阅读说明：本技术 Glyt1抑制剂的固体形式 (Solid forms of GLYT1 inhibitor ) 是由 P·西格尔 J·J·高 B-S·杨 于 2020-04-30 设计创作，主要内容包括：本发明揭示甘氨酸运输蛋白-1(GlyT1)的抑制剂的固体形式。本发明亦是关于制造该等固体形式的方法、包含该等固体形式的药物组合物及其用于对利用甘氨酸运输蛋白-1的抑制剂治疗有反应的医学病况的用途。(Solid forms of an inhibitor of glycine transporter-1 (GlyT1) are disclosed. The invention also relates to methods of manufacturing such solid forms, pharmaceutical compositions comprising such solid forms and their use for medical conditions responsive to treatment with an inhibitor of glycine transporter-1.)

1. A solid form I of Compound 1 having the structural formula,

wherein the form I of compound 1 is characterized by:

at least three XRPD peaks at 2 Θ angles selected from 4.6 °, 10.0 °, 16.7 °, 18.0 °, 19.0 °, 20.0 °, and 22.7 °; or

At least three at chemical shifts selected from 131.5ppm, 127.2ppm, 28.7ppm, and 25.7ppm¹³C solid state nuclear magnetic resonance peak; or

At least three at chemical shifts selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and-80.0 ppm¹⁹F solid state nmr peak.

2. The solid form I of Compound 1 according to claim 1, having at least four XRPD peaks at 2 θ 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 claim 1 or 2, having at least five XRPD peaks at 2 Θ 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 claims 1 to 3, having XRPD peaks at 2 θ angles selected from 4.6 °, 10.0 °, 16.7 °, 18.0 °, 19.0 °, 20.0 °, and 22.7 °.

5. Solid form I of Compound 1 according to claims 1 to 4, having a chemical shift at a chemical shift selected from 131.5ppm, 127.2ppm, 28.7ppm and 25.7ppm¹³C solid state nuclear magnetic resonance peak.

6. Solid form I of Compound 1 according to claims 1 to 5, having a chemical shift at a level selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and-80.0 ppm¹⁹F solid state nmr peak.

7. A solid form II of Compound 1 having the structural formula,

wherein the form II has characteristic X-ray powder diffraction (XRPD) peaks at the following d-values:

4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 ° (2 θ); or

A feature selected from¹³C solid state NMR chemical shift:

130.1ppm, 46.6ppm and 25.0 ppm; or

At least three characteristics at chemical shifts selected from-64.0, -65.6, -66.6, -78.2 and-79.1 ppm¹⁹F solid state nmr peak.

8. The solid form II of compound 1 according to claim 7, having at least four XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

9. The solid form II of compound 1 according to claim 7 or 8, having an XRPD peak at an angle 2 Θ selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

10. Solid form II of compound 1 according to claims 7 to 9, having a chemical shift at a level selected from-64.0, -65.6, -66.6, -78.2, and-79.1 ppm¹⁹F solid state nmr peak.

11. A solid form III of Compound 1 having the formula,

wherein the form III of compound 1 is characterized by:

at least three XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °; or

At least three at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

12. The solid form III of compound 1 according to claim 11, having at least four XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °.

13. The solid form III of compound 1 according to claim 11 or 12, having an XRPD peak at an angle 2 Θ selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °.

14. The solid form III of compound 1 according to claims 11 to 13, having at least four chemical shifts at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

15. Solid form III of compound 1 according to claims 11 to 14, having a structure selected fromAt chemical shifts of 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

16. A process for the manufacture of solid form I of compound 1 according to claim 1, comprising

(a) Heating compound 1 and tert-butyl methyl ether (TBME) or water to provide a slurry;

(b) cooling the slurry of step (a); and

(b) the resulting solid was collected as form I of compound 1.

17. The method of claim 16, wherein an amorphous form of compound 1 is used in step (a).

18. A method of making form II of compound 1 of claim 7, comprising:

(a) heating a mixture of compound 1 and 2-propanol to 70 ℃ to provide a solution;

(b) filtering the solution of step (a);

(c) cooling the filtrate from step (b) to 55 ℃;

(d) treating the cooled solution of step (c) with water;

(e) cooling the water treatment mixture of step (d) to 20 ℃; and

(f) the resulting solid was collected as form II of compound 1.

19. The method of claim 18, further comprising

(d1) Seeding the aqueous treatment solution of step (d);

(d2) mixing the seeded solution at 55 ℃; and

(d3) the seeded solution was treated with water and then cooled to 20 ℃.

20. The process of claim 18 or 19, wherein in step (a) a mixture of amorphous form of compound 1 or form I and form II of compound 1 is used.

21. A method of making a solid form III of compound 1 according to claim 11, comprising:

(a) heating a mixture of compound 1 (form II) and methanol to 50-55 ℃ to provide a solution;

(b) concentrating the solution of step (a) at 40-45 ℃;

(c) cooling the concentrated solution from step (b) to 25 ℃; and

(d) the resulting solid was collected as form III of compound 1.

22. The method of claim 21, wherein an amorphous form of compound 1 is used in step (a).

23. A pharmaceutical composition comprising a solid form of a compound according to any one of claims 1 to 15, optionally together with one or more inert carriers and/or diluents.

24. Use of a solid form of compound 1 according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 23 for the treatment and/or prevention of neurological or psychiatric disorders.

25. The use of claim 24, wherein the neurological or psychiatric disorder is selected from the group consisting of positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, and Alzheimer's Disease.

26. A solid form of a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 23 for use in the prevention and/or treatment of neurological or psychiatric disorders.

27. The solid form or pharmaceutical composition of claim 26, wherein the neurological or psychiatric disorder is selected from the group consisting of positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia, and alzheimer's disease.

28. A solid form of a compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 23 for use in the treatment or prevention of a neurological or psychiatric disorder.

29. The use according to claim 28, wherein the neurological or psychiatric disorder is selected from the group consisting of positive and negative symptoms of schizophrenia, cognitive impairment associated with schizophrenia and alzheimer's disease.

[ technical field ] A method for producing a semiconductor device

The present invention relates to solid forms of an inhibitor of glycine transporter-1 (GlyT 1). The invention also relates to methods of manufacturing such solid forms, pharmaceutical compositions comprising such solid forms and their use for medical conditions responsive to treatment with an inhibitor of glycine transporter-1.

[ Prior Art ]

Schizophrenia is a progressive and devastating psychiatric disorder characterized by paroxysmal positive symptoms (e.g., delusions, hallucinations, thought disorders, and psychosis) and persistent negative symptoms (e.g., bland mood, impaired attention, social withdrawal, and cognitive impairment) (Lewis DA and Lieberman JA,2000, Neuron,28: 325-33).

The hypothesis of schizophrenia was raised in the mid 1960 s based on psychotropic behavior of the glutamate system triggered by blockade of the compound such as phencyclidine (PCP) and related agents (ketamine) which are noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor. Interestingly, PCP-induced pseudopsychotic behavior in healthy volunteers incorporates both positive and negative symptoms as well as cognitive dysfunction, and thus closely resembles that of patients with schizophrenia (Javitt DC et al, 1999, biol. Psychiatry,45: 668-679; see also Jentsch and Roth,1999, Neuropsychopharmacology 20: 201-225). Thus, increasing NMDA receptor neurotransmission in the central nervous system offers the opportunity to develop novel therapeutic approaches for schizophrenia as well as other neurological and psychiatric disorders associated with NMDA-receptor and/or glutamic acid dysfunction. NMDA-receptors are ligand-gated ion channels consisting of a combination of two NR1 and two NR2 subunits, and require simultaneous binding of a glutamate at the NR2 subunit and a glycine as a co-agonist at the NR1 subunit to be initiated (Johnson and Ascher,1987, Nature 325: 529-531). One strategy to enhance NMDA receptor activity is to elevate glycine concentration in the synaptic NMDA receptor local microenvironment by inhibiting GlyT1 (Bergeron R. et al, 1998, Proc. Natl. Acad. Sci. USA 95: 15730-15734). Indeed, clinical studies using the direct glycine site agonist D-serine and the prototype GlyT1 inhibitor sarcosine, which increases glycine in the synaptic cleft, have demonstrated some efficacy for treating negative symptoms and to a lesser extent positive and cognitive symptoms of schizophrenia (Tsai et al, 2004, biol. Psychiatry 44: 1081-1089; Lane et al, 2005, biol. Psychiatry 63: 9-12). Recently, the clinical efficacy of the GlyT 1-inhibitor RG1678 tested as an adjuvant treatment to commercial antipsychotics in a phase II clinical trial on negative symptoms in schizophrenic patients has been reported (Umbricht et al, 2011, schizophr. bull.37(suppl.1): 324).

The efficacy of different GlyT 1-inhibitors in various animal models/tests for positive and negative symptoms of schizophrenia as well as several memory tasks has been reported in the literature. (Depoortere et al, 2005, Neuropsychopharmacology 30: 1963-.

Two different glycine transporter genes (GlyT1 and GlyT2) have been cloned from mammalian brain, which results in two transporters with 50% amino acid sequence homology. GlyT1 appears in four isoforms (la, lb, 1c and ld) due to alternative splicing and the use of alternative promoters. Only two of these isoforms (GlyTla and GlyTlb) are found in rodent brains. GlyT2 also exhibited some degree of heterogeneity. GlyT1 is known to be located in the CNS and some surrounding tissues, whereas GlyT2 is specifically located in the CNS, mainly in the hindbrain and spinal cord (Zavara et al, 1995, J.Neurosci.15: 3952-. GlyT1 is expressed in glia and neurons and was found to be located at the glutaminic acid synapse (Cubelos et al, 2005, Cereb. cortex 15: 448-.

Glycine transporter inhibitors are contemplated for use in the treatment of neurological and psychiatric disorders. The majority of diseases involved are psychosis, schizophrenia (Armer RE and Miller DJ,2001, exp. Opin. Ther. patents 11:563-572), psychotic mood disorders (e.g., major depression), mood disorders associated with psychotic disorders (e.g., acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia) (Pralong ET ET al, 2002, prog. Neurobiol.,67:173-202), autism (Carlsson ML,1998, J.Neural Tranns.105: 525-535), cognitive disorders (e.g., dementia, including age-related dementia and Alzheimer's type (Alzheimer's type) senile 572)), memory disorders, attention deficit disorders and pain in mammals (Armer RE and Miller 2001, exp. patent. 11: Op.) including humans).

Increasing NMDA receptor activation via 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 disorders, alzheimer's disease, or other neurological and psychiatric disorders.

Inhibition of GlyT1 is of high interest, particularly in cognitive impairment associated with alzheimer's disease or schizophrenia.

An inhibitory compound of particular interest is example 50 set forth in WO2013017657, having the structure shown below (hereinafter "compound 1"):

WO2013017657 mentions the structure but does not describe any specific solid form of compound 1. Thus, there is a need for solid forms of compound 1 that have advantageous pharmaceutical properties (e.g., processability, stability, and solubility).

[ summary of the invention ]

The present invention relates to novel solid forms of compound 1 (collectively referred to herein as "compounds of the invention").

The invention also relates to methods of making the compounds of the invention and their use as modulators of GlyT 1.

In another aspect, the invention relates to pharmaceutical compositions comprising a compound of the invention, optionally together with one or more inert carriers and/or diluents.

Another aspect of the present invention relates to a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and/or treatment of neurological or psychiatric disorders.

Yet another aspect of the present invention pertains to compounds of the present invention or pharmaceutical compositions comprising such compounds for use in the prevention and/or treatment of diseases or conditions that can be affected by GlyT1 inhibition, such as conditions associated with the positive and negative symptoms of schizophrenia as well as cognitive impairment associated with schizophrenia, alzheimer's disease and other neurological and psychiatric disorders. The use comprises manufacture of a medicament for treatment of a corresponding disease.

[ description of the drawings ]

Figure 1 shows the XRPD pattern of compound 1 (amorphous) prepared according to the procedure of WO 2013017657.

Figure 2 shows the X-ray powder diffraction (XRPD) pattern of form I of compound 1.

Figure 3 is a thermal analysis profile of form I of compound 1 as determined by DSC measurements.

FIG.4a is form I of Compound 1¹³C solid state NMR spectrum.

FIG.4b is form I of Compound 1¹⁹F solid state NMR spectrum.

Figure 5 shows the XRPD pattern of form II of compound 1.

Figure 6 is a thermal analysis profile of form II of compound 1 as determined by DSC measurements.

FIG.7a is form II of Compound 1¹³C solid state NMR spectrum.

FIG.7b is form II of Compound 1¹⁹F solid state NMR spectrum.

Figure 8 shows the XRPD pattern of form III of compound 1.

Figure 9 is a thermal analysis profile of form III of compound 1 as determined by DSC measurements.

FIG.10 is form III of Compound 1¹³C solid state NMR spectrum.

Figure 11 is an isothermal moisture sorption curve showing water uptake of form II of compound 1 and amorphous compound 1 when stored at different relative humidities at 25 ℃.

Fig.12a is a Raman spectrum of form I of compound 1 (Raman spectrum), fig.12b is a Raman spectrum of form II of compound 1, and fig.12c is a Raman spectrum of form III of compound 1.

[ embodiment ] A method for producing a semiconductor device

Abbreviations:

DSC differential scanning calorimetry

O.D. outer diameter

Relative humidity of RH

SSNMR solid-state nuclear magnetic resonance

XRPD X-ray powder diffraction

As discussed above, the present invention relates to a crystalline form of compound 1 as described herein as form I, form II or form III; and a mixture of at least two of form I, form II, or form III ("crystalline compounds of the invention"). WO2013017657 does not mention any crystalline form of the compound, any method of making a crystalline form of compound 1, or any property of a crystalline form of compound 1 described herein. The compounds of the present invention have advantageous properties (e.g. improved stability and reproducibility) compared to the amorphous form of compound 1 described in example 1 and WO2013017657 herein. Improvements over amorphous forms include, for example, lower hygroscopicity and a reduced tendency to convert to different solid forms. For example, when maintained at 90% relative humidity under a humid nitrogen purge for 6 hours, the water uptake of amorphous compound 1 at 25 ℃ is 1.4%. In contrast, form II of compound 1 (an exemplary compound of the invention) had only about 0.04% water uptake at 25 ℃ when maintained under a moist nitrogen sweep at 90% relative humidity for 6 hours. (see FIG. 11).

In one embodiment, the invention is directed to solid form I of compound 1.

In one embodiment, the invention is directed to solid form II of compound 1.

In one embodiment, the invention is directed to solid form III of compound 1.

Each of form I, form II, and form III can be prepared in a form 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; and in another embodiment, form III may be substantially free of form I and form II. As used herein, "substantially free" means that the solid compound contains at least about 75% of one crystalline form of compound 1 (e.g., form II), based on the total molar amount of form I, form II, and form III. The molar ratio of form I, form II or form III of compound 1 can be determined, for example, using the methods described herein.

In one embodiment, the crystalline compound of the present invention comprises 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 invention comprises at least 80% of compound 1 form I, based on the total molar amount of compound 1 form I, form II, and form III. In another embodiment, the crystalline compound of the invention comprises at least 90% of compound 1 form I, based on the total molar amount of compound 1 form I, form II, and form III. In another embodiment, the crystalline compound of the invention comprises at least 95% 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 invention comprises 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 invention comprises 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 invention comprises at least 90% 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 invention comprises at least 95% 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 invention comprises 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 invention comprises 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 invention comprises 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 invention comprises at least 95% form III of compound 1, based on the total molar amount of form I, form II, and form III of compound 1.

The invention also relates to compound 1 comprising at least two of form I, form II or form III. In one embodiment, the invention relates to compound 1 comprising a mixture of form I and form II; in another embodiment, the invention relates to compound 1 comprising a mixture of form I and form III; in another embodiment, the invention relates to compound 1 comprising a mixture of form II and form III; and in another embodiment, the invention relates to compound 1 comprising a mixture of form I, form II and form III.

The invention also relates to the combination of an amorphous form of compound 1 with one or more crystalline forms of compound 1 described herein as form I, form II or form III.

Characterization of

The compounds of the invention can be characterized by the methods described below. Methods of preparing each of form I, form II, or form III are described in the experimental section.

X-ray powder diffraction (XRPD)

X-ray powder diffraction analysis of the samples of form I, form II and form III was performed on a Bruker AXS X-ray powder diffractometer model D8 Advance using CuKa radiation (1.54A) in parabolic focus mode with a graphite monochromator and scintillation detector. Each pattern is obtained by scanning in steps of 4 sec/step in the range of 2 deg. -35 deg. 2T in steps of 0.05 deg. 2T. Exemplary XRPD spectra of form I, form II and form III are shown in figures 2, 5 and 8, respectively. An exemplary XRPD spectrum of the amorphous form of compound 1 is shown in fig. 1. Tables 1, 3 and 5 include X-ray powder diffraction (XRPD) characteristics of forms I, II and III, respectively. The values reported in tables 1, 3 and 5 have a standard deviation of ± 0.22 θ.

Differential Scanning Calorimetry (DSC)

DSC analysis was performed using a differential scanning calorimeter (Q2000, TA instruments, New Castle, DE) using the general procedure. About 5mg of powder was weighed into a crimped aluminum pan with a pinhole. The sample was heated from room temperature to 250 ℃ using Q2000 DSC at 10 ℃/min. Exemplary DSC traces for form I, form II, and form III are seen in figures 3, 6, and 9, respectively. The results are reported below.

Moisture absorption property

The isothermal moisture sorption curves were determined using a dynamic vapor sorption system (Advantage, DVS, London, UK). The samples were subjected stepwise to 0 to 90% RH in 10% steps at 25 ℃. Each sample was equilibrated at each RH step for at least 60min, and if the weight gain was less than 0.1% in 1 minute, equilibration was considered to be reached, and the maximum duration for each RH was 6 hours. Thus, end-on how quickly equilibrium is reached, each sample is held at a given RH for 1 to 6 hours.

Solid State NMR (SSNMR)

Of samples of form I, form II and form III¹³C Solid State NMR (SSNMR) data on a Bruker Avance III NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 9.4T (C: (C) (C))¹H＝400.46MHz,¹³C — 100.70 MHz). The samples were packaged in a 4mm o.d. zirconia rotor with Kel-f (r) drive tips (drive tip). A Bruker 4BL CP BB WVT type probe was used for data acquisition and the samples were rotated around a magic angle (54.74 °). Sample spectra were acquired using a 12kHz spin rate. Standard cross-polarized pulse trains are used with ramped Hartman-Hahn matched pulses on the proton channel at ambient temperature and pressure. The pulse sequence used a 3 ms contact pulse and a 5 second cyclic delay. Double pulse phase modulation (tpm) decoupling is also employed in the pulse train. Exponential line broadening is not used prior to Fourier transformation (Fourier transformation) of the free induction decay. Chemical shifts were referenced using an adamantane secondary standard with the high field resonance set at 29.5 ppm. The magic angle is obtained by using KBr powder at a rotation rate of 5kHz⁷⁹The Br signal is set. Exemplary forms I, II and III¹³The C SSNMR spectra are shown in FIGS. 4, 7 and 10, respectively. Tables 2a, 4a and 6 include those obtained from forms I, II and III, respectively¹³Chemical shifts obtained by C SSNMR spectroscopy. The values reported in tables 2a, 4a and 6 have a standard deviation of ± 0.2 ppm.

Of samples of form I, form II and form II¹⁹Solid State NMR (SSNMR) data on a Bruker Avance III NMR spectrometer (Bruker Bi)ospin, inc., Billerica, MA) at 9.4T, (ii)¹H＝400.46MHz,¹⁹F-376.76 MHz). Packing the sample in a bag withDrive tip in 3.2mm o.d. zirconia rotor. A Bruker 3.2BL BB type probe was used for data acquisition and the sample was rotated around the magic angle (54.74 °). Sample spectra were acquired using a 22kHz rotation rate. A standard spin echo pulse sequence was used with a cyclic delay of 12 seconds. Also use SPINAL-641H decoupling. Exponential line broadening is not used prior to the fourier transform of the free induction decay. Chemical shifts use the strongest signal from polyvinylidene fluoride (PVDF) as a reference, with resonance set at-91 ppm. The magic angle is obtained by using KBr powder at a rotation rate of 5kHz⁷⁹The Br signal is set. Exemplary forms I and II¹⁹The F SSNMR spectra are shown in FIGS. 4b and 7b, respectively. Tables 2b and 4b include those obtained from forms I and II, respectively¹⁹Chemical shifts obtained from F SSNMR spectroscopy. The values reported in tables 2b and 4b have a standard deviation of. + -. 0.2 ppm.

Raman spectroscopy

Raman spectra of the samples of form I, form II and form III were obtained on a Nicolet 6700FT-Raman module AEU0900515 spectrometer. Form II exhibited a raman scattering peak at 9011/cm, while 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.

Characterization 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 as determined by DSC measurements is shown in figure 3; form I of Compound 1¹³The C solid state NMR spectrum is shown in figure 4 a; and of form I of Compound 1¹⁹The F solid state NMR spectrum is shown in figure 4b.

Characteristic XRPD peaks of form I,¹³C solid state nuclear magnetic resonance peak and¹⁹the F solid state nmr peaks are provided in table 1, table 2a and table 2b, respectively.

Table 1X-ray powder diffraction (XRPD) characteristics of form I from figure 2.

Table 2a. form I from figure 4a¹³C NMR chemical shift.

Table 2b. form I from figure 4b¹⁹F NMR chemical shift.

Peak(s)	Chemical shift (ppm)
		1	-64.3
2	-64.8
		3	-65.9
4	-66.8
		5	-78.0
6	-78.5
		7	-79.3
8	-80.0

In one embodiment of the invention, form I of compound 1 is characterized by the XRPD pattern of figure 2.

In another embodiment of the invention, form I of compound 1 has the XRPD pattern shown in table 1.

In another embodiment of the invention, form I of compound 1 is characterized by at least three XRPD peaks at 2 Θ angles selected from 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

In another embodiment of the invention, form I of compound 1 is characterized by XRPD peaks at 2 Θ angles selected from 4.6 °, 10.0 °, 16.7 °, 19.0 °, 20.0 °, and 22.7 °.

In another embodiment of the invention, form I of compound 1 is characterized by XRPD peaks at 2 Θ angles selected from 4.6 °, 9.2 °, 10.0 °, 12.2 °, 16.7 °, 17.2 °, 18.5 °, 19.0 °, 20.0 °, 22.7 °. In yet another embodiment of the present invention, form I of compound 1 is as shown in table 2a¹³C solid state nmr peak. In yet another embodiment of the present invention, form I of compound 1 is as shown in table 2b¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form I of compound 1 is comprised of at least three chemical shifts at chemical shifts selected from 131.5ppm, 127.2ppm, 28.7ppm, and 25.7ppm¹³C solid state nmr peak.

In another embodiment of the invention, form I of Compound 1 is represented by chemical shifts at chemical shifts selected from 131.5ppm, 127.2ppm, 28.7ppm, and 25.7ppm¹³C solid state nmr peak.

In another embodiment of the invention, form I of compound 1 is represented by chemical shifts at chemical shifts selected from 167.2ppm, 159.4ppm, 156.9ppm, 131.5ppm, 115.4ppm, 127.2ppm, 46.8ppm, 45.7ppm, 28.7ppm, 25.7ppm, and 13.7ppm¹³C solid state nmr peak.

In another embodiment of the invention, form I of compound 1 has the structure shown in table 2b¹⁹And F, solid-state nuclear magnetic resonance characteristics.

In another embodiment of the invention, form I of Compound 1 is comprised of at least three chemical shifts at chemical shifts selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and-80.0 ppm¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form I of Compound 1 is comprised of at least five chemical shifts at chemical shifts selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and-80.0 ppm¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form I of Compound 1 is represented by chemical shifts at chemical shifts selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3, and-80.0 ppm¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form I of compound 1 has the XRPD pattern shown in table 1; or as shown in Table 2a¹³C solid state nuclear magnetic resonance peak; or as shown in Table 2b¹⁹F solid state nmr peak.

In another embodiment of the invention, form I of compound 1 is characterized by: at least three XRPD peaks at 2 Θ angles selected from 4.6 °, 10.0 °, 16.7 °, and 18.0 °; at least three at chemical shifts selected from 131.5ppm, 127.2ppm, 28.7ppm, and 25.7ppm¹³C solid state nuclear magnetic resonance peak; or at least three in the range selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5At chemical shifts of 79.3 and-80.0 ppm¹⁹F solid state nmr peak.

In another embodiment of the invention, form I of compound 1 is characterized by: XRPD peaks at 2 Θ angles selected from 4.6 °, 10.0 °, 16.7 °, and 18.0 °; at a chemical shift selected from 131.5ppm, 127.2ppm, 28.7ppm and 25.7ppm¹³C solid state nuclear magnetic resonance peak; or at a chemical shift selected from-64.3, -64.8, -65.9, -66.8, -78.0, -78.5, -79.3 and-80.0 ppm¹⁹F solid state nmr peak.

Characterization 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 as determined by DSC measurements is shown in figure 6; form II of Compound 1¹³The C solid state NMR spectrum is shown in figure 7 a; and of form II of Compound 1¹⁹The F solid state NMR spectrum is shown in fig.7 b.

Characteristic XRPD peaks of form II,¹³C solid state nuclear magnetic resonance peak and¹⁹the F solid state nmr peaks are provided in table 3, table 4a and table 4b, respectively.

Table 3. X-ray powder diffraction (XRPD) signature from figure 5 of form II.

Table 4a. form II from fig.7a¹³C NMR chemical shift.

Table 4b. form II from fig.7b¹⁹F NMR chemical shift.

Peak(s)	Chemical shift (ppm)
		1	-64.0
2	-65.6
		3	-66.6
4	-78.2
		5	-79.1

In one embodiment of the invention, form II of compound 1 is characterized by the XRPD pattern of figure 5.

In another embodiment of the invention, form II of compound 1 has the XRPD pattern shown in table 3.

In another embodiment of the invention, form II of compound 1 is characterized by at least three XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

In another embodiment of the invention, form II of compound 1 is characterized by at least four XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

In another embodiment of the invention, form II of compound 1 is characterized by XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °.

In another embodiment of the invention, form II of compound 1 is characterized by XRPD peaks at 2 Θ 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 structure shown in table 4a¹³C solid state nmr characteristics.

In another embodiment of the invention, form II of Compound 1 is prepared by chemical shifting at a chemical shift selected from 130.1ppm, 46.6ppm, and 25.0ppm¹³C solid state nmr peak.

In another embodiment of the invention, form II of compound 1 is comprised of chemical shifts at chemical shifts selected from 167.3ppm, 157.1ppm, 130.1ppm, 115.6ppm, 72.2ppm, 47.9ppm, 46.6ppm, 45.9ppm, 25.0ppm, and 12.9ppm¹³C solid state nmr peak.

In another embodiment of the invention, form II of compound 1 has the structure shown in table 4b¹⁹And F, solid-state nuclear magnetic resonance characteristics.

In another embodiment of the invention, form II of Compound 1 is comprised of at least three chemical shifts at chemical shifts selected from-64.0, -65.6, -66.6, -78.2, and-79.1 ppm¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form II of Compound 1 is represented by chemical shifts at chemical shifts selected from the group consisting of-64.0, -65.6, -66.6, -78.2, and-79.1 ppm¹⁹And F, solid-state nuclear magnetic resonance peak characterization.

In another embodiment of the invention, form II of compound 1 has the XRPD pattern shown in table 3; or as shown in Table 4a¹³C solid state nuclear magnetic resonance peak; or as shown in Table 4b¹⁹F solid state nmr peak.

In another embodiment of the invention, form II of compound 1 is characterized by: at least three are selected from 4.1 DEG,XRPD peaks at 2 θ angles of 4.6 °, 10.0 °, 16.7 °, and 18.0 °; at a chemical shift selected from 130.1ppm, 46.6ppm and 25.0ppm¹³C solid state nuclear magnetic resonance peak; or at least three at chemical shifts selected from-64.0, -65.6, -66.6, -78.2 and-79.1 ppm¹⁹F solid state nmr peak.

In another embodiment of the invention, form II of compound 1 is characterized by: at least four XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °; at a chemical shift selected from 130.1ppm, 46.6ppm and 25.0ppm¹³C solid state nuclear magnetic resonance peak; or at a chemical shift selected from-64.0, -65.6, -66.6, -78.2 and-79.1 ppm¹⁹F solid state nmr peak.

In another embodiment of the invention, form II of compound 1 is characterized by: XRPD peaks at 2 Θ angles selected from 4.1 °, 4.6 °, 10.0 °, 16.7 °, and 18.0 °; at a chemical shift selected from 130.1ppm, 46.6ppm and 25.0ppm¹³C solid state nuclear magnetic resonance peak; or at a chemical shift selected from-64.0, -65.6, -66.6, -78.2 and-79.1 ppm¹⁹F solid state nmr peak.

Characterization 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 as determined by DSC measurements is shown in figure 9; and form III of Compound 1¹³The C solid state NMR spectrum of (a) is shown in fig. 10.

Characteristic XRPD peaks of form III and¹³the C solid state nmr peaks are provided in table 5 and table 6, respectively.

TABLE 5X-ray powder diffraction (XRPD) characteristics of form III from FIG.8

TABLE 6 form III from FIG.10¹³C NMR chemical shift.

In one embodiment of the invention, form III of compound 1 is characterized by the XRPD pattern of fig. 8.

In another embodiment of the invention, form III of compound 1 has the XRPD pattern shown in table 5.

In another embodiment of the invention, form III of compound 1 is characterized by at least three XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °.

In another embodiment of the invention, form III of compound 1 is characterized by at least four XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °.

In another embodiment of the invention, form III of compound 1 is characterized by XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °.

In another embodiment of the invention, form III of compound 1 is characterized by XRPD peaks at 2 Θ 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 invention, form III of compound 1 has the structure shown in table 6¹³C solid state nmr characteristics.

In another embodiment of the invention, form III of compound 1 is formed from at least two chemical shifts at chemical shifts selected from the group consisting of 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is fromTwo less at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm and 14.3ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is comprised of at least two chemical shifts at chemical shifts selected from 156.6 and 132.5ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is formed from at least three chemical shifts at chemical shifts selected from the group consisting of 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is comprised of at least four chemical shifts at chemical shifts selected from the group consisting of 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is formed from chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is comprised of at chemical shifts selected from the group consisting of 156.6ppm, 156.0ppm, 134.2ppm, 132.5ppm, 47.6ppm, 46.0ppm, 44.6ppm, 25.5ppm, 14.3ppm, and 13.0ppm¹³C solid state nmr peak.

In another embodiment of the invention, form III of compound 1 is characterized by: at least three XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °; or at least three at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

In another embodiment of the invention, form III of compound 1 is characterized by: at least four XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °; or at least four at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

In another embodiment of the invention, form III of compound 1 is characterized by: XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °; or at least four at chemical shifts selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm, and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

In another embodiment of the invention, form III of compound 1 is characterized by: XRPD peaks at 2 Θ angles selected from 4.8 °, 9.7 °, 10.3 °, 13.9 °, and 24.6 °; or at a chemical shift selected from 156.6ppm, 134.2ppm, 46.0ppm, 25.5ppm and 14.3ppm¹³C solid state nuclear magnetic resonance peak.

In another embodiment of the invention, form III of compound 1 has the XRPD pattern shown in table 5 or shown in table 6¹³C solid state nuclear magnetic resonance peak.

Process for preparing form I, form II, form III and mixtures thereof

The invention also relates to methods of making solid forms of compound 1. In general, form I, form II, form III, and mixtures thereof can be obtained by dissolving compound 1 in a suitable solvent ("dissolution step"), preferably at a temperature above room temperature (e.g., 25 ℃), more preferably from about 45 ℃ to about 80 ℃. The heated solution is then cooled ("cooling step") to provide a solid/liquid comprising form I, form II, form III, or a mixture thereof as a solid. In some embodiments, the heated solution may be filtered prior to cooling. In other embodiments, the heated solution can be concentrated ("concentration step") before or during the cooling step. In other embodiments, the heated solution can be heated with a co-solvent ("co-solvent treatment step"). In some embodiments, the co-solvent (when used) may be added during the cooling step. In other embodiments, the cooling step comprises a gradual cooling ramp. In other embodiments, seeds or seed slurry (the "seeding step") are added during the cooling step. It is to be understood that any combination of the above can be used to obtain form I, form II, form III, and mixtures thereof. Once cooled, the resulting solid can be collected, washed with a suitable solvent, and dried to provide form I, form II, form III, or a mixture thereof.

Method for producing mixtures of form I and form II

In one embodiment, the invention relates to a method of making a mixture of form I and form II of compound 1, comprising:

(a) heating mixture compound 1 in 2-propanol to 70 ℃ to provide a solution;

(b) treating the solution obtained in step (a) with water while maintaining a temperature of 50 ℃ to 70 ℃;

(c) cooling the aqueous mixture of step (b) to 20 ℃; and

(d) the resulting solid was collected as a mixture of form I and form II of compound 1.

In one embodiment, an amorphous form of compound 1 is used in step (a).

Method of making form I

In another embodiment, the invention is directed to a method of making solid form I of compound 1 comprising:

(a) heating compound 1 and tert-butyl methyl ether (TBME) or water at 50 ℃ to provide a slurry;

(b) cooling the slurry of step (a); and

(c) the resulting solid was collected as form I of compound 1.

In one embodiment, the amorphous form of compound 1 is used in step (a) immediately above the embodiments.

In another embodiment, the invention is directed to either of the two embodiments immediately above further comprising concentrating the slurry of step (b) prior to cooling the slurry.

In another embodiment, the invention is directed to a method of making form I of compound 1 comprising:

(a) heating compound 1 and 2-propanol to 50-55 ℃ to provide a solution;

(b) cooling the solution of step (a) to 25 ℃;

(c) treating the cooled solution of step (b) with water; and

(d) the resulting solid was collected as form I of compound 1.

In another embodiment, the present invention is directed to the embodiment described immediately above wherein amorphous form of compound 1 or mixture form I and form II of compound 1 is used in step (a).

Method of making form II

In another embodiment, the invention is directed to a method of making form II of compound 1 comprising:

(a) heating a mixture of compound 1 and 2-propanol to 70 ℃ to provide a solution;

(b) filtering the solution of step (a);

(c) cooling the filtrate from step (b) to 55 ℃;

(d) treating the cooled solution of step (c) with water;

(e) cooling the water treatment mixture of step (d) to 20 ℃; and

(f) the resulting solid was collected as form II of compound 1.

In another embodiment, the invention is directed to the process described in the immediately preceding embodiment, further comprising seeding the aqueous treatment solution of step (d); further mixing the seeded solution at 55 ℃; and treating the seeded solution with water and then cooling to 20 ℃.

In another embodiment, the invention is directed to either of the two embodiments immediately above wherein amorphous form of compound 1 or mixture form I and form II of compound 1 is used in step (a).

In another embodiment, the invention is directed to a method of making form II of compound 1 comprising:

(a) heating a mixture of compound 1 (a mixture of form I and form II), 2-propanol and water to 55-60 ℃ to provide a solution;

(b) filtering the solution of step (a);

(c) heating the filtrate of step (b) to 68-70 ℃;

(d) treating the filtrate from step (c) with water while maintaining a temperature of 68-70 ℃;

(e) cooling the water treatment filtrate from step (d) to 62-66 ℃;

(f) seeding the aqueous treatment solution of step (d) with a seeding slurry comprising form II of compound 1, water, and isopropanol to provide a seeded mixture;

(g) cooling the seeded mixture of step (f) to 55 deg.C

(h) Mixing the seeded solution of step (e) at 55 ℃;

(i) treating the seeded solution of step (h) with water to provide a mixture;

(j) (ii) mixing the mixture of step (i) at 55 ℃;

(k) cooling the cooled mixture of step (j) to 20 ℃; and

(l) The resulting solid was collected as form II of compound 1.

In another embodiment, the present invention is directed to the embodiment described immediately above wherein amorphous form of compound 1 or mixture form I and form II of compound 1 is used in step (a).

Method of making form III

In another embodiment, the invention is directed to a method of making form III of compound 1 comprising:

(a) heating a mixture of compound 1 (form II) and methanol to 50-55 ℃ to provide a solution;

(b) concentrating the solution of step (a) at 40-45 ℃;

(c) cooling the concentrated solution from step (b) to 25 ℃; and

(d) the resulting solid was collected as form III of compound 1.

In another embodiment, the present invention is directed to the embodiment described immediately above wherein form I of compound 1 is used in step (a).

Method of treatment

The compounds of the present invention are selective inhibitors of glycine transporter-1 (GlyT 1). The pharmaceutical concepts discussed herein are considered of great interest as areas of application for the active compounds of the present invention. The active compounds of the present invention are useful in the development of pharmaceutical agents. The agents are preferably used for the treatment of diseases in which inhibition of GlyT1 may have a therapeutic, prophylactic or disease modifying effect. Preferably, the medicament is useful for treating diseases such as: psychosis, memory and learning disorders, schizophrenia (both positive and negative symptoms of schizophrenia and cognitive impairment associated with schizophrenia), dementia disorders (such as alzheimer's disease) and other diseases in which cognitive processes are impaired (e.g., attention deficit disorder, parkinson's disease, epilepsy, and/or bipolar disorders).

The agents are used in methods, preferably therapeutic methods, to improve perception, concentration, cognition, learning or memory, such as those that occur, inter alia, in conditions, diseases and/or syndromes such as:

mild cognitive impairment, amnesic mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, post-stroke dementia (post-stroke dementia), post-traumatic dementia, generalized concentration impairment, concentration impairment with learning and memory problems in children, alzheimer's disease, mild to moderate alzheimer's disease, moderate to severe alzheimer's disease, prodromal alzheimer's disease, dementia associated with lewy body disease, dementia with frontal degeneration (including Pick's syndrome), Parkinson's disease, progressive supranuclear palsy, dementia with corticobasal degeneration, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, Multiple sclerosis, thalassemia, Guinea's dementia, HIV dementia, epilepsy, temporal lobe epilepsy, Korsakoff's psychosis or cognitive impairment associated with schizophrenia, prodromal schizophrenia, major depression, Parkinson's disease, epilepsy, schizoaffective disorder or bipolar disorder.

Another aspect of the invention pertains to the treatment of diseases accessible by GlyT1 inhibition, in particular sleep disorders (such as insomnia or lethargy), bipolar disorders, depression, substance use disorders/abuse disorders, hearing disorders, attention deficit (hyperactivity) disorders, inflammatory pain, neuropathic pain, autism spectrum disorders or impulse control disorders.

The compounds of the invention are useful in or as medicaments.

Such an agent is preferably used in a therapeutic or prophylactic, preferably therapeutic, method in the treatment of CNS diseases.

In an alternative use, the agent is for the treatment of a CNS disease, the treatment of which is achieved by inhibition of GlyT 1.

In an alternative use, the medicament is for the treatment of a disease accessible by inhibition of GlyT 1.

In an alternative use, the agent is for use in a method of treatment of alzheimer's disease, schizophrenia (positive and negative symptoms) or cognitive impairment associated with alzheimer's disease or with schizophrenia.

In other aspects of the invention, the invention relates to a method of treating or preventing a condition or disease selected from the group of conditions and diseases listed above, wherein the method comprises administering a therapeutically effective amount of a compound of the invention to a human in need thereof.

A suitable daily dosage range for a compound of the invention is generally from 0.1 to 5000mg, preferably from 0.1 to 1000mg, preferably from 2 to 500mg, more preferably from 5 to 250mg, optimally from 10 to 100 mg. Dosage units (e.g. tablets) may preferably contain between 2 and 250mg, particularly preferably between 10 and 100mg, of an active compound according to the invention.

Another aspect of the invention relates to compounds of the invention for use in a method of treatment or as a medicament. If indicated, the treatment method or agent is preferably used to treat a condition or disease selected from the group of conditions or diseases outlined above in this section entitled "methods of treatment".

Another aspect of the invention relates to a compound of the invention for use in 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 "methods of treatment".

Pharmaceutical composition

Suitable formulations for administration of the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, sugar tablets, solutions, syrups, elixirs, sachets, injections, inhalants, powders and the like. The content of the pharmaceutically active compound will be in the range of 0.05 to 90wt. -%, preferably 0.1 to 50wt. -% of the total composition.

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

The term "active substance" denotes one or more compounds of form I, form II or form III. In the case of any of the combinations mentioned above with one or more other active substances, the term "active substance" may also comprise additional active substances. Standard procedures should be considered for preparing any of the pharmaceutical formulations mentioned herein.

Thus, coated tablets may be prepared by coating a core produced in a manner similar to a tablet with a material commonly used for tablet coating, such as, for example, curdlone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers for delayed release or to prevent incompatibilities. Similarly, the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

For oral administration, the tablets may of course contain, in addition to the above carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various additives such as starch (preferably potato starch), gelatin and the like. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substances may be combined with various taste-enhancing agents or colorants in addition to the excipients mentioned above.

The active ingredient/substance or active moiety can be conveniently administered in liquid form in a lipophilic or hydrophilic carrier system in admixture with a single carrier excipient or in admixture with a complex carrier medium composed of several components as a solution or suspension. Encapsulation of the liquid formulations in capsules, either soft (gelatin) or hard (gelatin) may provide a very convenient route to administer the pharmacologically active substances.

Syrups or elixirs containing the active substances according to the invention may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar; and flavoring agents, such as flavoring agents, e.g., vanillin or citrus extract. It may also contain suspension adjuvants or thickeners (e.g. sodium carboxymethylcellulose), wetting agents (e.g. condensation products of fatty alcohols with ethylene oxide) or preservatives (e.g. parabens).

Capsules containing the active substances of the invention can be prepared, for example, by mixing the active substance with an inert carrier, for example lactose or sorbitol, and packaging it in gelatin capsules.

Excipients that may be used include, for example, water; pharmaceutically acceptable organic solvents, such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol); carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersible silicic acid and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite liquor, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

The dose for oral administration to humans is 0.5-1000mg per administration, with one or more administrations per day.

However, depending on the body weight, route of administration, individual response to the active substance, nature of its formulation and time or interval of administration of the active substance, it may sometimes be desirable to deviate from the amounts specified. Thus, in some cases it may be sufficient to use a lower dose than the minimum given above, while in other cases the upper limit may have to be exceeded. When administered in large amounts, they may suitably be divided into a number of smaller doses to be dispersed throughout the day.

In one embodiment, the 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 invention is directed to a pharmaceutical composition comprising form I compound 1 and a pharmaceutically acceptable excipient.

In another embodiment, the invention is directed to a pharmaceutical composition comprising form II of compound 1 and a pharmaceutically acceptable excipient.

In another embodiment, the invention is directed to a pharmaceutical composition comprising form III of compound 1 and a pharmaceutically acceptable excipient.

In another embodiment, the invention is directed 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 invention without limiting its scope.

Combination therapy/combination with other active substances

The above polymorph form I, form II or form III can also be administered with other active compounds. The invention also relates to pharmaceutical formulations providing such a combination of active ingredients, one of which is the inventive solid form of compound 1.

These combinations can be fixed dose combinations (active ingredients to be combined are in the same pharmaceutical formulation) or free dose combinations (active ingredients are present in separate pharmaceutical formulations).

Thus, a further aspect of the invention is the combination of a compound of the invention with another active compound selected from the group of (for example): antipsychotic agents, such as, for example, haloperidol (haloperidol), clozapine (clozapine), risperidone (risperidone), quetiapine (quetiapine), aripiprazole (aripiprazole), asenapine (asenapine), and olanzapine (olanzapine); antidepressants, such as selective serotonin reuptake inhibitors and dual serotonin/norepinephrine reuptake inhibitors; mood stabilizers such as lithium valproate and lenodarone (lamotrigine); inhibitors of beta-secretase; gamma-secretase inhibitors; a gamma-secretase modulator; amylomimetic aggregation inhibitors, such as scyllo-inositol; neuroprotective and/or disease-modifying substances acting directly or indirectly; antioxidants, such as vitamin E, ginkgo biloba (ginko biloba) or ginkgolide (ginkgolide); anti-inflammatory substances, such as Cox inhibitors, NSAIDs additionally or exclusively having Abeta (Abeta) lowering properties; HMG-CoA reductase inhibitors such as statins; acetylcholinesterase inhibitors such as donepezil (donepezil), rivastigmine (rivastigmine), tacrine (tacrine), galantamine (galantamine); NMDA receptor antagonists, such as memantine (memantine); AMPA receptor agonists; AMPA receptor positive modulators, ampkinins (AMPkines), glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; substances that regulate the release of a specific force or neurotransmitter; substances that induce the secretion of growth hormone, such as ibutemoram mesylate (ibutamoren mesylate) and capromorelin (capromorelin); a CB-1 receptor antagonist or inverse agonist; antibiotics, such as minocycline (minocycline) or rifampin (rifampicin); PDE1, PDE2, PDE4, PDE5, PDE9 or PDE10 inhibitors, GABAA receptor inverse agonists; GABAA α 5 receptor inverse agonists; GABAA receptor antagonists; a nicotinic receptor agonist or partial agonist or positive modulator; an α 4 β 2 nicotinic receptor agonist or partial agonist or positive modulator; an alpha 7 nicotinic receptor agonist or partial agonist or positive allosteric modulator; histamine receptor H3 antagonists; a 5-HT4 receptor agonist or partial agonist; 5-HT6 receptor antagonists; alpha 2-adrenoceptor antagonists, calcium antagonists; a muscarinic receptor M1 agonist or partial agonist or positive modulator; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; a muscarinic receptor M4 positive allosteric modulator; a metabolic glutamate receptor 5 positive allosteric modulator; a metabotropic glutamate receptor 2 antagonist; a metabolic glutamate receptor 2/3 agonist; metabotropic glutamate receptor 2 positive allosteric modulators and other substances that modulate the receptor or enzyme in a manner that increases the potency and/or safety and/or reduces undesirable side effects of the active compounds of the present invention.

The compounds of the present invention may also be used in combination with immunotherapy, e.g., active immunization with a β or a portion thereof or passive immunization with a humanized anti-a β antibody or antibody fragment, to treat the above-mentioned diseases and conditions.

The compounds of the present invention may also be combined with antipsychotic agents such as flupiridol, flupentixol (flupentixol), flusperidol (flupiriline), chlorprothixene (chlorprothixene), prothioconazole (prothiocendal), levomepromazine (levopromethazine), clozapine, olanzapine, quetiapine, risperidone, paliperidone (paliperidone), amisulpride (amipride), ziprasidone (ziprasidone), aripiprazine (sulpiride), zotepine (zotepine), sertraline (sertindole), fluphenazine (fluphenazine), perphenazine (perphenazine), perprazine (pramoxine), pramiperidone (chlorprozine), pramiperidone (chlorprothidone), pramiperidone (chlorprozine), pramiperidone (clopidogrel (pramiperone), pramiperone (pramiperone).

The compounds of the invention may also be combined with antidepressants, such as amitriptyline imipramine hydrochloride (tofanil), imipramine maleate (surminol), lofepramine (lofepramine), desipramine (norpramine), doxepin (SINEQUAN, ZONALON), trimipramine (surminol).

Alternatively, the compounds of the present invention may also be combined with serotonin (5-HT) reuptake inhibitors, such as, for example, alaproclate, citalopram (citalopram) (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (clomipramine) (ANAFRANIL), duloxetine (duloxetine) (cymalta), femoxetine (felexine) (malexl), fenfluramine (fenfluramine) (pandimin), fenfluramine (norfluramine) (prod), fluvoxamine (fluvoxamine) (lumox), indaparine (indapine), milnacipramine (lonapapralean) (IXEL), paroxetine (parexitine) (PAXIL, seroxide), sertraline (serzoline) (strezol, luteolin), ziprasidone (ketotifen), ziprasidone (dexrazine) (doxylamine), ziprasidone (isoflufenadine) (doxylamine, isoflufenadine (isofluxadine), and isoflufenadine (isofluxadine) (doxine (isofazine), ziprasidone (dexrazine (isofazine) (doxine), and nefavudine (isofavudine).

The combination of the invention may be provided in one and the same dosage form, i.e. in the form of a combined preparation, e.g. the two components may be incorporated in one tablet, e.g. in different layers of the tablets.

The dosage or administration form is not limited; in the framework of the present invention, any suitable dosage form may be used. Exemplary dosage forms can be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, sugar tablets, suppositories; liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs; or gaseous formulations such as aerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active ingredient present. The ingredients are selected accordingly, depending on the route of administration and the dosage form.

The dosage of the above-mentioned combination partners may conveniently be generally 1/5 in the normally recommended lowest dose to 1/1 in the highest normally recommended dose.

Depending on the nature of the formulation, the dosage form is administered to the patient, for example, 1, 2, 3, or 4 times per day. In the case of delayed or extended release formulations or other pharmaceutical formulations, administration may be in different ways (e.g., once weekly or once monthly, etc.). The active compounds of the present invention are preferably administered 3 times or less, more preferably once or twice daily.

Examples

Example 1

Preparation of amorphous compound 1: the amorphous form of compound 1 ("amorphous compound 1") was prepared as described in example 50 of WO 2013017657. Chiral separation of a non-enantiomeric mixture (prepared according to example 49 of WO 2013017657) was performed as described in example 49, except that the flow rate was 12ml/min instead of 15 ml/min. The solvent was removed from the resulting eluate under reduced pressure to give amorphous compound 1 as a solid. A typical XRPD pattern obtained for a sample of amorphous compound 1 is shown in figure 1.

Example 2

Preparation of a mixture of form I and form II of compound 1: the reactor was charged with amorphous form of compound 1 (20g) and 2-propanol (75mL) and the contents were heated to 70 ℃. The resulting solution was treated with water (111mL) while maintaining the batch temperature at not less than 50 ℃. The reactor contents were then cooled to 20 ℃ over 1.5 hr. The solid was collected by filtration, washed with water, and dried at 40 ℃ under reduced pressure to provide a mixture of form I and form II of compound 1 (15.4g, 77% yield) based on the characterization method described herein and having a molar ratio of 61:39 as determined by raman spectroscopy (form I: form II).

Example 3A

Preparation of form I of compound 1: amorphous compound 1(50mg) was treated with 4ml of tert-butyl methyl ether (TBME) and the resulting slurry was stirred at 50 ℃ for 2 h. About 2ml of solvent was removed under reduced pressure. The mixture was then filtered and the solid was dried in a vacuum oven at 40 ℃ to provide form I of compound 1.

Form I of compound 1 can also be prepared according to the procedure immediately described 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 (14g,0.029mol) was dissolved in 2-propanol (140mL) and heated to 50-55 ℃. The resulting solution was allowed to cool to room temperature and then treated with water (500mL) while vigorously mixing. Agitation was then stopped and the reactor contents allowed to stand without agitation for at least 30 min. The resulting solid was then collected by filtration, washed with water and then heptane and air dried for 2 hours to provide 14.6g of form I of compound 1.

Example 4A

Preparation of form II of compound 1: the reactor was charged with a mixture of form I and form II of compound 1 (37g,0.072mol) and 140ml isopropanol and the reactor contents heated to about 70 ℃. The resulting solution was vacuum filtered (Buchner funnel equipped with filter paper) and the filtrate was cooled to about 55 ℃. The solution was then treated with water (111mL) and seeded with 0.74g of form I of compound 1 while vigorously mixing at 55 ℃ for at least 4 hours. Additional water (95.14g) was added to the stirred mixture over at least 6 hours, agitation was stopped, and the reactor contents were cooled to 20 ℃ over at least 4 hours. The resulting solid was then collected by filtration, washed with water and then heptane and air dried to provide form II of compound 1.

Similar results were obtained if form II or a mixture of form I and form II was seeded.

Example 4B

Preparation of form II of compound 1: the reactor was charged with a mixture of form I and form II of compound 1 (100g,0.195mol), isopropanol (500ml) and water (100 ml). The reactor contents were heated to 55-60 ℃ while stirring and the resulting solution was vacuum filtered (buchner funnel equipped with filter paper) at 55-60 ℃. The stirred filtrate was heated to 68-70 ℃, treated with 600mL of water while maintaining the temperature of 68-70 ℃, and cooled to 62-66 ℃ over 30 min. The solution was seeded with a seed slurry of form II of Compound 1 (2g) in a mixture of 20g water and 4g isopropanol, aged at 62-66 ℃ for 0.5h and cooled to 55 ℃ over 2-3 h. The resulting mixture was stirred at 55 ℃ for 2 hours, cooled to 20 ℃ over 4-6 hours and filtered. The solid was washed with water (200mL) and dried at 50-70 ℃ for at least 8 hours to provide form II of compound 1.

Example 5

Preparation of form III of compound 1: the reactor was charged with form II of compound 1 (20g,39mmol) and methanol (200mL) and the reactor contents heated to 50-55 ℃. The reactor contents were then concentrated to about 80ml under reduced pressure and at 40-45 ℃, cooled to room temperature over at least 1 hour, and stirred at room temperature for an additional 2 hours. The solid was collected by filtration, washed with heptane, and dried under reduced pressure at 50 ℃ for 10 hours to provide 19.46g of form III of compound 1.