Crystalline forms of piperazinyl-thiazole derivatives

Abstract

The present invention relates to crystalline forms of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone, methods for its preparation, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from said crystalline forms, and their use as CXCR3 receptor modulators in the treatment of various diseases and disorders associated with the CXCR3 receptor and its ligands.

Description

[Technical field]

[0001] The present invention relates to a crystalline form of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone (hereinafter also referred to as "compound"), a method for its preparation, a pharmaceutical composition having the crystalline form, a pharmaceutical composition prepared from the crystalline form, and its use as a CXCR3 receptor modulator in the treatment of various diseases and disorders associated with the CXCR3 receptor and its ligands. In particular, the Compounds in crystalline form are useful in treating diseases and disorders including (auto)immune / inflammatory mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrotic diseases; neurodegenerative disorders; and neoplastic diseases; in particular, rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic scleroderma, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, myasthenia gravis, type I diabetes, vitiligo, uveitis, inflammatory myopathies, xerophthalmia, thyroiditis including Graves' disease, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, and in particular, chronic myocardial infarction, ... In some embodiments, the compounds may be used alone or in pharmaceutical compositions for the prevention or treatment of chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis, influenza, cerebral malaria, liver cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's chorea, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, brain tumors, colon cancer, breast cancer and / or metastatic spread of cancer. [Background technology]

[0002] Chemokine receptors are a group of G protein-coupled receptors (GPCRs) that bind with high affinity to peptide chemokine ligands. The primary function of chemokine receptors is to guide the trafficking of leukocytes to lymphoid organs and tissues under resting and inflammatory conditions, although some chemokine receptors are known to have roles on non-hematopoietic cells and their precursor cells.

[0003] The chemokine receptor CXCR3 is a G protein-coupled receptor that binds the inflammatory chemokines CXCL9 (originally called MIG, interferon-gamma [INF-γ]-induced monokine), CXCL10 (IP-10, INF-γ-induced protein 10), and CXCL11 (I-TAC, INF-γ-induced T cell alpha chemoattractant). CXCR3 is expressed primarily on activated T helper type 1 (Th1) lymphocytes, but is also present on natural killer cells, macrophages, dendritic cells, and a subset of B lymphocytes. The three CXCR3 ligands are expressed primarily under inflammatory conditions, with very low expression in healthy tissues. Cells that can express CXCR3 ligands after exposure to inflammatory cytokines, such as interferon-γ or TNF-α, include various stromal cells, such as endothelial cells, fibroblasts, epithelial cells, and keratinocytes, but also hematopoietic cells, such as macrophages and monocytes. The interaction of CXCR3 with its ligands (hereafter referred to as the CXCR3 axis) is involved in guiding receptor-bearing cells to specific sites in the body, particularly sites of inflammation, immune disorders and immune dysfunction, and is also associated with tissue damage, apoptosis induction, cell growth and angiogenesis inhibition (angiostasis). CXCR3 and its ligands are highly upregulated and expressed in a variety of pathological conditions, including autoimmune disorders, inflammation, infection, transplant rejection, fibrosis, neurodegeneration and cancer.

[0004] The role of the CXCR3 system in autoimmune disorders is supported by several preclinical and clinical observations. Autoimmune disorders in which elevated levels of CXCR3 ligands or increased numbers of CXCR3-positive cells have been demonstrated include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis, multiple sclerosis (MS), inflammatory bowel disease (IBD; including Crohn's and ulcerative colitis), and type I diabetes (Groom, JR & Luster, AD Immunol Cell Biol 2011, 89, 207; Groom, JR & Luster, ADExp Cell Res 2011, 317, 620; Lacotte, S., Brun, S., Muller, S. & Dumortier, H. Ann NY Acad Sci 2009, 1173, 310). As expression of CXCR3 ligands is very low in healthy tissues, the above correlative evidence strongly suggests a role for CXCR3 in human autoimmune diseases. Furthermore, Ruschpler and coworkers (Ruschpler, P. et al., Arthritis Res Ther 2003, 5(5), R241-252) described increased levels of CXCR3 ligands in synovial tissue of rheumatoid arthritis (RA) patients. They also showed CXCR3 expression on mast cells and suggested that these cells may play an important role in the pathology of RA. The authors state: "These findings suggest that the substantial expression of CXCR3 protein on mast cells in synovial tissue from RA patients, together with the elevated levels of the chemokines CXCL9 and CXCL10, play an important role in the pathophysiology of RA." Mohan and coworkers (Mohan, K. et al., J Immunol 2007, 179(12), 8463-8469) suggest that expression of CXCR3 on T cells may play an essential role in the recruitment of T cells to inflamed joints and contribute to the development of arthritis in animal models of RA. Enghard et al. (Enghard, P. et al., Arthritis Rheum 2009, 60(1), 199-206) describe that CXCR3-expressing T cells are recruited into the inflamed kidney and are also elevated in the urine of lupus patients.They suggest that these CXCR3-expressing cells are a useful biomarker of nephritis activity in SLE and that the CXCR3 system may be a potential target for future treatment. Steinmetz and coworkers (Steinmetz, OM, et al., J Immunol 2009, 183(7), 4693-4704) have shown that mice lacking the CXCR3 receptor have attenuated disease development in mouse models of both SLE and lupus nephritis, and have proposed that CXCR3 is a promising therapeutic target for the disease. Furthermore, Menke et al. (Menke, J., et al., J Am Soc Nephrol 2008, 19(6), 1177-1189) have shown that mice lacking CXCR3 or the CXCR3 ligand CXCL9 (MIG) have milder disease development in two mouse models of lupus nephritis. Comini-Frota et al. (Comini-Frota, ER et al., CNS Drugs 2011, 25(11), 971-981) show that the levels of CXCR3 ligand CXCL10 correlate with pathological lesions (T1 and T2) in the CNS of multiple sclerosis (MS) patients. They conclude that their observations are consistent with previous observations that CXCR3-expressing CD4 T cells in the peripheral blood of MS patients correlate with CNS lesions in MS patients. Furthermore, a study by Uzawa et al. (Uzawa, A. et al., "Expression of chemokine receptors on peripheral blood lymphocytes in multiple sclerosis and neuromyelitis optica." BMC Neurol 2010, 10, 113) shows that the percentage of CXCR3-expressing T cells in peripheral blood correlates with disease activity in MS patients. Furthermore, Sporici and coworkers (Sporici, R. et al., Eur J Immunol 2010, 40(10), 2751-2761) present data from preclinical models of MS indicating that CXCR3 expression on T cells is important for disease induction.Schroepf et al. (Schroepf, S. et al., Inflamm Bowel Dis 2010, 16(11), 1882-1890) present data showing that the CXCR3 system (CXCR3 receptor and its ligands) is overexpressed in both pediatric Crohn's disease and pediatric ulcerative colitis. Uno and coworkers. (Uno, S. et al., Endocr J 2010, 57(11), 991-996) provides evidence for a key role of the CXCR3 axis in the pathophysiology of type I diabetes. The team was able to show that the CXCR3 ligand CXCL10 was expressed in still intact beta cells of the patient's pancreas and that infiltrating T cells expressed CXCR3. They therefore conclude that the interaction between CXCL10 and CXCR3 contributes to the pathology of type I diabetes. Chen and coworkers (Chen, SC et al., Arch Dermatol Res 2010, 302(2), 113-123) showed that the mRNA levels of CXCR3 and its ligands CXCL9, 10 and 11 were significantly elevated in psoriatic lesions compared to non-lesional samples. Using quantitative image analysis, the authors showed a significant increase in the number of both epithelial and dermal CXCR3-expressing cells in lesions compared to non-lesional biopsies. The majority of CXCR3-expressing cells were found in the dermis and were shown to be T lymphocytes. Finally, the authors conclude that "CXCR3 is a highly attractive target for the treatment of psoriatic skin due to its role in the migration of activated T lymphocytes into the dermis of the disease." Loos et al. (Loos, T. et al., Lab Invest 2006, 86(9), 902-916) describes the observation of significantly elevated CXCL9 levels in the synovial fluid of patients with spondyloarthropathies (i.e. ankylosing spondylitis or psoriatic arthritis) or rheumatoid arthritis. The authors therefore conclude that CXCL9, a CXCR3 ligand, is an important chemokine in autoimmune arthritis, including psoriatic arthritis. A study by Antonelli and coworkers (Antonelli, A. et al., Rheumatology (Oxford) 2008, 47(1), 45-49) shows that serum levels of the CXCR3-binding chemokine, CXCL10, are high in newly diagnosed systemic sclerosis. High values ​​of CXCL10 were associated with a more severe clinical picture (pulmonary and renal involvement).

[0005] In the skin of vitiligo patients, pathogenic melanocyte-specific CD8+ T cells were found to express CXCR3 (Boniface, K. et al., J Invest Dermatol 2018, 138(2), 355), and serum CXCL10 levels were associated with disease severity (Wang, XX. et al., Br J Dermatol 2016, 174(6), 1318). Studies in a vitiligo mouse model highlighted the important role of the CXCR3 / CXCL10 axis in the pathology of the disease. Blockade of this system by using anti-CXCL10 antibodies or by using anti-CXCR3-depleting antibodies has been shown to prevent and reverse pigment loss in a mouse model of vitiligo (Rashighi, M. et al., Sci Transl Med 2014, 6(223), 223ra23; Richmond JM et al., J Invest Dermatol 2017, 137(4), 982-5).

[0006] Preclinical disease models using CXCR3-deficient mice, mice lacking one of the CXCR3 ligands, or antibodies blocking CXCR3 or one of its ligands further support the role of the CXCR3 system in immunopathology. For example, mice lacking either CXCR3 or the CXCR3 ligand CXCL9 have been shown to have reduced symptoms in a lupus nephritis model (Menke, J. et al., J Am Soc Nephrol 2008, 19, 1177). There is both clinical and preclinical evidence for the involvement of the CXCR3 system in the pathology of interstitial cystitis. Sakthivel and coworkers (Sakthivel, SK et al., J Immune Based Ther. Vaccines 2008, 6, 6.) showed that in a mouse model of interstitial cystitis, blockade of the CXCR3 ligand CXCL10 can reduce the severity of the disease. In a clinical setting, Ogawa et al. (Ogawa, T. et al., J Urol 2010, 183(3), 1206-1212) showed that CXCR3-binding chemokines were overrepresented in biopsies from patients compared with healthy controls and were biomarkers of interstitial cystitis. Similarly, blocking CXCL10 with an antibody reduced symptoms in a rat model of rheumatoid arthritis (Mohan, K. & Issekutz, T.B.J. Immunol 2007, 179, 8463). Similarly, in a mouse model of inflammatory bowel disease, CXCL10 blocking antibodies were able to prevent symptoms in a therapeutic setting (Singh, UP et al., J Interferon Cytokine Res 2008, 28, 31). Also, experiments using tissues from CXCR3-deficient mice suggest a role for CXCR3 in celiac disease and other autoimmune disorders (Lammers, KM et al., Gastroenterology 2008, 135, 194). Feferman et al. (Feferman, T. et al., J Neuroimmunol 2009, 209(1-2), 87-95), who previously demonstrated overexpression of CXCR3 and CXCL10 in myasthenia gravis, further investigated the role of CXCR3 and its ligand, CXCL10, in a preclinical model of the disease. They found that blockade of either CXCL10 with a blocking antibody or CXCR3 with a small molecule antagonist could suppress the pathology in this mouse model of myasthenia gravis. They concluded that blockade of CXCR3 / IP-10 signaling could be considered a potential treatment for myasthenia gravis. Howard et al. (Howard, OM et al., Blood 2005, 105(11), 4207-4214) investigated tissue-specific autoantigens found in uveitis and showed that these may be chemotactic factors for human normal immune cells, specifically lymphocytes and immature DCs. They specifically show that these autoantigens induce migration of CXCR3-expressing cells.

[0007] Inflammatory diseases associated with increased expression of the CXCR3 system include chronic obstructive pulmonary disease (COPD), asthma, sarcoidosis, atherosclerosis and myocarditis (Groom, JR & Luster, AD Immunol Cell Biol 2011, 89, 207; Groom, JR & Luster, AD Exp Cell Res 2011, 317, 620).

[0008] One study showed that CXCR3-positive cells were increased in the lungs of smokers with COPD compared with healthy controls, and immune responsiveness to the CXCR3-ligand, CXCL10, was found in the bronchiolar epithelium of smokers with COPD but not in the bronchiolar epithelium of smoking and nonsmoking control subjects (Saetta, M. et al., Am J Med 2014, 144:131–132). J Respir Crit Care Med 2002, 165, 1404). These findings suggest that the CXCR3 system may be involved in the recruitment of immune cells in the peripheral airways of smokers with COPD. Consistent with these findings, a preclinical study of COPD revealed that CXCR3-deficient mice exhibited attenuated acute lung inflammation induced by cigarette smoke (Nie, L. et al., Respir Res 2008, 9, 82). There is preclinical evidence for the involvement of CXCR3 and CXCR3-binding chemokines in asthma. Suzaki et al. (Suzaki, Y. et al., Eur Respir J 2008, 31(4), 783-789) showed that small molecule antagonists of the receptors CXCR3 and CCR5 could prevent the development of asthma symptoms in a mouse model. Lin and coworkers (Lin, Y. et al., Respir Res 2011, 12, 123) performed a similar study in CXCR3-deficient mice and concluded that CXCR3 may be a novel therapeutic target for asthma. Busuttil and coworkers (Busuttil, A. et al., Eur Respir J 2009, 34(3), 676-686) investigated the pathogenesis of pulmonary sarcoidosis and concluded that cells of both lymphocytic and monocytic lineages express CXCR3 and are involved in the formation of sarcoid lung granulomas, and that the CXCR3 ligands CXCL9 and CXCL11 are upregulated in sarcoid bronchoalveolar fluid (BALF). Crescioli and coworkers (Crescioli, C. et al., Eur J Cell Biol 2012, 91(2), 13 9-149) analyzed the pathophysiology of myocarditis and found that in inflamed muscles, skeletal muscle cells actively secrete CXCL10, which can then attract CXCR3-expressing Th1 T cells, thus causing self-promote inflammation. They concluded that targeting CXCL10 may be able to control the aberrant immune response in this condition. Since CXCL10 is a cognate ligand for CXCR3, it makes sense that inhibition of CXCR3 with an antagonist would be beneficial. CXCR3 ligands are increased in the plasma and lungs of patients developing acute respiratory distress syndrome. This increase was associated with the severity of the disease (Jiang, Y. et al., Am J Respir Crit Care Med 2005, 171(8), 850; Bautista, E. et al., Exp Mol Pathol 2013, 94(3), 486; Yang, Y. et al., J Allergy Clin Immunol 2020, 146(1), 119-27 e4). The CXCR3 system has been shown to be a key factor in the development of acute respiratory distress syndrome induced in animal models by different conditions such as acid aspiration, viral infection, sepsis, and pneumonia. Knockdown of CXCL10 or CXCR3 or the use of anti-CXCL10 or anti-CXCR3 agents has been shown to reverse acute lung injury, reduce lung inflammation, pulmonary edema, and improve lung function (Ichikawa, A. et al., Am J Respir Crit Care Med 2013, 187(1), 65; Lang, S. et al., PLoS One 2017, 12(1), e0169100; Zhu, X. et al., J Surg Res 2016, 204(2), 288). In a study of atherosclerosis, CXCR3 expression was found on all T cells within human atherosclerotic lesions. The CXCR3 ligands CXCL9, CXCL10 and CXCL11 are all found in endothelial and smooth muscle cells associated with these lesions, suggesting that they are involved in the recruitment and maintenance of CXCR3-positive cells, in particular activated T lymphocytes, observed within vascular wall lesions during atherogenesis (Mach, F. et al., J Clin. Invest 1999, 104, 1041). Van Wanrooij et al. Wanrooij, EJ et al., Arterioscler Thromb Vasc Biol 2008, 28(2), 251-257) showed that treatment with a CXCR3 antagonist caused a reduction in atherosclerotic lesion formation in a mouse model by blocking direct migration of CXCR3-expressing effector immune cells from the circulation into atherosclerotic plaques. The role of CXCR3 in the development of atherosclerosis is further supported by preclinical studies: CXCR3 gene deletion in ApoE-deficient mice significantly reduces the development of atherosclerotic lesions in the abdominal aorta (Veillard, NR et al., Circulation 2005, 112, 870).

[0009] Yoon and co-workers (Yoon, KC, et al., Invest Ophthalmol Vis Sci 2010, 51(2), 643-650) studied components of the CXCR3 system (CXCR3 and its ligands CXCL9, 10, 11) on the ocular surface of patients with dry eye disease (also called dry eye syndrome). CXCR3 and CXCR3 ligands were elevated on the ocular surface in patients with both inflammatory and autoimmune dry eye disease (patients with Sjögren's syndrome).

[0010] Cameron et al. (Cameron, CM et al., J Virol 2008, 82(22), 11308-11317) studied the pandemic influenza strain H5N1 in ferrets, which is considered suitable for studying influenza pathology. They first document that following influenza infection, the CXCR3 ligand CXCL10 is highly upregulated. They then tested the effect of a small molecule CXCR3 antagonist on the course of H5N1 infection in ferrets. The results were a reduction in the severity of symptoms and a delay in mass mortality compared to vehicle treatment.

[0011] Campanella and coworkers (Campanella, G.S. et al., Proc Natl Acad Sci USA 2008, 105(12), 4814-4819) investigated the influence of the CXCR3 system on the development of cerebral malaria in a preclinical model. They concluded that CXCR3 on CD8 T cells is required for the recruitment of T cells into the brain and the development of cerebral malaria in mice, suggesting that the CXCR3 ligands CXCL9 and CXCL10 play distinct and non-redundant roles in the pathogenesis of the disease. It can therefore be argued that CXCR3 antagonists may be suitable therapeutic tools for the treatment of cerebral malaria.

[0012] The CXCR3 system has also been suggested to play a central role in the toxicity associated with rejection after organ and bone marrow transplantation (Groom, JR & Luster, ADExp Cell Res 2011, 317, 620). Preclinically, CXCR3-deficient mice show significant resistance to allograft rejection (Hancock, WW et al., J Exp Med 2000, 192, 1515). In their literature review, Romagnani et al. (Romagnani, P. et al., Clin Chim Acta 2012, 413(17-18), 1364-1373) conclude that the CXCR3 ligand, CXCL10, is useful not only as a biomarker to predict the severity of rejection and to monitor the inflammatory state of organ recipients, but also as a therapeutic target for graft-versus-host disease and transplanted organs in general. In a preclinical model of lung transplant rejection, Seung et al. (Seung, E. et al., J Immunol 2011, 186(12), 6830-6838) show that CXCR3-deficient effector T cells have a reduced ability to induce lethal lung inflammation and thus tissue rejection. The authors conclude that inhibition of CXCR3 on effector T cells may be of therapeutic benefit in preventing lung transplant rejection. Matl et al. (Matl, I. et al., Kidney Blood Press Res 2010, 33(1), 7-14) describe that kidney transplant patients with high mRNA levels of the CXCR3 ligand CXCL10 (IP-10) were found to be at risk for early kidney graft loss. Thus, CXCL10 and thus its receptor CXCR3 are likely involved in the pathology of kidney transplant rejection, and therefore CXCR3 inhibition may be a therapeutic strategy for the prevention of kidney graft loss. He et al. (He, S. et al., J Immunol 2008, 181(11), 7581-7592) show that antibody-mediated blockade of CXCR3 has beneficial effects in preclinical models of graft-versus-host disease.

[0013] Plasma concentrations of CXCR3 ligands also positively correlate with various liver pathologies, including cirrhosis and fibrosis in humans (Tacke, F. et al., Liver Int 2011, 31(6), 840).

[0014] In oncology, blocking the CXCR3 system has been proposed to help limit the spread of cancer cells by metastasis. For example, administration of the small molecule CXCR3 receptor antagonist AMG487 was able to limit metastasis of tumor cells to the lungs (Pradelli, E. et al., Int J Cancer 2009, 125, 2586). Walser and coworkers (Walser, TC et al., Cancer Res 2006, 66(15), 7701-7707) showed that a small molecular weight CXCR3 antagonist has the ability to inhibit tumor metastasis. In this study, the spread of mouse breast tumors to the lungs could be inhibited by CXCR3 inhibition. Functional proof of the role of CXCR3 in the suppression of B-cell chronic lymphocytic leukemia (CLL) was reported by Trentin and coworkers (Trentin, L. et al., J Clin Invest 1999, 104, 115). Furthermore, in preclinical models of brain tumors / glioblastoma, Liu and coworkers (Liu, C. et al., Carcinogenesis 2011, 32(2), 129-137) demonstrated that pharmacological inhibition of CXCR3 with a small molecule inhibitor reduced tumor It was shown that the survival of mice bearing CXCR3 was increased. Previously, Maru et al. (Maru, SV et al., J Neuroimmunol 2008, 199(1-2), 35-45.) showed increased production of CXCL10 and increased expression of its receptor, CXCR3, in brain tumor glioma cells. CXCL10 induced an ERK1 / 2-dependent increase in cell proliferation. Amy Fulton (Fulton, AM Curr Oncol Rep 2009, 11(2), 125-131) surveyed the literature evidence for the involvement of CXCR3 in cancer. CXCR3 has been detected on many malignant cell lines and is associated with patient outcomes in colon and breast cancer as well as melanoma, she states. In these diseases, high CXCR3 expression is associated with more aggressive disease.

[0015] In the central nervous system, blocking the CXCR3 system has beneficial effects and may prevent neurodegeneration. Increased expression of CXCL10 in the CNS has been shown in ischemia, Alzheimer's disease, multiple sclerosis (MS) and human immunodeficiency virus (HIV)-encephalitis. For example, two research groups have described a general role of CXCR3 and its ligand CXCL10 in neurodegenerative disorders and neuronal disfunction or death. Cho et al. (Cho, J. et al., J Neuroimmunol 2009, 207(1-2), 92-100) describe that rat neurons can express CXCR3 and that CXCL10 can degenerate neuronal function. The authors hypothesize that this interaction between CXCR3 and CXCL10 may contribute to the degeneration of central nervous system function in chronic neuroinflammatory or neurodegenerative disorders. Van Weering et al. (van Weering, HR et al., Hippocampus 2011, 21(2):220-232.) found a region-specific role for CXCL10 / CXCR3 signaling in neuron-glia and glia-glia interactions under pathological conditions in mice. Using mice lacking CXCR3, they concluded that CXCR3 on microglial cells is important for neuronal death under excitotoxic conditions. Taken together, these two publications show that CXCR3 and CXCL10 can cause neuronal injury or even death in preclinical models. Xia et al. (Xia, MQ et al., J Neuroimmunol 2000, 108(1-2), 227-235) show that the CXCR3 ligand CXCL10 is observed in a subpopulation of astrocytes in normal brain and is significantly elevated in astrocytes in Alzheimer's disease brain. They also show that CXCL10 and CXCL9 can induce signals in rat neurons.Vergote and coworkers (Vergote, D. et al., Proc Natl Acad Sci USA 2006, 103(50), 19182-19187) observed that in patients with HIV-associated dementia, the chemokine CXCL12 is present in a truncated form lacking the first four amino acids (CXCL12(5-67)). Unlike full-length CXCL12, this truncated form no longer signals through the chemokine receptor CXCR4, but can instead signal through CXCR3. The authors conclude that this novel interaction causes neuronal pathology. In vivo, they showed that neuroinflammation, neuronal loss and neurobehavioral abnormalities caused by the truncated form of CXCL12 were prevented by a CXCR3 antagonist. In a study aimed at identifying drug-like molecules with neuroprotective effects against HTT fragment-induced neurodegeneration in a Huntington's disease model, two CXCR3 receptor antagonists were identified (Reinhart, PH et al., Neurobiol Dis 2011, 43, 248). Press and coworkers (Press, R. et al., J Clin Immunol 2003, 23(4), 259-267.) state that infiltration of spinal nerve roots and peripheral nerves by macrophages and T cells is a rather consistent immunopathological finding in patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). They studied inflammatory mediators in the cerebrospinal fluid of GBS and CIDP patients and found that levels of the CXCR3 ligand CXCL10 were elevated in both pathologies, and We hypothesize that CXCL10 is involved in the pathogenesis of these two diseases.

[0016] The "compound" can be prepared according to the procedures described in WO2016 / 113344. Summary of the Invention

[0017] It has been found that certain crystalline forms of the Compound are found under certain conditions. The crystalline forms of the Compound are novel and would have advantageous properties in terms of the possible use of the Compound as a pharmaceutical active ingredient. Such advantageous properties would include better flow properties; lower hygroscopicity; better properties for tablet production (e.g. sufficiently high melting point); better reproducibility in production (e.g. better filtration parameters, better formation reproducibility and / or better sedimentation); and / or consistent morphology. Such crystalline forms of the Compound would be particularly suitable for the preparation of certain pharmaceutical compositions. The crystalline form 1 of the Compound is a non-solvated, non-hydrated solid form and thus differs from the crystalline forms 2 and 3. The non-solvated forms have the advantage that uncontrolled desolvation cannot occur, since the solvated solid forms tend to desolvate over time. Another disadvantage of the solvated solid forms is the amount of residual solvent content in the pharmaceutical composition, which may exceed the recommended acceptable daily intake (specified by the ICH recommendations). [Brief description of the drawings]

[0018] [Figure 1]FIG. 1 shows the powder X-ray diffraction diagram of the crystalline form 1 of Compound, measured using XRPD method 1 (described in Experimental Procedures) and shown for Cu Kα radiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the counts on the vertical axis. The X-ray diffraction diagram shows peaks with the following percentage relative intensities compared to the most intense peak in the diagram at the indicated refraction angles 2θ (relative peak intensities are given in brackets) (selected peaks with a relative intensity of more than 10% from the range 3-30° 2θ are reported): 5.8° (20%), 8.9° (18%), 9.1° (13%), 11.3° (14%), 12.1° (37%), 12.7° (1 3%), 14.3°(100%), 15.5°(33%), 16.4°(15%), 16.7°(96%), 17.2°(64%), 17.9°(24%), 18.2°(25%), 18.5°(20%), 20.4°(13%), 20.7°(12%), 21.1°(21%), 21.3°(13%), 21.7°(11%), 22.3°(14%), 22.5°(20%), 23.3°(12%), 24.7°(28%) and 26.9°(25%). [Diagram 2] Figure 2 shows the powder X-ray diffraction diagram of Compound in crystalline form 2 obtained from acetone, measured using XRPD method 2 (described in Experimental Procedures) and shown for Cu Kα radiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the counts are plotted on the vertical axis. The X-ray diffraction diagram shows peaks with the following percentage relative intensities compared to the most intense peak in the diagram at the indicated refraction angles 2 theta (relative peak intensities are given in brackets) (selected peaks with a relative intensity of greater than 10% from the 3-30° 2 theta range are reported): 8.6° (11%), 9.6° (19%), 14.2° (22%), 14.7° (44%), 15.0° (22%), 16.0° (55%), 16.7° (100%), 17.3° (70%), 18.7° (26%), 20.5° (77%), 22.3° (53%) and 22.7° (33%). [Diagram 3]Figure 3 shows the powder X-ray diffraction diagram of Compound in crystalline form 3, measured using XRPD method 2 (described in Experimental Procedures) and shown for Cu Kα radiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the counts are plotted on the vertical axis. The X-ray diffraction diagram shows peaks with the following percentage relative intensities (relative peak intensities are given in brackets) compared to the most intense peak in the diagram at the indicated refraction angles 2 theta (selected peaks with a relative intensity of greater than 10% from the 3-30° 2 theta range are reported): 8.7° (23%), 9.8° (25%), 11.4° (10%), 13.4° (16%), 14.2° (14%), 15.3° (13%), 16.4° (55%), 17.0° (100%), 17.7° (37%), 19.7° (13%), 20.6° (24%), 21.3° (40%), 21.8° (29%) and 28.5° (34%). [Figure 4] Figure 4 shows a differential scanning calorimetry (DSC) thermogram of Compound in crystalline form 1. In the DSC thermogram of Figure 4, temperature (°C) is plotted on the horizontal axis and heat flow (mW) is plotted on the vertical axis. [Diagram 5] Figure 5 shows a gravimetric vapor sorption diagram for crystalline Form 1 of Compound obtained from Example 1. In the gravimetric vapor sorption diagram of Figure 5, relative humidity (% RH) is plotted on the horizontal axis and mass change (% dm) is plotted on the vertical axis. [Figure 6] Figure 6 shows the thermogravimetric analysis (TGA) of Compound 2 in crystalline form. In the thermogravimetric analysis diagram of Figure 6, temperature (°C) is plotted on the horizontal axis and relative mass (%) is plotted on the vertical axis.

[0019] For the avoidance of any doubt, the above peaks describe the experimental results of the X-ray powder diffraction shown in Figures 1-3. In contrast to the above list of peaks, it should be understood that only selected characteristic peaks are necessary to completely and unambiguously characterize each crystalline form of the Compound of the present invention.

[0020] Detailed Description of the Invention 1) A first aspect of the present invention relates to a crystalline form of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone ("Compound"), characterized by the presence of peaks at the following refraction angles 2θ: 14.3°, 16.7° and 17.2° in a powder X-ray diffraction diagram.

[0021] The crystalline form according to embodiment 1) is intended to encompass the "compound" in crystalline form of the free base (ie not in the form of a salt).

[0022] Furthermore, the above crystalline forms of the "Compound" may have non-coordinating and / or coordinating solvents (particularly non-coordinating and / or coordinating water). Coordinating solvents (particularly coordinating water) are used herein as a term for crystalline solvates (particularly crystalline hydrates). Similarly, non-coordinating solvents (particularly water) are used herein as a term for physically adsorbed or physically trapped solvents (particularly water; as defined by Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates). The crystalline form 1 of the "Compound" does not have coordinating water, but may have non-coordinating water or another non-coordinating solvent.

[0023] The "Compound" in crystalline form 1 has a melting point of T=169±3° C. as measured by DSC. The "Compound" in crystalline form 1 is not hygroscopic according to Ph.Eur. (European Pharmacopeia 10.0, section 5.11).

[0024] 2) Another embodiment relates to a crystalline form of the Compound according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 14.3°, 15.5°, 16.4°, 16.7° and 17.2°.

[0025] 3) Another embodiment has the following refraction angle 2θ: 5.8° in the powder X-ray diffraction diagram; The present invention relates to a crystalline form of the Compound according to embodiment 1), characterized by the presence of peaks at 8.9°, 12.1°, 14.3°, 15.5°, 16.4°, 16.7°, 17.2°, 18.5° and 26.9°.

[0026] 4) Another embodiment relates to a crystalline form of the Compound according to embodiment 1), which exhibits an X-ray powder diffraction pattern essentially as shown in FIG.

[0027] 5) Another embodiment relates to a crystalline form of the Compound, characterized by the presence of peaks at the following refraction angles 2θ: 16.0°, 16.7° and 20.5° in a powder X-ray diffraction diagram.

[0028] Depending on the solvent used for crystallization (acetone or THF), the Compound in crystalline form 2 may have coordinating and / or non-coordinating solvents.

[0029] 6) Another embodiment relates to a crystalline form of the Compound according to embodiment 5), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 9.6°, 16.0°, 16.7°, 17.3° and 20.5°.

[0030] 7) Another embodiment relates to a crystalline form of the Compound according to embodiment 5), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 8.6°, 9.6°, 14.7°, 15.0°, 16.0°, 16.7°, 17.3°, 18.7° and 20.5°.

[0031] 8) Another embodiment relates to a crystalline form of the Compound, characterized by the presence of peaks at the following refraction angles 2θ: 9.8°, 17.0° and 17.7° in a powder X-ray diffraction diagram.

[0032] The Compound in crystalline form 3 is an acetonitrile solvate.

[0033] 9) Another embodiment relates to a crystalline form of the Compound according to embodiment 8), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 8.7°, 9.8°, 13.4°, 17.0° and 17.7°.

[0034] 10) Another embodiment relates to a crystalline form of the Compound according to embodiment 8), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 8.7°, 9.8°, 11.4°, 13.4°, 14.2°, 15.3°, 16.4°, 17.0°, 17.7° and 19.7°.

[0035] 11) Another embodiment relates to a crystalline form, such as an essentially pure crystalline form, of the compound 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone, which can be obtained by mixing about 5 mg of amorphous Compound with about 0.02 mL of a solvent selected from ethyl acetate, isopropanol or tert.-butyl methyl ether and storing the mixture for about 5 days.

[0036] 12) Another embodiment relates to a crystalline form of the Compound according to embodiment 11), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 14.3°, 16.7° and 17.2°.

[0037] 13) Another embodiment relates to a crystalline form of the Compound according to embodiment 11), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 14.3°, 15.5°, 16.4°, 16.7° and 17.2°.

[0038] 14) Another embodiment relates to a crystalline form of the Compound according to embodiment 11), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 5.8°, 8.9°, 12.1°, 14.3°, 15.5°, 16.4°, 16.7°, 17.2°, 18.5° and 26.9°.

[0039] 15) Another embodiment relates to a crystalline form of the Compound according to embodiment 11), which has an X-ray powder diffraction pattern essentially as shown in FIG.

[0040] 16) Another embodiment relates to a crystalline form of the Compound according to any one of embodiments 1) to 4) or 11) to 15), having a melting point of about 169° C. (particularly 169±3° C.) as determined by differential scanning calorimetry.

[0041] Differential scanning calorimetry (DSC) data may be measured by heating a sample of the Compound (particularly 1-5 mg) at 10° C. per minute in the range of −20° C. to 200° C. (and particularly by the methods described in the Experimental Section).

[0042] 17) Another embodiment relates to a crystalline form of the Compound according to any one of embodiments 1) to 4) or 11) to 16), which exhibits a gravimetric moisture sorption profile essentially as shown in FIG. 5, said gravimetric moisture sorption profile being measured at about 25° C. (particularly at 25° C.).

[0043] 18) Another embodiment relates to a crystalline form of the "compound" according to any one of embodiments 1) to 4), obtainable by the method of embodiment 11).

[0044] Thus, based on the subordination of the different embodiments 1) to 18) disclosed above, the following embodiments are possible, contemplated, and specifically disclosed herein as individual embodiments: 1, 2+1, 3+1, 4+1, 5, 6+5, 7+5, 8, 9+8, 10+8, 11, 12+11, 13+11, 14+11, 15+11, 16+1, 16+2+1, 16+3+1, 16+4+1, 16+11, 16+12+11, 16+13+11, 16+14+11, 16+15+11, 17+1, 17+2+1, 17+3+1 , 17+4+1, 17+11, 17+12+11, 17+13+11, 17+14+11, 17+15+11, 17+16+1, 17+16+2+1, 17+16+3+1, 17+16+4+1, 17+16+11, 17+16+12+11, 17+16+13+11, 17+16+14+11, 17+16+15+11, 18; In the above table, the numbers refer to the embodiments according to the above numbers, and "+" indicates dependency on other embodiments. The various embodiments are individually separated by commas. In other words, for example, "16+2+1" means embodiment 16) which is dependent on embodiment 2) which is dependent on embodiment 1), i.e. embodiment "16+2+1" corresponds to embodiment 1) further characterized by the features of embodiments 2) and 16).

[0045] For the avoidance of any doubt, whenever one of the above embodiments refers to "peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram," it is to be understood that the powder X-ray diffraction diagram was obtained using combined Cu Kα1 and Kα2 radiation, without removing Kα2; and the accuracy of the 2θ values ​​provided herein is within the range of + / - 0.1 to 0.2°. In particular, when specifying a refraction angle 2θ for a peak in the embodiments and claims of the present invention, the 2θ values ​​stated may vary from -0.2° to the given value. said value +0.2° (2θ+ / −0.2°); and preferably said value −0.1° to said value +0.1° (2θ+ / −0.1°).

[0046] When the plural forms are used for compounds, solids, pharmaceutical compositions, diseases, etc., they are intended to refer to the singular compound, solid, pharmaceutical composition, disease, etc. as well.

[0047] The definitions set forth herein are uniformly applied to the subject matter defined in any one of the aspects 1) to 18) and apply mutatis mutandis throughout the specification and claims unless a broader or narrower definition is given by a specific definition. It is understood that a definition or preferred definition of a term or expression may independently (and together) define and replace the respective term or expression in any or preferred definition of any or all other terms or expressions defined herein.

[0048] The term "enantiomerically enriched" is understood in the context of the present invention to mean, in particular, that at least 90, preferably at least 95, and most preferably at least 99 percent by weight of the "compound" is present in the form of one enantiomer of the "compound." The "compound" is understood to be present in the enantiomerically enriched absolute (R)-configuration.

[0049] The term "essentially pure" is understood in the context of the present invention to mean in particular that at least 90, preferably at least 95, and most preferably at least 99 percent by weight of the crystals of the "compound" are present in the crystalline form of the present invention.

[0050] For example, when defining the presence of a peak in an X-ray powder diffraction diagram, a common way is to do this in terms of the S / N ratio (S=signal, N=noise). According to this definition, when stating that a peak must be present in an X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having a S / N ratio (S=signal, N=noise) greater than x (x being a number greater than 1), usually greater than 2, in particular greater than 3.

[0051] In the context of the statement that a crystalline form essentially exhibits the powder X-ray diffraction pattern depicted in Figure 1, the term "essentially" means that at least the main peaks of the diagram depicted in said figure, i.e. peaks having a relative intensity of more than 20%, in particular more than 10%, compared to the most intense peak in the diagram, must be present. However, a person skilled in the art of powder X-ray diffraction should be aware that the relative intensities of powder X-ray diffraction diagrams can be subject to strong intensity variations due to preferred orientation effects.

[0052] When not used in reference to temperature, the term "about" placed before a numerical value "X" means in this application between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X, in particular X. In the specific case of temperatures, the term "about" placed before a temperature "Y" means in this application between a temperature Y-5°C and Y+5°C, preferably between Y-3°C and Y+3°C, in particular Y. Room temperature means a temperature of about 25°C.

[0053] Whenever the words "between" or "to" are used to describe a numerical range, the endpoints of the stated range are expressly intended to be included in the range. For example: when a temperature range is described as being between 40° C. and 80° C. (or 40° C. to 80° C.), it is meant that the endpoints 40° C. and 80° C. are included in the range; or when a variable is defined as an integer between 1 and 4 (or 1 to 4), it is meant that the variable is the integer 1, 2, 3, or 4.

[0054] The crystalline forms, in particular essentially pure crystalline forms, of the Compound according to any one of the embodiments 1) to 18) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral (e.g., in particular oral) or parenteral (including topical application or inhalation) administration.

[0055] 19) Thus, another embodiment relates to a crystalline form of the compound according to any one of embodiments 1) to 18) (in particular 1) to 4) or 11) to 17)), 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone ("the Compound"), for use as a medicament.

[0056] A crystalline solid, especially an essentially pure crystalline solid, of the Compound according to any one of the embodiments 1) to 18) (especially 1) to 4) or 11) to 17) may be used as the sole component or as a mixture with other crystalline or amorphous forms of the Compound.

[0057] The preparation of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the crystalline form of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharma- ceutically acceptable solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0058] 20) A further aspect of the present invention relates to a pharmaceutical composition having as an active ingredient a crystalline form of the "compound" according to any one of aspects 1) to 18) (in particular a crystalline form of the "compound" according to any one of aspects 1) to 4) or 11) to 17) and further comprising at least one pharma- ceutically acceptable carrier material.

[0059] 21) A further aspect of the present invention relates to a crystalline form of a Compound according to any one of the aspects 1) to 18) (in particular according to any one of the aspects 1) to 4) or 11) to 17) for use in the manufacture of a pharmaceutical composition comprising the Compound as an active ingredient and at least one pharma- ceutically acceptable carrier material.

[0060] The crystalline form defined in any one of aspects 1) to 18) (particularly the crystalline form defined in any one of aspects 1) to 4) or 11) to 17)) is useful for the prevention or treatment of a disorder associated with dysfunction of the CXCR3 receptor or dysfunction of a ligand that transmits signals via CXCR3.

[0061] Such disorders associated with a malfunction of the CXCR3 receptor or its ligands are diseases or disorders for which a modulator of the human CXCR3 receptor is required. The above disorders may be defined as including, in particular, (auto)immune / inflammatory mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrotic diseases; neurodegenerative disorders and neoplastic diseases.

[0062] 22) A further aspect of the present invention relates to a crystalline form of a "compound" according to any one of aspects 1) to 18) (in particular according to any one of aspects 1) to 4) or 11) to 17) for use in the prevention or treatment of a disorder selected from: an (auto)immune / inflammatory mediated disorder; a pulmonary disorder; a cardiovascular disorder; an infectious disease; a fibrotic disease; a neurodegenerative disorder; or a neoplastic disease.

[0063] (Auto)immune / inflammatory mediated disorders include rheumatoid arthritis (RA); multiple sclerosis (MS); inflammatory bowel disease (IBD; including Crohn's disease and ulcerative colitis); primary biliary cirrhosis (PBC); autoimmune hepatitis; systemic lupus erythematosus (SLE); lupus nephritis; antiphospholipid syndrome; Sjogren's syndrome; sarcoidosis; systemic sclerosis; spondyloarthritis; psoriasis; psoriatic arthritis; interstitial cystitis; celiac disease; Hashimoto's thyroiditis, lymphocytic thyroiditis. , Graves' disease, thyroiditis, myasthenia gravis, diabetes mellitus type I, uveitis, episcleritis, scleritis, Kawasaki disease, uveititis, posterior uveitis, Behcet's disease-associated uveitis, uveomeningocolitis syndrome, vitiligo, allergic encephalomyelitis, atopic diseases such as rhinitis, conjunctivitis, dermatitis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, myopathies (including inflammatory myopathies), obesity, and transplant-related disorders. Transplant-related disorders may be defined to include transplant rejection, such as rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin, acute and / or chronic graft-versus-host disease, and chronic allograft vasculopathy.

[0064] Pulmonary disorders may be defined to include acute lung injury; acute respiratory distress syndrome; asthma; and chronic obstructive pulmonary disease (COPD).

[0065] Cardiovascular disorders may be defined as including atherosclerosis; and myocarditis.

[0066] Infectious diseases may be defined to include diseases and complications caused by a variety of infectious agents such as malaria, cerebral malaria, leprosy, tuberculosis, influenza, toxoplasmosis, dengue fever, hepatitis B and C, herpes simplex, Leishmania, Chlamydia trachomatis, Lyme disease and West Nile virus.

[0067] Fibrotic diseases may be defined to include liver cirrhosis, idiopathic pulmonary fibrosis, renal fibrosis, endomyocardial fibrosis, systemic sclerosis and arthrofibrosis.

[0068] Neurodegenerative disorders may be defined to include conditions involving neurodegeneration and neuronal death such as multiple sclerosis (including relapsing-remitting multiple sclerosis and progressive multiple sclerosis), Alzheimer's disease, Parkinson's disease, Huntington's chorea, HIV-associated dementia, prion-mediated neurodegeneration, epilepsy, stroke, cerebral ischemia, cerebral palsy, neuromyelitis optica, clinically isolated syndrome, Alpers' disease, amyotrophic lateral sclerosis (ALS), senile dementia, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, narcolepsy, glossopharyngeal neuralgia, mild cognitive impairment, cognitive decline, spinal muscular atrophy, and cerebral malaria.

[0069] Neoplastic diseases may be defined to include colorectal cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumors, hematoma, basophilic adenoma, prolactinoma, hyperprolactinemia, adenoma, endometrial cancer, colon cancer; all types of cancer such as chronic lymphocytic leukemia (CLL); and (particularly) metastatic spread of cancer.

[0070] 23) A preferred embodiment of the present invention relates to a crystalline form of a "compound" according to any one of embodiments 1) to 18) (in particular according to any one of embodiments 1) to 4) or 11) to 17) for use in the prevention or treatment of disorders selected from one, some or all of the following groups of diseases and disorders: 1) Rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, sarcoidosis, systemic sclerosis, spondyloarthritis, psoriasis, psoriatic arthritis, interstitial cystitis; (auto)immune / inflammatory mediated diseases selected from: Chronic Obesity, Myasthenia gravis, Type I diabetes mellitus, uveitis, inflammatory myopathies, xerophthalmia, thyroiditis including Graves' disease, vitiligo, transplant rejection, acute and / or chronic graft-versus-host disease, and (skin) fibrosis; 2) Pulmonary diseases selected from acute lung injury, acute respiratory distress syndrome, asthma and chronic obstructive pulmonary disease; 3) cardiovascular disease selected from atherosclerosis and myocarditis; 4) an infectious disease selected from influenza and cerebral malaria; 5) fibrotic diseases selected from cirrhosis; 6) A neurodegenerative disorder selected from Alzheimer's disease, neurodegeneration, Huntington's chorea, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barré syndrome; 7) A neoplastic disease selected from brain cancer, colon cancer, breast cancer and metastatic spread of cancer.

[0071] 24) In another preferred embodiment of the present invention, the present invention is directed to the treatment of rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic scleroderma, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, myasthenia gravis, type I diabetes mellitus, vitiligo, uveitis, inflammatory myopathy, xerophthalmia, thyroiditis including Graves' disease, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, and the like. The present invention relates to a crystalline form of the "Compound" according to any one of aspects 1) to 18) (in particular according to any one of aspects 1) to 4) or 11) to 17) for use in the prophylaxis or treatment of a disorder selected from the group consisting of chronic inflammatory demyelinating polyneuropathy, atherosclerosis, myocarditis, influenza, cerebral malaria, liver cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's chorea, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, brain tumor, colon cancer, breast cancer, and metastatic spread of cancer.

[0072] For the avoidance of any doubt, when a crystalline form of a "compound" is described as being useful for the prevention and / or treatment of a disease, such a crystalline form of the "compound" is also suitable for use in the manufacture of a medicament for the prevention or treatment of the disease. In particular, when a crystalline form of a "compound" is described as being useful for the prevention and / or treatment of a disease according to any one of aspects 22) to 24), such a crystalline form of the "compound" is also suitable for use in the manufacture of a medicament for the prevention or treatment of the disease.

[0073] The present invention also relates to a method for preventing or treating a disease mentioned herein, comprising administering a pharma- ceutically effective amount of a crystalline form of a "compound" according to any one of embodiments 1) to 18) (particularly according to any one of embodiments 1) to 4) or 11) to 17) or a pharmaceutical composition according to embodiment 20) to a subject in need thereof (particularly a patient in need thereof).

[0074] The present invention also relates to a method for the preparation of a pharmaceutical composition having a "compound" as an active ingredient and further having at least one pharma- ceutically acceptable carrier material, said preparation of said pharmaceutical composition comprising the step of mixing a crystalline form of "compound" according to any one of embodiments 1) to 18) (in particular according to any one of embodiments 1) to 4) or 11) to 17) with at least one pharma- ceutically acceptable carrier material.

[0075] The present invention also relates to a method for preparing enantiomerically enriched forms of the Compound, and to a method for preparing and characterizing crystalline forms of the Compound according to any one of the embodiments 1) to 18), in particular according to any one of the embodiments 1) to 4) or 11) to 17), which are described in embodiment 11) and in the procedures in the experimental section below. EXAMPLES

[0076] Experimental Method Abbreviations (used above or below): CNS Central Nervous System DSC Differential Scanning Calorimetry EtOAc Ethyl acetate Fig GVS Gravimetric Vapor Sorption HPLC High Performance Liquid Chromatography MeCN Acetonitrile MeOH Methanol min NMR nuclear magnetic resonance RH Relative Humidity s seconds tBME tert.-Butyl methyl ether TGA thermogravimetric analysis THF Tetrahydrofuran XRPD X-ray powder diffraction

[0077] All solvents and reagents were used as obtained from commercial sources unless otherwise noted.

[0078] Temperatures are given in degrees Celsius (° C.). Unless otherwise noted, reactions are carried out at room temperature (RT).

[0079] In mixtures, the proportions of solvents or eluents or mixtures of reagents in liquid form are expressed as volumetric relationships (v / v) unless otherwise specified.

[0080] X-ray powder diffraction analysis (XRPD) XRPD method 1 Powder X-ray diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operating in reflection mode (coupled 2 theta / theta). Typically, a Cu X-ray tube was scanned at 40 kV / 40 mA. A step size of 0.02° (2θ) and a step time of 76.8 seconds were applied over a scan range of 3-50° 2θ. The divergence and antiscatter slits were fixedly set at 0.3°. The powder was lightly pressed into a silicon single crystal sample holder with a depth of 0.5 mm and the sample was rotated in its own plane during the measurement. Diffraction data are reported using Cu Kα (λ=1.5418 Å) radiation. As is typical for previously recorded powder X-ray diffraction patterns, the accuracy of the 2θ values ​​provided herein is within the range of + / - 0.1-0.2°.

[0081] XRPD method 2 Powder X-ray diffraction patterns were collected on a Bruker D8 GADDS-HTS diffractometer equipped with an automated XYZ stage, a laser video microscope with auto sample positioning, and a Vantec-500 detector operating in reflection mode. Typically, a Cu X-ray tube is scanned at 40 kV / 40 mA. The X-ray optics consist of a single Goebel multilayer mirror coupled with a 0.5 mm pinhole collimator. Typically, a single frame was recorded over 180 s with goniometer positions of 4° theta 1 and 16° theta 2 and a detector distance of 20 cm. The frame was integrated over the 2θ range of 5-35°. Samples scanned under ambient conditions were prepared as flat specimens using the as-received powder without grinding. Approximately 5-10 mg of sample was lightly pressed onto a glass slide to obtain a flat surface. The sample was not moved during the measurement time. Diffraction data are reported using Cu Kα (λ=1.5418 Å) radiation. To date, As is typically the case for powder X-ray diffraction patterns recorded herein, the accuracy of the 2θ values ​​provided herein is within + / - 0.1 to 0.2°.

[0082] Differential Scanning Calorimetry (DSC) DSC data were collected on a PerkinElmer DSC8500 with Pyris Software 2.1.1.0106. The instrument was calibrated for energy and temperature using indium standards. Typically, 1-5 mg samples were measured in non-hermetic aluminum pans at temperatures ranging from -20°C to 200°C for 10°C min. -1 The sample was heated at 200°C for 20 min. A nitrogen purge was applied over the sample at 20 mL min. -1 The melting point was maintained at 100° C. The peak temperature is reported for the melting point.

[0083] Gravimetric Vapor Sorption (GVS) Moisture sorption isotherms were collected on a Hiden Isochema dynamic vapor sorption analyzer IGASORP HAS-036-080 running on Isochema HIsorp 2019 software version 4.02.0070. Typically, approximately 30 mg of sample is placed in the sample holder and subjected to stepwise equilibration at predefined relative humidity (RH) set points at 25 °C. Sample mass is recorded at these set points and used to generate moisture sorption isotherms. Relative humidity set points used were 40% to 0% RH, then 0% to 95% RH, at 5% RH intervals. Data presented consist of moisture sorption isotherms in the range 5% to 90% of samples subjected to increasing relative humidity. The change in mass between 40% and 80% relative humidity in the first sorption scan is evaluated for the determination of hygroscopicity. Grading is performed similar to the European Pharmacopoeia (Ph.Eur.) 10.0, section 5.11.

[0084] Thermogravimetric analysis (TGA) TGA data were collected on a Mettler Toledo STARe System (TGA / SDTA851e module). Typically, samples of approximately 5 mg were analyzed in standard TGA aluminum pans with automatically drilled holes at temperatures ranging from 30 to 250 °C for 10 °C min. -1 A nitrogen gas purge was maintained over the sample during the measurements.

[0085] I-Chemistry The "compound" can be prepared according to the procedures described in WO2016 / 113344 (Example 35).

[0086] Reference Example 1: 0.2 mL of a 25 mg / mL solution of Compound in MeOH is dispensed into 4 mL glass vials and evaporated in a Combindancer apparatus (Hettich, Switzerland) to produce a 5 mg film of amorphous, transparent Compound in each vial.

[0087] Example 1: Crystalline Form 1 of "Compound" In a 4 mL standard glass vial, 0.02 mL of EtOAc, isopropanol or tBME is added to 5 mg of amorphous "Compound" obtained according to Reference Example 1. After capping and vortexing for about 30 seconds, the vial is stored in the dark for 5 days. When analyzed without drying, the resulting solid is crystalline form 1 of "Compound".

[0088] In a separate experiment, 1 mL of a 1:2 v / v mixture of MeCN / tBME is added to 100 mg of Compound, and the mixture is heated to 55° C. at a heating rate of 0.1° C. / min and cooled to 20° C. at a cooling rate of 0.1° C. / min. After standing overnight, the solid is isolated by filter centrifugation and dried at 40° C. / 10 mbar for 15 min to obtain crystalline form 1 of Compound.

[0089] [Table 1]

[0090] Example 2: Crystalline Form 2 of "Compound" 0.15 mL of acetone is added to 150 mg of "Compound" (e.g., obtained from Example 1) in a standard glass HPLC vial, and the suspension in the capped vial is shaken for 24 hours at 25° C. The resulting solid is crystalline form 2 of "Compound".

[0091] Thermogravimetric analysis of the solid residue after isolation by filter-centrifugation and drying at 10 mbar for 1 h showed a stepwise weight loss of about 1.1% of acetone, confirming the solvated nature of crystalline form 2.

[0092] [Table 2]

[0093] Example 3: Crystalline Form 3 of "Compound" In a 4 mL standard glass vial, 0.02 mL of MeCN is added to 5 mg of amorphous "Compound" obtained according to Reference Example 1. After capping and vortexing for about 30 seconds, the vial is stored in the dark for 5 days. When analyzed without drying, the resulting solid is crystalline form 3 of "Compound".

[0094] In a separate experiment, 0.04 mL of MeCN is added to 20 mg of "Compound" (e.g., from Example 1) in a standard glass HPLC vial, and the suspension in the capped vial is subjected to temperature cycling while stirring with a magnetic stir bar. Temperature cycling (heating from 20° C. to 40° C. in 1 hour and cooling from 40° C. to 20° C. in 4 hours) and stirring for 25 hours are performed in a Polar Bear apparatus (Cambridge reactor design, UK). When analyzed without drying, the resulting solid is crystalline form 3 of "Compound".

[0095] When measured while sufficient MeCN is still present, crystalline form 3 is observed by XRPD. Upon isolation by filter centrifugation or isolation and drying under reduced pressure, conversion of crystalline form 3 to crystalline form 1 occurs, indicating the metastability of crystalline form 3 in the absence of sufficient MeCN. The combination of the facts that crystalline form 3 is only observed in the presence of sufficient MeCN, that crystalline form 3 is obtained from crystalline form 1 in suspension, and that crystalline form 3 is metastable in the absence of sufficient MeCN indicates that crystalline form 3 has a MeCN solvate structure.

[0096]

Table 3

Claims

1. Crystals of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone in a crystalline form characterized by the presence of peaks at the following refraction angles 2θ: 14.3°, 16.7° and 17.2° in a powder X-ray diffraction diagram.

2. The crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to claim 1, characterized in its crystalline form by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 14.3°, 15.5°, 16.4°, 16.7° and 17.2°.

3. The crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to claim 1, characterized in its crystalline form by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 5.8°, 8.9°, 12.1°, 14.3°, 15.5°, 16.4°, 16.7°, 17.2°, 18.5° and 26.9°.

4. 5±0.5 mg of amorphous 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone with 0.02±0.002 mL of a solvent selected from ethyl acetate, isopropanol, or tert.-butyl methyl ether, and storing the mixture for 5±0.5 days. A method for producing crystals of (4,4)triazol-1-yl)-ethanone.

5. The method of claim 4, wherein the crystals have a crystalline form characterized by the presence of peaks at the following refraction angles 2θ: 14.3°, 16.7° and 17.2° in a powder X-ray diffraction diagram.

6. The method of claim 4, wherein the crystals have a crystalline form characterized by the presence of peaks at the following refraction angles 2θ: 14.3°, 15.5°, 16.4°, 16.7° and 17.2° in a powder X-ray diffraction diagram.

7. The method of claim 4, wherein the crystals have a crystalline form characterized by the presence of peaks at the following refraction angles 2θ: 5.8°, 8.9°, 12.1°, 14.3°, 15.5°, 16.4°, 16.7°, 17.2°, 18.5° and 26.9° in a powder X-ray diffraction diagram.

8. A crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to any one of claims 1 to 3, having a melting point of 169±5°C as determined by differential scanning calorimetry.

9. A crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to any one of claims 1 to 3 for use as a pharmaceutical.

10. A pharmaceutical composition comprising the crystalline form of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to any one of claims 1 to 3 as an active ingredient, and further comprising at least one pharma- ceutically acceptable carrier material.

11. 4. A crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone according to any one of claims 1 to 3 for use in the manufacture of a pharmaceutical composition, the pharmaceutical composition comprising 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone as an active ingredient and further comprising at least one pharma- ceutically acceptable carrier material.

12. A pharmaceutical for the prevention or treatment of a disorder selected from (auto)immune / inflammatory mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrotic diseases; neurodegenerative disorders; or neoplastic diseases, comprising a crystal of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-piperazin-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone as defined in any one of claims 1 to 3 as an active ingredient.

13. A method for treating rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, A pharmaceutical agent for the prevention or treatment of a disorder selected from myasthenia gravis, type I diabetes mellitus, vitiligo, uveitis, inflammatory myopathy, xerophthalmia, thyroiditis including Graves' disease, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis, influenza, cerebral malaria, liver cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's chorea, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, brain tumor, colon cancer, breast cancer, and metastatic spread of cancer.

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