Crystalline form of piperazinyl-thiazole derivatives

Abstract

This provides the crystalline form of piperazinyl-thiazole derivatives. [Solution] The present invention relates to the crystalline form of 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone, a method for producing the same, a pharmaceutical composition having the crystalline form, a pharmaceutical composition produced from the crystalline form, and the use of the same as a CXCR3 receptor modulator in the treatment of various diseases and disorders related to 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 producing the same, a pharmaceutical composition having the crystalline form, a pharmaceutical composition produced from such a crystalline form, and their use as CXCR3 receptor modulators in the treatment of various diseases and disorders related to the CXCR3 receptor and its ligands. In particular, the crystalline form of the "compound" is for 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 sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, myasthenia gravis, type I diabetes, vitiligo, uveitis, inflammatory myopathy, dry eye disease, 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, cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colorectal cancer, breast cancer and / or prevention or treatment of cancer metastasis and spread, and may be used alone or in a pharmaceutical composition.

Background Art

[0002] Chemokine receptors are a group of G protein-coupled receptors (GPCRs) that bind with high affinity to peptide chemokine ligands. The main function of chemokine receptors is to guide the transport of leukocytes to lymphoid organs and tissues during rest and inflammation, but certain chemokine receptors are known to have roles in non-hematopoietic cells and their progenitor cells.

[0003] The chemokine receptor CXCR3 is a G protein-coupled receptor that binds to the inflammatory chemokines CXCL9 (originally called MIG, an interferon-γ [INF-γ]-induced monokine), CXCL10 (IP-10, INF-γ-induced protein 10), and CXCL11 (I-TAC, INF-γ-induced T cell α-chemotactic factor). CXCR3 is primarily expressed on activated T helper type 1 (Th1) lymphocytes, but is also present on natural killer cells, macrophages, dendritic cells, and B lymphocyte subsets. The three CXCR3 ligands are mainly expressed under inflammatory conditions, with very low expression in healthy tissues. For example, 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, as well as hematopoietic cells such as macrophages and monocytes. The interaction between CXCR3 and its ligands (hereinafter referred to as the CXCR3 axis) is involved in guiding receptor-carrying cells to specific sites in the body, particularly sites of inflammation, immune dysfunction, and impaired immune function. It is also associated with tissue damage, apoptosis induction, cell growth, and angiogenesis suppression (angiostasis). CXCR3 and its ligands are upregulated and strongly expressed in various pathological conditions, including autoimmune disorders, inflammation, infections, transplant rejection, fibrosis, neurodegeneration, and cancer.

[0004] The role of the CXCR3 system in autoimmune disorders has been supported by several preclinical and clinical observations. Histological analysis of serum levels or inflammatory lesions in patients has confirmed the role of CXCR3. Autoimmune disorders in which elevated ligand levels or increased CXCR3-positive cell counts have been observed 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 1 diabetes mellitus (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). Given the very low expression of CXCR3 ligands in healthy tissues, the above correlative evidence strongly suggests a role for CXCR3 in human autoimmune diseases. Furthermore, Ruschpler and collaborators (Ruschpler, P. et al., Arthritis Res Ther 2003, 5(5), R241-252) have described elevated levels of CXCR3 ligand in the synovial tissue of rheumatoid arthritis (RA) patients. They also showed CXCR3 expression on mast cells and suggested that these cells may play a crucial role in the pathophysiology of RA. The authors state: "These findings suggest that substantial expression of the CXCR3 protein on mast cells in the synovial tissue of RA patients, along with elevated levels of the chemokines CXCL9 and CXCL10, plays a crucial role in the pathophysiology of RA." Mohan and his collaborators (Mohan, K. et al., J Immunol 2007, 179(12), 8463-8469) have suggested that CXCR3 expression on T cells plays an essential role in the recruitment of T cells to inflamed joints and may contribute to the development of arthritis in animal models of rheumatoid arthritis. Enghard et al. (Enghard, P. et al., Arthritis Rheum 2009, 60(1), 199-206) have described that CXCR3-expressing T cells are recruited into inflamed kidneys and are increased in the urine of lupus patients.They suggest that these CXCR3-expressing cells are a useful biomarker for nephritis activity in SLE, and that the CXCR3 system may be a potential target for future treatments. Steinmetz and collaborators (Steinmetz, OM et al., J Immunol 2009, 183(7), 4693-4704) have shown that disease onset is attenuated in CXCR3 receptor-deficient mice in both SLE and lupus nephritis mouse models, suggesting that CXCR3 is a promising therapeutic target for this disease. Furthermore, Menke et al. (Menke, J. et al., J Am Soc Nephrol 2008, 19(6), 1177-1189) have shown that disease onset is milder in CXCR3 or CXCL9 (MIG), a CXCR3 ligand, deficient mice in two mouse models of lupus nephritis. Comini-Frota et al. (Comini-Frota, ER et al., CNS Drugs 2011, 25(11), 971-981) showed that levels of CXCL10, a CXCR3 ligand, are associated with pathological lesions (T1 and T2) in the CNS of multiple sclerosis (MS) patients. They concluded that their observations are consistent with previous observations that CXCR3-expressing CD4 T cells in the peripheral blood of MS patients are associated 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) showed that the percentage of CXCR3-expressing T cells in the peripheral blood is associated with disease activity in MS patients. Furthermore, Sporici and his collaborators (Sporici, R. et al., Eur J Immunol 2010, 40(10), 2751-2761) have presented data from a preclinical model of MS suggesting 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) have presented data showing that the CXCR3 system (CXCR3 receptor and its ligand) is overexpressed in both childhood Crohn's disease and childhood ulcerative colitis. Uno and collaborators. The study by Uno, S. et al. (Endocr J 2010, 57(11), 991-996) provides evidence that the CXCR3 system plays a crucial role in the pathophysiology of type 1 diabetes. This team was able to demonstrate that CXCL10, a CXCR3 ligand, is expressed in intact beta cells of the patient's pancreas, and that infiltrating T cells express CXCR3. Therefore, they conclude that the interaction between CXCL10 and CXCR3 contributes to the pathology of type 1 diabetes. Chen and collaborators (Chen, SC et al., Arch Dermatol Res 2010, 302(2), 113-123) showed that mRNA levels of CXCR3 and its ligands, CXCL9, 10, and 11, were significantly elevated in psoriatic lesions compared to non-lesion 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-lesion biopsies. The majority of CXCR3-expressing cells were found in the dermis and were shown to be T lymphocytes. Finally, the authors conclude that "due to its role in the migration of activated T lymphocytes into the dermis of psoriatic skin, CXCR3 is a very attractive target for the treatment of this disease." (Loos et al., Lab Invest) A study (2006, 86(9), 902-916) described the observation of significantly elevated CXCL9 levels in the synovial fluid of patients with spondyloarthropathy (i.e., ankylosing spondylitis or psoriatic arthritis) or rheumatoid arthritis. Therefore, the authors concluded that CXCL9, a CXCR3 ligand, is an important chemokine in autoimmune arthritis, including psoriatic arthritis. A study by Antonelli and collaborators (Antonelli, A. et al., Rheumatology (Oxford) 2008, 47(1), 45-49) showed elevated serum levels of the CXCR3-bound chemokine, CXCL10, in newly diagnosed systemic sclerosis. High levels of CXCL10 were associated with a more severe clinical presentation (involvement of the lungs and kidneys).

[0005] In the skin of vitiligo patients, pathogenic melanocyte-specific CD8-positive 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 mouse model of vitiligo highlighted the important role of the CXCR3 / CXCL10 system in the pathology of this disease. Blocking this system using an anti-CXCL10 antibody or an anti-CXCR3 depletion antibody 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] The role of the CXCR3 system in immunopathology has been further supported by preclinical disease models using CXCR3-deficient mice, mice lacking one of the CXCR3 ligands, or antibodies blocking CXCR3 or one of its ligands. For example, mice lacking either CXCR3 or its ligand CXCL9 have been shown to exhibit reduced symptoms in lupus nephritis models (Menke, J. et al., J Am Soc Nephrol 2008, 19, 1177). Both clinical and preclinical evidence exists for the involvement of the CXCR3 system in the pathology of interstitial cystitis. (Sakthivel and collaborators (Sakthivel, SK et al., J Immune Based Ther) Vaccines (2008, 6, 6.) showed that blocking CXCL10, a CXCR3 ligand, can reduce the severity of interstitial cystitis in a mouse model of the disease. In clinical practice, Ogawa et al. (Ogawa, T. et al., J Urol 2010, 183(3), 1206-1212) found that CXCR3-binding chemokines were excessively present in patient biopsies compared to healthy controls, and that they are a biomarker for interstitial cystitis. This suggests the possibility of this happening. Similarly, in a rat model of rheumatoid arthritis, blocking CXCL10 with antibodies reduced symptoms (Mohan, K. & Issekutz, TBJ). (Immunol 2007, 179, 8463). Similarly, in a mouse model of inflammatory bowel disease, symptoms could be prevented in a therapeutic environment using a CXCL10 blocking antibody (Singh, UP et al., J Interferon Cytokine Res 2008, 28, 31). Furthermore, experiments using tissue from CXCR3-deficient mice have suggested 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) previously demonstrated the overexpression of CXCR3 and CXCL10 in myasthenia gravis, and further investigated the roles of CXCR3 and its ligand, CXCL10, in a preclinical model of this disease. They found that blocking either CXCL10 using a blocking antibody or CXCR3 using a small molecule antagonist could suppress the pathology of this mouse model of myasthenia gravis. They concluded that blocking CXCR3 / IP-10 signaling could be a potential treatment for myasthenia gravis. Howard et al. (Howard, OM et al., Blood 2005, 105(11), 4207-4214) studied tissue-specific autoantigens found in uveitis and showed that these may be chemotactic factors for normal human immune cells, specifically lymphocytes and immature DCs. They specifically demonstrated 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, ADImmunol Cell Biol 2011, 89, 207; Groom, JR & Luster, ADExp Cell Res 2011, 317, 620).

[0008] One study showed that CXCR3-positive cells were increased in the lungs of smokers with COPD compared to healthy individuals, and that immune responses to the CXCR3 ligand, CXCL10, were observed in the bronchiolar epithelium of smokers with COPD, but not in the bronchiolar epithelium of smokers and non-smokers (Saetta, M. et al., Am 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, preclinical studies of COPD have shown that CXCR3-deficient mice exhibit reduced incidence of tobacco smoke-induced acute pneumonia (Nie, L. et al., Respir Res 2008, 9, 82). Preclinical evidence exists regarding 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 can prevent the development of asthma symptoms in a mouse model. Lin and collaborators (Lin, Y. et al., Respir Res 2011, 12, 123) conducted a similar study in CXCR3-deficient mice and concluded that CXCR3 may be a novel therapeutic target for asthma. Busuttil and his collaborators (Busuttil, A. et al., Eur Respir J 2009, 34(3), 676-686) investigated the pathogenesis of pulmonary sarcoidosis and concluded that both lymphocytes and monocyte-derived cells express CXCR3, are involved in the formation of sarcoid lung granulomas, and that CXCR3 ligands CXCL9 and CXCL11 are upregulated in sarcoid bronchoalveolar fluid (BALF).Crescioli and his collaborators (Crescioli, C. et al., Eur J Cell Biol 2012, 91(2), 139-149) 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, leading to self-promoting inflammation. They concluded that targeting CXCL10 may allow for control of the abnormal immune response in this condition. Since CXCL10 is a cognitive ligand for CXCR3, it makes sense that inhibition of CXCR3 by an antagonist would be beneficial. CXCR3 ligand levels are elevated 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 an important factor in the development of acute respiratory distress syndrome induced by different conditions such as acid inhalation, viral infection, sepsis, and pneumonia in animal models. Knockdown of CXCL10 or CXCR3, or the use of anti-CXCL10 or anti-CXCR3 agents, has been shown to restore acute lung injury, reduce lung inflammation and 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 one study on atherosclerosis, CXCR3 expression was found on all T cells in human atherosclerotic lesions.CXCR3 ligands CXCL9, CXCL10, and CXCL11 were 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, particularly activated T lymphocytes observed within vascular wall lesions during atheroma formation (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 reduces atherosclerotic lesion formation in a mouse model by blocking the 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 collaborators (Yoon, KC et al., Invest Ophthalmol Vis Sci 2010, 51(2), 643-650) studied the components of the CXCR3 system (CXCR3 and its ligands CXCL9, 10, 11) on the ocular surface of patients with xerophthalmic disease (also known as dry eye syndrome). Elevated levels of CXCR3 and CXCR3 ligands were observed on the ocular surface in both patients with inflammatory xerophthalmic disease and patients with autoimmune xerophthalmic disease (patients with Sjögren's syndrome).

[0010] Cameron et al. (Cameron, CM et al., J Virol 2008, 82(22), 11308-11317) studied the globally circulating ferret influenza strain H5N1, which they considered suitable for studying influenza pathology. They first described that following influenza infection, the CXCR3 ligand CXCL10 is highly upregulated. Next, they tested the effect of small-molecule CXCR3 antagonists on the H5N1 infection process in ferrets. The results showed a reduction in symptom severity and a delay in mass mortality compared to vehicle treatment.

[0011] Campanella and collaborators (Campanella, GS et al., Proc Natl Acad Sci USA 2008, 105(12), 4814-4819) studied 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 necessary for T cell recruitment into the brain and for the development of mouse cerebral malaria, suggesting that CXCR3 ligands CXCL9 and CXCL10 play distinct and non-redundant roles in the pathogenesis of this disease. Therefore, it can be argued that CXCR3 antagonists may be an appropriate therapeutic tool for treating cerebral malaria.

[0012] The CXCR3 lineage has been suggested to play a central role in 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). Romagnani et al. (Romagnani, P. et al., Clin Chim Acta 2012, 413(17-18), 1364-1373) concluded in their literature review that CXCL10, a CXCR3 ligand, is not only useful as a biomarker for predicting rejection severity and monitoring the inflammatory state of organ recipients, but also as a therapeutic target for graft-versus-host disease and transplant 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) showed that CXCR3-deficient effector T cells have a reduced ability to induce lethal pneumonia and thus tissue rejection. The authors conclude that inhibition of CXCR3 on effector T cells may be therapeutically beneficial for preventing lung transplant rejection. Matl et al. (Matl, I. et al., Kidney Blood Press Res 2010, 33(1), 7-14) described that kidney transplant patients with high mRNA levels of CXCL10 (IP-10), a CXCR3 ligand, were at risk of early kidney graft loss. Therefore, CXCL10, and by extension its receptor CXCR3, are likely involved in the pathology of kidney transplant rejection, and thus CXCR3 inhibition may be a therapeutic strategy to prevent kidney graft loss. He et al. (He, S. et al., J Immunol 2008, 181(11), 7581-7592) showed that antibody-mediated CXCR3 blockade had beneficial effects in a preclinical model of graft-versus-host disease.

[0013] Plasma concentrations of CXCR3 ligand are positively correlated with various liver conditions in humans, including cirrhosis and fibrosis (Tacke, F. et al., Liver Int 2011, 31(6), 840).

[0014] In the field of oncology, blocking the CXCR3 system has been proposed to help limit the spread of cancer cells through metastasis. For example, administration of AMG487, a small-molecule CXCR3 receptor antagonist, was able to limit the metastasis of tumor cells to the lungs (Pradelli, E. et al., Int J Cancer 2009, 125, 2586). Walser and collaborators (Walser, TC et al., Cancer Res 2006, 66(15), 7701-7707) demonstrated that small-molecule CXCR3 antagonists have the ability to inhibit tumor metastasis. In this study, the spread of mouse mammary tumors to the lungs was inhibited by CXCR3 inhibition. Functional evidence of the role of CXCR3 in the suppression of B-cell chronic lymphocytic leukemia (CLL) was reported by Trentin and his collaborators (Trentin, L. et al., J Clin Invest 1999, 104, 115). Furthermore, in a preclinical model of brain tumor / glioblastoma, Liu and his collaborators (Liu, C. et al., Carcinogenesis 2011, 32(2), 129-137) found that pharmacological inhibition of CXCR3 with small molecule inhibitors leads to tumor The study demonstrated increased survival in the carrier mice. Previously, Maru et al. (Maru, SV et al., J Neuroimmunol 2008, 199(1-2), 35-45) showed increased CXCL10 production and increased expression of its receptor, CXCR3, in brain tumor glioma cells. CXCL10 induced ERK1 / 2-dependent enhancement of cell proliferation. Amy Fulton (Fulton, AM Curr Oncol Rep 2009, 11(2), 125-131) investigated the literature evidence regarding the involvement of CXCR3 in cancer. She states that CXCR3 has been detected on many malignant cell lines and is associated with patient outcomes in colorectal and breast cancer, as well as melanoma. 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 the general roles of CXCR3 and its ligand, CXCL10, in neurodegenerative disorders and neuronal dysfunction or neuronal cell 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 functional degeneration of the central nervous system in chronic neuroinflammation or neurodegenerative disorders. Van Weering et al. (van Weering, HR et al., Hippocampus 2011, 21(2):220-232) identified a region-specific role of CXCL10 / CXCR3 signaling in neuron-glia and glial-glia interactions under pathological conditions in mice. Using mice lacking CXCR3, they concluded that CXCR3 on microglia cells is important for neuronal cell death under excitotoxic conditions. In summary, these two studies demonstrate that CXCR3 and CXCL10 can induce neuronal damage or even death in preclinical models. Xia et al. (Xia, MQ et al., J Neuroimmunol 2000, 108(1-2), 227-235) showed that CXCL10, a CXCR3 ligand, is observed in a subpopulation of astrocytes in normal brains and is significantly elevated in astrocytes in Alzheimer's disease brains. They also demonstrated that CXCL10 and CXCL9 can induce signals in rat neurons.Vergote and collaborators (Vergote, D. et al., Proc Natl Acad Sci USA 2006, 103(50), 19182-19187) observed that the chemokine CXCL12 existed in a deletion form (CXCL12(5-67)) lacking the first four amino acids in patients with HIV-associated dementia. Unlike full-length CXCL12, this deletion form no longer signals via the chemokine receptor CXCR4, but can instead signal via CXCR3. The authors concluded that this novel interaction causes neuronal pathogenesis. In vivo, they showed that neuroinflammation, neuronal loss, and neurobehavioral abnormalities caused by the CXCL12 deletion form 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 collaborators (Press, R. et al., J Clin Immunol 2003, 23(4), 259-267) stated that macrophage and T cell infiltration of spinal nerve roots and peripheral nerves is a rather consistent immunopathological finding in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). They studied inflammatory mediators in the cerebrospinal fluid of GBS and CIDP patients and found elevated levels of the CXCR3 ligand CXCL10 in both conditions. We hypothesize that CXCL10 is involved in the pathogenesis of these two diseases.

[0016] The "compound" can be manufactured according to the procedure described in WO2016 / 113344. [Overview of the project]

[0017] It has been found that a specific crystalline form of the "compound" can be found under specific conditions. This crystalline form of the "compound" is novel and will have advantageous properties in terms of the usability of the "compound" as a pharmaceutically active ingredient. Such advantageous properties will include better flow properties; lower hygroscopicity; better properties for tablet manufacturing (e.g., sufficiently high melting point); better reproducibility in manufacturing (e.g., better filtration parameters, better formation reproducibility and / or better sedimentation); and / or consistent morphology. Such crystalline forms of the "compound" will be particularly suitable for methods of manufacturing certain pharmaceutical compositions. Crystalline form 1 of the "compound" is a non-solvated, non-hydrated solid form and is therefore different from crystalline forms 2 and 3. Since the solvated solid form tends to desolvate over time, the non-solvated form is advantageous in that uncontrolled desolvation cannot occur. Another disadvantage of the solvated solid form is the amount of residual solvent in the pharmaceutical composition, which may exceed the recommended permissible daily intake (as specified by the ICH recommendations). [Brief explanation of the drawing]

[0018] [Figure 1]Figure 1 shows the powder X-ray diffraction diagram of the "compound" in crystal form 1, which was measured using the XRPD method 1 (described in the experimental method) and is shown for Cu Kα irradiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the count is plotted on the vertical axis. The X-ray diffraction diagram shows peaks with relative intensities of the following percentages compared to the strongest peak in the diagram at the shown refraction angle 2theta (relative peak intensities are indicated in parentheses) (selected peaks with relative intensities greater than 10% from 2theta in the range of 3-30° 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%). [Figure 2] Figure 2 shows the powder X-ray diffraction diagram of the crystalline form 2 "compound" obtained from acetone. This powder X-ray diffraction diagram was measured using the XRPD method 2 (described in the experimental procedure) and is shown for Cu Kα irradiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the count is plotted on the vertical axis. The X-ray diffraction diagram shows peaks with the following percentage relative intensities compared to the strongest peak in the diagram at the indicated refraction angle of 2 theta (relative peak intensities are indicated in parentheses): (Selected peaks with a relative intensity greater than 10% from 2 thetas in the range of 3-30° 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%). [Figure 3]Figure 3 shows the powder X-ray diffraction diagram of the "compound" of crystalline form 3. This powder X-ray diffraction diagram was measured using XRPD method 2 (described in the experimental method) and is shown for Cu Kα irradiation. In the diagram, the diffraction angle 2θ is plotted on the horizontal axis and the count is plotted on the vertical axis. The X-ray diffraction diagram shows peaks having the following percentage relative intensities compared to the strongest peak in the diagram at the indicated diffraction angle 2 theta (the relative peak intensity is described in parentheses): (Report selected peaks having a relative intensity greater than 10% from 2 theta in the range of 3 - 30°): 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 the differential scanning calorimetry (DSC) thermogram of the "compound" of 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. [Figure 5] Figure 5 shows the gravimetric vapor adsorption diagram of the "compound" of crystalline form 1 obtained from Example 1. In the gravimetric vapor adsorption 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 the "compound" of crystalline form 2. 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] To avoid any ambiguity, the above peaks describe the experimental results of powder X-ray diffraction shown in Figures 1 - 3. In contrast to the above list of peaks, it should be understood that only the selected characteristic peaks are necessary to fully and clearly characterize the "compound" of each crystalline form 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 (the "Compound"), characterized by the presence of peaks at the following diffraction angles 2θ in the powder X-ray diffraction diagram: 14.3°, 16.7° and 17.2°.

[0021] The crystalline form according to embodiment 1) shall include the crystalline form of the "Compound" in the free base form (i.e., not in the form of a salt).

[0022] Furthermore, the above crystalline form of the "Compound" may have non-coordinating and / or coordinating solvents (especially non-coordinating and / or coordinating water). Coordinating solvents (especially coordinating water) are used herein as terms for crystalline solvates (especially crystalline hydrates). Similarly, non-coordinating solvents (especially water) are used herein as terms for physically adsorbed or physically trapped solvents (especially water; defined by Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. 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 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 aspect relates to the crystalline form of the “compound” according to aspect 1), characterized by the presence of peaks at the following refraction angles 2θ: 14.3°, 15.5°, 16.4°, 16.7° and 17.2° in the powder X-ray diffraction diagram.

[0025] 3) Another embodiment is the following refraction angle 2θ:5.8° in the powder X-ray diffraction diagram, This relates to the crystalline form of a "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 aspect relates to the crystalline form of the “compound” according to aspect 1), which essentially exhibits the powder X-ray diffraction pattern shown in Figure 1.

[0027] 5) Another aspect relates to the crystalline form of the “compound” as characterized by the presence of peaks at the following refraction angles 2θ: 16.0°, 16.7°, and 20.5° in the 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 aspect relates to the crystalline form of the “compound” according to aspect 5), characterized by the presence of peaks at the following refraction angles 2θ: 9.6°, 16.0°, 16.7°, 17.3° and 20.5° in the powder X-ray diffraction diagram.

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

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

[0032] The compound with crystal form 3 is acetonitrile solvate.

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

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

[0035] 11) Another embodiment relates to the crystalline form of the compound, 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone, for example, an essentially pure crystalline form, 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.-butylmethyl ether, and storing the mixture for about 5 days.

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

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

[0038] 14) Another aspect relates to the crystalline form of the “compound” according to aspect 11), characterized by the presence of peaks in the powder X-ray diffraction diagram 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°.

[0039] 15) Another aspect relates to the crystalline form of the “compound” according to aspect 11), which essentially exhibits the powder X-ray diffraction pattern shown in Figure 1.

[0040] 16) Another aspect relates to a crystalline form of a “compound” according to any one of aspects 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" (especially 1-5 mg) at 10°C per minute in the range of -20°C to 200°C (and in particular by the method described in the Experiment section).

[0042] 17) Another aspect relates to a crystalline form of a “compound” according to any one of aspects 1) to 4) or 11) to 16), which essentially shows the gravimetric water adsorption profile shown in Figure 5, and the gravimetric water adsorption profile is measured at approximately 25°C (particularly at 25°C).

[0043] 18) Another aspect relates to the crystalline form of a “compound” according to any one of aspects 1) to 4), which can be obtained by the method of aspect 11).

[0044] Accordingly, based on the dependencies of the different embodiments 1) to 18) disclosed earlier, the following embodiments are possible, intended, and are specifically disclosed herein as individual forms: 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 table above, the numbers represent the corresponding aspects, and the "+" indicates a subordinate relationship to other aspects. Various aspects are separated individually by commas. In other words, for example, "16+2+1" means aspect 16), which is subordinate to aspect 2) and subordinate to aspect 1), that is, aspect "16+2+1" corresponds to aspect 1), which is further characterized by the features of aspects 2) and 16).

[0045] To avoid any doubt, whenever one of the above embodiments refers to "a peak at the following refraction angle 2θ in a powder X-ray diffraction diagram," it should be understood that the powder X-ray diffraction diagram was obtained using combined Cu Kα1 and Kα2 radiation without removing Kα2, and that 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 2theta (2θ) for a peak in the embodiments and claims of the present invention, the stated 2θ value should be understood to be between -0.2° and +0.2° (2θ+ / -0.2°); and preferably between -0.1° and +0.1° (2θ+ / -0.1°).

[0046] When the plural form is used for compounds, solids, pharmaceutical compositions, diseases, etc., it is intended to also refer to a single compound, solid, pharmaceutical composition, disease, etc.

[0047] The definitions set forth herein apply uniformly to the subject matter defined in any one of embodiments 1) to 18), and shall apply throughout this specification and claims with necessary modifications unless a broader or narrower definition is provided by a specific definition. Naturally, a definition or preferred definition of a term or expression may independently (and together with) define and replace any or all other terms or expressions defined herein or in their preferred definitions.

[0048] In the context of the present invention, the term “enantiomer enriched” is understood 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 of the enantiomers of the “compound.” The “compound” is understood to be present in the enantiomer enriched absolute (R) configuration.

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

[0050] For example, when defining the presence of a peak in a powder X-ray diffraction diagram, the usual method is to do so in terms of the signal-to-noise ratio (S=signal, N=noise). According to this definition, when we say that a peak must exist in a powder X-ray diffraction diagram, it is understood that the peak in the powder X-ray diffraction diagram is defined by having a signal-to-noise ratio (S=signal, N=noise) greater than x (where x is a number greater than 1), usually greater than 2, and especially greater than 3.

[0051] In the context of the statement that the crystal form essentially exhibits the powder X-ray diffraction pattern shown in Figure 1, the term "essentially" means that there must be at least one major peak in the diagram shown in the figure, i.e., a peak with a relative intensity greater than 20%, and especially greater than 10%, compared to the strongest peak in the diagram. However, those skilled in the art of powder X-ray diffraction should be aware that the relative intensities of a powder X-ray diffraction diagram can be subject to strong intensity variations due to favorable orientation effects.

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

[0053] Whenever the words “between” or “from” are used to describe a numerical range, the endpoints of the indicated range are explicitly included within that range. For example, if a temperature range is described as between 40°C and 80°C (or from 40°C to 80°C), it means that the endpoints, 40°C and 80°C, are included within that range. Or, if a variable number is defined as an integer between 1 and 4 (or from 1 to 4), it means that the variable number is the integer 1, 2, 3, or 4.

[0054] A crystalline form of a "compound" according to any one of embodiments 1) to 18), particularly an essentially pure crystalline form, can be used as a pharmaceutical, for example, in the form of a pharmaceutical composition for enteral administration (e.g., particularly orally) or parenteral administration (including topical application or inhalation).

[0055] 19) Therefore, another aspect relates to the crystalline form of a compound according to any one of aspects 1) to 18) (particularly 1) to 4) or 11) to 17)) for use as a pharmaceutical, 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone ("the compound").

[0056] Crystalline solids of the "compound" according to any one of embodiments 1) to 18) (especially 1) to 4) or 11) to 17)), particularly essentially pure crystalline solids, may be used as a single component or in mixtures with other crystalline or amorphous forms of the "compound".

[0057] The pharmaceutical composition can be manufactured 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 with optionally other therapeutically beneficial substances, along with a suitable non-toxic, inert, pharmaceutically acceptable solid or liquid carrier material and, if necessary, a conventional pharmaceutically acceptable adjuvant, to form a pharmaceutical dosage.

[0058] 20) Further aspects of the present invention relate to a pharmaceutical composition having as an active ingredient a crystalline form of a "compound" according to any one of embodiments 1) to 18) (particularly a crystalline form of a "compound" according to any one of embodiments 1) to 4) or 11) to 17), and further comprising at least one pharmaceutically acceptable carrier material.

[0059] 21) Further aspects of the present invention relate 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 manufacture of a pharmaceutical composition, wherein the pharmaceutical composition has the "compound" as an active ingredient and further has at least one pharmaceutically acceptable carrier material.

[0060] The crystalline forms defined in any one of embodiments 1) to 18) (in particular, the crystalline forms defined in any one of embodiments 1) to 4) or 11) to 17)) are useful for the prevention or treatment of disorders associated with CXCR3 receptor dysfunction or dysfunction of ligands that signal via CXCR3.

[0061] Disorders associated with dysfunction of the CXCR3 receptor or its ligands are diseases or disorders requiring modulation of the human CXCR3 receptor. These disorders may be defined as including, in particular, (auto)immune / inflammatory-mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrous diseases; neurodegenerative disorders and neoplastic diseases.

[0062] 22) Further aspects of the present invention relate to crystalline forms of “compounds” 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 (auto)immune / inflammatory-mediated disorders; lung disorders; cardiovascular disorders; infectious diseases; fibrotic diseases; neurodegenerative disorders; or neoplastic diseases.

[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; Sjögren's syndrome; sarcoidosis; systemic sclerosis; spondyloarthritis; psoriasis; psoriatic arthritis; interstitial cystitis; celiac disease; Hashimoto's thyroiditis; lymphocytic thyroiditis. Thyroiditis such as Graves' disease; myasthenia gravis; type 1 diabetes mellitus; uveitis; episcleritis; scleritis; Kawasaki disease; retinouveitis; posterior uveitis; Behçet's disease-associated uveitis; uveomingitis syndrome; vitiligo; allergic encephalomyelitis; atopic diseases such as rhinitis, conjunctivitis, and dermatitis; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; myopathy (including inflammatory myopathy); obesity; and transplant-related disorders. Transplant-related disorders may be defined as including transplant rejection, such as rejection of transplanted organs like kidneys, liver, heart, lungs, pancreas, cornea, and skin; acute and / or chronic graft-versus-host disease; and chronic allograft vasculopathy.

[0064] Lung injury may be defined as encompassing acute lung injury; acute respiratory distress syndrome; asthma; and chronic obstructive pulmonary disease (COPD).

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

[0066] Infectious diseases may be defined as encompassing diseases caused by various infectious agents, including malaria, cerebral malaria, leprosy, tuberculosis, influenza, toxoplasmosis, dengue fever, hepatitis B and C, herpes simplex, leishmania, Chlamydia trachomatis, Lyme disease, and West Nile virus, as well as their complications.

[0067] Fibrotic diseases may be defined as encompassing liver cirrhosis, idiopathic pulmonary fibrosis, renal fibrosis, endocardial cardiomyopathy, systemic scleroderma, and arthral fibrosis.

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

[0069] Neoplastic diseases may be defined as encompassing all types of cancer, including colorectal cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, splenic cancer, kidney cancer, bladder cancer, uterine cancer, ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumors, hematomas, basophilic adenomas, prolactinomas, hyperprolactinemia, adenomas, endometrial cancer, colon cancer; chronic lymphocytic leukemia (CLL); and (in particular) the metastasis and spread of cancer.

[0070] 23) Preferred embodiments of the present invention relate to the 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 a disorder selected from one, some or all of the diseases and disorders of the following group: 1) Rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, systemic lupus erythematosus, lupus nephritis, Sjögren's syndrome, sarcoidosis, systemic sclerosis, spondyloarthritis, psoriasis, psoriatic arthritis, interstitial cystitis; ceria (Auto)immune / inflammatory-mediated diseases selected from (cutaneous) fibrosis, (skin) fibrosis; 2) Lung diseases selected from acute lung injury, acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease; 3) Cardiovascular diseases selected from atherosclerosis and myocarditis; 4) Infectious diseases selected from influenza and cerebral malaria; 5) Fibrotic diseases selected from liver cirrhosis; 6) Neurodegenerative disorders selected from Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, and Guillain-Barré syndrome; 7) Neoplastic diseases selected from brain tumors, colorectal cancer, breast cancer, and metastatic and spreading cancer.

[0071] 24) Another preferred embodiment of the present invention relates to rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, celiac disease, myasthenia gravis, type 1 diabetes mellitus, vitiligo, uveitis, inflammatory myopathy, xerophthalmolytic disease, thyroiditis including Graves' disease, transplant rejection, acute and / or chronic graft-versus-host disease, acute lung injury, acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease. The present invention relates to the 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 diseases, atherosclerosis, myocarditis, influenza, cerebral malaria, cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colorectal cancer, breast cancer, and metastatic and spreading cancer.

[0072] To avoid any doubt, if a crystalline form of a “compound” is described as useful for the prevention and / or treatment of a certain disease, then such a crystalline form of the “compound” is also suitable for use in the manufacture of a medicament for the prevention or treatment of said disease. In particular, if a crystalline form of the “compound” is described as useful for the prevention and / or treatment of a disease according to any one of embodiments 22) to 24), then such a crystalline form of the “compound” is also suitable for use in the manufacture of a medicament for the prevention or treatment of said disease.

[0073] The present invention also relates to a method for preventing or treating a disease as referred to herein, comprising administering a pharmaceutically effective amount of 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) or a pharmaceutical composition according to embodiment 20) to a subject (in particular a patient) who needs it.

[0074] The present invention also relates to a method for producing a pharmaceutical composition having a "compound" as an active ingredient and further having at least one pharmaceutically acceptable carrier material, wherein the production of the pharmaceutical composition comprises a step of mixing a crystalline form of the "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 pharmaceutically acceptable carrier material.

[0075] The present invention also relates to a method for producing an enantiomer-enriched form of the “compound,” and to a method for producing and characterizing a crystalline form of the “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). The method is described in embodiment 11) and in the procedure of the Experiments section below. [Examples]

[0076] Experimental methods Abbreviations (used in the above or below): CNS (Central Nervous System) DSC (Differential Scanning Calorimetry) HCl ethyl acetate Fig. GVS Gravimetric Vapor Adsorption HPLC (High-Performance Liquid Chromatography) MeCN acetonitrile MeOH methanol min NMR nuclear magnetic resonance RH (Relative Humidity) s seconds tBME tert.-butylmethyl ether TGA thermogravimetric analysis THF (Tetrahydrofuran) XRPD (Powder X-ray Diffraction)

[0077] All solvents and reagents are used as they are obtained from their commercial suppliers unless otherwise specified.

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

[0079] In a mixture, the proportions of the solvent, eluent, or reagent mixture in liquid form are expressed as volume relationships (v / v) unless otherwise specified.

[0080] Powder X-ray 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, the 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 2θ scanning range of 3–50°. The divergence and antiscatter slits were fixed at 0.3°. The powder was slightly pressed into a silicon single-crystal sample holder to a depth of 0.5 mm, and the sample rotated within its own plane during the measurement. Diffraction data are reported using Cu Kα (λ=1.5418 Å) irradiation. As is generally the case with powder X-ray diffraction patterns recorded to date, 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 using 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 was scanned at 40 kV / 40 mA. The X-ray optics consisted of a single Goebel multilayer mirror connected to a 0.5 mm pinhole collimator. Typically, a single frame was recorded over 180 s at goniometer positions of theta 1 at 4° and theta 2 at 16° and a detector distance of 20 cm. The frame was integrated over a 2θ range of 5–35°. Samples scanned under ambient conditions were prepared as planar samples using the powder as received 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) irradiation. As is generally the case with powder X-ray diffraction patterns recorded, the precision of the 2θ values ​​provided herein is in the range of + / -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 incubated in an unsealed aluminum pan at temperatures ranging from -20°C to 200°C for 10°C min. -1 The sample was heated. Nitrogen purged on the sample for 20 mL min. -1 It was maintained at that temperature. The peak temperature for the melting point is reported.

[0083] Gravimetric vapor adsorption (GVS) Moisture adsorption isotherms were collected on a Hiden Isochema IGASORP HAS-036-080 dynamic vapor adsorption analyzer operating with Isochema HIsorp 2019 software version 4.02.0070. Typically, approximately 30 mg of sample was placed in the sample holder and subjected to stepwise equilibration at 25°C at predetermined relative humidity (RH) setpoints. Sample mass was recorded at these setpoints and used to create moisture adsorption isotherms. The relative humidity setpoints used were 40%–0%RH, followed by 0%–95%RH, at 5%RH intervals. The data shown consist of moisture adsorption isotherms in the 5%–90% range of the sample subjected to increasing relative humidity. The change in mass between 40% and 80% relative humidity in the first adsorption scan was evaluated to determine hygroscopicity. Grading was performed in accordance with the European Pharmacopoeia (Ph.Eur.) 10.0, section 5.11.

[0084] Thermogravimetric analysis (TGA) TGA data were collected on the Mettler Toledo STARe System (TGA / SDTA851e module). Typically, approximately 5 mg of sample was collected in an automatically drilled standard TGA aluminum pan at temperatures ranging from 30°C to 250°C for 10°C min. -1 The sample was heated. Nitrogen gas purging was maintained over the sample during the measurement.

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

[0086] Reference Example 1: A 0.2 mL solution of the "compound" at a concentration of 25 mg / mL in MeOH is distributed into 4 mL glass vials and evaporated in a Combinedancer apparatus (Hettich, Switzerland) to form a 5 mg amorphous, transparent film of the "compound" on each vial.

[0087] Example 1: "Compound" of crystalline form 1 In a 4 mL standard glass vial, add 0.02 mL of siRNA, isopropanol, or tBME to 5 mg of amorphous "compound" obtained in Reference Example 1. Close the lid, vortex for approximately 30 seconds, and then store the vial in the dark for 5 days. When analyzed without drying, the resulting solid is the "compound" of crystalline form 1.

[0088] In another experiment, 100 mg of the "compound" was added to 1 mL of a 1:2 v / v mixture of MeCN / tBME. The mixture was 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 was isolated by filter centrifugation and dried at 40°C / 10 mbar for 15 min to obtain the "compound" in crystalline form 1.

[0089] [Table 1]

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

[0091] Thermogravimetric analysis of the solid residue after isolation by filter-centrifugation and drying at 10 mbar for 1 hour showed a stepwise weight loss of approximately 1.1% of acetone, which confirms its properties as a solvate of crystalline form 2.

[0092] [Table 2]

[0093] Example 3: "Compound" of crystalline form 3 In a 4 mL standard glass vial, add 0.02 mL of MeCN to 5 mg of amorphous "compound" obtained in Reference Example 1. Close the lid, vortex for approximately 30 seconds, and then store the vial in the dark for 5 days. When analyzed without drying, the resulting solid is the "compound" of crystalline form 3.

[0094] In another experiment, 0.04 mL of MeCN was added to 20 mg of the "compound" (e.g., obtained from Example 1) in a standard glass HPLC vial, and the suspension in the sealed vial was subjected to a temperature change cycle while being stirred with a magnetic stirring rod. The temperature cycle (repeated heating from 20°C to 40°C for 1 hour and cooling from 40°C to 20°C for 4 hours) and stirring for 25 hours were performed in a Polar Bear apparatus (Cambridge reactor design, UK). When analyzed without drying, the resulting solid was the "compound" of crystalline form 3.

[0095] When measured in the presence of sufficient MeCN, crystalline form 3 is observed by XRPD. Upon isolation by filtered centrifugation, or upon isolation and drying under reduced pressure, a conversion from crystalline form 3 to crystalline form 1 occurs, demonstrating the metastable nature of crystalline form 3 in the absence of sufficient MeCN. The combination of the fact that crystalline form 3 is observed only 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 solvated structure.

[0096] Table 3

Claims

1. A crystal of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone, characterized by the presence of peaks at the following refraction angles 2θ: 14.3°±0.2°, 15.5°±0.2°, 16.4°±0.2°, 16.7°±0.2° and 17.2°±0.2° in the powder X-ray diffraction diagram, The aforementioned crystal is not in an acetonitrile solvation structure.

2. A crystal of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone according to claim 1, characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 5.8°±0.2°, 8.9°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 15.5°±0.2°, 16.4°±0.2°, 16.7°±0.2°, 17.2°±0.2°, 18.5°±0.2° and 26.9°±0.2°, The aforementioned crystal is not in an acetonitrile solvation structure.

3. Crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone according to claim 1, having a melting point of 169 ± 5°C determined by differential scanning calorimetry.

4. Crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone according to claim 2, having a melting point of 169 ± 5°C determined by differential scanning calorimetry.

5. Crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone, as described in any one of claims 1 to 4, for use as a pharmaceutical.

6. A pharmaceutical composition comprising crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone as an active ingredient, and further comprising at least one pharmaceutically acceptable carrier material.

7. A crystal of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone for use in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition is 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4] A crystal having triazole-1-yl)-ethanone as an active ingredient, and further comprising at least one pharmaceutically acceptable carrier material.

8. A prophylactic agent for disorders selected from (auto)immune / inflammatory-mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrous diseases; neurodegenerative disorders; or neoplastic diseases, comprising crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone as an active ingredient.

9. A therapeutic agent for disorders selected from (auto)immune / inflammatory-mediated disorders; pulmonary disorders; cardiovascular disorders; infectious diseases; fibrous diseases; neurodegenerative disorders; or neoplastic diseases, comprising crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone as an active ingredient.

10. The active ingredient comprises crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-etanone as described in any one of claims 1 to 4, and is effective for rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, and ceria. A prophylactic agent for disorders selected from the following: Buck's disease, myasthenia gravis, type 1 diabetes, vitiligo, uveitis, inflammatory myopathy, xerophthalmolytic disease, 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, cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colorectal cancer, breast cancer, and metastatic spread of cancer.

11. The active ingredient comprises crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-etanone as described in any one of claims 1 to 4, and is effective for rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, sarcoidosis, systemic sclerosis, psoriasis, psoriatic arthritis, interstitial cystitis, and ceria. A therapeutic agent for disorders selected from among: Buck's disease, myasthenia gravis, type 1 diabetes, vitiligo, uveitis, inflammatory myopathy, xerophthalmolytic disease, 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, cirrhosis, Alzheimer's disease, neurodegeneration, Huntington's disease, neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, brain tumors, colorectal cancer, breast cancer, and metastatic spread of cancer.

12. A prophylactic agent for vitiligo, comprising crystals of 1-{(R)-2-(2-hydroxyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone as an active ingredient.

13. As an active ingredient, 1-{(R)-2-(2-hydrogen) A therapeutic agent for vitiligo containing crystals of xyethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethylpyrimidine-5-yl)-thiazole-5-yl]-piperazine-1-yl}-2-(3-methyl-[1,2,4]triazole-1-yl)-ethanone.

Images