanning calorimetry was performed using a differential scanning calorimetry (DSC) apparatus (X-DSC7000, manufactured by Hitachi High-Tech Science Corporation). Moisture adsorption / desorption tests were performed using a moisture adsorption analyzer (DVS-1, manufactured by Surface Measurement Systems Limited) or a moisture adsorption analyzer (DVS intrinsic, manufactured by Surface Measurement Systems Limited). Thermogravimetry-differential thermal analysis (TG-DTA) was performed using a TG-DTA measuring device (TG / DTA7200, manufactured by Hitachi High-Tech Science Corporation). Related substances were measured using high-performance liquid chromatography (Class-VP system, manufactured by Shimadzu Corporation). A thermo-hygrostat (IG420, manufactured by Yamato Scientific Co., Ltd.) was used to adjust the temperature during crystallization. A parallel organic synthesis reactor (ChemiStation, manufactured by Tokyo Rikakikai Co., Ltd.) was used for stirring at a constant temperature during crystallization.

[0288] Percentages are by volume for solvents used in chromatography and by weight for others. Other abbreviations used in the text have the following meanings: DMSO: dimethyl sulfoxide THF: tetrahydrofuran MIBK: methyl isobutyl ketone TBME: tert-butyl methyl ether BFPT: 2-bromo-5-(2-fluoropropan-2-yl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one RFPT: (2R)-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxylic acid RFCB: (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide DPRL: D-proline DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene NMP: N-methyl-2-pyrrolidone DIPEA: N,N-diisopropylethylamine BAMI: benzylamine AcOH: acetic acid EtOH: ethanol T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide HPLC: high performance liquid chromatography

[0289] (Analysis methods) 1. Powder X-ray diffraction (XRPD) Powder / solid samples: The sample is placed in the wells of a dedicated SUS well plate (4φmm / well, 96 wells, included with the instrument) with a film (MYLAR (registered trademark) POLYESTER FILM, Chemplex INDUSTRIES, INC) sandwiched between them to form a measurement plate. The amount of sample is enough to fill the film in the well (approximately 1 mg to 2 mg). Suspension residue (using a 96-well filtration plate): The suspension is filtered through a 96-well filtration plate (MILLIPORE MultiScreen (registered trademark) HTS Hi Flow FC), and the drip sheet is removed to form a measurement plate. Suspension residue (using filter paper): The suspension is filtered through filter paper, and the filter paper is fixed to a dedicated SUS well plate (8φmm / well, 48 wells, included with the instrument) to form a measurement plate. Alternatively, the residue on the filter paper is removed and treated as a powder sample. The measurement plate containing the sample is placed on a dedicated HTS sample stage and measured using the transmission method. To reduce orientation, the sample and plate are vibrated by 4 mm. Measurements are also taken five times, with the incident angle shifted by -2, -1, 0, 1, and 2°, and the results are simply integrated. <Operational Conditions> X-ray generator: X-ray tube (anticathode: copper, tube voltage: 45 kV, tube current: 40 mA) Incident optical system: focusing condenser mirror Receiving optical system: high-speed semiconductor array detector (X-Celerator), extended receiving arm Sample stage: HTS sample stage (vibrates 4 mm in the X-axis direction) Number of integrations: 5 (incident angle changed by -2, -1, 0, 1, and 2°) Measurement range: 2θ = 3° to 40° Scan speed: 0.668451° / sec Step: 0.0167°

[0290] 2. Differential Scanning Calorimetry (DSC) An appropriate amount of sample (approximately 2 mg) is filled into an RDC Pan (P / N: 52-023P), and an RDC Pan Cover (P / N: 52-023C) is placed on top and crimped to form a sample pan. Separately, an empty pan is prepared in the same manner. Measurement is performed using the empty pan as a control under the following operating conditions. <Operating conditions> Heating rate: 10 K / min Atmosphere: Nitrogen 40 mL / min

[0291] 3. Thermogravimetry and Differential Thermal Analysis (TG-DTA) An appropriate amount of sample (approximately 4 mg) is placed in an Open Sample Pan φ5 (P / N: SSC000E030) to form a sample pan. Measurements are performed using an empty pan as a control under the following operating conditions. <Operating conditions> Heating rate: 10 K / min Atmosphere: Nitrogen 200 mL / min

[0292] 4. Moisture adsorption / desorption test Moisture adsorption / desorption measurement data was collected using a moisture adsorption measuring device (DVS-1, manufactured by Surface Measurement Systems Limited or DVS intrinsic, manufactured by Surface Measurement Systems Limited). An appropriate amount of sample (approximately 5 mg) was placed in a dedicated cell whose tare weight had been corrected in advance, and the sample was hung on the precision balance of the device to precisely measure the weight at the start of the measurement. The weight change when the humidity was gradually changed according to the measurement conditions was recorded over time, and the equilibrium weight at each humidity was determined. The weight calculated from the amount of moisture at the time of drying (0% RH) or at the start confirmed by another method was used as the anhydrous standard, and the rate of weight change at each humidity, or the hydration number, was determined and expressed as an isothermal adsorption curve.

[0293] 5. Take an appropriate amount (1 μL to 10 μL) of the sample solution for measuring related substances and perform a liquid chromatography test under the following operating conditions to determine the area percentage of each peak. <Operating conditions> Detector: Photodiode array (measurement wavelength 200 nm to 400 nm) Column: Inertsil ODS-3V 4.6 mm i.d. x 150 mm, 3 μm Column temperature: Constant temperature around 40°C Mobile phase A: Water / trifluoroacetic acid mixture (2000:1) Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2000:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 19 below to control the concentration gradient.

[0294]

[0295] Flow rate: 1.0mL / min

[0296] Test Example 1 (Crystal Polymorph Screening: Crystallization Experiment of Compound (I) from Various Solvents) (Test Method) As a result of confirming the solubility of Compound (I) in a single solvent, it was found that Compound (I) was not soluble in TBME, diisopropyl ether, heptane, toluene, or water even when used in an amount 100 times that of the solvent at room temperature (solubility: 10 mg / mL or less). Therefore, in the crystallization experiment, diisopropyl ether, heptane, toluene, or water was selected as a poor solvent. In addition, DMSO, NMP, methanol, ethanol, 2-propanol, 2-butanol, THF, acetonitrile, chloroform, cyclohexanone, ethyl acetate, or acetone was selected as a good solvent. Furthermore, the crystallization conditions of compound (I) were investigated in mixed solvent systems with each good solvent, where the ratio (v / v%) of the poor solvent was diisopropyl ether (30, 50, 70, or 90 v / v%), heptane (30, 50, 70, or 90 v / v%), toluene (50, 70, 90, or 95 v / v%), or water (50, 60, 70, 80, 90, or 95 v / v%) (Table 20).

[0297]

[0298] (Test Results) When ethyl acetate, ethanol, or 2-butanol was used as the good solvent, type A crystals were obtained, but when DMSO, NMP, methanol, or chloroform was used as the good solvent, amorphous compound (I) was obtained. Type B crystals were obtained when a mixed solvent system of THF / water or acetonitrile / water with a specific blending ratio was used. On the other hand, among the above crystallization conditions, type C crystals were obtained only when a mixed solvent system of acetone / heptane (50:50) was used, and type D crystals were obtained only when a mixed solvent system of acetone / heptane (30:70) was used.

[0299] (Preparation of Seed Crystals) Example 1 (Preparation of Type A Crystals of Compound (I)) Approximately 200 mg of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339 was placed in a test tube (2 mL), and ethyl acetate (1 mL) was added. The mixture was stirred overnight (19 hours) in a parallel organic synthesis reactor set to 40°C or 60°C with a stirrer tip and a lid, and then allowed to stand for 4 hours. The supernatant was removed, and the mixture was dried under reduced pressure to obtain Type A crystals of compound (I). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the Type A crystals under the above conditions. The powder X-ray diffraction pattern of the Type A crystals is shown in Figure 1, and the relative intensity, when the peak intensity at a diffraction angle of approximately 13.7° represented by 2θ is set to 100, is shown in Table 7. The TG-DTA measurement results indicated that the melting point was approximately 157°C.

[0300] Example 2 (Preparation of Type B Crystals of Compound (I)) 2-propanol / water (=1 / 1) (0.4 mL) was added to approximately 100 mg of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339, and the mixture was stirred. The supernatant was removed to obtain Type B crystals of Compound (I). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the Type B crystals under the conditions described above. The powder X-ray diffraction pattern of the Type B crystals is shown in FIG. 2, and the relative intensity, where the peak intensity at a diffraction angle of approximately 7.4° represented by 2θ is set to 100, is shown in Table 8. The TG-DTA measurement results indicated that the melting point was approximately 132°C.

[0301] Example 3 (Preparation of C-type crystals of compound (I)) Approximately 200 mg of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339 was placed in a test tube (2 mL), and acetone / heptane (=1 / 1) (1 mL) was added. The mixture was stirred for 6 days in a parallel organic synthesis reactor equipped with a stirrer tip, capped, and set at 30°C, and then allowed to stand. The supernatant was removed, and the mixture was dried under reduced pressure to obtain C-type crystals of compound (I). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the C-type crystals under the above-mentioned conditions. The powder X-ray diffraction pattern, DSC curve, and TG-DTA curve of the C-type crystals are shown in Figure 3, Figure 11, and Figure 12, respectively. The relative intensities, where the peak intensity at a diffraction angle of approximately 8.1° represented by 2θ in the powder X-ray diffraction analysis of the C-type crystals is set to 100, are shown in Table 9. The TG-DTA measurement results showed that the melting point was about 172° C. Furthermore, a moisture adsorption / desorption test (DVS) was carried out on the C-type crystals under the above conditions, and the measurement results are shown in FIG.

[0302] Example 4 (Preparation of D-type crystals of Compound (I)) Approximately 200 mg of the A-type crystals of Compound (I) obtained in Example 1 were placed in a test tube (2 mL), and ethyl acetate (1 mL) was added. The mixture was stirred overnight (19 hours) in a parallel organic synthesis reactor set at 60°C with a stirrer tip and a lid, resulting in partial transformation to D-type crystals. After further stirring at 35°C to 40°C for 2 to 3 days, heptane was added and the mixture was allowed to stand. The supernatant was removed, and the mixture was dried under reduced pressure to obtain D-type crystals of Compound (I). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the D-type crystals under the above-mentioned conditions. The powder X-ray diffraction pattern, DSC curve, and TG-DTA curve of the D-type crystals are shown in Figure 4, Figure 15, and Figure 16, respectively. The relative intensities, where the peak intensity at a diffraction angle of approximately 7.6°, represented by 2θ, in the powder X-ray diffraction analysis of the D-type crystals is set to 100, are shown in Table 10. The TG-DTA measurement results showed that the melting point was approximately 158° C. to 163° C. Furthermore, a moisture adsorption / desorption test (DVS) was carried out on the D-type crystals under the above conditions, and the measurement results are shown in FIG.

[0303] Example 5 (Preparation of E-type Crystals of Compound (I)) Approximately 200 mg of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339 was placed in a test tube (2 mL), and DMSO / toluene (=1 / 99) (1 mL) was added. The mixture was stirred at room temperature for one month in a parallel organic synthesis reactor with a stirrer tip and the lid closed, followed by drying under reduced pressure to obtain E-type crystals of compound (I) as a DMSO solvate. Powder X-ray diffraction analysis and thermal analysis (TG-DTA) were performed on the E-type crystals under the above conditions. The powder X-ray diffraction pattern of the E-type crystals is shown in FIG. 5, and the relative intensity, where the peak intensity at a diffraction angle of approximately 18.3° represented by 2θ is set to 100, is shown in Table 11. The TG-DTA measurement results indicated that the melting point was approximately 124°C.

[0304] Example 6 (Preparation of F-type crystals of compound (I)) In a 50 mL Kolben, acetone (4 mL) was added to 1.00 g of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339. The mixture was stirred at room temperature, resulting in complete dissolution and precipitation of white crystals. Due to poor stirring, acetone (2 mL) and heptane (6 mL) were added, and the mixture was stirred at room temperature for 15 hours. The crystals were collected by filtration, washed with acetone / heptane (= 1 / 2) (20 mL), and air-dried to obtain F-type crystals of compound (I) (0.892 g, yield: 89.2%). Powder X-ray diffraction analysis and thermal analysis (TG-DTA) were performed on the F-type crystals under the above conditions. The powder X-ray diffraction pattern of the F-type crystals showed a pattern similar to that of the acetonitrile solvate of the F-type crystals obtained in step (c-1) of Example 11 (described below) (FIG. 6). The relative intensity, with the peak intensity at a diffraction angle of about 4.55° represented by 2θ set at 100, is shown in Table 12. From the results of TG-DTA measurement, the melting point was about 124°C.

[0305] Example 7 (Preparation of G-type crystals of Compound (I)) The F-type crystals of Compound (I) (850 mg) obtained in Example 6 were dried under reduced pressure at 40°C for 22 hours to obtain G-type crystals of Compound (I) (781 mg). Powder X-ray diffraction analysis and thermal analysis (TG-DTA) were performed on the G-type crystals under the conditions described above. The powder X-ray diffraction pattern of the G-type crystals is shown in Figure 7, and the relative intensity, when the peak intensity at a diffraction angle of approximately 5.08° represented by 2θ is set to 100, is shown in Table 13. The TG-DTA measurement results indicated that the melting point was approximately 119°C.

[0306] Example 8 (Preparation of H-type crystals of Compound (I)) A 15φ test tube was charged with the B-type crystals of Compound (I) obtained in Example 2 (0.3 g) and TBME, and the mixture was stirred with an external bath set at 25°C. The slurry was filtered using a small centrifuge and washed with TBME (0.6 mL, 2.0 v / w). The wet crystals were dried under reduced pressure with an external bath set at 40°C until a constant weight was obtained, thereby obtaining H-type crystals of Compound (I). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the H-type crystals under the above-mentioned conditions. The powder X-ray diffraction pattern of the H-type crystals is shown in Figure 8, and the relative intensity, where the peak intensity at a diffraction angle of approximately 13.4° represented by 2θ is set to 100, is shown in Table 14. The TG-DTA measurement results indicated that the melting point was approximately 161°C.

[0307] Example 9 (Preparation of Form I Crystals of Compound (I)) In a 24φ test tube, acetic acid (3 mL) was added to 1.00 g of compound (I) (amorphous form) obtained by the method described in Example 482 of WO 2015 / 163339. The mixture was stirred at room temperature, resulting in complete dissolution and precipitation of white crystals. Due to poor stirring, acetic acid (1 mL) and isopropyl acetate (6 mL) were added, and the mixture was stirred at room temperature for 19 hours. The crystals were filtered, washed with isopropyl acetate (2 mL), and air-dried to obtain Form I crystals of compound (I) (0.778 g, yield: 77.8%) as an acetic acid solvate. Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the Form I crystals under the above conditions. The powder X-ray diffraction pattern of the Form I crystals is shown in FIG. 9, and the relative intensity, when the peak intensity at a diffraction angle of approximately 5.34 ° represented by 2θ is taken as 100, is shown in Table 15. The melting point was found to be about 112°C by TG-DTA measurement.

[0308] Example 10 (Preparation of Type J Crystals of Compound (I)) The type A crystals (5.00 g) of Compound (I) obtained in Example 1 were uniformly spread on a Petri dish and placed in a specimen dryer heated to 155°C. The temperature setting of the specimen dryer was adjusted so that the temperature near the Petri dish was 160°C to 175°C. The crystals melted from the edge of the Petri dish, becoming a yellow oil and then a yellow solid. After the entire Petri dish had solidified, the Petri dish was removed from the specimen dryer and allowed to cool, yielding type J crude crystals (5.00 g) of Compound (I). In a 24φ test tube, ethyl acetate (6 mL) was added to the type J crude crystals (2.00 g), and the mixture was suspended and stirred at an external bath temperature of 25°C for 2 hours. Heptane (2 mL) was added, and the mixture was stirred for an additional 30 minutes, filtered, and dried under reduced pressure in an evaporator with an external bath of 50°C to obtain type J crystals of Compound (I) (1.61 g, yield: 80.5%). Powder X-ray diffraction analysis and thermal analysis (DSC and TG-DTA) were performed on the J-type crystal under the above conditions. The powder X-ray diffraction pattern of the J-type crystal is shown in Figure 10, and the relative intensity, where the peak intensity at a diffraction angle of approximately 18.7° represented by 2θ is set to 100, is shown in Table 16. The TG-DTA measurement results indicated that the melting point was approximately 180°C.

[0309] Test Example 2 (Interconversion Between Each Crystal Polymorph: Crystal Form Transition Experiment) (Test Method) 5 mg to 10 mg of each of two crystalline forms of Compound (I) (A-type crystals and B-type crystals, A-type crystals and D-type crystals, D-type crystals and E-type crystals, F-type crystals and D-type crystals, D-type crystals and G-type crystals, H-type crystals and D-type crystals, D-type crystals and I-type crystals, C-type crystals and D-type crystals, C-type crystals and F-type crystals, C-type crystals and A-type crystals, C-type crystals and D-type crystals, C-type crystals and H-type crystals, C-type crystals and J-type crystals, C-type crystals and K-type crystals, or C-type crystals and L-type crystals) were mixed in a 2 mL LC vial to prepare suspensions (200 μL to 1 mL) in each medium, and each vial was fitted with a stirrer tip, capped, and stirred at each temperature. Portions of each suspension were taken at appropriate times and filtered, and the residues were subjected to XRPD analysis. (Test Results) The results are shown in Table 21 below. According to Table 21, among the crystalline polymorphs of compound (I), it was confirmed that C-type crystals and D-type crystals are stable forms. Furthermore, even when C-type crystals (20 mg) were suspended and washed in various mixed solvent systems (800 μL) in a 2 mL LC vial at room temperature for a long period (1 month), no polymorphs other than C-type crystals were obtained. However, when D-type crystals were suspended and washed under the same conditions, C-type crystals were also obtained in some solvent systems in addition to D-type crystals. This indicates that C-type crystals are the most stable form at room temperature.

[0310]

[0311] Test Example 3 (Solubility Measurement of Type C Crystals and Type D Crystals in Various Media at 25°C) (Test Method) (1) An appropriate amount of type C crystals or type D crystals was placed in a 2 mL LC vial, and 1.2 mL of each medium (ethanol / water (=3 / 7), MIBK, ethyl acetate, 2-propanol) was added to each vial. Each vial was capped with a stirrer tip and stirred at 25°C for 30 hours. The resulting suspension was placed in a centrifuge tube (brown, 2 mL) and centrifuged at 25°C for 1 minute. Each supernatant (approximately 0.6 mL) was taken using a thermosyringe (2.5 mL) and filtered (Millex-LG, PTFE 0.20 μm). A few drops of the first filtrate were discarded, and the next filtrate was used for measurement. (2) An appropriate amount of type C crystals or type D crystals was placed in a 5 mL Falcon tube, and water (3.0 mL) was added to each vial to prepare a suspension. The tubes were placed on their sides and fixed, and shaken for 30 hours at 25°C. The resulting suspensions were centrifuged at 25°C for 1 minute. Each supernatant (approximately 0.6 mL) was taken using a Thermosyringe (2.5 mL) and filtered (Millex-LG, PTFE 0.20 μm). A few drops of the first filtrate were discarded, and the next filtrate was used for measurement. (Measurement Method) 100 μL of each filtrate was accurately measured, and acetonitrile was added to make exactly 10 mL to prepare a sample solution. Separately, type A crystals (10.60 mg) were taken, and acetonitrile was added to make exactly 100 mL to prepare a standard solution. 1 μL each of the sample solution and standard solution (10 μL of water) was quantified by liquid chromatography under the following analytical conditions. Each suspension was also filtered, and the residues were subjected to XRPD analysis. (Analysis conditions) Detector: Photodiode array detector (measurement wavelength: 220 nm) Column: Capcell pak MG-II, 3 μm (3.0 mmφ×35 mm) Column temperature: Constant temperature around 40°C Mobile phase A: Water / trifluoroacetic acid mixture (2000:1) Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2000:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 22 below to control the concentration gradient.

[0312]

[0313] Flow rate: 1.0 mL / min (Test results) The results are shown in Figure 20. Figure 20 confirms that the C-type crystals have a lower solubility (mg / mL) in various media than the D-type crystals (solubility ratio (D-type crystals / C-type crystals) = approximately 1.2). This also indicates that the C-type crystals are a more stable crystal form at room temperature than the D-type crystals.

[0314] Example 11 (Practical method for producing C-type crystals of compound (I) (alternative to Example 3)) An example of a production method for obtaining C-type crystals of compound (I) with high purity and high yield with good reproducibility is shown below, but the production method of the present invention is not limited to the following method. The starting material, BFPT (compound of formula (1)), used was that obtained by the method described in Reference Example 91 of WO 2015 / 163339.

[0315] (Step (a-1)) Synthesis of RFPT (compound of formula (2))

[0316]

[0317] Under a nitrogen atmosphere, NMP (285 kg, 5 parts by weight) was charged and stirred. BFPT (compound of formula (1)) (57 kg, 1 equivalent (1 part by weight) (standard)) and DPRL (44.9 kg, 2 equivalents) were charged into a reaction vessel, and washed down with NMP (7.98 kg, 0.14 parts by weight). DBU (119 kg, 4 equivalents) was added dropwise at an internal temperature of 5°C to 20°C, and the internal temperature was raised to 30°C to 45°C (target 40°C). After completion of the reaction, the internal temperature was cooled to 20°C to 30°C, and solution A was obtained. Under a nitrogen atmosphere, 20.0% hydrochloric acid (267 kg, 7.5 equivalents) and water (1620 kg, 28.5 parts by weight) were charged into a separate reaction vessel and stirred. At an internal temperature of 20°C to 30°C, the entire amount of solution A was added dropwise, and the mixture was washed with water (115 kg, 2.02 parts by weight). After stirring at the same temperature for at least 1 hour, the crystals were filtered and washed three times with water (143 kg, 2.5 parts by weight), yielding wet crystals of RFPT. The wet crystals were dried under reduced pressure at an external temperature of 40°C or lower, yielding RFPT (compound of formula (2)) (60.5±3.2 kg, yield: 95±5%).

[0318] (Step (b-1)) Synthesis of Form I Crystal of RFCB (Compound (I))

[0319]

[0320] Under a nitrogen atmosphere, DIPEA (71.5 kg, 3 equivalents) and acetonitrile (78.3 kg, 1.3 parts by weight) were charged into a reaction vessel and stirred. RFPT (compound of formula (2)) (60.2 kg, 1 equivalent (1 part by weight) (standard)) was charged at an internal temperature of 20 ° C to 30 ° C, and washed in with acetonitrile (9.03 kg, 0.15 parts by weight). After confirming dissolution, BAMI (23.7 kg, 1.2 equivalents) was charged at the same temperature and washed in with acetonitrile (3.01 kg, 0.05 parts by weight). The reaction mixture was heated to an internal temperature of 50 ° C to 60 ° C (target 50 ° C to 55 ° C), and a 50% T3P acetonitrile solution (176 kg, 1.5 equivalents) was added dropwise at the same temperature, and then washed in with acetonitrile (4.21 kg, 0.07 parts by weight). The mixture was stirred at the same temperature, and after completion of the reaction, the internal temperature was cooled to 5 ° C. to 15 ° C. (target 5 ° C. to 10 ° C.), and at the same temperature, AcOH (63.2 kg, 1.05 parts by weight), and a seed crystal of type I crystal of RFCB (compound (I)) prepared separately was added, and the mixture was stirred at the same temperature. After confirming the precipitation of crystals, water (1080 kg, 18 parts by weight) was added dropwise over 1 hour at the same temperature, and after the dropwise addition was completed, the crystals were stirred at the same temperature for 1 hour or more and then filtered. The internal temperature was cooled to 5 ° C. to 15 ° C., and the crystals were washed with a mixture of AcOH (15.7 kg, 0.26 parts by weight) and water (286 kg, 4.75 parts by weight) and water (301 kg, 5 parts by weight), to obtain wet crystals. The wet crystals were dried under reduced pressure at an external temperature of 50°C or less to obtain type I crystals of RFCB (compound (I)) (74.6±8.8 kg, yield: 85±10%) as an acetic acid solvate. Powder X-ray diffraction analysis was carried out on type I crystals (acetic acid solvate) of RFCB (compound (I)) under the same conditions as above. As a result, a powder X-ray diffraction pattern similar to that shown in Figure 9 was observed.

[0321] (Step (c-1)) Synthesis of F-type crystals of RFCB (compound (I)) Under a nitrogen atmosphere, RFCB (compound (I)) type I crystals (74.3 kg, 1 equivalent (1 part by weight) (standard)), acetonitrile (93.6 kg, 1.26 parts by weight) and purified water (29.7 kg, 0.4 parts by weight) were charged into a reaction vessel and stirred. Dissolution was confirmed at an internal temperature of 40 ° C. to 55 ° C., and after dust removal filtration, the mixture was washed with a mixture of acetonitrile (23.0 kg, 0.31 parts by weight) and purified water (7.43 kg, 0.1 parts by weight). The internal temperature was cooled to 5 ° C. to 25 ° C. (target 10 ° C.), purified water (111 kg, 1.5 parts by weight) and separately prepared F-type crystals of RFCB (compound (I)) were added, and the mixture was stirred at the same temperature. After confirming the precipitation of crystals, purified water (1190 kg, 16 parts by weight) was added dropwise at the same temperature over 1 hour or more, and after the completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour or more. The crystals were collected by filtration and washed with a mixture of acetonitrile (29.0 kg, 0.39 parts by weight) and purified water (334 kg, 4.50 parts by weight) cooled to an internal temperature of 1 ° C to 20 ° C to obtain wet crystals. The wet crystals were dried under reduced pressure at an external temperature of 50 ° C or less to obtain F-type crystals of RFCB (compound (I)) (58.4 ± 6.5 kg, yield: 90 ± 10%) as an acetonitrile solvate. Powder X-ray diffraction analysis of the F-type crystals of RFCB (compound (I)) (acetonitrile solvate) was performed under the same conditions as above. As a result, a powder X-ray diffraction pattern similar to that in Figure 6 was observed, and diffraction peaks similar to those in Table 12 were observed.

[0322] (Step (d-1)) Synthesis of C-type crystals of RFCB (compound (I)) Under a nitrogen atmosphere, EtOH (275 kg, 4.74 parts by weight) and purified water (813 kg, 14 parts by weight) were charged into a reaction vessel and stirred. At an internal temperature of 1 ° C to 35 ° C, F-type crystals of RFCB (compound (I)) (58.1 kg, 1 equivalent (1 part by weight) (standard)) were charged, and the internal temperature was raised to 30 ° C to 45 ° C (target 40 ° C to 45 ° C), and seed crystals of C-type crystals of RFCB (compound (I)) (0.581 kg to 2.91 kg, 0.01 parts by weight to 0.05 parts by weight) were added at the same temperature and stirred. After completion of the crystal transition, the mixture was cooled to an internal temperature of 5°C to 15°C (target temperature: 5°C to 10°C) and stirred for at least 1 hour. The crystals were collected by filtration and washed with a separately prepared mixture of EtOH (69.1 kg, 1.19 parts by weight) and purified water (203 kg, 3.5 parts by weight), yielding wet crystals. The wet crystals were dried under reduced pressure at an external temperature of 50°C or below to obtain C-type crystals of RFCB (Compound (I)) (52.3±5.8 kg, yield: 90±10%) as the free anhydrate. Powder X-ray diffraction analysis was performed on the C-type crystals of RFCB (Compound (I)) under the same conditions as above. The result showed a powder X-ray diffraction pattern similar to that shown in Figure 3. The results of measurement of related substances on the C-type crystals obtained by this method under the same conditions as above are shown in Figure 14. According to Figure 14, the purity was confirmed to be 99.90%. The C-type crystals obtained by this method decomposed by 0.1% or less even when subjected to storage conditions (severe test) at 60° C. for 1 week. Furthermore, even when the C-type crystals obtained by this method were subjected to long-term suspension washing for 1 month in various organic solvents (ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-propanol, ethanol, acetone, 1-propanol, 1-butanol, propylene glycol, tert-butanol, etc.) or mixed solvents, no crystal form transition was observed and they remained as C-type crystals.

[0323] From the above results, it was found that the C-type crystal of Compound (I) is the most stable crystal form at room temperature.

[0324] Examples of the formulation of the present invention include the following formulations, but the present invention is not limited to these formulation examples.

[0325] Formulation Example 1 (Production of Capsules) 1) Example 11 (C-type crystals of Compound (I)) 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0326] Formulation Example 2 (Tablet Production) 1) Example 11 (C-type crystals of compound (I)) 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4) Carmellose calcium 44 g 5) Magnesium stearate 1 g The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. This sized powder is mixed with 14 g of 4) and 1 g of 5), and tableted using a tablet press. In this way, 1,000 tablets containing 10 mg of Example 11 (C-type crystals of compound (I)) per tablet are obtained.

[0327] Example 12 (Preclinical Study) Compound (I) and other KAT-2 inhibitors (Compounds 2 and 3 described below) were subjected to a comprehensive series of preclinical studies, including the following (1) to (7): (1) Inhibitory Ki (nM) against human KAT2 (2) Measurement of CSF exposure ratio: Ratio of CSF exposure amount after 3 hours to Ki in monkeys (Ccsf / Ki) (3) Intrinsic liver clearance (CLint) in monkeys and humans (4) Bioavailability (BA%) in rats, dogs, and monkeys (5) Unbound CSF / plasma ratio in monkeys (CSF Kp,u) (6) Half-life (T1 / 2) of compound orally administered to monkeys (7) Solubility in simulated intestinal fluid (SIF) (mg / mL)

[0328]

[0329] The results are shown in Table 23. As can be seen from the results shown in Table 23, compound (I) (administered as type C crystals) exhibits excellent in vitro and in vivo pharmacokinetic parameters, as well as excellent CSF solubility and a high ratio of CSF concentration to KAT2 Ki.

[0330]

[0331] Additionally, compound (I) and another KAT-2 inhibitor (compound 2) were subjected to in vivo safety testing in monkeys.

[0332] The results are shown in Table 24. As can be seen from Table 24, compound (I) was also found to have an excellent safety margin in both the monkey telemetry experiment and the 2-week toxicity test using monkeys. Here, the Cmax-based safety ratio is the ratio of the Cmax of the maximum dose at which no adverse events are observed (NOAEL) to the Cmax of the predicted effective dose. Also, the AUC-based safety ratio is the ratio of the AUC of the maximum dose at which no adverse events are observed (NOAEL) to the AUC of the predicted effective dose.

[0333]

[0334] All experiments described in this example were performed using methodology commonly used by those skilled in the art.

[0335] Example 13 (Determination of kynurenic acid (KYNA) levels in the brains of marmosets treated with L-kynurenine) Example 13 was carried out to test the ability of compound (I) to reduce kynurenic acid (KYNA) levels in the brains of marmosets treated with L-kynurenine.

[0336] First, three marmosets were orally administered with the vehicle alone, 3 mg / kg of A-form crystals of Compound (I), or 10 mg / kg of A-form crystals of Compound (I).

[0337] Two hours later, marmosets were administered L-kynurenine (L-KYN) (10 mg / kg, iv). After another hour, brains were harvested and KYNA and L-KYN concentrations were measured in different brain regions, including the prefrontal cortex and hippocampus.

[0338] The results are shown in Figure 21. As a result, compound (I) dose-dependently decreased the KYNA / L-KYN ratio and ３０ was 3.1 mg / kg (calculated from the geometric mean of the prefrontal cortex and hippocampus).

[0339] Example 14 (Confirmation of the cognitive-enhancing effect of Compound (I)) The cognitive-enhancing effect of Compound (I) was verified by measuring the attenuation of the increase in delta power (amplitude of delta waves) and theta power (amplitude of theta waves) caused by scopolamine. Scopolamine is a cholinergic antagonist that inhibits acetylcholine neurotransmitter function, and shows an increase in delta power and theta power (in electroencephalogram), and is widely used to test the cognitive-enhancing effect of cholinergic drugs.

[0340] Marmosets (n=8 / group) were administered scopolamine (40 μg / kg) or scopolamine and Compound (I) 30 mg / kg (administered as C-type crystals). The amplitudes of delta waves (0.5-4.0 Hz) and theta waves (4-8 Hz) were measured in the EEG at 30, 60, 120, 180, 240, and 360 minutes, and the percent changes were calculated, normalized to the EEG amplitudes of marmosets given the vehicle.

[0341] At each time point, a two-way ANOVA with Sidak's correction was performed against the vehicle group.

[0342] Figure 22A shows the results of scopolamine administration alone. The changes in delta power after scopolamine administration alone were statistically significant at 60, 120, 180, and 240 minutes (p<0.01, p<0.0001, p<0.01, and p<0.05), representing changes from baseline of 98%, 139%, 89%, and 76%, respectively. The changes in theta power after scopolamine administration alone were statistically significant at 60 and 120 minutes (p<0.0001 and p<0.05), representing changes from baseline of 224% and 131%, respectively.

[0343] Figure 22B shows the results of administering scopolamine and Compound (I) in combination. Administration of scopolamine and Compound (I) in combination significantly attenuated changes in delta power and theta power. No statistically significant differences from baseline were observed at any time point. Changes in delta power ranged from 46 to 82%, and changes in theta power ranged from 7 to 41%.

[0344] These results demonstrate that Compound (I) attenuates the effects of cholinergic blockade with an efficacy comparable to that of cholinesterase inhibitors, demonstrating that Compound (I) is a potent cognitive enhancer for the treatment of diseases such as schizophrenia (e.g., the treatment of cognitive impairment associated with schizophrenia (CIAS)) and Alzheimer's disease.

[0345] Example 15 (Human Phase I Clinical Trial) A human Phase I clinical trial with a randomized, double-blind, placebo-controlled, dose-escalation design was conducted to test the safety, tolerability, and pharmacokinetics of Compound (I).

[0346] Part 1 was a single ascending dose study, and Part 2 was a multiple ascending dose study. The objectives of Parts 1 and 2 were to evaluate the safety and tolerability of Compound (I) following single and multiple ascending doses. Secondary objectives were to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of Compound (I) following single and multiple ascending doses.

[0347] (Test conditions) - Single ascending dose study (SAD) Group 1: Compound (I) A mg or placebo, administered in a single oral tablet dose. Group 2: Compound (I) B mg or placebo, administered in a single oral tablet dose. Group 3: Compound (I) C mg or placebo, administered in a single oral tablet dose. Group 4: Compound (I) D mg or placebo, administered in a single oral tablet dose. Group 5: Compound (I) E mg or placebo, administered in a single oral tablet dose. - Multiple ascending dose study (MAD) Group 1: Compound (I) G mg or placebo, administered in an oral tablet dose for 7 days. Group 2: Compound (I) H mg or placebo, administered in an oral tablet dose for 7 days. Group 3: Compound (I) I mg or placebo, administered in an oral tablet dose for 7 days.

[0348] (Outcome measures) Treatment-emergent adverse events were monitored from the time of primary endpoint administration until the final follow-up after the last dose (approximately 8 days after administration in the MAD group and 5 days after administration in the SAD group).

[0349] Secondary endpoints: Single Ascending Dose Study (SAD) Cmax (SAD): Maximum plasma concentration Cmax (SAD) was determined by monitoring from baseline (pre-dose) until 72 hours post-dose. Cmax was determined directly from the concentration-time profile for each dose of SAD. tmax (SAD): Time to reach maximum plasma concentration tmax (SAD) was determined by monitoring from baseline (pre-dose) until 72 hours post-dose. tmax was determined directly from the concentration-time profile for each dose of SAD. AUCinf (SAD): Area under the concentration-time curve extrapolated from pre-dose (time 0) to infinity AUCinf (SAD) was determined by monitoring from baseline (pre-dose) until 72 hours post-dose. AUCinf was calculated using the linear-logarithmic trapezoidal rule for each dose of SAD.

[0350] Single Ascending Dose Study (MAD) Cmax on Day 1 (MAD): Cmax on Day 1 (MAD) was determined by monitoring from baseline (pre-dose) through 24 hours post-dose. Cmax was determined directly from the concentration-time profile for each dose of MAD. tmax on Day 1 (MAD): tmax on Day 1 (MAD) was determined by monitoring from baseline (pre-dose) through 24 hours post-dose. tmax was determined directly from the concentration-time profile for each dose of MAD. Cmax,ss (MAD): Cmax,ss (MAD) was determined from baseline (pre-dose) through 96 hours post-dose on Day 7. Cmax,ss was determined by calculating the maximum plasma concentration observed during the dosing interval at steady state for each dose of MAD. tmax,ss (MAD): tmax,ss (MAD) was measured from baseline (pre-dose) through 96 hours post-dose on Day 7. tmax,ss was determined directly from the steady-state concentration-time profile for each dose of MAD. AUCtau (MAD): Area under the concentration-time curve. AUCtau (MAD) on Days 1 and 7 was determined from baseline (pre-dose) through 96 hours post-dose on Day 7. AUCtau (MAD) was determined over the dosing interval for each dose of MAD. AUCinf (MAD): Area under the concentration-time curve extrapolated from pre-dose (time 0) to infinity. AUCinf (MAD) was determined from baseline (pre-dose) through 96 hours post-dose on Day 7. AUCinf (MAD) was calculated using the linear-logarithmic trapezoidal rule for each dose of MAD.

[0351] (Evaluation Results) The results of this study demonstrated that Compound (I) was safe and well-tolerated and exhibited excellent pharmacokinetic (PK) properties in both plasma and cerebrospinal fluid (CSF), suggesting adequate penetration and exposure of Compound (I) in the central nervous system (CNS).

[0352] The study also examined exploratory pharmacodynamic (PD) endpoints, and Compound (I) demonstrated statistically significant improvements in electroencephalographic (EEG) activity associated with cognitive pathways, including increased gamma power and improved beta / alpha ratios, providing early suggestive evidence of improved cognitive function.

[0353] Furthermore, it was shown to dose-dependently decrease cerebrospinal fluid (CSF) kynurenic acid (KYNA) levels, which have been shown to be elevated in patients with schizophrenia and are thought to be a major precipitating factor in CIAS.

[0354] KYNA concentrations in cerebrospinal fluid were reduced by 40-70% from baseline. KYNA concentrations in schizophrenic patients are often approximately 60% higher than in healthy individuals. A 40% reduction in KYNA concentrations in schizophrenic patients would reduce KYNA concentrations to levels observed in healthy individuals.

[0355] According to the present invention, novel and stable crystalline polymorphs of Compound (I) are provided: C-type crystals and D-type crystals. Furthermore, according to the present invention, a practical production method can be provided that can reproducibly obtain C-type crystals, which are the most stable crystalline form of Compound (I) and are useful as a drug substance for Compound (I), with high purity and high yield, and that can be scaled up. Furthermore, the crystalline Compound (I) of the present invention, particularly the C-type crystals, has excellent KAT2 inhibitory activity and is therefore useful as a pharmaceutical for treating or preventing various diseases in which KAT2 is involved (e.g., schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive dysfunction, dementia, depression, and stress vulnerability). Therefore, according to the present invention, novel crystalline polymorphs of Compound (I), methods for preparing these polymorphs, pharmaceutical compositions containing one or more novel crystalline polymorphs, medical kits containing such crystalline polymorphs and / or pharmaceutical compositions, and pharmaceutical uses of such crystalline polymorphs and pharmaceutical compositions can be provided. Additionally, the present invention provides a method for treating cognitive impairment (e.g., CIAS) in a subject (patient), the method comprising administering to such subject a therapeutically effective amount of Compound (I).

Claims

Form C crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.

2. The crystal according to claim 1, which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, and about 13.7° in powder X-ray diffraction.

2. The crystal according to claim 1, which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, about 13.4°, about 13.7°, and about 15.7° in powder X-ray diffraction.

2. The crystal according to claim 1, which has diffraction peaks at diffraction angles (2θ) of about 6.7°, about 8.1°, about 13.4°, about 13.7°, about 15.7°, about 16.4°, and about 18.3° in powder X-ray diffraction.

2. The crystal according to claim 1, which has diffraction peaks at diffraction angles (2θ) of 6.7±0.2°, 8.1±0.2°, 15.7±0.2°, 21.5±0.2°, 21.8±0.2°, 25.5±0.2°, and 27.3±0.2° in powder X-ray diffraction. 　 The crystal according to claim 5, further having a diffraction peak at a diffraction angle (2θ) of 13.7±0.2°. 　 The crystal according to claim 5 or 6, further having a diffraction peak at a diffraction angle (2θ) of 16.4±0.2°. 　 In the powder X-ray diffraction spectrum, the following table: The crystal according to claim 1, having a diffraction peak expressed by the diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below.

2. The crystal of claim 1, which exhibits a powder X-ray diffraction pattern substantially as shown in FIG.

10. The crystal according to any one of claims 1 to 9, which exhibits an extrapolated onset temperature of about 172°C in differential scanning calorimetry.

11. The crystal according to any one of claims 1 to 10, wherein the enthalpy of the endothermic peak is about 83.9 mJ / mg in differential scanning calorimetry. Form D crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide. 　 The crystal according to claim 12, which has diffraction peaks at diffraction angles (2θ) of about 7.6°, about 9.1°, and about 13.0° in powder X-ray diffraction. 　 The crystal according to claim 12, which has diffraction peaks at diffraction angles (2θ) of about 5.5°, about 7.6°, about 9.1°, about 13.0°, and about 15.9° in powder X-ray diffraction. 　 The crystal according to claim 12, which has diffraction peaks at diffraction angles (2θ) of about 5.5°, about 7.6°, about 9.1°, about 13.0°, about 15.9°, about 17.8°, and about 19.6° in powder X-ray diffraction. 　 The crystal according to claim 12, which has diffraction peaks at diffraction angles (2θ) of 7.6±0.2°, 9.1±0.2°, 13.0±0.2°, 17.8±0.2°, 19.6±0.2°, and 21.9±0.2° in powder X-ray diffraction. 　 The crystal according to claim 16, further having a diffraction peak at a diffraction angle (2θ) of 15.9±0.2°. 　 The crystal according to claim 16 or 17, further comprising a diffraction peak at a diffraction angle (2θ) of 28.9±0.2°. 　 In the powder X-ray diffraction spectrum, the following table: The crystal according to claim 12, having a diffraction peak expressed by the diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below.

13. The crystal of claim 12, which exhibits a powder X-ray diffraction pattern substantially as shown in Figure 4.

21. The crystal according to any one of claims 12 to 20, which has a melting point of about 158°C in differential scanning calorimetry.

22. The crystal according to any one of claims 12 to 21, wherein the enthalpy of the endothermic peak in differential scanning calorimetry is about 72.1 mJ / mg. Type B crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.

24. The crystal according to claim 23, which has diffraction peaks at diffraction angles (2θ) of about 5.2°, about 5.9°, and about 7.4° in powder X-ray diffraction.

24. The crystal according to claim 23, which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 5.2°, about 5.9°, about 7.4°, and about 22.2° in powder X-ray diffraction.

24. The crystal according to claim 23, which has diffraction peaks at diffraction angles (2θ) of 4.5±0.2°, 5.2±0.2°, 5.9±0.2°, 7.4±0.2°, 8.3±0.2°, and 22.2±0.2° in powder X-ray diffraction. 　 The crystal according to claim 26, further having a diffraction peak at a diffraction angle (2θ) of 23.1±0.2°. 　 The crystal according to claim 26 or 27, further having a diffraction peak at a diffraction angle (2θ) of 19.7±0.2°. 　 In the powder X-ray diffraction spectrum, the following table: The crystal according to claim 23, having a diffraction peak expressed by the diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below.

24. The crystal of claim 23, which exhibits a powder X-ray diffraction pattern substantially as shown in Figure 2.

31. The crystal according to any one of claims 1 to 30, wherein the purity of the crystal is 70% or more. 　 A pharmaceutical composition comprising the crystal of any one of claims 1 to 31 and a pharmaceutically acceptable carrier.

33. The pharmaceutical composition of claim 32, in the form of granules, fine granules, powder, capsules or tablets. 　 The pharmaceutical composition according to claim 32 or 33, for the prevention and / or treatment of a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression and stress vulnerability.

34. The pharmaceutical composition of claim 32 or 33 for inhibiting KAT2. 　 A KAT2 inhibitor comprising the crystal of any one of claims 1 to 31. A method for producing type C crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, comprising: (a) Equation (1): is reacted with D-proline in the presence of a base to obtain a compound represented by formula (2): a step of converting the compound represented by the formula: (b) amidating the compound of formula (2) with benzylamine in the presence of a condensing agent and a base, adding acetic acid at 5°C to 15°C, stirring at the same temperature, and crystallizing to obtain Form I crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide; (c) dissolving the type I crystals in a mixed solvent of acetonitrile / water at an internal temperature of 40°C to 55°C, followed by cooling to 5°C to 25°C, stirring, and crystallizing the solution to convert the type I crystals into type F crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide; (d) dissolving the F-type crystals in an ethanol / water mixed solvent at an internal temperature of 30°C to 45°C, followed by cooling to 5°C to 15°C, stirring, and crystallization to convert them into C-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.

38. The process according to claim 37, wherein the condensing agent is propylphosphonic anhydride (T3P). 　 The production method according to claim 37, wherein the crystallization in the step (b) is carried out by adding, as seed crystals, Form I crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide prepared by another method. 　 The production method according to claim 37, wherein the crystallization in the step (c) is carried out by adding type F crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide prepared by another method as seed crystals. 　 The production method according to claim 37, wherein the crystallization in the step (d) is carried out by adding, as seed crystals, type C crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide prepared by another method. A method for producing C-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, comprising adding seed crystals of C-type crystals to a suspension of A-type crystals, D-type crystals, F-type crystals, H-type crystals, J-type crystals, K-type crystals, or L-type crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, stirring, and allowing to crystallize, thereby obtaining C-type crystals. Form I crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.

44. The crystal according to claim 43, which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, and about 13.1° in powder X-ray diffraction.

44. The crystal according to claim 43, which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, about 7.4°, about 10.8°, and about 13.1° in powder X-ray diffraction.

44. The crystal according to claim 43, which has diffraction peaks at diffraction angles (2θ) of about 5.3°, about 7.0°, about 7.4°, about 10.8°, about 13.1°, about 16.2°, and about 18.8° in powder X-ray diffraction. 　 In the powder X-ray diffraction spectrum, the following table: The crystal according to claim 43, having a diffraction peak expressed at diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below.

44. The crystal of claim 43, which exhibits a powder X-ray diffraction pattern substantially as shown in Figure 9. 　 A crystal according to any one of claims 43 to 48, which has a melting point of about 112°C in simultaneous differential scanning calorimetry and thermogravimetry. Form F crystal of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide.

51. The crystal according to claim 50, which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, and about 9.1° in powder X-ray diffraction.

51. The crystal according to claim 50, which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, about 9.1°, about 11.2°, and about 17.4° in powder X-ray diffraction.

51. The crystal according to claim 50, which has diffraction peaks at diffraction angles (2θ) of about 4.5°, about 8.8°, about 9.1°, about 11.2°, about 17.4°, about 17.7°, and about 19.0° in powder X-ray diffraction. 　 In the powder X-ray diffraction spectrum, the following table:

51. The crystal according to claim 50, having a diffraction peak expressed at diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below. 　 A crystal according to any one of claims 50 to 54, which has a melting point of about 124°C in simultaneous differential scanning calorimetry and thermogravimetry. Form E crystals of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide. 　 In the powder X-ray diffraction spectrum, the following table:

57. The crystal according to claim 56, having a diffraction peak expressed at diffraction angles Pos. [°2Th.] (2θ) and relative intensities as shown below. 　 A method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, the method comprising administering a therapeutically effective amount of (2R)—N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of formula (I) to a subject in need thereof to treat the disease. A method for treating a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-associated cognitive impairment, dementia, depression, and stress vulnerability, the method comprising administering a therapeutically effective amount of the crystal of any one of claims 1 to 31 or 43 to 57, or a therapeutically effective amount of the pharmaceutical composition of claim 32 or 33 to a subject in need thereof to treat the disease.

60. The method of claim 58 or 59, wherein the disease is schizophrenia.

60. The method of claim 58 or 59, wherein the disease is bipolar disorder or attention-deficit / hyperactivity disorder.

60. The method of claim 58 or 59, wherein the disease is Alzheimer's disease, major depression, autism, age-associated cognitive impairment, or dementia.

100. A method of inhibiting KAT2, comprising contacting KAT2 with a crystal of any one of claims 1-31 or 43-57, thereby inhibiting KAT2.

1. A method of treating cognitive dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of Formula (I) to treat the cognitive dysfunction. A method for treating cognitive dysfunction, comprising administering to a subject in need thereof a therapeutically effective amount of the crystal of any one of claims 1 to 31, 43 to 57, or a therapeutically effective amount of the pharmaceutical composition of claim 32 or 33, to treat the cognitive dysfunction.

66. The method of claim 64 or 65, wherein the subject has been diagnosed with a disease selected from the group consisting of schizophrenia, bipolar disorder, attention-deficit / hyperactivity disorder, Alzheimer's disease, major depression, autism, vascular dementia, HIV encephalopathy, age-related cognitive impairment, dementia, depression, and stress vulnerability.

67. The method of claim 66, wherein the disease is schizophrenia.

67. The method of claim 66, wherein the disease is bipolar disorder or attention-deficit / hyperactivity disorder.

67. The method of claim 66, wherein the disease is Alzheimer's disease.

67. The method of claim 66, wherein the disease is major depression, autism, age-related cognitive impairment, or dementia.

1. A method of treating cognitive impairment associated with schizophrenia (CIAS), comprising administering to a subject in need thereof a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide of Formula (I) to treat the cognitive impairment. A method for treating cognitive impairment associated with schizophrenia (CIAS), comprising administering to a subject in need thereof a therapeutically effective amount of a crystal according to any one of claims 1 to 31, 43 to 57, or a therapeutically effective amount of a pharmaceutical composition according to claim 32 or 33, to treat the cognitive impairment.

73. The method of any of claims 58 to 72, wherein the concentration of kynurenic acid (KYNA) in cerebrospinal fluid (CSF) is reduced by at least 40%.

74. The method of any of claims 58 to 73, wherein the treatment enhances glutamate signaling and / or acetylcholine signaling as measured by an increase in gamma wave amplitude and the ratio of alpha wave amplitude to beta wave amplitude (beta / alpha ratio).

75. The method of any of claims 58-74, wherein the treatment increases the concentration of glutamate in the subject's cerebrospinal fluid (CSF) relative to before treatment.

76. The method of any of claims 58 to 75, wherein the subject is a human. The method of any one of claims 58 to 76, wherein a therapeutically effective amount of (2R)-N-benzyl-1-[5-(2-fluoropropan-2-yl)-7-oxo-6,7-dihydro[1,3]thiazolo[5,4-d]pyrimidin-2-yl]pyrrolidine-2-carboxamide, a therapeutically effective amount of the crystal of any one of claims 1 to 31, 43 to 57, or a therapeutically effective amount of the pharmaceutical composition of claim 32 or 33 is orally administered.

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