BACKGROUND OF THE INVENTION

The present invention relates to crystalline salt forms of the following compound (I) which is an inhibitor of RORy (retinoic acid receptor related orphan receptor gamma) that can be used for the treatment of (chronic) inflammatory diseases. The crystalline salt forms of compound (I) of the present invention show good formulation properties such as high kinetic dissolution and high crystallinity.

RORy is a transcription factor belonging to the steroid hormone receptor superfamily (review in Jetten 2006, Adv. Dev. Biol. 16: 313-355). RORy has been identified as a transcriptional factor that is required for the differentiation of T cells and secretion of Interleukin 17 (IL-17) from a subset of T cells termed Thn cells (Ivanov 2006, Cell, 126, 1121-1133).

The rationale for the use of a RORy targeted therapy for the treatment of chronic inflammatory disesases is based on the emerging evidence that Thn cells and the cytokine IL-17 contribute to the initiation and progression of the pathogenesis of several diseases. Inhibitors of RORy are known from, for example, WO2015/160654 or WO2013/169704.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : A) XRPD spectra from 5-30 °29 of crystalline phosphate salt of compound

(I)

B) XRPD spectra from 5-30 °29 of crystalline oxalate salt of compound (I) Figure 2: A) Exemplary trace from 0-200 min of kinetic solubility experiment of crystalline phosphate salt of compound (I)

B) Exemplary trace from 0-200 min of kinetic solubility experiment of crystalline oxalate salt of compound (I)

Figure 3: A) DSC trace of crystalline phosphate salt of compound (I)

B) TGA trace of crystalline phosphate salt of compound (I)

Figure 4: A) DSC trace of crystalline oxalate salt of compound (I)

B) TGA trace of crystalline oxalate salt of compound (I)

Figure 5: A) DSC trace of the crystalline edisylate salt of compound (I)

B) DSC trace of the crystalline napadisylate salt of compound (I)

Figure 6: A) ¹³ C-ssNMR of oxalate salt of compound (I)

B) ¹³ C-SSNMR of phosphate salt of compound (I)

Figure 7: A) DVS Isotherm of crystalline oxalate salt of compound (I)

B) DVS Isotherm of crystalline phosphate salt of compound (I)

DETAILED DESCRIPTION OF THE INVENTION

The development of medicaments containing a given active pharmaceutical ingredient for different patient groups requires the adaption of the pharmaceutical compositions to the need of the specific patient populations. Small children, for example, will often not be able to swallow tablets sized for adults, or there might be patient populations that require a dissoluble formulation.

During the development process of a new active pharmaceutical ingredient for oral delivery, solubility data are used to make key decisions on the developability throughout the process.

Thermodynamic solubility of a compound is the concentration of the compound in solution when excess solid is present at constant temperature and pressure. Thermodynamic solubility, also termed equilibrium solubility, represents the saturation and therefore the maximal, time-independent concentration of a compound in equilibrium with an excess of undissolved solid phase and is an intrinsic property that affects the potential for drug absorption after oral administration.

In addition to thermodynamic solubility of a drug, which represents an equilibrium measure, the rate at which solid drug passes into solution, also termed dissolution rate or kinetic solubility, is important in drug absorption and therefore in pharmaceutical development. Kinetic solubility is therefore an important factor when evaluating the impact of specific physical forms of a certain compound on its absorption in the intestine. Forms of higher energy than the thermodynamically most stable form (which are also called “metastable forms”) can exist as specific polymorphs, hydrates, solvates, co-crystals, salt or amorphous forms of a certain compound. The so-called supersaturated state where upon dissolution the amount of drug dissolved exceeds the equilibrium solubility in a medium can be more pronounced in these forms of higher energy. This effect of supersaturation can be applied in a formulation strategy to achieve increased drug concentrations in the intestinal lumen. The intestinal supersaturation can also occur when a basic drug (that may be the thermodynamically most stable form or metastable form) is dissolved in the acidic gastric fluids, and is then transferred into the intestinal lumen, which has a higher pH (Strindberg et al., European Journal of Pharmaceutics and Biopharmaceutics 151 (2020) 108-115).

However, supersaturation is not predictable, neither with regard to the amount of dissolved drug nor with regard to the duration of supersaturation.

The duration of the supersaturated state should exceed the rate of transit time in the intestinal lumen for absorption to be optimal. By increasing the concentration of a drug at the absorption site, enhancing the intestinal absorption may be possible and the increase in intestinal drug concentration has the potential to increase drug bioavailability.

As the transit time of substances through the small intestine is usually between 0-6 h (Hua, Frontiers in Pharmacology 2020 (524)) depending on the dietary state of the person, once supersaturation is achieved, it should be maintained for another at least 60 min, preferably at least 70 min, most preferably at least 90 min. Surprisingly is has been found that the crystalline salt forms of compound (I) of the present invention have the required properties. ABBREVIATIONS AND DEFINITIONS

API Active pharmaceutical ingredient

DSC Differential scanning calorimetry

DVS Dynamic vapour sorption

Edisylate Salt of ethane-l,2-disulfonic acid

FaSSIF fasted state simulated intestinal media

Napadisylate Salt of naphthalene-l,5-disulfonic acid ppm Parts per million

RT Room temperature

RORy Retinoic acid receptor related orphan receptor gamma

SS-NMR Solid state nuclear magnetic resonance

TGA Thermogravimetric analysis

Torr Unit of pressure; 1 torr equals 133.32 Pa

XRPD X-Ray Powder Diffraction

WL Wave length

“Supersaturation ratio”: The supersaturation ratio is the ratio of the concentration of solute in solution, at a given time, in the kinetic solubility experiment to the solute's equilibrium solubility in the same media.

“Substantially pure”: The term “substantially pure” as used herein means at least 95% (w/w) pure, preferably 99% (w/w) pure, where 95% (w/w) pure means not more than 5% (w/w), and 99% (w/w) pure means not more than 1% (w/w), of any other form of the Com- pound (I) being present (other crystalline form, amorphous form, co-crystal, salt forms or similar). EXPERIMENTAL DETAILS

Production of compound (I)

The synthesis of the compound of formula (I) is known from WO2015/160654.

Production of phosphate salt of compound (I)

The crystalline phosphate salt of the compound of formula (I) is produced by dissolution of the compound of formula (I) in hot acetonitrile (75 °C), followed by cooling the solution to approx. 40 °C, and addition of phosphoric acid. The slurry is then stirred for 2h at 55-60 °C, followed by cooling to RT. The phosphate salt of compound (I) is then isolated by filtration and dried under vacuum (around 200 tor) at 50 °C for 18 h.

Production of oxalate salt of compound (I)

The crystalline oxalate salt of the compound of formula (I) is produced by dissolution of the compound of formula (I) in hot acetonitrile (75 °C), followed by cooling the solution to approx. 40 °C, and addition of oxalic acid. The slurry is then stirred for 2h at 55-60 °C, followed by cooling to RT. The oxalate salt of compound (I) is then isolated by filtration and dried under vacuum (around 200 tor) at 50 °C for 18 h.

Production of edisylate salt of compound (I)

The crystalline edisylate salt of the compound of formula (I) is produced from a saturated solution in ethyl acetate. It has a ratio of APTCounterion of 1 :0.5, with 1,2-ethanedisul- fonic acid as counter ion.

Production of napadisylate salt of compound (I)

The crystalline napadisylate salt of the compound of formula (I) is recovered from a solution with a half molar equivalent (in relation to API) of 1,5-napthalenedisulfonic acid in 1 ,2-dimethoxy ethane.

X-Ray Powder Diffraction (XRPD) Diagram

The data underlying the diagrams in figures 1 and 3 were obtained on a Bruker AXS X-Ray Powder Diffractometer Model D8 Advance, using Cu K _ai radiation (1.54A) in parafocusing mode with a graphite monochromator and a scintillation detector. The pattern was obtained by scanning over a range of 2°- 35° 20, step size of 0.05° 20, with a step time of 4 sec per step.

Table 1 lists the X-ray powder diffraction (XRPD) characteristic peaks for the crystalline phosphate salt of compound (I).

Table 2 lists the XRPD characteristic peaks for the crystalline oxalate salt of compound (I). The values in Tables 1-2 are reported with a margin of error of ± 0.2° 20. Since some margin of error is possible either due to the sample preparation or the the assignment of peaks, the preferred method of determining whether an unknown form of compound (I) is a form described in the present application is to overlay the XRPD spectrum of the sample over the XRPD spectrum provided for the respective form.

Kinetic solubility measurements

The kinetic solubility of each solid form was measured using the small scale pDiss Profiler dissolution apparatus (Pion Inc., Billerica, MA) with in situ fiber optic UV probes for real time detection.

Approximately 4 mg of active drug substance were added to 20 mL of fasted simulated intestinal media (using commercially available FaSSIF powder from Biorelevant, Inc.) preheated at 37 °C and stirred at a speed of 150 RPM (rotations per minute) throughout the experiment.

The UV spectra (200-720 nm) was recorded at specified time intervals throughout the experiment and the concentration of the dissolved drug was calculated using the AUC (area under curve) of the second derivative spectra between 328-335 nm. This second derivative of the UV spectra was used to normalize the effects of turbidity during the experiment. Equilibrium solubility values for calculation of the supersaturation ratio were taken after 24 h from the Pion System.

For the phosphate salt of compound I, the kinetic solubility measurement yielded a maximum concentration of 153 pg/ml between 0 and 200 min, reaching a supersaturation ratio of 15, the equilibrium solubility being 10 pg/ml. An exemplary trace of kinetic solubility experiment between 0 and 200 min can be found in Figure 2A. For the oxalate salt of compound I, the kinetic solubility measurement yielded a maximum concentration of 193 pg/ml between 0 and 200 min, reaching a supersaturation ratio of 21, the equilibrium solubility being 9 pg/ml. An exemplary trace of kinetic solubility experiment between 0 and 200 min can be found in Figure 2B.

DSC analysis

Melting properties of the napadisylate salt of compound (I) and the edisylate salt of compound (I) were obtained on a heat flux DSC3+STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy with a small piece of indium and zinc. Samples (circa 2 mg) were sealed in standard 40 pL aluminum pans, pin-holed and heated in the DSC from 25°C to 300°C, at a heating rate of 10K per minute. Dry N2 gas, at a flow rate of 50 mL/min was used to purge the DSC equipment during measurement.

The DSC analysis of the phosphate salt of compound (I) and the oxalate salt of compound (I) was performed with a differential scanning calorimeter (DSC Q2000 or 2500, TA instruments, New Castle, DE). About 5 mg of powder was weighted in a crimped aluminum pan with a pin hole. The sample was heated at 10K per minute from 22 °C to 250°C.

The melting point for the crystalline phosphate salt of compound (I) determined by DSC is 204 °C ± 5 °C, for a product with higher puritiy, e.g. substantially pure salt forms, the margin of error is ± 3°C. An exemplary trace can be see in figure 3A.

The melting point for the crystalline oxalate salt of compound (I) determined by DSC is 170 °C ± 5 °C, for a product with higher puritiy, e.g. substantially pure salt forms, the margin of error is ± 3°C. An exemplary trace is depicted in figure 4A.

The DSC curve for the crystalline edisylate salt of compound (I) is depicted in Figure 5A and shows a broad endothermic event between 70 °C and 150 °C. Further broad endo/exo- thermic events were recorded between 150 °C and 220 °C.

The DSC curve for the crystalline napadisylate salt of compound (I) is depicted in Figure 5B and shows broad endothermic events between 25 °C and 50 °C, 130 °C and 180 °C, 185 °C to 220 °C.

Thermogravimetric analysis TGA data were collected on a a thermogravimetric analyzer (TGA Q500 or 550, TA instruments, New Castle, DE). 1-5 mg of sample are loaded onto the tared TGA pan and heated at a heating rate of 10 K per minute from 22 °C to 300 °C under dry nitrogen.

An exemplary TGA trace of the crystalline phosphate salt of compound (I) is depicted in figure 3B and shows a mass loss of < 1.0 % (w/w) up to 200 °C.

For the crystalline oxalate salt of compound (I), an exemplary TGA trace of the crystalline oxalate salt of compound (I) can be seen in Figure 4B. This shows a weight loss of approx. 14 % (w/w) up to 230 °C.

Dynamical vapor sorption (DVS)

Water sorption isotherms are determined using a dynamic vapor sorption system (Advantage, DVS, London, UK). The samples are subjected to relative humidity (RH) values between 0% RH - 90% RH in a stepwise manner with a step size of 10% at 25°C. Each sample is equilibrated at each RH step for at least 60 min, and equilibrium is assumed if weight increase is less than 0.1% within one minute, and the maximum duration on each RH is 6 hours.

The crystalline oxalate salt of compound (I) takes up less than < 1.5 % water at 90 % RH, see Figure 7A where a water uptake of approximately 1.3% is depicted).

The crystalline phosphate salt of compound (I) takes up > 5 % water at 90 % RH, see Figure 7B (where a water uptake of approximately 7.4% is depicted).

Solid-state NMR (SSNMR)

¹³ C Solid-state NMR (SSNMR) data for samples of Form I, is acquired on a Bruker Avance III HD NMR spectrometer (Bruker Biospin, Inc., Billerica, MA) at 11.7 T ('14=500.28 MHZ, ¹³ C=125.81 MHZ). Samples are packed in 4 mm O.D. zirconia rotors with Kel-F(R) drive tips. A Bruker model BL4 VTN probe is used for data acquisition and sample spinning about the magic-angle (54.74 degrees). Sample spectrum acquisition uses a spinning rate of 12 kHz. A standard cross-polarization pulse sequence is used with a ramped Hartman- Hahn match pulse on the proton channel at ambient temperature and pressure. The pulse sequence uses an 8 millisecond contact pulse and a 6 second recycle delay. SPINAL64 decoupling and TOSS sideband suppression are also employed in the pulse sequence. No exponential line broadening is used prior to Fourier transformation of the free induction decay. Chemical shifts are referenced using the secondary standard of adamantane, with the low frequency resonance being set to 29.5 ppm. The magic-angle is set using the ⁷⁹ Br signal from KBr powder at a spinning rate of 5 kHz. Exemplary ¹³ C SSNMR spectrum of the salt forms are found in Figure 6. Table 3 includes the chemical shifts obtained from the ¹³ C SSNMR spectrum acquired for the oxalate salt of compound I, table 4 for the phosphate salt of compound I.

The values in Tables 3-4 are reported with a margin of error of ± 0.2° 20. Since some margin of error is possible either due to the sample preparation or the assignment of peaks, the preferred method of determining whether an unknown form of compound (I) is a form described in the present application is to overlay the ¹³ C SSNMR spectrum of the sample over the ¹³ C SSNMR spectrum provided for the respective form.

GENERAL ADMINISTRATION AND PHARMACEUTICAL COMPOSITIONS When used as pharmaceuticals, the compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and generally comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier. The compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like.

The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. In general, the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes. Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted modes of administration of pharmaceutical compositions. Thus, administration can be, for example, orally, buc- cally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof. Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), American Pharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish, Pharmaceutical.

Suitable tablets may be obtained, for example, by mixing one or more compounds of the invention with known excipients, for example inert diluents, carriers, disintegrates, adjuvants, surfactants, binders and/or lubricants. Examples for suitable tablets are

A standard hypromellose film-coat can be applied on tablet cores e.g. as found in Kurt H. Bauer, Karl-Heinz Frbmming, Claus Fiihrer; Pharmazeutische Technologic, 5. Auflage, Gustav Fischer Verlag Stuttgart 1997.

Pharmaceutical compositions according to the present invention can be used for the treatment of an inflammatory disease, including but not limited to autoimmune and allergic diseases.

THERAPEUTIC USE

RORy is a transcription factor belonging to the steroid hormone receptor superfamily (review in Jetten 2006, Adv. Dev. Biol. 16: 313-355). RORy has been identified as a transcriptional factor that is required for the differentiation of T cells and secretion of Interleukin 17 (IL-17) from a subset of T cells termed Thn cells (Ivanov 2006, Cell, 126, 1121-1133). The rationale for the use of a RORy targeted therapy for the treatment of chronic inflammatory disesases is based on the emerging evidence that Thn cells and the cytokine IL-17 contribute to the initiation and progression of the pathogenesis of several diseases.

The present invention is therefore directed to crystalline salt forms of compound (I) which are useful in the treatment of a disease and/or condition wherein the activity of RORy modulators is of therapeutic benefit, including but not limited to the treatment of autoimmune or allergic disorders. Such disorders include for example: rheumatoid arthritis, psoriasis, psoriasis vulgaris, generalized pustular psoriasis (GPP), erythrodermic psoriasis (EP), systemic lupus erythromatosis, lupus nephritis, systemic sclerosis, vasculitis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, type I diabetes, Crohn’s disease, ulcerative colitis, graft versus host disease, axial spondyloarthritis, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, atherosclerosis, uveitis and non-radiographic spondyloarthropathy, non-alcoholic steatohepatitis.