Solid forms of SGC activators

Abstract

Solid forms of activators of soluble guanylate cyclase (sGC) are disclosed. The invention also relates to processes for preparing these solid forms, pharmaceutical compositions comprising these solid forms, and their use for treating medical conditions responsive to the treatment with sGC activators.

Description

Technical Field

[0001] The present invention relates to solid forms of activators of soluble guanylate cyclase (sGC). 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 sGC activators. Background Art

[0002] Compound 1 is an sGC activator and has the structure shown below:

[0003]

[0004] Compound 1 can be used to treat several kidney- and liver-related disorders, which include (for example) chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), cirrhosis, and portal hypertension. Other diseases and disorders treatable with 1 are set forth, for example, in WO 2014 / 039434 and WO 2020 / 011804. The preparation of 1 is set forth in WO 2014 / 039434. (See compound 114.) However, no specific solid form of compound 1 is set forth in the processes described in WO 2014 / 039434. Accordingly, there is a need for solid forms of compound 1 having favorable pharmaceutical properties such as processability, stability, and solubility. Summary of the Invention

[0005] The present invention relates to new solid forms of compound 1 (collectively referred to herein as "the compounds of the present invention").

[0006] The present invention also relates to methods for preparing the compounds of the present invention and their use as sGC activators.

[0007] In another aspect, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention and optionally one or more inert carriers and / or diluents.

[0008] Another aspect of the present invention relates to the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for the prevention and / or treatment of disorders of the kidney and liver.

[0009] Yet another aspect of the present invention relates to the compounds of the present invention or pharmaceutical compositions comprising these compounds for the prevention and / or treatment of diseases or disorders (such as chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), cirrhosis, portal hypertension, and systemic sclerosis (scleroderma)) that can be affected by sGC activation. The use includes manufacturing a medicament for treating the corresponding diseases or disorders described herein.

[0010] In one embodiment, the present invention relates to any crystalline form of Compound 1 as set forth in Table 1 (“the compounds of the present invention”).

[0011] Table 1. Crystalline forms of Compound 1 of the present invention.

[0012] Solid form Molecular formula Form I <![CDATA[C 34 H 38 N4O5]]> Form III <![CDATA[C 34 H 38 N4O5·H2O]]> Form IV <![CDATA[C 34 H 38 N4O5·ACN·H2O]]> Form V <![CDATA[C 34 H 38 N4O5·H2O]]>

[0013] One embodiment of the present invention relates to crystalline Form I of Compound 1 (“Form I”). Form I is an anhydrate and a solvate.

[0014] In another embodiment, the present invention relates to crystalline Form III of Compound 1 (“Form III”). Form III is a 1:1 adduct with water (“monohydrate”).

[0015] In another embodiment, the present invention relates to crystalline Form IV of Compound 1 (“Form IV”). Form IV is a 1:1:1 adduct with acetonitrile and water.

[0016] In another embodiment, the present invention relates to crystalline Form V of Compound 1 (“Form V”). Form V is a 1:1 adduct with water (“monohydrate”). BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1A is the X-ray powder diffraction (XRPD) pattern of Form I of Compound 1.

[0018] Figure 1B is of Form I of Compound 1 13 C ssNMR spectrum.

[0019] Figure 1C is the thermal analysis chart of Form I of Compound 1 determined by DSC measurement.

[0020] Figure 1D is the thermal analysis chart of Form I of Compound 1 determined by TGA.

[0021] Figure 1E is the Raman spectrum of Form I of Compound 1.

[0022] Figure 2A is the XRPD pattern of Form III of Compound 1.

[0023] Figure 2B is of Form III of Compound 1 13 C ssNMR spectrum.

[0024] Figure 2C is the thermal analysis chart of Form III of Compound 1 determined by DSC measurement.

[0025] Figure 2D It is the thermogram of Form III of Compound 1 determined by TGA.

[0026] Figure 2E It is the Raman spectrum of Form III of Compound 1.

[0027] Figure 3A It is the XRPD pattern of Form IV of Compound 1.

[0028] Figure 3B It is of Form IV of Compound 1 13 C ssNMR spectrum. The asterisk indicates the signal from the Form I impurity.

[0029] Figure 3C It is the thermogram of Form IV of Compound 1 determined by DSC measurement.

[0030] Figure 3D It is the thermogram of Form IV of Compound 1 determined by TGA.

[0031] Figure 4A It is the XRPD pattern of Form V of Compound 1.

[0032] Figure 4B It is of Form V of Compound 1 13 C ssNMR spectrum.

[0033] Figure 4C It is the thermogram of Form V of Compound 1 determined by DSC measurement.

[0034] Figure 4D It is the thermogram of Form V of Compound 1 determined by TGA.

[0035] Figure 5 It is the XRPD pattern of the amorphous form of Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0037] Abbreviations:

[0038] ACN Acetonitrile

[0039] DSC Differential Scanning Calorimetry

[0040] TGA Thermogravimetric Analysis

[0041] MEK Methyl Ethyl Ketone or 2-Butanone

[0042] O.D. Outer Diameter

[0043] RH Relative Humidity

[0044] SSNMR Solid State Nuclear Magnetic Resonance

[0045] THF Tetrahydrofuran

[0046] XRPD X-ray powder diffraction

[0047] As discussed above, the present invention relates to crystalline forms of Compound 1. More particularly, the present invention relates to the crystalline forms of Compound 1 as set forth in Table 1. The present invention also relates to compositions comprising the crystalline compounds of the present invention and the use of these compounds and compositions for the treatment of diseases or disorders that respond to treatment with an sGC activator.

[0048] In certain embodiments, the present invention relates to mixtures of at least two crystalline forms of Compound 1 as set forth in Table 1, compositions comprising such mixtures of crystalline forms, and the use of these crystalline forms and mixtures for the treatment of diseases or disorders that respond to treatment with an sGC activator.

[0049] The preparation of Compound 1 is described in WO 2014 / 039434, but that disclosure does not mention any crystalline forms of Compound 1, any method for preparing crystalline forms of Compound 1, or any properties of the crystalline forms of Compound 1 as set forth herein. As set forth herein, Compound 1 prepared according to the method described in WO 2014 / 039434 is amorphous (see Figure 5 ).

[0050] Compared to the amorphous form of Compound 1, Forms I, III, and V have particularly advantageous properties (e.g., improved stability and reproducibility). Improvements over the amorphous form include, for example, lower hygroscopicity, a reduced tendency to transform into different solid forms, improved flowability, increased bulk density, and greater resistance to mechanical stress. For example, compared to the anhydrous form (Form I) and the monohydrate forms (Forms III, V), the amorphous form of Compound 1 has higher hygroscopicity and is unstable at high RH and will transform into Form III.

[0051] Form IV can be used to treat the diseases or disorders set forth herein and can also be used as a precursor for preparing Form V.

[0052] In one embodiment, the present invention relates to Form I that is substantially free of any other form of Compound 1, including the amorphous form and crystalline Forms III, IV, and V of the present invention. As used herein, the term "substantially free of" means that the solid compound contains at least about 75% of Form I of Compound 1, based on the total molar amount of any other form of Compound 1. The amount of any form of Compound 1 that may be present in Form I can be determined, for example, using the methods set forth herein.

[0053] In another embodiment, the present invention relates to Form III that is substantially free of any other form of Compound 1, including the amorphous form and crystalline Forms I, IV, and V of the present invention. As used herein, the term "substantially free" means that based on the total molar amount of any other form of Compound 1, the solid compound contains at least about 75% of Form III of Compound 1. The amount of any form of Compound 1 that may be present in Form III can be determined, for example, using the methods described herein.

[0054] In another embodiment, the present invention relates to Form V that is substantially free of any other form of Compound 1, including the amorphous form and crystalline Forms I, III, and IV of the present invention. As used herein, the term "substantially free" means that based on the total molar amount of any other form of Compound 1, the solid compound contains at least about 75% of Form V of Compound 1. The amount of any form of Compound 1 that may be present in Form V can be determined, for example, using the methods described herein.

[0055] Characterization

[0056] The compounds of the present invention are characterized by the methods described below. The methods for preparing the compounds of the present invention are set forth in the experimental section.

[0057] X-ray powder diffraction (XRPD)

[0058] XRPD was performed using CuKa radiation (1.54 Å) in a parabolic focusing mode with a Bruker AXS X-ray powder diffractometer model D8 Advance equipped with a graphite monochromator and a scintillation detector. Each pattern was obtained by scanning in the 2° to 35° 2θ range (step size 0.05° 2θ, step time 4 sec / step). Exemplary XRPD spectra of the compounds of the present invention are shown in Figure 1A 、 2A 、3A and 4A. Figure 5 An exemplary XRPD spectrum of the amorphous form of Compound 1 is shown in. The X-ray powder diffraction (XRPD) characteristics of the compounds of the present invention reported herein have a standard deviation of ±0.2 2θ.

[0059] Differential scanning calorimetry (DSC)

[0060] DSC analysis was performed using this general procedure with a differential scanning calorimeter (Q2000, TA instruments, New Castle, DE). Approximately 5 mg of the powder was weighed into a crimped aluminum pan with a pinhole. The sample was heated from room temperature to 300 °C at a rate of 10 °C / min using the Q2000 DSC. Exemplary DSC traces of the compounds of the present invention are shown in Figure 1C 、 2C, 3C and 4C. The results are reported below.

[0061] Thermogravimetric analysis (TGA)

[0062] The TGA analysis was performed using a TA TGA 2500 (TA instruments, New Castle, DE) with the following general procedure. Approximately 5 mg of the powder was weighed into a platinum pan. Then the sample was heated from room temperature to 300 °C at a rate of 10 °C / min using the TA TGA 2500. Exemplary TGA traces of the compounds of the present invention are shown in Figure 1D , 2D , 3D and 4D. The results are reported below.

[0063] Dynamic vapor sorption (DVS)

[0064] The moisture sorption isotherms were determined using a dynamic vapor sorption system (Advantage 1, DVS, London, UK; DVS Intrinsic Plus, Surface Measurement Systems, Allentown, PA). Approximately 5 - 10 mg of the solid was weighed into a tared aluminum pan. The sample was subjected to 0 to 90% RH in 5 - 10% steps at 25 °C. The equilibrium criterion at a specified %RH was 0.002% dm / dt over 5 minutes or 360 minutes. Each sample was equilibrated for at least 60 min at each RH step and was assumed to be at equilibrium if the weight gain was less than 0.1% in one minute, and the maximum duration at each RH step was 6 hours. Thus, each sample was held at a given RH for 1 to 6 hours depending on the rate of attaining equilibrium.

[0065] 13 13C solid-state NMR (SSNMR)

[0066] 13C solid-state NMR (SSNMR) data of samples of Form I, Form III (monohydrate), Form IV (ACN / H2O solvate), and Form V (monohydrate) were acquired on a Bruker Avance III HD NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 11.7 T 13 13C solid-state NMR (SSNMR) data ( 1 1H = 500.28 MHz, 13C = 125.81 MHz). The sample was encapsulated in a 4 mm O.D. zirconia rotor with a Kel-F(R) drive cap. Data were acquired using a Bruker model BL4 VTN probe and the sample was spun about the magic angle (54.74 degrees). The sample spectra were acquired using a spin rate of 12 kHz. At ambient temperature and pressure, a standard cross-polarization pulse sequence with ramped Hartman-Hahn matching pulses was used on the proton channel. For Form I, Form III (hydrate), Form IV (ACN / H2O solvate), and Form V (hydrate), the pulse sequence used a 4 ms contact pulse and recycle delays of 20, 3, 10, and 3.64 s, respectively. SPINAL64 decoupling and TOSS sideband suppression were also employed in the pulse sequence. No exponential line broadening was used prior to Fourier transformation of the free induction decay. Chemical shifts were referenced to the secondary standard of adamantane and the high frequency resonance was set to 38.48 ppm. The 79 Br signal from KBr powder was used to set the magic angle at a spin rate of 5 kHz. Exemplary 13 13C SSNMR spectra of the sample are shown in Figure 1B 、 2B 、3B, and 3C and in the table below. The reported chemical shifts have an uncertainty of ±0.3 ppm.

[0067] Raman

[0068] Raman data were acquired using an 830 nm laser with 0.6 W power on a transmission Raman system (Agilent TRS100, SN 6032). The exposure time for the experiment was 0.4 s and 20 accumulations were made. Exemplary Raman spectra of the samples of Form I and Form III of the present invention are shown in Figure 1E and 2E and the results are reported in the table below.

[0069] Properties of Form I

[0070] Figure 1A shows the X-ray powder diffraction (XRPD) pattern of Form I of Compound 1; Figure 1B shows the 13 13C solid state NMR spectrum of Form I of Compound 1; Figure 1C and 1D show the thermal analysis profiles of Form I of Compound 1 determined by DSC and TGA measurements, respectively; and Figure 1E shows the Raman spectrum of Form I of Compound 1.

[0071] Characteristic XRPD peaks, 13 13C solid state nuclear magnetic resonance peaks, and Raman peaks are provided in Tables 2, 3, and 4, respectively.

[0072] Table 2. Form I Figure 1A X-ray powder diffraction (XRPD) characteristics of .

[0073]

[0074]

[0075] Table 3. Form I Figure 1B In 13 C NMR chemical shift.

[0076]

[0077]

[0078] Table 4. Raman peaks and intensities of Form I ( Figure 1E ).

[0079]

[0080]

[0081] In one embodiment of the invention, Form I of Compound 1 is characterized by Figure 1A XRPD pattern of.

[0082] In another embodiment of the present invention, Form I of Compound 1 has the XRPD characteristics shown in Table 2.

[0083] In another embodiment of the invention, Form I of Compound 1 is characterized by at least three XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°.

[0084] In another embodiment of the invention, Form I of Compound 1 is characterized by at least five XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°.

[0085] In another embodiment of the invention, Form I of Compound 1 is characterized by an XRPD peak at a 2θ angle selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6°, and 26.2°.

[0086] In one embodiment of the invention, Form I of Compound 1 is characterized by Figure 1B of 13 C solid-state NMR spectroscopy.

[0087] In another embodiment of the present invention, Form I of Compound 1 has the13 C solid-state NMR characteristics.

[0088] In another embodiment of the present invention, Form I of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 166.3 ppm, 146.1 ppm, 65.2 ppm, 52.7 ppm, and 44.2 ppm.

[0089] In another embodiment of the present invention, Form I of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 166.3 ppm, 152.9 ppm, 146.1 ppm, 140.6 ppm, 65.2 ppm, 52.7 ppm, 44.2 ppm, 31.5 ppm, and 29.3 ppm.

[0090] In one embodiment of the present invention, Form I of Compound 1 is characterized by a thermal analysis spectrum determined by DSC as shown in Figure 1C There is an endothermic event, the melting point of Compound I starts at 200 °C and has a peak temperature of 202 °C.

[0091] In another embodiment of the present invention, Form I of Compound 1 is characterized by a thermal analysis spectrum determined by TGA as shown in Figure 1D which does not show a significant loss (>0.5%) when heated up to 200 °C (the melting point of Compound 1).

[0092] In one embodiment of the present invention, Form I of Compound 1 is characterized by a Raman spectrum as shown in Figure 1E In another embodiment of the present invention, Form I of Compound 1 has the Raman characteristics shown in Table 4.

[0093] Samples of Form I are maintained at 25 °C and 60% relative humidity for at least 9 months and at 40 °C and 75% relative humidity for at least 6 months. Under both storage conditions, the samples of Form I show no increase in water content, no increase in impurity content, no change in particle size distribution, and no change in Raman spectrum.

[0094] Properties of Form III

[0095] Properties of Form III

[0096] Respectively, Figure 2A the X-ray powder diffraction (XRPD) pattern of Form III of Compound 1 is shown in Figure 2B the 13 C solid-state NMR spectrum of Form III of Compound 1 is shown in Figure 2C and 2DThe thermoanalytical spectra of Form III of Compound 1 determined by DSC and TGA measurements are shown in; and Figure 2E The Raman spectrum of Form III of Compound 1 is shown in.

[0097] Table 5, Table 6 and Table 7 provide the characteristic XRPD peaks of Form III, 13 13C solid-state NMR peaks and Raman peaks, respectively.

[0098] Table 5. Characteristic of Form III Figure 2A X-ray powder diffraction (XRPD) properties in.

[0099]

[0100]

[0101] Table 6. Characteristic of Form III Figure 2D in 13 13C NMR chemical shifts.

[0102]

[0103]

[0104] Table 7. Raman peaks and intensities of Form III ( Figure 2E ).

[0105]

[0106]

[0107] In one embodiment of the present invention, Form III of Compound 1 is characterized by Figure 2A XRPD pattern.

[0108] In another embodiment of the present invention, Form III of Compound 1 has the XRPD properties shown in Table 4.

[0109] In another embodiment of the present invention, Form III of Compound 1 is characterized by XRPD peaks at at least three 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6° and 22.9°.

[0110] In another embodiment of the present invention, Form III of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6° and 22.9°.

[0111] In one embodiment of the present invention, Form III of Compound 1 is characterized by Figure 2B of 13C solid-state NMR spectroscopy.

[0112] In another embodiment of the present invention, Form III of Compound 1 has the 13 C solid-state NMR characteristics shown in Table 5.

[0113] In another embodiment of the present invention, Form III of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, and 42.7 ppm.

[0114] In another embodiment of the present invention, Form IIII of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 143.9 ppm, 142.8 ppm, 137.8 ppm, 113.2 ppm, 110.8 ppm, 73.0 ppm, 65.2 ppm, 61.7 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, 42.7 ppm, 42.0 ppm, and 41.7 ppm.

[0115] In one embodiment of the present invention, Form III of Compound 1 is characterized by a Figure 2C thermoanalytical profile determined by DSC as shown in. There are two features in the DSC: an endotherm starting at 83 °C and having a peak temperature of 98 °C. Subsequently, a second endotherm starting at 195 °C and having a peak temperature of 199 °C.

[0116] In another embodiment of the present invention, Form III of Compound 1 is characterized by a Figure 2D thermoanalytical profile determined by TGA as shown in, wherein heating from 25 °C to 100 °C (before the melting of Form III of Compound I) has a 3.6% loss.

[0117] In one embodiment of the present invention, Form III of Compound 1 is characterized by a Figure 2E Raman spectrum as shown in.

[0118] In another embodiment of the present invention, Form III of Compound 1 has the Raman characteristics shown in Table 7.

[0119] Characteristics of Form IV

[0120] Respectively, Figure 3A shows the X-ray powder diffraction (XRPD) pattern of Form IV of Compound 1; Figure 3B shows the13 C solid state NMR spectroscopy; and Figure 3C and 3D shows the thermogram of Form IV of Compound 1 determined by DSC and TGA measurements.

[0121] Table 8 and Table 9 provide the characteristic XRPD peaks of Form IV and 13 C solid state nuclear magnetic resonance peaks, respectively.

[0122] Table 8. Figure 3A X-ray powder diffraction (XRPD) characteristics of

[0123]

[0124]

[0125] Table 9. Figure 3B in 13 C NMR chemical shifts.

[0126]

[0127]

[0128] In one embodiment of the present invention, Form IV of Compound 1 is characterized by Figure 3A XRPD pattern.

[0129] In another embodiment of the present invention, Form IV of Compound 1 has the XRPD characteristics shown in Table 8.

[0130] In another embodiment of the present invention, Form IV of Compound 1 is characterized by XRPD peaks at at least three 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6° and 28.3°.

[0131] In another embodiment of the present invention, Form IV of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6° and 28.3°.

[0132] In another embodiment of the present invention, Form IV of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 12.5°, 13.1°, 17.4°, 22.6°, 26.3°, 27.3° and 28.3°.

[0133] In one embodiment of the present invention, Form IV of Compound 1 is characterized by Figure 3B of 13 C solid state NMR spectrum.

[0134] In another embodiment of the present invention, Form IV of Compound 1 has the 13 C solid-state NMR properties shown in Table 9.

[0135] In another embodiment of the present invention, Form IV of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 169.8 ppm, 107.8 ppm, 30.6 ppm, and 2.6 ppm.

[0136] In another embodiment of the present invention, Form IV of Compound 1 is characterized by 13 C solid-state nuclear magnetic resonance peaks at chemical shifts selected from 169.8 ppm, 139.1 ppm, 107.8 ppm, 75.1 ppm, 30.6 ppm, and 2.6 ppm.

[0137] In one embodiment of the present invention, Form IV of Compound 1 is characterized by a Figure 3C thermoanalytical profile determined by DSC as shown in. There are two consecutive endotherms with peak temperatures of 75 °C (starting point: 67 °C) and 105 °C (starting point: 96 °C). There is an exotherm at 137 °C (which has a peak temperature of 149 °C), followed by a final exotherm starting at 199 °C, which has a peak temperature of 201 °C.

[0138] In another embodiment of the present invention, Form IV of Compound 1 is characterized by a Figure 3D thermoanalytical profile determined by TGA as shown in. The total loss from 25 °C to 125 °C is 2.9%.

[0139] Properties of Form V

[0140] Respectively, Figure 4A shows the X-ray powder diffraction (XRPD) pattern of Form V of Compound 1; Figure 4B shows the 13 C solid-state NMR spectrum of Form V of Compound 1; and Figure 4C and 4D show the thermoanalytical profiles of Form V of Compound 1 determined by DSC and TGA measurements.

[0141] Table 10 and Table 11 respectively provide the characteristic XRPD peaks and 13 C solid-state nuclear magnetic resonance peaks of Form V.

[0142] Table 10. Figure 4A X-ray powder diffraction (XRPD) properties of Form V in.

[0143]

[0144]

[0145] Table 11. For Form V of Figure 4B in 13 13C NMR chemical shifts.

[0146]

[0147]

[0148] In one embodiment of the present invention, Form V of Compound 1 is characterized by Figure 4A XRPD pattern.

[0149] In another embodiment of the present invention, Form V of Compound 1 has the XRPD characteristics shown in Table 10.

[0150] In another embodiment of the present invention, Form V of Compound 1 is characterized by XRPD peaks at at least three 2θ angles selected from 5.6°, 10.5°, 12.9°, and 22.8°.

[0151] In another embodiment of the present invention, Form V of Compound 1 is characterized by XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, 17.9°, 18.7°, 20.1°, 20.8°, and 22.8°.

[0152] In one embodiment of the present invention, Form V of Compound 1 is characterized by Figure 4B of 13 13C solid-state NMR spectrum.

[0153] In another embodiment of the present invention, Form V of Compound 1 has the 13 13C solid-state NMR characteristics shown in Table 11.

[0154] In another embodiment of the present invention, Form V of Compound 1 is characterized by 13C solid-state NMR peaks at chemical shifts selected from 155.4 ppm, 116.4 ppm, 74.6 ppm, 71.5 ppm, and 29.6 ppm 13 13C solid-state NMR peaks.

[0155] In another embodiment of the present invention, Form V of Compound 1 is characterized by 13C solid-state NMR peaks at chemical shifts selected from 169.3 ppm, 155.4 ppm, 150.4 ppm, 116.4 ppm, 108.0 ppm, 74.6 ppm, 71.5 ppm, 67.7 ppm, 29.6 ppm, and 26.0 ppm 13 13C solid-state NMR peaks.

[0156] In one embodiment of the present invention, Form V of Compound 1 is characterized by a thermal analysis profile determined by DSC as shown in Figure 4C There are multiple thermal events: the first endotherm starts at 107 °C and has a peak temperature of 119 °C, the subsequent exotherm starts at 154 °C (peak temperature 164 °C), and the final endotherm has a peak temperature of 196 °C and starts at 194 °C.

[0157] In another embodiment of the present invention, Form V of Compound 1 is characterized by a thermal analysis profile determined by TGA as shown in Figure 4D The total loss upon heating from 25 °C to 140 °C is 3.0%.

[0158] Methods for preparing the compounds of the present invention

[0159] The specific conditions for preparing the solid forms of Compound 1 of the present invention are set forth in the Examples. Generally, the compounds of the present invention can be obtained by dissolving Compound 1 in a suitable solvent at a temperature preferably above room temperature, more preferably from about 45 °C to about 80 °C (“dissolution step”). The heated solution is then cooled (“cooling step”) to provide a solid / liquid comprising the compounds of the present invention. In certain embodiments, the heated solution can be filtered before cooling. In other embodiments, the heated solution can be concentrated (“concentration step”) before or during the cooling step. In still other embodiments, the heated solution can be treated with a co-solvent (“co-solvent treatment step”). In certain embodiments, the co-solvent can be added during the cooling step (when used). In still other embodiments, the cooling step comprises a stepwise cooling ramp. In still other embodiments, seeds or a seed slurry are added before or during the cooling step (“seeding step”). It should be understood that any combination of the above can be used to obtain the compounds of the present invention and their mixtures. After cooling, the resulting solid can be collected, washed with a suitable solvent and dried to provide the compounds of the present invention or their mixtures.

[0160] In one embodiment, reactive crystallization with a pH swing is used to obtain Form I. Compound 1 is dissolved in an alkaline aqueous solution (NaOH or ammonia). The pH is adjusted with an acid (HCl or citric acid) and seeded with Form I. The pH is slowly neutralized with the acid as the solid phase of the slurry grows. The solid is collected, washed with a suitable solvent and dried.

[0161] Methods of therapeutic application

[0162] The compounds disclosed herein are effective in activating soluble guanylate cyclase. Activation or enhancement of soluble guanylate cyclase is an attractive approach for the prevention and treatment of certain diseases and disorders. Non-limiting examples of such diseases or disorders include those described in WO 2014 / 039434 and WO 2020 / 011804.

[0163] In another embodiment, the present invention relates to methods for treating diseases and disorders including:

[0164] Cardiovascular and related diseases, including hypertension, atherosclerosis, peripheral arterial disease, restenosis, stroke, heart failure, coronary artery spasm, cerebral vasospasm, ischemia / reperfusion injury, thromboembolic pulmonary hypertension, pulmonary arterial hypertension, stable and unstable angina, and thromboembolic disorders;

[0165] Inflammatory diseases, including psoriasis, multiple sclerosis, arthritis, asthma, and chronic obstructive pulmonary disease; hepatic fibrosis disorders, including (but not limited to) cirrhosis of any etiology, fibrosis of specific regions of the liver (e.g., periportal fibrosis) that can be caused by immune injury, hemodynamic effects, and / or other etiologies;

[0166] Renal fibrosis disorders, including (but not limited to) glomerulosclerosis, focal glomerulosclerosis, glomerular basement membrane fibrosis, interstitial fibrosis, diabetic nephropathy, IgA nephropathy, lupus nephropathy, membranous nephropathy, hypertension, hemolytic uremic syndrome, multiple glomerulonephritis, interstitial nephritis, tubulointerstitial nephritis with immune and non-immune etiologies, caused by immune injury, hemodynamic effects, diabetes (type I and type 2);

[0167] Pulmonary fibrosis disorders (diffuse and focal), caused by immune and non-immune etiologies, including (but not limited to) idiopathic pulmonary fibrosis, pulmonary fibrosis (caused by exposure to toxins, chemicals, drugs), and cystic fibrosis;

[0168] Cardiac fibrosis disorders caused by immune and non-immune etiologies, including ischemic heart disease (coronary artery disease), and transient and / or sustained reduction in blood flow in one or more coronary vessels (including those possibly associated with interventions on coronary arteries or veins, cardiac surgery, and / or use of cardiopulmonary bypass procedures), and myocarditis caused by viral and non-viral etiologies, and immune-related myocardial injury possibly resulting from cross-reactivity with other antigens to which the human body is exposed;

[0169] Other diseases mediated at least in part by reduced soluble guanylate cyclase activity, such as kidney diseases, diabetes, urological disorders (including overactive bladder, benign prostatic hyperplasia, and erectile dysfunction), and neurological disorders (including Alzheimer's disease, Parkinson's disease, and neuropathic pain).

[0170] In another embodiment, the present invention relates to the use of the compounds of the present invention for the treatment, alleviation or slowing of the progression of chronic kidney disease (CKD) (including rapidly progressive CKD), non-alcoholic steatohepatitis (NASH), all-cause cirrhosis, clinically significant portal hypertension (CSPH), and systemic sclerosis (scleroderma).

[0171] According to one embodiment, the present invention relates to a method for treating, preventing non-alcoholic steatohepatitis (NASH) in a patient in need thereof and slowing its progression, characterized by administering to the patient a pharmaceutical composition or pharmaceutical dosage form as defined above and below.

[0172] In one embodiment, the compounds of the present invention can be used to treat NASH accompanied by fibrosis (e.g., F1 to F4).

[0173] In another embodiment, the compounds of the present invention can be used to treat cirrhosis with and without clinically significant portal hypertension.

[0174] In another embodiment, the present invention relates to treating a patient with compensated NASH cirrhosis accompanied by clinically significant portal hypertension (CSPH). Portal pressure is the blood pressure in the hepatic portal vein and is typically between 5 and 10 mmHg. An elevated portal pressure is called portal hypertension and has numerous sequelae (e.g., ascites and hepatic encephalopathy). In one embodiment of the present invention, CSPH is defined as a hepatic venous pressure gradient (HVPG) of ≥10 mm / Hg. Accordingly, another embodiment of the present invention relates to treating a patient with compensated NASH cirrhosis accompanied by a venous pressure gradient (HVPG) ≥10 mm / Hg.

[0175] In another embodiment, the present invention relates to treating portal hypertension in a cirrhotic patient, wherein the cirrhosis is due to any cause (all-cause cirrhosis). The causes include (but are not limited to) NASH, alcoholic liver disease (ALD), hepatitis C, hepatitis B, chronic primary liver diseases (primary sclerosing cholangitis, primary biliary cirrhosis).

[0176] According to another aspect, the present invention relates to a method for treating non-alcoholic steatohepatitis (NASH, NAS≥4) in a patient in need thereof, especially NASH accompanied by liver fibrosis (e.g., NASH accompanied by stage 2 and 3 liver fibrosis), characterized by administering to the patient a pharmaceutical composition comprising a compound of formula (I) as the active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, preferably the pharmaceutical composition of the present invention.

[0177] In one embodiment, the present invention relates to the use of the compounds of the present invention for the preparation of a medicament for treating, preventing non-alcoholic steatohepatitis (NASH) or one or more other conditions or diseases or slowing their progression, said other conditions or diseases being selected from the group of conditions or diseases outlined in the section above titled "Methods of Therapeutic Application".

[0178] In one embodiment, the present invention relates to the compounds of the present invention for treating, preventing non-alcoholic steatohepatitis (NASH) or one or more other conditions or diseases or slowing their progression, said other conditions or diseases being selected from the group of conditions or diseases outlined in the section above titled "Methods of Therapeutic Application".

[0179] Another aspect of the present invention relates to the compounds of the present invention for the manufacture of a medicament for treating a condition or disease selected from the group of conditions or diseases outlined in the section above titled "Methods of Therapeutic Application".

[0180] The effect of administering the pharmaceutical composition to a patient suffering from NASH and / or liver fibrosis can be observed by changes in liver inflammation and / or related biomarkers of liver function (such as ALT (alanine aminotransferase), AST (aspartate aminotransferase), AP (alkaline phosphatase), γ-GT (γ-glutamyltransferase), CK-18 (cytokeratin 18) fragments or HVPG (hepatic venous pressure gradient)), in particular by a decrease.

[0181] Furthermore, the effect of administering the pharmaceutical composition to a patient suffering from NASH and / or liver fibrosis can be observed by improvements in, for example, the degree or stage of steatosis, fibrosis, liver stiffness or health-related quality of life.

[0182] For therapeutic applications, the compounds of the present invention can be administered via a pharmaceutical composition in any conventional pharmaceutical dosage form and in any conventional manner. Conventional dosage forms generally comprise a pharmaceutically acceptable carrier suitable for the particular dosage form selected. Routes of administration include (but are not limited to) intravenous, intramuscular, subcutaneous, intra-synovial, by infusion, sublingual, transdermal, oral, topical or by inhalation. Preferred modes of administration are oral and intravenous.

[0183] The preferred dose for oral administration of the compounds of the present invention is from 0.1 to 100 mg; or from 1 to 25 mg; or from 1 to 10 mg; or from 1 to 5 mg. In another embodiment, the preferred dose for oral administration of the compounds of the present invention is selected from 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

[0184] In one embodiment, the compounds of the invention may be administered once, twice, three times or more times daily. In another embodiment, the compounds of the invention may be administered once, twice, three times or more times weekly.

[0185] The compounds of the invention may be administered alone or in combination with adjuvants which should enhance the stability of the inhibitor, facilitate in certain embodiments the administration of the pharmaceutical composition containing it, provide increased dissolution or dispersion, increase inhibitory activity, provide adjuvant therapy and the like and which contain other active ingredients. In one embodiment, for example, a plurality of the compounds of the invention may be administered. Advantageously, these combination therapies utilize lower doses of conventional therapeutic agents, thereby avoiding possible toxicities and adverse side effects that occur when using those agents as monotherapy. The compounds of the invention may be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. Advantageously, these compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising these combinations of compounds contain at least about 5%, but more preferably at least about 20% of the compound of formula (I) (w / w) or combinations thereof. The optimal percentage (w / w) of the compounds of the invention may vary and is well known to those skilled in the art. Alternatively, the compounds of the invention and conventional therapeutic agents or other adjuvants may be administered separately (sequentially or in parallel). Separate administration allows for greater flexibility in the dosing regimen.

[0186] As mentioned above, the dosage forms of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for dosage forms. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffering substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, cachets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing these dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th Edition, Lea and Febiger (1990)). The dosage values and requirements of the compounds of the present invention can be selected by those skilled in the art according to the available methods and techniques applicable to a particular patient. In some embodiments, for a 70 kg patient, the dosage value ranges from about 1 to 1000 mg / dose. Although one dose per day may be sufficient, up to 5 doses per day may be administered. For oral doses, up to 2000 mg / day may be required. As is understood by those skilled in the art, lower or higher doses may be required depending on specific factors. For example, specific dosages and treatment regimens will depend on factors such as the general health characteristics of the patient, the severity and course of the patient's condition or the treatment of the condition, and the judgment of the treating physician.

[0187] In one embodiment, for example, a plurality of the compounds of the present invention may be administered. Advantageously, these combination therapies utilize lower doses of conventional therapeutic agents, thereby avoiding possible toxicities and adverse side effects that occur when using those agents as monotherapies. The compounds of the present invention may be physically combined with conventional therapeutic agents or other adjuvants into a single pharmaceutical composition. Advantageously, these compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical composition comprising these combinations of compounds contains at least about 5%, but more preferably at least about 20% of the compound of formula (I) (w / w) or a combination thereof. The optimal percentage (w / w) of the compounds of the present invention may vary and is well known to those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants may be administered separately (sequentially or in parallel). Separate administration allows for greater flexibility in the dosing regimen. Examples

[0188] The amorphous form of Compound 1 (“Amorphous Compound 1”) was prepared as described in Example 114 of WO 2014 / 039434. The solvent was removed from the resulting eluate under reduced pressure to provide solid Amorphous Compound 1. Figure 5 The typical XRPD pattern obtained for Amorphous Compound 1 is shown in.

[0189] Example 1a

[0190] Preparation of Form I of Compound 1

[0191] The amorphous form of Compound 1 (1.2 g) was treated with MeOH (12 g) and heated to 60 °C with stirring. The resulting slurry was treated with water (1 mL) and THF (8 mL). The mixture was stirred at 60 °C for an additional 1 hour, cooled to 20 °C over 4 hours, and stirred at 20 °C overnight. The solid was collected by filtration and dried to afford Form I of Compound 1 (1.03 g).

[0192] Example 1b

[0193] Preparation of Form I of Compound 1

[0194] The amorphous form of Compound 1 was treated with an aqueous solution of concentrated hydrochloric acid in THF and water (THF / H2O 97 / 3) to afford the HCl salt of Compound 1. The HCl salt of Compound 1 (4.45 kg) was treated with 2 equivalents of NaOH in water (50% NaOH in 1.15 kg of water) to afford the sodium salt of the Compound 1 salt in the form of a clear solution. The solution was filtered precisely and the pH of the filtrate was adjusted with an aqueous solution of dilute HCl to provide a pH of the solution of 8.6 to 9.0. Then the solution was seeded with Form 1 of Compound 1 obtained as described above (0.004 kg) to initiate crystallization. The seeded mixture was treated with an additional amount of dilute HCl until the pH of the mixture reached about 7.2 - 7.9. The reaction mixture was cooled to 20 °C, aged for several hours and centrifuged and filtered. The solid was washed with water (110 kg) followed by acetone (6.8 kg). Then the solid was dried under reduced pressure at about 40 °C using a nitrogen stream to afford Form I (4.08 kg).

[0195] Example 1c

[0196] Preparation of Form I of Compound 1

[0197] The amorphous form of Compound 1 (7 g) was suspended in EtOH (56 mL) and water (31 mL). 7 g of ammonia solution (25% w / w) was added to this solution over 5 min to form a clear pale yellow solution. The solution was heated to 50 °C with stirring and maintained for 15 min. Citric acid (11 g of 50% w / w solution) was added over 45 min until the pH reached within the range of 8.0 to 7.2. The solution was seeded with Form 1 (7 mg, prepared as described above) and the mixture was maintained for 15 min. Then an additional 2.65 g of citric acid solution (50% w / w) was added over 120 min until a pH of approximately 6.0 was reached. The resulting slurry was cooled to 25 °C over 60 minutes. The solid was collected by filtration, washed with 50 mL of H2O and dried to afford Form I of Compound 1 (6.723 g).

[0198] Example 2a

[0199] Preparation of Form III of Compound 1

[0200] The amorphous form of Compound 1 (10 mg) was added to a pan for dynamic vapor sorption analysis. The solid was gradually exposed to 40% to 95% to 0% to 95% to 0% RH at 25 °C. Form III was isolated after completion of the stepwise exposure.

[0201] Example 2b

[0202] Preparation of Form III of Compound 1

[0203] The amorphous form of Compound 1 (100 mg) was treated with water (1.0 mL). The mixture was agitated using a magnetic stir bar at room temperature and the solid was collected to afford Form III.

[0204] Example 3a

[0205] Preparation of Form IV of Compound 1

[0206] Form I of Compound 1 (1 g) was dissolved in 5 mL of 70% water in acetonitrile (ACN) to form a saturated solution. The solution was stirred using a magnetic stir bar at room temperature for 72 hours. The resulting crystals were collected as Form IV. The stoichiometric ratio of Form IV (Compound 1:ACN:H2O, 1:1:1) was determined by single crystal X-ray diffraction.

[0207] Example 3b

[0208] Preparation of Form IV of Compound 1

[0209] Treat Form I (1 g) of Compound 1 with 5 mL of 70% water in acetonitrile (ACN). Stir the mixture with a magnetic stir bar at room temperature for 48 h. Collect the resulting crystals as Form IV.

[0210] Example 4a

[0211] Preparation of Form V of Compound 1

[0212] Air-dry the Form IV crystals (prepared as described above) on a bench at room temperature for 24 h to afford Form V. Determine the stoichiometric ratio of Form V (Compound 1:H2O, 1:1) by single crystal X-ray diffraction.

[0213] Example 4b

[0214] Preparation of Form V of Compound 1

[0215] Treat Form I (2 g) of Compound 1 with 10 mL of 70% water in acetonitrile (ACN) and seed with Form IV from Example 3b. Stir the mixture with a magnetic stir bar at room temperature for 24 h. Then separate the solid by filtration and dry overnight at 60 °C under reduced pressure to afford Form V.

Claims

1. A solid crystalline form of Compound 1, wherein the solid crystalline form of Compound 1 is selected from the group consisting of: i) Form I, which is characterized by: at least three XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6° and 26.2°; or 13 The C solid-state nuclear magnetic resonance peaks are at chemical shifts selected from 166.3 ppm, 146.1 ppm, 65.2 ppm, 52.7 ppm, and 44.2 ppm; ii) Form III, which is characterized by: at least three XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6° and 22.9°; or 13 The solid-state nuclear magnetic resonance peaks of C are at chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, and 42.7 ppm; iii) Form IV, which is characterized by: at least three XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 17.4°, 22.6° and 28.3°; or 13 The C solid-state nuclear magnetic resonance peaks are at chemical shifts selected from 169.8 ppm, 107.8 ppm, 30.6 ppm, and 2.6 ppm; and iv) Form V, which is characterized by: at least three XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9° and 22.8°; or 13 The solid-state nuclear magnetic resonance peaks of C are at chemical shifts selected from 155.4 ppm, 116.4 ppm, 74.6 ppm, 71.5 ppm, and 29.6 ppm.

2. The solid crystalline form of Compound 1 according to claim 1, which is Form I further characterized by: XRPD peaks at 2θ angles selected from 4.1°, 8.2°, 11.9°, 17.0°, 21.8°, 22.6° and 26.2°; or 13 The C solid-state nuclear magnetic resonance peaks are at chemical shifts selected from 166.3 ppm, 152.9 ppm, 146.1 ppm, 140.6 ppm, 65.2 ppm, 52.7 ppm, 44.2 ppm, 31.5 ppm, and 29.3 ppm.

3. The solid crystalline form of Compound 1 according to claim 1, which is Form III further characterized by: XRPD peaks at 2θ angles selected from 7.7°, 11.5°, 12.5°, 16.6° and 22.9°; or 13 The solid-state nuclear magnetic resonance peaks of C are at chemical shifts selected from 168.4 ppm, 167.4 ppm, 151.5 ppm, 143.9 ppm, 142.8 ppm, 137.8 ppm, 113.2 ppm, 110.8 ppm, 73.0 ppm, 65.2 ppm, 61.7 ppm, 60.6 ppm, 51.4 ppm, 47.7 ppm, 42.7 ppm, 42.0 ppm, and 41.7 ppm.

4. The solid crystalline form of Compound 1 according to claim 1, which is Form IV further characterized by: XRPD peaks at 2θ angles selected from 5.7°, 10.0°, 12.5°, 13.1°, 17.4°, 22.6°, 26.3°, 27.3° and 28.3°; or 13 The C solid-state nuclear magnetic resonance peaks are at chemical shifts selected from 169.8 ppm, 139.1 ppm, 107.8 ppm, 75.1 ppm, 30.6 ppm, and 2.6 ppm.

5. The solid crystalline form of Compound 1 according to claim 1, which is Form V further characterized by: XRPD peaks at 2θ angles selected from 5.6°, 10.5°, 12.9°, 17.9°, 18.7°, 20.1°, 20.8° and 22.8°.

6. A pharmaceutical composition comprising any one of Form I, Form III or Form V according to claims 1 to 3 and 5, and optionally one or more inert carriers and / or diluents.

7. A pharmaceutical composition comprising Form I according to claim 2 and optionally one or more inert carriers and / or diluents.

8. A pharmaceutical composition comprising Form III according to claim 3 and optionally one or more inert carriers and / or diluents.

9. A pharmaceutical composition comprising Form V according to claim 5 and optionally one or more inert carriers and / or diluents.

10. A method for treating and / or preventing a disease or disorder responsive to treatment with an sGC activator, which comprises administering to a patient in need a pharmaceutically effective amount of Form I, Form III or Form V according to claim 1.

11. The method of claim 1, wherein the disease or disorder responsive to treatment with an sGC activator is selected from the group consisting of: chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), cirrhosis, portal hypertension, and systemic sclerosis (scleroderma).

12. Use of a compound as claimed in claim 1 for the manufacture of a medicament for treating, preventing or slowing the progression of a disease or disorder responsive to treatment with an sGC activator.

13. Use of a pharmaceutical composition as claimed in claim 6 for the manufacture of a medicament for treating, preventing or slowing the progression of a disease or disorder responsive to treatment with an sGC activator.

14. The use of claim 13 or 14, wherein the disease or disorder responsive to treatment with an sGC activator is selected from the group consisting of: chronic kidney disease, diabetic kidney disease, non-alcoholic steatohepatitis (NASH), cirrhosis, portal hypertension, and systemic sclerosis (scleroderma).

15. A method for producing Form I of compound 1 as claimed in claim 1, comprising: (i) adding an aqueous alkaline solution to a suspension of compound 1, ethanol and water to provide a solution, (ii) heating the solution of step (i) to 50 °C, (iii) treating the solution of step (ii) with an acid until the pH reaches within the range of 8.0 to 7.2, (iv) adding a seed crystal of Form I of compound 1 to the solution of step (iii) to provide a seeded mixture, (v) treating the seeded mixture of step (iv) with an acid until the pH reaches 6.0, (vi) cooling the mixture of step (v), and (vii) separating the solid from the mixture of step (vi) to provide Form I of compound 1.

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