Solid Forms of GlyT1 Inhibitors

Abstract

To provide solid forms of an inhibitor of glycine transporter-1 (GlyT1), methods of making these solid forms, pharmaceutical compositions comprising these solid forms, and their use for medical conditions responsive to treatment with an inhibitor of glycine transporter-1.SOLUTION: Disclosed are solid forms of an inhibitor of glycine transporter-1 (GlyT1). The invention also relates to methods of making these solid forms, pharmaceutical compositions comprising these solid forms, and their use for medical conditions responsive to treatment with an inhibitor of glycine transporter-1.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to solid forms of inhibitors of glycine transporter-1 (GlyT1). The present invention also relates to methods for preparing these solid forms, pharmaceutical compositions comprising these solid forms, and their use for medical conditions responsive to treatment with inhibitors of glycine transporter-1.

Background Art

[0002] Schizophrenia is a progressive and debilitating neuropsychiatric disorder characterized by transient positive symptoms such as delusions, hallucinations, thought disorders and psychosis, as well as persistent negative symptoms such as flattened affect, reduced attention, social withdrawal and cognitive impairment (Lewis DA and Lieberman JA, 2000, Neuron, 28: 325-33).

[0003] In the mid-1960s, a hypothesis of schizophrenia was proposed based on the psychotic effects caused by the blockade of the glutamatergic system by compounds such as phencyclidine (PCP) and related agents (e.g., ketamine), which are non-competitive antagonists of the N-methyl-D-aspartic acid (NMDA) receptor. Interestingly, in healthy volunteers, PCP-induced psychotic effects, in combination with positive and negative symptoms, as well as cognitive dysfunction, thus closely resemble schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45:668-679). See also Jentsch and Roth, 1999, Neuropsychopharmacology 20:201-225). Thus, an increased NMDA receptor neurotransmission in the central nervous system provides an opportunity to develop novel treatment approaches for schizophrenia, as well as other neurological and psychiatric disorders associated with NMDA receptor and / or glutamatergic dysfunction. The NMDA receptor is a ligand-gated ion channel composed of a combination of two NR1 and two NR2 subunits, and requires the simultaneous binding of glutamate in the NR2 subunit and glycine as a co-agonist in the NR1 subunit for activation (Johnson and Ascher, 1987, Nature 325:529-531). One strategy to enhance NMDA receptor activity is to increase glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibiting GlyT1 (Bergeron R. et al., 1998, Proc. Natl. Acad. Sci. USA 95:15730-15734).Indeed, clinical studies using D-serine, a direct glycine-site agonist that increases glycine in the synaptic cleft, and sarcosine, a prototype GlyT1 inhibitor, have demonstrated some efficacy for treating the negative symptoms of schizophrenia, as well as some, albeit lesser, efficacy for treating positive and cognitive symptoms (Tsai et al., 2004, Biol. Psychiatry 44:1081-1089; Lane et al., 2005, Biol. Psychiatry 63:9-12). Recently, in patients with schizophrenia, RG1678, a GlyT1 inhibitor tested in a Phase II clinical trial as an adjunct treatment to marketed antipsychotics, was reported to be clinically effective for negative symptoms (Umbricht et al., 2011, Schizophr. Bull. 37(Suppl.1):324).

[0004] Efficacy in various animal models / tests for positive and negative symptoms of schizophrenia, as well as in some memory tasks, has been reported in the literature for various GlyT1 inhibitors (Depoortere et al., 2005, Neuropsychopharmacology 30:1963-1985; Boulay et al., 2008, Pharmacol. Biochem. Behav. 91:47-58, Karasawa et al., 2008, Behav. Brain Res. 186:78-83; Shimazaki et al., 2010, Psychopharmacology 209:263-270; Kinney et al., 2003, J. Neurosci. 23:7586-7591). Two individual glycine transporter genes have been cloned from mammalian brain (GlyT1 and GlyT2), resulting in two transporters with 50% amino acid sequence homology. GlyT1 represents four isoforms (1a, 1b, 1c and 1d) resulting from alternative splicing and alternative promoter use. Only two of these isoforms have been found in rodent brain (GlyT1a and GlyT1b). GlyT2 also exhibits some heterogeneity. GlyT1 is known to be located in the CNS and some peripheral tissues, while GlyT2 is CNS-specific, mainly in the hindbrain and spinal cord (Zafra et al., 1995, J. Neurosci. 15:3952-3969). GlyT1 is expressed in glia and neurons and has been found to be located at glutamatergic synapses (Cubelos et al., 2005, Cereb. Cortex 15:448-459).

[0005] Glycine transporter inhibitors are being investigated for the treatment of neurological and psychiatric disorders. Most of the associated disease states are related to psychosis, schizophrenia (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents 11: 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders related to mental disorders such as acute mania or depression, mood disorders related to bipolar disorder, and mood disorders related to schizophrenia (Pralong ET et. al., 2002, Prog. Neurobiol., 67:173-202), autism spectrum disorder (Carlsson ML, 1998, J. Neural Trans. 105:525-535), cognitive disorders such as dementia including age-related dementia and Alzheimer's type senile dementia, memory impairment in mammals including humans, attention deficit disorder and pain (Armer RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11:563-572).

[0006] Increased activation of the NMDA receptor due to GlyT1 inhibition can treat psychosis, schizophrenia (positive, negative, and cognitive symptoms), dementia, and other diseases in which cognitive processes are impaired (such as attention deficit disorder, Alzheimer's disease, or other neurological and mental disorders).

[0007] Inhibition of GlyT1 is of particular interest with respect to cognitive impairments associated with Alzheimer's disease or schizophrenia. Particularly interesting inhibitory compounds are those of Example 50 described in WO2013017657, which have the structure shown below (hereinafter in this specification "Compound 1"):

Chemical formula

[0008] WO2013017657 describes its structure but does not describe any specific solid forms of Compound 1. Therefore, there is a need for solid forms of Compound 1 having advantageous pharmaceutical properties such as processability, stability, and solubility.

Summary of the Invention

[0009] The present invention relates to novel solid forms of Compound 1 (collectively herein "the compounds of the present invention"). The present invention also relates to methods for preparing the compounds of the present invention and their use as modulators of GlyT1.

[0010] In a further aspect, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention, optionally together with one or more inert carriers and / or diluents. A further aspect of the present invention relates to the compounds of the present invention, or pharmaceutical compositions comprising the compounds of the present invention, for use in the prevention and / or treatment of neurological or mental disorders. Yet another aspect of the present invention relates to the use of the compounds of the present invention, or pharmaceutical compositions comprising said compounds, for the prevention and / or treatment of diseases or conditions that can be affected by inhibition of GlyT1, such as conditions related to the positive and negative symptoms of schizophrenia, and cognitive impairments associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders. Such use includes the manufacture of a medicament for treating the corresponding diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

Figure 2

Figure 3

Figure 4a

Figure 4b

Figure 5

Figure 6

Figure 7a

Figure 7b

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12a

Figure 12b

Figure 12c

Mode for Carrying Out the Invention

[0012] Abbreviation

Table 1

[0013] In one embodiment, the present invention relates to Solid Form I of Compound 1. In one embodiment, the present invention relates to Solid Form II of Compound 1. In one embodiment, the present invention relates to Solid Form III of Compound 1. Form I, Form II and Form III can each be prepared in a form that is substantially free of the other two polymorphs. For example, in one embodiment, Form I may be substantially free of Form II and Form III. In another embodiment, Form II may be substantially free of Form I and Form III. In another embodiment, Form III may be substantially free of Form I and Form II. As used herein, "substantially free of" means that the solid compound contains at least about 75% of one crystalline form of Compound 1 (e.g., Form II) relative to the total molar amount of Form I, Form II and Form III. The molar ratios of Form I, Form II or Form III of Compound 1 can be determined, for example, using the methods described herein.

[0014] In one embodiment, the crystalline compound of the present invention contains at least 75% of Form I of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 80% of Form I of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 90% of Form I of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 95% of Form I of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1.

[0015] In another embodiment, the crystalline compound of the present invention contains at least 75% of Form II of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 80% of Form II of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 90% of Form II of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 95% of Form II of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1.

[0016] In another embodiment, the crystalline compound of the present invention contains at least 75% of Form III of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 80% of Form III of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 90% of Form III of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. In another embodiment, the crystalline compound of the present invention contains at least 95% of Form III of Compound 1, based on the total molar amount of Form I, Form II, and Form III of Compound 1. The present invention also relates to Compound 1 comprising at least two of Form I, Form II, or Form III. In one embodiment, the present invention relates to Compound 1 comprising a mixture of Form I and Form II. In another embodiment, the present invention relates to Compound 1 comprising a mixture of Form I and Form III. In another embodiment, the present invention relates to Compound 1 comprising a mixture of Form II and Form III. In another embodiment, the present invention relates to Compound 1 comprising a mixture of Form I, Form II, and Form III. The present invention also relates to a combination of an amorphous form of Compound 1 and one or more crystalline forms of Compound 1 as described herein as Form I, Form II, or Form III.

[0017] Characterization: The compounds of the present invention can be characterized by the methods described below. The methods for preparing each of Form I, Form II, or Form III are described in the experimental section.

[0018] X-Ray Powder Diffraction (XRPD): X-ray powder diffraction analysis of samples of Form I, Form II, and Form III is performed on a Bruker AXS X-Ray powder diffractometer model D8 Advance using CuKα irradiation (1.54 Å) in parafocusing mode with a graphite monochromator and a scintillation detector. The patterns are each obtained by scanning over a 2-degree range (35 degrees 2θ, step size of 0.05 degrees 2θ, step time of 4 seconds per step). Exemplary XRPD spectra of Form I, Form II, and Form III are found in Figures 2, 5, and 8, respectively. An exemplary XRPD spectrum of the amorphous form of Compound 1 is shown in Figure 1. Tables 1, 3, and 5 contain the X-ray powder diffraction (XRPD) characteristics of Forms I, II, and III, respectively. The reported values in Tables 1, 3, and 5 have a standard deviation of ±0.2 2θ. Differential Scanning Calorimetry (DSC) DSC analysis is performed using general procedures on a differential scanning calorimeter (Q2000, TA instruments, New Castle, DE). Approximately 5 mg of powder was weighed into a corrugated aluminum pan with a pinhole. This sample was heated from room temperature to 250 °C at 10 °C / min using the Q2000 DSC. Exemplary DSC traces for Forms I, II, and III are found in FIGS. 3, 6, and 9, respectively. The results are reported below.

[0019] Water sorption Water sorption isotherms are determined using a dynamic vapor sorption system (Advantage, DVS, London, UK). At 25 °C, the sample is exposed stepwise from 0 to 90% RH in 10% increments. Each sample is equilibrated at each RH step for at least 60 minutes and considered at equilibrium if the mass increase within 1 minute is less than 0.1%, with a maximum period of 6 hours for each RH. Thus, each sample is held at a given RH for 1 - 6 hours depending on how quickly it reaches equilibrium.

[0020] Solid state NMR (SSNMR) Regarding samples of Form I, Form II, and Form III 13 13C solid state NMR (SSNMR) data are acquired at 9.4 T on a Bruker Avance III NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) ( 1 1H = 400.46 MHz, 13C = 100.70 MHz). The sample is encapsulated in a 4 mm outer diameter zirconia rotor equipped with a Kel-F (registered trademark) drive tip. A Bruker model 4BL CP BB WVT probe is used for data acquisition, and the sample is rotated around the magic angle (54.74 degrees). The acquisition of the sample spectrum uses a rotation speed of 12 kHz. The standard cross-polarization pulse sequence is used with a Hartmann-Hahn match pulse with a gradient on the proton channel at ambient temperature and ambient pressure. The pulse sequence uses a 3 millisecond contact pulse and a 5 second recycle delay. 2-pulse phase modulation (tppm) decoupling is also used in the pulse sequence. Exponential line broadening is not used before the Fourier transform of the free induction decay. The chemical shift is referenced using adamantane as a secondary standard, and its high-field resonance is set at 29.5 ppm. The magic angle is set using the 79 Br signal from KBr powder at a rotation speed of 5 kHz. Exemplary 13 C SSNMR spectra of Form I, Form II, and Form III are found in Figures 4, 7, and 10, respectively. Tables 2a, 4a, and 6 contain the chemical shifts obtained from the 13 C SSNMR spectra acquired for Forms I, II, and III, respectively. The reported values in Tables 2a, 4a, and 6 have a standard deviation of ±0.2 ppm.

[0021] Regarding samples of Form I, Form II, and Form II 19 F solid-state NMR (SSNMR) data are acquired at 9.4 T on a Bruker Avance III NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) ([[]] 1 H = 400.46 MHz, 19F = 376.76 MHz). The sample is encapsulated in a 3.2 mm outer diameter zirconia rotor equipped with a Kel-F (registered trademark) drive tip. A Bruker model 3.2BL BB probe is used for data acquisition, and the sample is rotated around the magic angle (54.74 degrees). The sample spectrum is acquired at a rotation speed of 22 kHz. A standard spin echo pulse sequence is used with a waiting time of 12 seconds. SPINAL-64 1H decoupling is also used. Exponential line broadening is not used before Fourier transformation of the free induction decay. The chemical shift is referenced using the highest intensity signal derived from polyvinylidene fluoride (PVDF), and its resonance is set to -91 ppm. The magic angle is set using the 79 Br signal from KBr powder at a rotation speed of 5 kHz. Exemplary 19 F SSNMR spectra of Forms I and II are found in Figures 4b and 7b, respectively. Tables 2b and 4b contain the chemical shifts obtained from the 19 F SSNMR spectra acquired for Forms I and II, respectively. The reported values in Tables 2 b and 4b have a standard deviation of ±0.2 ppm.

[0022] Raman Spectra Raman spectra for samples of Forms I, II, and III are acquired with a Nicolet6700 FT-Raman module AEU0900515 spectrometer. Form II exhibits a Raman scattering peak at 901 1 / cm, which is not observed in Forms I and III. The relative intensity of this peak can be used to estimate the relative amount of Form II present in the crystalline form of Compound 1.

[0023] Characteristics of Form I The X-ray powder diffraction (XRPD) pattern of Form I of Compound 1 is shown in Figure 2. The thermal analysis profile of Form I of Compound 1 determined by DSC measurement is shown in Figure 3. The 13 C solid NMR spectrum of Form I of Compound 1 is shown in Figure 4a. The 19The solid-state NMR spectrum of F is shown in Figure 4b.

[0024] Characteristic XRPD peaks: for Form I 13 The 13C solid-state nuclear magnetic resonance peaks and 19 the 19F solid-state nuclear magnetic resonance peaks are presented in Table 1, Table 2a, and Table 2b, respectively. [Table 2] [Table 3] [Table 4]

[0025] In one embodiment of the present invention, Form I of Compound 1 is characterized by the XRPD pattern of Figure 2. In another embodiment of the present invention, Form I of Compound 1 has the XRPD characteristics shown in Table 1. In another embodiment of the present invention, Form I of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, and 18.0°.

[0026] In another embodiment of the present invention, Form I of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, 19.0°, 20.0°, and 22.7°. In another embodiment of the present invention, Form I of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.6°, 9.2°, 10.0°, 12.2°, 16.7°, 17.2°, 18.5°, 19.0°, 20.0°, and 22.7°. In yet another embodiment of the present invention, Form I of Compound 1 is characterized by the 13C solid-state nuclear magnetic resonance peaks shown in Table 2a. 13 In yet another embodiment of the present invention, Form I of Compound 1 is characterized by the 19F solid-state nuclear magnetic resonance peaks shown in Table 2b. 19 In yet another embodiment of the present invention, Form I of Compound 1 is characterized by the 19F solid-state nuclear magnetic resonance peaks shown in Table 2b.

[0027] In another embodiment of the present invention, Form I of Compound 1 has at least three 13 13C solid nuclear magnetic resonance peaks characterized by chemical shifts selected from 131.5 ppm, 127.2 ppm, 28.7 ppm, and 25.7 ppm.

[0028] In another embodiment of the present invention, Form I of Compound 1 has 13 13C solid nuclear magnetic resonance peaks characterized by chemical shifts selected from 131.5 ppm, 127.2 ppm, 28.7 ppm, and 25.7 ppm.

[0029] In another embodiment of the present invention, Form I of Compound 1 has 13C solid nuclear magnetic resonance peaks characterized by chemical shifts selected from 167.2 ppm, 159.4 ppm, 156.9 ppm, 131.5 ppm, 115.4 ppm, 127.2 ppm, 46.8 ppm, 45.7 ppm, 28.7 ppm, 25.7 ppm, and 13.7 ppm. 13 13C solid nuclear magnetic resonance peaks characterized by chemical shifts selected from 167.2 ppm, 159.4 ppm, 156.9 ppm, 131.5 ppm, 115.4 ppm, 127.2 ppm, 46.8 ppm, 45.7 ppm, 28.7 ppm, 25.7 ppm, and 13.7 ppm. In another embodiment of the present invention, Form I of Compound 1 has the 19 19F solid nuclear magnetic resonance characteristics shown in Table 2b. In another embodiment of the present invention, Form I of Compound 1 has at least three 19 19F solid nuclear magnetic resonance peaks characterized by chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and -80.0 ppm.

[0030] In another embodiment of the present invention, Form I of Compound 1 has at least five 19 19F solid nuclear magnetic resonance peaks characterized by chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and -80.0 ppm. In another embodiment of the present invention, Form I of Compound 1 has 19 19F solid nuclear magnetic resonance peaks characterized by chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and -80.0 ppm. In another embodiment of the present invention, Form I of Compound 1 has the XRPD characteristics shown in Table 1, or the 13 13C solid state nuclear magnetic resonance peaks shown in Table 2a, or the 19 19F solid state nuclear magnetic resonance peaks shown in Table 2b. In another embodiment of the present invention, Form I of Compound 1 has at least three XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7° and 18.0°; at least three 13 13C solid state nuclear magnetic resonance peaks at chemical shifts selected from 131.5 ppm, 127.2 ppm, 28.7 ppm and 25.7 ppm; or at least three 19 19F solid state nuclear magnetic resonance peaks at chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and -80.0 ppm. In another embodiment of the present invention, Form I of Compound 1 has XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7° and 18.0°; 13 13C solid state nuclear magnetic resonance peaks at chemical shifts selected from 131.5 ppm, 127.2 ppm, 28.7 ppm and 25.7 ppm; or 19 19F solid state nuclear magnetic resonance peaks at chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and -80.0 ppm.

[0031] Characteristics of Form II The X-ray powder diffraction (XRPD) pattern of Form II of Compound 1 is shown in Figure 5. The thermal analysis profile of Form II of Compound 1 determined by DSC measurement is shown in Figure 6. The 13 13C solid state NMR spectrum of Form II of Compound 1 is shown in Figure 7a. The 19 19F solid state NMR spectrum of Form II of Compound 1 is shown in Figure 7b.

[0032] Characteristic XRPD peaks: for Form II 13 13C solid state nuclear magnetic resonance peaks and 19The F solid nuclear magnetic resonance peaks are presented in Table 3, Table 4a, and Table 4b, respectively.

Table 5

Table 6

Table 7

[0033] In one embodiment of the present invention, Form II of Compound 1 is characterized by the XRPD pattern of Figure 5. In another embodiment of the present invention, Form II of Compound 1 has the XRPD characteristics shown in Table 3.

[0034] In another embodiment of the present invention, Form II of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7°, and 18.0°. In another embodiment of the present invention, Form II of Compound 1 is characterized by at least four XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7°, and 18.0°.

[0035] In another embodiment of the present invention, Form II of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7°, and 18.0°. In another embodiment of the present invention, Form II of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 15.8°, 18.0°, 18.5°, 19.1°, 20.0°, 20.9°, 22.7°, and 23.3°. In yet another embodiment of the present invention, Form II of Compound 1 has the 13 solid nuclear magnetic resonance characteristics shown in Table 4a.

[0036] In another embodiment of the present invention, Form II of Compound 1 is at chemical shifts selected from 130.1 ppm, 46.6 ppm, and 25.0 ppm 13 characterized by 13C solid-state nuclear magnetic resonance peaks. In another embodiment of the present invention, Form II of Compound 1 is at chemical shifts selected from 167.3 ppm, 157.1 ppm, 130.1 ppm, 115.6 ppm, 72.2 ppm, 47.9 ppm, 46.6 ppm, 45.9 ppm, 25.0 ppm, and 12.9 ppm 13 characterized by 13C solid-state nuclear magnetic resonance peaks. In another embodiment of the present invention, Form II of Compound 1 has the 19 19F solid-state nuclear magnetic resonance characteristics shown in Table 4b. In another embodiment of the present invention, Form II of Compound 1 has at least three 19 19F solid-state nuclear magnetic resonance peaks at chemical shifts selected from -64.0, -65.6, -66.6, -78.2, and -79.1 ppm.

[0037] In another embodiment of the present invention, Form II of Compound 1 has 19 19F solid-state nuclear magnetic resonance peaks at chemical shifts selected from -64.0, -65.6, -66.6, -78.2, and -79.1 ppm. In another embodiment of the present invention, Form II of Compound 1 has the XRPD characteristics shown in Table 3, or the 13 13C solid-state nuclear magnetic resonance peaks shown in Table 4a, or the 19 19F solid-state nuclear magnetic resonance peaks shown in Table 4b.

[0038] In another embodiment of the present invention, Form II of Compound 1 has at least three XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7°, and 18.0°; 13C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 130.1 ppm, 46.6 ppm, and 25.0 ppm; or at least three 13 19F solid-state nuclear magnetic resonance peaks at chemical shifts selected from -64.0, -65.6, -66.6, -78.2, and -79.1 ppm19 It is characterized by F solid nuclear magnetic resonance peaks. In another embodiment of the present invention, Form II of Compound 1 has at least four XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7° and 18.0°; chemical shifts selected from 130.1 ppm, 46.6 ppm and 25.0 ppm of 13 13C solid nuclear magnetic resonance peaks; or chemical shifts selected from -64.0, -65.6, -66.6, -78.2 and -79.1 ppm of 19 F solid nuclear magnetic resonance peaks. In another embodiment of the present invention, Form II of Compound 1 has XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7° and 18.0°; chemical shifts selected from 130.1 ppm, 46.6 ppm and 25.0 ppm of 13 13C solid nuclear magnetic resonance peaks; or chemical shifts selected from -64.0, -65.6, -66.6, -78.2 and -79.1 ppm of 19 F solid nuclear magnetic resonance peaks.

[0039] Characteristics of Form III The X-ray powder diffraction (XRPD) pattern of Form III of Compound 1 is shown in Figure 8. The thermal analysis profile of Form III of Compound 1 determined by DSC measurement is shown in Figure 9. The 13 13C solid NMR spectrum of Form III of Compound 1 is shown in Figure 10.

[0040] Characteristic XRPD peaks and 13 13C solid nuclear magnetic resonance peaks for Form III are presented in Table 5 and Table 6, respectively.

Table 8

Table 9

[0041] In another embodiment of the present invention, Form III of Compound 1 has the XRPD characteristics shown in Table 5. In another embodiment of the present invention, Form III of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°. In another embodiment of the present invention, Form III of Compound 1 is characterized by at least four XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°. In another embodiment of the present invention, Form III of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°.

[0042] In another embodiment of the present invention, Form III of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 4.8°, 8.1°, 9.7°, 10.3°, 13.9°, 19.3°, 19.6°, 23.3° and 24.6°. In another embodiment of the present invention, Form III of Compound 1 has the 13 C solid nuclear magnetic resonance characteristics shown in Table 6. In another embodiment of the present invention, Form III of Compound 1 is characterized by at least two 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm. In another embodiment of the present invention, Form III of Compound 1 is characterized by at least two 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm.

[0043] In another embodiment of the present invention, Form III of Compound 1 is characterized by at least two 13It is characterized by the C solid nuclear magnetic resonance peaks. In another embodiment of the present invention, Form III of Compound 1 has at least three 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm, and 14.3 ppm. In another embodiment of the present invention, Form III of Compound 1 has at least four 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm, and 14.3 ppm.

[0044] In another embodiment of the present invention, Form III of Compound 1 has 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm, and 14.3 ppm.

[0045] In another embodiment of the present invention, Form III of Compound 1 has 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 156.0 ppm, 134.2 ppm, 132.5 ppm, 47.6 ppm, 46.0 ppm, 44.6 ppm, 25.5 ppm, 14.3 ppm, and 13.0 ppm. In another embodiment of the present invention, Form III of Compound 1 has at least three XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9°, and 24.6°; or at least three 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm, and 14.3 ppm. In another embodiment of the present invention, Form III of Compound 1 has at least four XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°; or at least four 13 13C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm.

[0046] In another embodiment of the present invention, Form III of Compound 1 has XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°; or at least four 13 13C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm. In another embodiment of the present invention, Form III of Compound 1 has XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°; or at 13 13C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm. In another embodiment of the present invention, Form III of Compound 1 has the XRPD characteristics shown in Table 5, or the 13 13C solid nuclear magnetic resonance peaks shown in Table 6.

[0047] Methods for preparing Form I, Form II, Form III and mixtures thereof The present invention also relates to a method for preparing a solid form of Compound 1. Generally, Form I, Form II, Form III and mixtures thereof can be obtained by dissolving Compound 1 in a suitable solvent at a temperature higher than room temperature, for example, 25 °C, more preferably at about 45 °C to about 80 °C (the "dissolving step"). Next, the heated solution is cooled (the "cooling step") to obtain a solid / liquid containing Form I, Form II, Form III or a mixture thereof as a solid. In some embodiments, the heated solution can be filtered before cooling. In other embodiments, the heated solution may be concentrated before or during the cooling step (the "concentrating step"). In still other embodiments, the heated solution may be treated with a co-solvent (the "co-solvent treatment step"). In some embodiments, the co-solvent (if used) can be added during the cooling step. In still other embodiments, the cooling step includes stepwise gradient cooling. In still other embodiments, a seed crystal or seed slurry is added during the cooling step (the "seeding step"). It is understood that Form I, Form II, Form III and mixtures thereof can be obtained using any combination of the above. Once cooled, the resulting solid is collected, washed with a suitable solvent and dried to obtain Form I, Form II, Form III or a mixture thereof.

[0048] Method for preparing a mixture of Form I and Form II In one embodiment, the present invention is a method for preparing a mixture of Form I and Form II of Compound 1, comprising: (a) heating a mixture of Compound 1 in 2-propanol to 70 °C to obtain a solution; (b) treating the solution obtained in step (a) with water while maintaining the temperature at 50 °C to 70 °C; (c) cooling the aqueous mixture of step (b) to 20 °C; and (d) collecting the resulting solid as a mixture of Form I and Form II of Compound 1. The present invention relates to a method comprising the above steps. In one embodiment, the amorphous form of Compound 1 is used in step (a).

[0049] Method for preparing Form I In another embodiment, the present invention is a method for preparing the solid Form I of Compound 1, comprising: (a) heating Compound 1 and tert-butyl methyl ether (TBME) or water at 50 °C to obtain a slurry; (b) cooling the slurry of step (a); and (c) collecting the solid obtained as Form I of Compound 1. The present invention relates to a method comprising the above steps. In one embodiment, the amorphous form of Compound 1 is used in step (a) of the immediately preceding embodiment.

[0050] In another embodiment, the present invention relates to one of the two immediately preceding embodiments, further comprising concentrating the slurry of step (b) before cooling the slurry in step (b). In another embodiment, the present invention is a method for preparing Form I of Compound 1, comprising: (a) heating Compound 1 and 2-propanol to 50 - 55 °C to obtain a solution; (b) cooling the solution of step (a) to 25 °C; (c) treating the cooled solution of step (b) with water; and (d) collecting the solid obtained as Form I of Compound 1. The present invention relates to a method comprising the above steps. In another embodiment, the present invention relates to an embodiment described immediately above, wherein the amorphous form of Compound 1, or a mixture of Form I and Form II of Compound 1, is used in step (a).

[0051] Method for preparing Form II In another embodiment, the present invention is a method for preparing Form II of Compound 1, comprising: (a) Step of heating a mixture of compound 1 and 2-propanol to 70° to obtain a solution, (b) Step of filtering the solution of step (a), (c) Step of cooling the filtrate from step (b) to 55°C, (d) Step of treating the cooled solution of step (c) with water, (e) Step of cooling the water-treated mixture of step (d) to 20°C, and (f) Step of collecting the solid obtained as Form II of compound 1 relates to a method comprising.

[0052] In another embodiment, the present invention further comprises the steps of adding seed crystals to the water-treated solution of step (d), further mixing the solution with added seed crystals at 55°C, and cooling to 20°C after treating the solution with added seed crystals with water, and relates to the method described in the immediately preceding embodiment. In another embodiment, the present invention relates to one of the two embodiments described immediately above, wherein the amorphous form of compound 1, or a mixture of Form I and Form II of compound 1, is used in step (a).

[0053] In another embodiment, the present invention is a method for preparing Form II of compound 1, comprising (a) Step of heating a mixture consisting of compound 1 (a mixture of Form I and Form II), 2-propanol and water to 55 - 60°C to obtain a solution, (b) Step of filtering the solution of step (a), (c) Step of heating the filtrate of step (b) to 68 - 70°C, (d) Step of treating the filtrate derived from step (c) with water while maintaining the temperature at 68°C - 70°C, (e) Step of cooling the water-treated filtrate derived from step (d) to 62 - 66°C, (f) Step of adding seed crystals to the water-treated solution of step (d) using a seed crystal slurry containing Form II of compound 1, water and isopropanol to obtain a mixture with added seed crystals, (g) Step of cooling the mixture with seeds added in step (f) to 55 °C (h) Step of mixing the solution with seeds added in step (e) at 55 °C (i) Step of treating the solution with seeds added in step (h) with water to obtain a mixture (j) Step of mixing the mixture in step (i) at 55 °C (k) Step of cooling the cooled mixture in step (j) to 20 °C, and (l) Step of collecting the solid obtained as Form II of Compound 1 relates to a method comprising In another embodiment, the present invention relates to an embodiment which is the embodiment described immediately above, wherein the amorphous form of Compound 1, or a mixture of Form I and Form II of Compound 1, is used in step (a).

[0054] Method for preparing Form III In another embodiment, the present invention relates to a method for preparing Form III of Compound 1, comprising (a) Step of heating a mixture of Compound 1 (Form II) and methanol to 50 - 55 °C to obtain a solution (b) Step of concentrating the solution in step (a) at 40 - 45 °C (c) Step of cooling the concentrated solution from step (b) to 25 °C, and (d) Step of collecting the solid obtained as Form III of Compound 1 relates to a method comprising In another embodiment, the present invention relates to an embodiment which is the embodiment described immediately above, wherein Form I of Compound 1 is used in step (a).

[0055] Treatment method The compounds of the present invention are selective inhibitors of glycine transporter 1 (GlyT1). The medical concepts discussed herein are considered to be of great interest as fields of application for the active compounds of the present invention. The active compounds of the present invention can be used in the development of medicaments. Such medicaments are preferably used in the treatment of diseases where inhibition of GlyT1 can bring about a therapeutic, prophylactic or disease-modifying effect. Preferably, the medicament is used for treating psychosis, memory and learning dysfunctions, schizophrenia (positive and negative symptoms of schizophrenia and cognitive impairments associated with schizophrenia), dementia such as Alzheimer's, and other diseases with impaired cognitive processes such as attention deficit disorder, Parkinson's disease, epilepsy and / or bipolar disorder.

[0056] In particular, the medicament mild cognitive impairment, amnestic mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic encephalopathy, general concentration disorder, concentration disorder associated with learning and memory problems in children, Alzheimer's disease, mild Alzheimer's disease, mild to moderate Alzheimer's disease, moderate to severe Alzheimer's disease, prodromal Alzheimer's disease, Lewy body dementia, dementia associated with frontal lobe degeneration (including Pick's syndrome), Parkinson's disease, progressive supranuclear palsy, dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jakob dementia, HIV dementia, encephalitis, temporal lobe epilepsy, Korsakoff's psychosis or cognitive impairment associated with schizophrenia, prodromal schizophrenia, major depressive disorder, depression, Parkinson's disease, epilepsy, schizoaffective disorder or bipolar disorder such as those occurring in conditions, diseases and / or syndromes, for a method of improving perception, concentration, cognition, learning or memory, preferably for use in therapy.

[0057] Another aspect of the present invention relates to the treatment of diseases that can be exploited by GlyT1 inhibition, in particular sleep disorders such as insomnia or narcolepsy, bipolar disorder, depression, substance use / abuse disorders, auditory disorders, attention deficit (hyperactivity) disorder, inflammatory pain, neuropathic pain, autism spectrum disorder or impulse control disorders. The compounds of the present invention can be used in medicine or as a medicine. Such a medicine is preferably for a treatment or prevention method in the treatment of CNS diseases, preferably for a treatment method. In an alternative use, the medicine is for treating CNS diseases, and the treatment is available by inhibition of GlyT1. In an alternative use, the medicine is for treating diseases that can be exploited by inhibition of GlyT1. In an alternative use, the medicine is for use in a method for the treatment of Alzheimer's disease, schizophrenia (positive and negative symptoms), or cognitive impairment associated with Alzheimer's disease or schizophrenia. In a further aspect of the present invention, the present invention is a method for treating or preventing a condition or disease selected from the group listed above for conditions and diseases, comprising administering to a human in need thereof a therapeutically effective amount of a compound according to the present invention.

[0058] The applicable dosage range per day of the compounds of the present invention is usually 0.1 - 5000 mg, preferably 0.1 - 1000 mg, preferably 2 - 500 mg, more preferably 5 - 250 mg, most preferably 10 - 100 mg. Dosage units (for example, tablets) can preferably contain the active compound according to the present invention between 2 - 250 mg, particularly preferably between 10 - 100 mg. Another aspect of the present invention relates to the compounds of the present invention for use in a treatment method or for use as a medicine. The treatment method or medicine, if indicated, is preferably for the treatment of a condition or disease selected from the group of conditions or diseases outlined above in this item entitled "Method of Treatment". Another aspect of the present invention relates to the use of the compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease selected from the group of conditions or diseases outlined above in this section entitled "Method of Treatment".

[0059] Pharmaceutical composition Suitable preparations for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants and powders. The content of the pharmaceutically active compound should generally be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the composition.

[0060] Suitable tablets can be obtained, for example, by mixing the active substance with known excipients such as inert diluents like calcium carbonate, calcium phosphate, lactose / lactose monohydrate or microcrystalline cellulose; disintegrants such as corn starch, alginic acid or croscarmellose sodium; binders such as starch or gelatin; lubricants such as magnesium stearate or talc; and / or agents for effecting delayed release such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain several layers.

[0061] The term "active substance" represents one or more of the compounds of Form I, Form II or Form III. When being one of the aforementioned combinations with one or more other active substances, the term "active substance" may also include additional active substances. Standard procedures should be considered for the preparation of any pharmaceutical formulation mentioned herein. Accordingly, coated tablets can be prepared by coating a core produced in the same manner as tablets with substances commonly used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. For the achievement of delayed release or the prevention of incompatibility, the core may also consist of several layers. Similarly, the tablet coating can potentially consist of a number or layers for the achievement of delayed release using the above excipients for tablets. In the case of oral administration, tablets may naturally contain, in addition to the carriers described above, various additives such as starch, preferably potato starch, gelatin, and additives such as sodium citrate, calcium carbonate and dicalcium phosphate. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tabletting process. In the case of aqueous suspensions, the active substance may be combined with various flavor enhancers or colorants in addition to the above excipients. The active ingredient / substance or active moiety can conveniently be administered in either a liquid state, either as a solution or suspension, mixed with a single carrier excipient or a complex carrier composed of several constituents, either in a lipophilic carrier system or a hydrophilic carrier system. Encapsulation of such a liquid formulation into either a soft (gelatin) capsule or a hard (gelatin) capsule is likely to provide a very convenient way of administering such a pharmaceutically active substance.

[0062] Syrups or elixirs containing the active substance according to the invention may further contain sweeteners such as saccharin, cyclamate, glycerol or sugar, and flavor enhancers, such as flavoring agents like vanilla or orange extract. They may also contain suspending adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate. The capsule containing the active substance of the present invention can be prepared, for example, by mixing the active substance with an inert carrier such as lactose or sorbitol and packing them into gelatin capsules.

[0063] Excipients that can be used include, for example, water, pharmaceutically acceptable organic solvents (paraffin (e.g., petroleum fraction), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), etc.), carriers (e.g., natural inorganic powders (e.g., kaolin, clay, talc, chalk), synthetic inorganic powders (e.g., highly dispersed silicic acid and silicates), etc.), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, sulfite pulp waste liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

[0064] The dosage for oral administration in the case of humans is 0.5 to 1000 mg per administration, with one or multiple administrations per day.

[0065] However, sometimes it may be necessary to deviate from the specified amount depending on the body weight, the route of administration, the individual's response to the active substance, the nature of the formulation, and the time or interval at which the active substance is administered. Therefore, in some cases, use below the minimum dosage shown above may be sufficient, while in other cases, it may be necessary to exceed the upper limit. When administering in large amounts, it may be advisable to divide it into several smaller dosages over a day. In one embodiment, the present invention relates to a pharmaceutical composition comprising Form I, Form II, Form III, or a mixture of at least two of Form I, Form II and Form III, and a pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a pharmaceutical composition comprising Form I of Compound 1 and a pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a pharmaceutical composition comprising Form II of Compound 1 and a pharmaceutically acceptable excipient.

[0066] In another embodiment, the present invention relates to a pharmaceutical composition comprising Form III of Compound 1 and a pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a pharmaceutical composition comprising at least two of Form I, Form II and Form III of Compound 1, and a pharmaceutically acceptable excipient. The following further examples of pharmaceutical dosage forms illustrate the present invention without limiting its scope.

[0067]

Table 10

[0068] Such combinations can be fixed-dose combinations (where the active ingredients combined are the subject of the same pharmaceutical dosage form) or free combination dosages (where the active ingredients are individual pharmaceutical formulations).

[0069] Accordingly, a further aspect of the present invention is a compound of the present invention in combination with, for example, antipsychotics (such as haloperidol, clozapine, risperidone, quetiapine, aripiprazole, asenapine and olanzapine); antidepressants (such as selective serotonin reuptake inhibitors and dual serotonin / norepinephrine reuptake inhibitors); mood stabilizers (such as lithium valproate and lamotrigine); beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase modulators; amyloid aggregation inhibitors (such as siro-inositol); direct or indirect acting neuroprotective and / or disease modifying substances; antioxidants (such as vitamin E, ginko biloba or ginkolides); anti-inflammatory substances (such as Cox inhibitors, NSAIDs having the property of further or exclusively reducing Aβ (amyloid beta)); HMG-CoA reductase inhibitors (such as statins); acetylcholinesterase inhibitors (such as donepezil, rivastigmine, tacrine, galantamine); NMDA receptor antagonists (such as memantine); AMPA receptor agonists; AMPA receptor positive modulators, AMP kainate, glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; substances that modulate the concentration or release of neurotransmitters; substances that induce the secretion of growth hormones such as ibutamoren mesylate and capromorelin; CB-1 receptor antagonists or inverse agonists; antibiotics (such as minocycline or rifampicin); PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or positive modulators; alpha7 nicotinic receptor agonists or partial agonists or positive allosteric modulators; histamine receptor H3 antagonists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists;Alpha-2 adrenergic receptor antagonists, calcium antagonists; muscarinic receptor M1 agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; muscarinic receptor M4 positive allosteric modulators; metabotropic glutamate receptor 5, positive allosteric modulators; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate receptor 2 / 3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators, and a combination with another active compound selected from the group of other substances that modulate receptors or enzymes in a manner such that the effectiveness and / or safety of the active compounds according to the invention is improved and / or undesirable side effects are reduced.;

[0070] The compounds of the invention may also be used in combination with immunotherapy for treating the above-mentioned diseases and conditions, for example, active immunization with A beta or a part thereof, or passive immunization with a humanized anti-A beta antibody or antibody fragment.;

[0071] The compounds of the invention may also be combined with antipsychotics such as haloperidol, flupentixol, fluspirilene, chlorprothixene, protipendyl, levomepromazine, clozapine, olanzapine, quetiapine, risperidone, paliperidone, amisulpride, diprasidone, aripiprazole, sulpiride, zotepine, sertindole, fluphenazine, perphenazine, perazine, promazine, chlorpromazine, levomepromazine, benperidol, bromperidol, pimozide, melperone, pipamperone, iloperidone, asenapine, perospirone, bronantherine and lurasidone.;

[0072] The compounds of the present invention may also be combined with antidepressants such as amitriptyline hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL). Alternatively, the compounds of the present invention may also be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), dimelazine (NORMUD, ZELMID), bici-fazine, desvenlafaxine (PRISTIQ), brasofensum and tesofensine.

[0073] The combination according to the present invention may be provided in one and the same dosage form, i.e., in the form of a combined preparation. For example, the two components may be incorporated into one tablet, for example, in different layers of the tablet. The dosage or dosage form is not limited. In the framework of the present invention, any suitable dosage form may be used. By way of example, the dosage form may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, etc., liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, etc., or gas preparations such as aerosols, sprays, etc. It is advantageous for the dosage form to be formulated in dosage units, and each dosage unit is adapted to provide a single dose of each active component present. Therefore, the components are selected depending on the route of administration and the dosage form. The dosage for the above combination partners can usually conveniently range from 1 / 5 of the usually recommended minimum dosage to 1 / 1 of the usually recommended dosage. The dosage form is administered to the patient once, twice, three times or four times a day, for example, depending on the nature of the preparation. In the case of delayed-release preparations or sustained-release preparations or other pharmaceutical preparations, the same substance may be applied differently (for example, once a week or once a month, etc.). The active compounds of the present invention are preferably administered in three or fewer doses, more preferably either once a day or twice a day.

Examples

[0074] (Example 1) Preparation of amorphous compound 1: The amorphous form of compound 1 (“amorphous compound 1”) is prepared as described in Example 50 of WO2013017657. The chiral separation of the diastereomer mixture (prepared according to Example 49 of WO2013017657) is carried out as described in Example 49, except that the flow rate is 12 ml / min instead of 15 ml / min. The solvent is removed from the obtained eluate under reduced pressure to obtain amorphous compound 1 as a solid. The typical XRPD pattern obtained for a sample of amorphous compound 1 is shown in Figure 1.

[0075] (Example 2) Preparation of a mixture of Form I and Form II of compound 1: The amorphous form of compound 1 (20 g) and 2-propanol (75 mL) are charged into a reactor, and the contents are heated to 70 °C. While maintaining the batch temperature above 50 °C, the obtained solution is treated with water (111 mL). Next, the contents of the reactor are cooled to 20 °C over 1.5 hours. The solid is collected by filtration, rinsed with water, and dried at 40 °C under reduced pressure to prepare a mixture of Form I and Form II of compound 1 (15.4 g, 77% yield) based on the characterization methods described herein, and when determined by Raman spectroscopy, it has a molar ratio of 61:39 (Form I:Form II).

[0076] (Example 3A) Preparation of Form I of Compound 1: Amorphous Compound 1 (50 mg) is treated with 4 ml of tert-butyl methyl ether (TBME), and the resulting slurry is stirred at 50 °C for 2 hours. Approximately 2 ml of the solvent is removed under reduced pressure. Next, this mixture is filtered, and the solid is dried in a vacuum oven at 40 °C overnight to obtain Form I of Compound 1. Form I of Compound 1 can also be prepared by following the procedure described immediately above using water instead of TBME. (Example 3B) Preparation of Form I of Compound 1: A mixture of Form I and Form II of Compound 1 (14 g, 0.029 mol) is dissolved in 2-propanol (140 mL) and heated to 50 - 55 °C. The resulting solution is cooled to room temperature and then treated with water (500 mL) while mixing vigorously. Next, stirring is stopped, and the contents of the reactor are allowed to stand without stirring for at least 30 minutes. Next, the resulting solid is collected by filtration, washed with water and then with heptane, and air-dried for 2 hours to obtain 14.6 g of Form I of Compound 1.

[0077] (Example 4A) Preparation of Form II of Compound 1: A mixture of Form I and Form II of Compound 1 (37 g, 0.072 mol) and 140 ml of isopropanol are charged into a reactor, and the contents of this reactor are heated to about 70 °C. The resulting solution is vacuum-filtered (Büchner funnel with filter paper), and the filtrate is cooled to about 55 °C. Next, this solution is treated with water (111 mL), and while mixing vigorously at 55 °C for at least 4 hours, it is seeded with 0.74 g of Form I of Compound 1. Additional water (95.14 g) is added to the stirred mixture over at least 6 hours, stirring is stopped, and the contents of the reactor are cooled to 20 °C over at least 4 hours. Next, the resulting solid is collected by filtration, washed with water and then with heptane, and air-dried to obtain Form II of Compound 1. Similar results are obtained when seeding is carried out using Form II, or a mixture of Form I and Form II.

[0078] (Example 4B) Preparation of Form II of Compound 1: Charge a reactor with a mixture of Form I and Form II of Compound 1 (100 g, 0.195 mol), isopropanol (500 mL), and water (100 mL). Heat the contents of the reactor to 55 - 60 °C with stirring, and at 55 - 60 °C, filter the resulting solution under vacuum (Büchner funnel equipped with filter paper). Heat the stirred filtrate to 68 - 70 °C, treat it with 600 mL of water while maintaining the temperature at 68 - 70 °C, and cool it to 62 - 66 °C over 30 minutes. Seed the solution with a seed crystal slurry of Form II of Compound 1 (2 g) in a mixture of 20 g of water and 4 g of isopropyl alcohol, age at 62 - 66 °C for 0.5 hour, and cool the solution to 55 °C over 2 - 3 hours. Stir the resulting mixture at 55 °C for 2 hours, cool it to 20 °C over 4 - 6 hours, and filter. Wash the solid with water (200 mL) and dry it at 50 - 70 °C for at least 8 hours to obtain Form II of Compound 1.

[0079] (Example 5) Preparation of Form III of Compound 1: Charge a reactor with Form II of Compound 1 (20 g, 39 mmol) and methanol (200 mL), and heat the contents of the reactor to 50 - 55 °C. Next, concentrate the contents of the reactor to about 80 mL under reduced pressure at 40 - 45 °C, cool it to room temperature over at least 1 hour, and stir at room temperature for an additional 2 hours. Collect the solid by filtration, wash it with heptane, and dry it at 50 °C under reduced pressure for 10 hours to obtain 19.46 g of Form III of Compound 1. Another aspect of the present invention may be as follows. 〔1〕The following structural formula: TIFF0007714727000012.tif4640 1 A solid form I of Compound 1 having wherein Form I of Compound 1 at least three XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, 18.0°, 19.0°, 20.0° and 22.7°, or at least three 13 131.5 ppm, 127.2 ppm, 28.7 ppm and 25.7 ppm, or at least three 19 C solid nuclear magnetic resonance peaks at chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and -80.0 ppm F solid nuclear magnetic resonance peaks Solid form I of Compound 1, characterized by 〔2〕The solid form I of Compound 1 according to the above 〔1〕, characterized by at least four XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, 18.0°, 19.0°, 20.0° and 22.7°. 〔3〕The solid form I of Compound 1 according to the above 〔1〕 or 〔2〕, characterized by at least five XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, 18.0°, 19.0°, 20.0° and 22.7°. 〔4〕The solid form I of Compound 1 according to any one of the above 〔1〕 to 〔3〕, characterized by XRPD peaks at 2θ angles selected from 4.6°, 10.0°, 16.7°, 18.0°, 19.0°, 20.0° and 22.7°. 13 〔5〕The solid form I of Compound 1 according to any one of the above 〔1〕 to 〔4〕, characterized by C solid nuclear magnetic resonance peaks at chemical shifts selected from 131.5 ppm, 127.2 ppm, 28.7 ppm and 25.7 ppm. 19 〔6〕The solid form I of Compound 1 according to any one of the above 〔1〕 to 〔5〕, characterized by F solid nuclear magnetic resonance peaks at chemical shifts selected from -64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and -80.0 ppm. TIFF0007714727000013.tif4640 2 〔7〕The following structural formula: A solid form II of Compound 1 having wherein Form II has the following d values: 4.1°, 4.6°, 10.0°, 16.7° and 18.0° (2-theta) characteristic X-ray reflections at, or 130.1 ppm, 46.6 ppm and 25.0 ppm characteristic 13 C solid NMR chemical shifts selected from, or at least three characteristic 19 F solid nuclear magnetic resonance peaks at chemical shifts selected from -64.0, -65.6, -66.6, -78.2 and -79.1 ppm Compound 1 in solid form II having. [8] Solid form II of Compound 1 as described in [7] above, characterized by at least four XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7° and 18.0°. [9] Solid form II of Compound 1 as described in [7] or [8] above, characterized by XRPD peaks at 2θ angles selected from 4.1°, 4.6°, 10.0°, 16.7° and 18.0°.

[10] At chemical shifts selected from -64.0, -65.6, -66.6, -78.2 and -79.1 ppm 19 Solid form I of Compound 1 as described in any one of [7] to [9] above, characterized by

[11] The following structural formula: TIFF0007714727000014.tif4640 1 Compound 1 in solid form III having, wherein Form III of Compound 1 is: at least three XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°, or at least three 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm Compound 1 in solid form III characterized by.

[12] Solid form III of Compound 1 as described in

[11] above, characterized by at least four XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°.

[13] Solid form III of Compound 1 as described in

[11] or

[12] above, characterized by XRPD peaks at 2θ angles selected from 4.8°, 9.7°, 10.3°, 13.9° and 24.6°.

[14] At least four 13 C solid nuclear magnetic resonance peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm and 14.3 ppm, characterizing the solid form III of Compound 1 as described in any one of

[11] to

[13] . 〔15〕Solid state NMR peaks at chemical shifts selected from 156.6 ppm, 134.2 ppm, 46.0 ppm, 25.5 ppm, and 14.3 ppm 13 Solid form III of Compound 1 according to any one of items 〔11〕 to 〔14〕 above, characterized by the 〔16〕A method for preparing solid form I of Compound 1 according to item 〔1〕 above, comprising: (a) heating Compound 1 and tert-butyl methyl ether (TBME) or water to obtain a slurry; (b) cooling the slurry of step (a); and (c) collecting the solid obtained as form I of Compound 1. A method comprising the above steps. 〔17〕The method according to item 〔16〕 above, wherein the amorphous form of Compound 1 is used in step (a). 〔18〕A method for preparing form II of Compound 1 according to item 〔7〕 above, comprising: (a) heating a mixture of Compound 1 and 2-propanol to 70 °C to obtain a solution; (b) filtering the solution of step (a); (c) cooling the filtrate from step (b) to 55 °C; (d) treating the cooled solution of step (c) with water; (e) cooling the water-treated mixture of step (d) to 20 °C; and (f) collecting the solid obtained as form II of Compound 1. A method comprising the above steps. 〔19〕The method according to item 〔18〕 above, further comprising: (d1) adding seeds to the water-treated solution of step (d); (d2) mixing the seeded solution at 55 °C; and (d3) treating the seeded solution with water before cooling to 20 °C. 〔20〕The method according to item 〔18〕 or 〔19〕 above, wherein the amorphous form of Compound 1, or a mixture of form I and form II of Compound 1, is used in step (a). 〔21〕A method for preparing solid form III of Compound 1 according to item 〔11〕 above, comprising: (a) heating a mixture of Compound 1 and methanol to 50 - 55 °C to obtain a solution; (b) concentrating the solution of step (a) at 40 - 45 °C; (c) cooling the concentrated solution from step (b) to 25 °C; and (d) collecting the solid obtained as form III of Compound 1. A method comprising the above steps. 〔22〕The method according to item 〔21〕 above, wherein the amorphous form of Compound 1 is used in step (a). 〔23〕A pharmaceutical composition comprising the solid form of the compound according to any one of 〔1〕 to 〔15〕 above, optionally together with one or more inert carriers and / or diluents. 〔24〕A method of using the solid form of the compound 1 according to any one of 〔1〕 to 〔15〕 above, or the pharmaceutical composition according to 〔23〕 above, for treating and / or preventing neurological or mental disorders. 〔25〕The method according to 〔24〕 above, wherein the neurological or mental disorder is selected from the positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, and Alzheimer's disease. 〔26〕The solid form of the compound according to any one of 〔1〕 to 〔15〕 above, or the pharmaceutical composition according to 〔23〕 above, for use in the prevention and / or treatment of neurological or mental disorders. 〔27〕The solid form for use according to 〔26〕 above, wherein the neurological or mental disorder is selected from the positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, and Alzheimer's disease. 〔28〕The solid form of the compound according to any one of 〔1〕 to 〔15〕 above, or the pharmaceutical composition according to 〔23〕 above, for use in the manufacture of a medicament for treating or preventing neurological or mental disorders. 〔29〕The use according to 〔28〕 above, wherein the neurological or mental disorder is selected from the positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, and Alzheimer's disease.

Claims

1. A crystalline polymorph I of Compound 1 having the following structural formula: 1 wherein the crystalline polymorph I of Compound 1 has XRPD peaks at 2θ angles of 4.6 ± 0.2°, 10.0 ± 0.2°, 16.7 ± 0.2°, 18.0 ± 0.2°, 19.0 ± 0.2°, 20.0 ± 0.2° and 22.7 ± 0.2°, or 13C solid nuclear magnetic resonance peaks at chemical shifts of 131.5 ± 0.2 ppm, 127.2 ± 0.2 ppm, 28.7 ± 0.2 ppm and 25.7 ± 0.2 ppm, or 19F solid nuclear magnetic resonance peaks at chemical shifts of -64.3 ± 0.2, -64.8 ± 0.2, -65.9 ± 0.2, -66.8 ± 0.2, -78.0 ± 0.2, -78.5 ± 0.2, -79.3 ± 0.2 and -80.0 ± 0.2 ppm Characterized by the crystalline polymorph I of Compound 1.

2. A crystalline polymorph III of Compound 1 having the following structural formula: wherein the crystalline polymorph III of Compound 1 has 1 XRPD peaks at 2θ angles of 4.8 ± 0.2°, 9.7 ± 0.2°, 10.3 ± 0.2°, 13.9 ± 0.2° and 24.6 ± 0.2°, or 13C solid nuclear magnetic resonance peaks at chemical shifts of 156.6 ± 0.2 ppm, 134.2 ± 0.2 ppm, 46.0 ± 0.2 ppm, 25.5 ± 0.2 ppm and 14.3 ± 0.2 ppm Characterized by the crystalline polymorph III of Compound 1.

3. A method for preparing the crystalline polymorph I of Compound 1 according to Claim 1, comprising (a) heating Compound 1 and tert-butyl methyl ether (TBME) or water to obtain a slurry; (b) cooling the slurry of step (a); and (c) collecting the solid obtained as the crystalline polymorph I of Compound 1.

4. The amorphous form of Compound 1 is used in step (a) of the method according to Claim 3.

5. A method for preparing the crystalline polymorph III of Compound 1 according to Claim 2, comprising (a) heating a mixture of Compound 1 and methanol to 50 - 55 °C to obtain a solution; (b) concentrating the solution of step (a) at 40 - 45 °C; (c) cooling the concentrated solution from step (b) to 25 °C; and (d) collecting the solid obtained as the crystalline polymorph III of Compound 1.

6. The amorphous form of Compound 1 is used in step (a) of the method according to Claim 5. ​ ​ ​ ​

7. A pharmaceutical composition comprising a crystalline polymorph of the compound according to claim 1 or 2, optionally containing the crystalline polymorph together with one or more inert carriers and / or diluents.

8. The pharmaceutical composition according to claim 7 for use in the prevention and / or treatment of neurological or psychiatric disorders.

9. The pharmaceutical composition according to claim 8, wherein the neurological or psychiatric disorder is selected from the positive and negative symptoms of schizophrenia and the cognitive impairment associated with schizophrenia.

10. Use of a crystalline polymorph of the compound according to claim 1 or 2 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for the treatment or prevention of neurological or psychiatric disorders.

11. The use according to claim 10, wherein the neurological or psychiatric disorder is selected from the positive and negative symptoms of schizophrenia and the cognitive impairment associated with schizophrenia.

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