Crystalline forms of IL-17 inhibitors

Abstract

The present application relates to crystalline forms of small molecule IL-17 inhibitors.

Description

Technical Field

[0001] The present disclosure relates to a crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide. The present disclosure also relates to the use of the crystalline form for the manufacture of a medicament for the treatment of diseases and disorders that are typically improved by inhibiting IL-17. Such diseases and disorders may include autoimmune diseases and inflammatory conditions, particularly psoriasis. Background Art

[0002] Polymorphism refers to the existence of more than one crystalline form of a substance.

[0003] The solid state form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, dissolution rate in gastrointestinal fluids, and in vivo bioavailability. When the same composition of matter crystallizes in different lattice arrangements, a crystalline form will occur, resulting in different thermodynamic properties and stability specific to a particular crystalline form. Crystal forms can also include different hydrates or solvates of the same compound. When deciding which crystalline form is preferred, many properties of the crystalline form are compared and the preferred crystalline form is selected based on many physical property variables. In some cases where it is believed that certain aspects (such as ease of preparation, stability, etc.) are critical, it is entirely possible that one crystalline form may be preferred. In other cases, another different crystalline form may be preferred due to a greater dissolution rate and / or superior bioavailability.

[0004] Therefore, the ability of a chemical substance to crystallize in more than one crystalline form can have a profound impact on the shelf life, solubility, formulation characteristics, and processing characteristics of a drug. In addition, the action of a drug may be affected by the polymorphic form of the drug molecule. Different polymorphs may have different uptake rates in the body, resulting in lower or higher biological activity than desired. In extreme cases, undesirable polymorphs may even show toxicity. The appearance of unknown crystalline forms during the manufacturing process may have a significant impact.

[0005] It is not possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in therapeutic compositions, or which polymorphs will display such desired properties. However, knowing which crystalline forms a drug may occur in certain circumstances enables researchers to maximize the desired properties of a compound, such as solubility, formulation characteristics, processing characteristics, and shelf life. Knowing these factors early in the development of a new drug may mean a drug that is more active, more stable, or less expensive to manufacture. Summary of the invention

[0006] The compound 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide is an inhibitor of interleukin-17 (IL-17). The IL-17 family cytokines are important regulators of inflammatory responses and are involved in the immune response to infection. The family consists of six members, IL-17A to IL-17F. IL-17A (commonly referred to as IL-17) is the prototypical member of the family, which was originally identified as a cytokine produced by a subset of CD4+ T cells, which is now known as Th17 (Matsuzaki et al. Microbiol. Immunol. [Microbiology and Immunology] 2018, 62, 1-13).

[0007] IL-17 is a T cell-derived cytokine present in, for example, rheumatoid arthritis (RA) that acts as a proinflammatory cytokine, particularly in combination with IL-1 and TNF-α (Chabaud et al. Arthritis Rheum. 1999, 42, 963-970; Awane M et al. J. Immunol. 1999, 162, 5337-5344). IL-17 induces MMP production and downregulates TIMPs (Jovanovic et al. J. Rheumatol. 2001, 28, 712-718), and blockade of IL-1 and IL-17 has a synergistic effect on inflammation and bone destruction in vivo (Chabaud et al. Arthritis Rheum 2001, 44, 1293-1303). Inappropriate or excessive production of IL-17 has been implicated in the pathology of various diseases and disorders, such as rheumatoid arthritis (Witowski et al. Cell. Mol. Life Sci. 2004, 61, 567-579), osteoarthritis, bone implant loosening, acute transplant rejection (Antonysamy et al. J. Immunol. 1999, 162, 577-584; Van Kooten et al. J. Am. Soc. Nephrol. 1998, 9, 1526-1534), sepsis, septic shock or endotoxic shock, allergies, asthma (Molet et al. J. Allergy Clin. Immunol. [Journal of Allergy and Clinical Immunology] 2001, 108, 430-438), bone loss, psoriasis (Teunissen et al. J. Invest. Dermatol. [Journal of Dermatological Research] 1998, 111, 645-649), ischemia, systemic sclerosis (Kurasawa et al. Arthritis Rheum. [Arthritis and Rheumatism] 2000, 43, 2455-2463), stroke and other inflammatory disorders. Antibodies against IL-17 have been proposed for the treatment of IL-17-mediated diseases and disorders; see, for example, WO 95 / 18826 or WO 2006 / 013107. One of the major problems associated with such antibody-based treatments is that they require repeated subcutaneous injections. Such injections may be associated with pain, bruising at the injection site, skin irritation or skin infection. Small molecule IL-17 modulators are described in WO 2020 / 127685 (Liu et al. Sci. Rep. 2016, 6, 30859), WO 2013 / 116682 and WO 2014 / 066726.

[0008] There is a need to provide a solid form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide having physicochemical properties that allow for the reliable manufacture, storage of bulk product, and / or the reliable manufacture of safe and effective pharmaceutical products containing 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide.

[0009] 2,4-Dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide is described in Example 1 of currently unpublished patent application PCT / IB2021 / 060092 filed on November 1, 2021, which claims priority to unpublished European patent application No. 20205121.5 filed on November 2, 2020, both of which are incorporated by reference in their entirety. As described in PCT / IB2021 / 060092, 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide is an IL-17 inhibitor having the structure of formula (I):

[0010]

[0011] The activity of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide as assessed by in vitro methods is described in PCT / IB2021 / 060092, such that the compound exhibits valuable pharmacological properties and is therefore suitable for treatment related to IL-17. The cell assays and TR-FRET assays described in PCT / IB2021 / 060092 and the data obtained for 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide are provided as follows:

[0012] Human IL-17A x IL-17RA TR-FRET assay

[0013] Dilutions of test compounds in DMSO were plated onto white small volume 384-well plates (Greiner, #784075). Specifically, solutions with gradient concentrations (5 mM to 150 nM; sixteen 2-fold dilution steps) were dispensed at 0.2 μL / well to produce final assay concentrations ranging from 100 μM to 3 nM. Each compound concentration was tested in duplicate.

[0014] All components of the assay were diluted in PBS containing: 0.05% Tween 20 (Sigma, #P1379, 5% stock in water), 1 mM EDTA (Invitrogen, #15575-038; 0.5 M stock, pH 8), and 0.05% bovine serum albumin (Roche; 5% stock in water). The final total assay volume was 10 μL. Reagents were added using a Multidrop Combi instrument (ThermoFisher, #5840320); between reagents, the instrument was flushed with buffer:

[0015] (i) Biotinylated human IL-17A (PN106276; stock: 55.87 μM) was added at 5 μL / well from a 10 nM intermediate dilution to yield a final assay concentration of 5 nM. Each assay plate contained a "low control" in which buffer was added in place of IL-17A.

[0016] (ii) After incubation for 30 min at RT, 2.5 μL / well of AF647-labeled human IL-17RA (PN110235; stock solution: 2.91 μM) was added from a 120 nM intermediate solution to yield a final assay concentration of 30 nM.

[0017] (iii) After incubation for 30 min at RT, 2.5 μL / well of Eu-streptavidin (PerkinElmer, #AD0062; stock solution: 500 μg / mL = 8.3 μM) was added from an intermediate dilution of 4 nM to give a final concentration of 1 nM.

[0018] After 30 to 60 minutes of incubation, FRET was measured in an EnVision 2101 Multilabel-Reader (PerkinElmer) with excitation at 320 nm and emission at 615 and 665 nm (project "TR-FRET Screening", instrument: NIBR-00013163).

[0019] Each plate contains the test compounds in columns 1-22 and controls in columns 23 and 24. The neutral control (NC) contains all the assay components, but DMSO is used instead of the test compound. The active control (AC) simulates complete inhibition of IL-17 ligand interaction, which is achieved by replacing the biotinylated cytokine with buffer. The fluorescence values ​​emitted at 615nm and 665nm are loaded into the evaluation software Helios. In the normalization step, the values ​​of the plate reader are converted to activity % using the following formula:

[0020] Activity % = -100*(x-NC) / (AC-NC)

[0021] NC and AC are the median values ​​of the neutral control wells and the active control wells on the same plate.

[0022] IC50 values ​​were obtained from the activity data for each compound concentration using a 4-parameter logistic function ("Hill-slope model") in Helios.

[0023] IL-6 release from NHDF cells (normal human dermal fibroblasts)

[0024] NHDF cells isolated from normal adult mesoderm, connective tissue, were cultured in fibroblast growth medium containing 2% supplements. Cells were detached from plastic using accutase solution, washed and seeded at a density of 5 x 103 / well in fibroblast growth medium lacking supplements in 96-well plates. Cells were allowed to adhere overnight before incubation with the compound / cytokine mixture.

[0025] The compound stock solution (10mM in DMSO) was serially diluted in fibroblast growth medium containing 0.2% supplement in a 96-well plate to give a maximum assay concentration of 10μM. The diluted compound was pre-incubated with recombinant human IL-17AA or IL-17AF+human TNF-α on a shaker for 30 minutes at room temperature. NHDF cells were resuspended in fibroblast growth medium / 0.2% supplement (100μl / well), and then cytokine / compound mixture (100μl / well) was added to the cells to give a final compound starting concentration of 10μM. At 37°C (5% CO2), the cells were incubated with the compound / cytokine mixture for 24 hours. During the culture period, the final concentration of IL-17AA was 30pM, the final concentration of IL-17AF was 250pM, and the final concentration of TNF-α was 6pM. The final DMSO or plasma concentration was 0.1% or 20%, respectively. All compound incubations were performed in duplicate. According to the manufacturer's instructions, the supernatant was collected to quantify IL-6 by ELISA. The optical density was measured at 450nm by EnVision multi-label plate reader (Perkin Elmer). The IL-6 level produced after TNF-α stimulation was subtracted from the IL-6 produced after IL-17 / TNF-α co-stimulation. These IL-17-specific IL-6 concentrations were used to calculate the IC50 value. The IC50 value of the inhibitor was then determined using a sigmoidal dose-response curve fitting model (Excel Xlfit, Model 205).

[0026] The potency of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide in the cell assay and TR-FRET assay is presented in the table below:

[0027]

[0028] PCT / IB2021 / 060092 does not provide information on the crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide. The preparation method of Example 1 described in PCT / IB2021 / 060092 provides an amorphous form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide, as described by Figure 1 As demonstrated by the XRPD spectrum shown.

[0029] In one aspect, the present invention provides a crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide in free form (i.e., non-salt form). In a specific embodiment, the crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide in free form is anhydrous. In an embodiment, the crystalline form includes the crystalline form designated as Form A herein.

[0030] In another aspect, the present invention provides two forms of crystalline forms of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide in free form in the form of a hydrate. In an embodiment, the two hydrate forms include those designated herein as H A and H B form.

[0031] This article is designated as Type A, H A Type and H B Examples of types are names used herein to identify a particular form (e.g., "Type A" or "Type H"). A Type" or "H B "Type") and should not be considered as limiting to any other material having similar or identical physical and chemical characteristics, but rather it should be understood that these designations are merely identifiers that should be interpreted in light of the characteristic information also presented herein.

[0032] Preferably, Form A is substantially pure. More preferably, Form A is substantially phase pure.

[0033] In one aspect, the present invention also provides crystalline forms A, H and B of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide. A or H BUse for preparing a medicament. The medicament is used to treat disorders in a subject in need thereof, wherein these disorders are mediated by IL-17 or improved by inhibiting IL-17 (particularly IL-17A and / or IL-17F). In particular, the use mentioned is Form A. Diseases mediated by IL-17 or improved by inhibiting IL-17 (particularly IL-17A and / or IL-17F) are particularly psoriasis. The medicament is particularly formulated for topical administration. Therefore, the crystalline form of the compound of formula (I) as described herein can be used to prepare a topical medicament. The topical medicament is particularly useful for treating psoriasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 An XRPD spectrum of the amorphous form of the compound having Formula (I) is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0035] Figure 2 An XRPD spectrum of an anhydrous crystalline form of the compound of Formula (I), designated herein as Form A, is provided, showing degrees 2θ (2-θ) on the X-axis and relative intensity on the Y-axis.

[0036] Figure 3 A DSC of an anhydrous crystalline form of the compound of formula (I), designated herein as Form A, is provided.

[0037] Figure 4 The TGA of the anhydrous crystalline form of the compound of formula (I), designated herein as Form A, is provided.

[0038] Figure 5 Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H A The XRPD spectrum of the present invention shows the 2θ (2-θ) degree on the X-axis and the relative intensity on the Y-axis.

[0039] Fig. 6A and Figure 6B Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H A DSC thermogram of the .

[0040] Fig. 7A and Figure 7B Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H A TGA diagram of (type).

[0041] Figure 8 Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H B The XRPD spectrum of the present invention shows the 2θ (2-θ) degree on the X-axis and the relative intensity on the Y-axis.

[0042] Fig. 9 Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H B type) DSC.

[0043] Fig.10 Provided is a hydrated crystalline form of a compound of formula (I) (designated herein as H B type) TGA.

[0044] Type A, Type H are listed in Tables 1, 2 and 3 below, respectively. A Type and H B A more detailed list of XRPD peaks for each of the types is provided, wherein relative intensity % (I / I0 x 100) is also provided. It should be understood that due to, for example, instrumental variations (including differences between instruments), there is inherent variability in the values ​​measured in degrees 2θ (°2θ) in the X-ray powder diffraction spectrum or X-ray powder diffraction pattern. Similarly, it should be understood that there is a variability of up to ± 0.2°2θ in the XRPD peak measurements, but such peaks will still be considered to represent a specific solid state form of the crystalline material described herein. It should also be understood that due to, for example, sample preparation and / or storage and / or environmental conditions, other measurements from XRPD experiments and DSC / TGA experiments (such as relative intensity and water content) may vary, but the measurements will still be considered to represent a specific solid state form of the crystalline material described herein. DETAILED DESCRIPTION

[0045] definition

[0046] As used herein, the terms "about" and "substantially" indicate that for features such as endotherms, endothermic peaks, exotherms, baseline shifts, temperatures, etc., their values ​​may vary. With respect to X-ray diffraction peak positions, "about" or "substantially" means taking into account typical peak position and intensity variability. For example, it will be understood by those skilled in the art that peak positions (2θ) will show some variability between devices, typically up to 0.2°. Occasionally, the variability may be higher than 0.2°, depending on differences in device calibration. In addition, it will be understood by those skilled in the art that relative peak intensity will show variability between devices as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be used only as a qualitative measurement. For DSC, the observed temperature change will depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​reported herein for DSC / TGA thermograms may vary by ±5°C (and still be considered to be the characteristics of the specific crystalline forms described herein). When used in the context of other features such as weight percentage (% by weight), reaction temperature, the term "about" indicates a change of ±5%.

[0047] The terms "crystalline form(s)" or "crystalline modification(s)" or "polymorph(s)" or "polymorph(s)" will be used interchangeably herein. "Polymorph(s)" as used herein refers to crystalline forms having the same chemical composition but differing in the spatial arrangement of the molecules, atoms, and / or ions forming the crystal. Each polymorph differs in thermodynamic stability, physical parameters, x-ray structure, and method of preparation.

[0048] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that are not crystallized. Amorphous solids do not show a well-defined X-ray diffraction pattern.

[0049] As used herein, "substantially pure" when used with respect to a form means a compound having a purity greater than 90%, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99%, by weight, based on the weight of the compound, and also including a purity of the compound of formula (I) equal to about 100% by weight. The remaining material comprises one or more other forms of the compound, and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of a compound of formula (I) may be considered substantially pure because it has a purity greater than 90% by weight as measured by means known and generally accepted in the art at this time, wherein the remaining less than 10% by weight of the material comprises one or more other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities.

[0050] As used herein, "substantially phase pure" when used with respect to any crystalline form of a compound of formula (I) means a compound having a phase purity of greater than about 90%, including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99%, by weight, based on the weight of the compound (on anhydrous basis), and also including a phase purity of the compound of formula (I) equal to about 100% by weight. The terms "phase pure" or "phase purity" herein refer to the phase homogeneity with respect to a particular solid state form of a compound of formula (I) and do not necessarily imply a high degree of chemical purity in the absence of an explicit statement to that effect. Phase purity can be determined according to methods known in the art, for example, quantitative phase analysis using XRPD using one or more approaches known in the art, for example, by external standard methods, direct comparison of line (peak) features (which are attributed to different phases in a particular spectrum), or by internal standard methods. However, the presence of amorphous material may complicate XRPD quantification of phase purity. Therefore, other methods that can be used to determine phase purity include, for example, solid-state NMR spectroscopy, Raman and / or infrared spectroscopy. Those skilled in the art will readily understand these methods, and how to use these additional (or alternative) methods to determine phase purity.

[0051] As used herein, "substantially chemically pure" when used with respect to any crystalline form of a compound of Formula (I) means a compound having a chemical purity of greater than about 90%, including greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and about 99%, based on the weight of the compound (on anhydrous basis), and also including a chemical purity of the compound of Formula (I) equal to about 100% by weight. The remaining materials typically include other compounds (such as, for example, other stereoisomers of the compound of Formula (I)), reaction impurities, starting materials, reagents, by-products, solvents, and / or other processing impurities resulting from the preparation and / or isolation and / or purification of a particular crystalline form. For example, if it has been determined that a crystalline form of a compound of formula (I) has a chemical purity greater than about 90% by weight as measured by standard and generally accepted methods known in the art, it can be considered to be substantially chemically pure, wherein the remaining less than about 10% by weight constitutes other materials, such as other stereoisomers of the compound of formula (I), reaction impurities, starting materials, reagents, by-products, solvents and / or processing impurities. Chemical purity can be determined according to methods known in the art, for example, high performance liquid chromatography (HPLC), LC-MS (liquid chromatography-mass spectrometry), nuclear magnetic resonance (NMR) spectroscopy, or infrared spectroscopy. Those skilled in the art will readily understand these methods, as well as how to use these additional (or alternative) methods to determine chemical purity.

[0052] As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound of formula (I). The term "seed" can also be used as a verb to describe the following behavior: introducing one or more crystals of the crystalline compound of formula (I) into an environment (including but not limited to, for example, a solution, a mixture, a suspension, or a dispersion), thereby resulting in the formation of more crystals of the crystalline compound of formula (I) or the growth of the introduced crystals of the crystalline compound of formula (I).

[0053] As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. The subject refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human.

[0054] As used herein, a subject is "in need of" or "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0055] As used herein, the terms "a", "an", "the" and similar terms used in the context of the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0056] Unless otherwise indicated herein or otherwise clearly contradictory to context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is only intended to better illustrate the present invention, without limiting the scope of the present invention otherwise claimed.

[0057] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom or disorder, or a disease, or a significant decrease in the baseline activity of a biological activity or process.

[0058] As used herein, the term "treat, treating or treatment" of any disease or disorder refers, in one embodiment, to improving a disease or disorder (i.e., slowing down or preventing or reducing the development of a disease or at least one of its clinical symptoms). In another embodiment, "treat" refers to alleviating or improving at least one physical parameter, including those that the patient may not be able to discern. In yet another embodiment, "treat", "treating or treatment" refers to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In one embodiment, "treat" or "treating" refers to delaying the progression of a disease or disorder.

[0059] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset of the disease or disorder.

[0060] The term "comprising" encompasses "including" as well as "consisting of;" for example, a composition comprising X may consist only of X, or may include additionally, such as X and Y.

[0061] Crystal form:

[0062] The present disclosure relates to crystalline forms of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide (a compound of formula (I)), which are described and characterized herein.

[0063] In one embodiment, the present disclosure provides an anhydrous crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide.

[0064] In one embodiment, the present disclosure provides a crystalline form (Form A) of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide having an X-ray powder diffraction (XRPD) pattern comprising a representative peak at 18.8±0.2°2θ expressed in °2θ measured at a temperature of about 23°C. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 4.9±0.2°2θ and 12.0±0.2°2θ. In one aspect of the previous embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 11.5±0.2°2θ and 25.9±0.2°2θ. In one aspect of the foregoing embodiment, the XRPD pattern of Form A of the compound of Formula (I) may further comprise one, two, three, or four representative peaks selected from 15.5±0.2°2θ, 19.5±0.2°2θ, 20.5±0.2°2θ, 22.1±0.2°2θ, and 23.4±0.2°2θ. The XRPD pattern of Form A of the compound of Formula (I) may include one or more representative peaks selected from 4.9±0.2°2θ, 11.5±0.2°2θ, 12.0±0.2°2θ, 15.5±0.2°2θ, 18.8±0.2°2θ, 19.5±0.2°2θ, 20.5±0.2°2θ, 22.1±0.2°2θ, 23.4±0.2°2θ, and 25.9±0.2°2θ measured at a temperature of about 23° C. The XRPD pattern of Form A may include one or more (e.g., two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 1 and measured at a temperature of about 23° C.

[0065] In another aspect of the above embodiment, Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising three or more 2θ values ​​selected from the group consisting of 4.9±0.2°2θ, 11.5±0.2°2θ, 12.0±0.2°2θ, 15.5±0.2°2θ, 18.8±0.2°2θ, 19.5±0.2°2θ, 20.5±0.2°2θ, 22.1±0.2°2θ, 23.4±0.2°2θ and 25.9±0.2°2θ measured at a temperature of about 23°C.

[0066] In another aspect of the above embodiment, Form A of the compound having Formula (I) is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 4.9±0.2°2θ, 11.5±0.2°2θ, 12.0±0.2°2θ, 15.5±0.2°2θ, 18.8±0.2°2θ, 19.5±0.2°2θ, 20.5±0.2°2θ, 22.1±0.2°2θ, 23.4±0.2°2θ and 25.9±0.2°2θ measured at a temperature of about 23°C.

[0067] In yet another aspect of the above embodiment, Form A of the compound of formula (I) has substantially Figure 2 XRPD pattern shown.

[0068] The crystalline form A of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide can be thermally characterized. In one embodiment, the crystalline form A of the compound of formula (I) has a thermal profile as measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, the thermal profile comprising an endothermic peak starting at about 186°C (corresponding to melting). In one embodiment, the crystalline form A of the compound of formula (I) has a thermal profile as measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, the thermal profile comprising an endothermic peak starting at about 3°C ​​(attributed to the loss of residual water) and an endothermic peak starting at about 186°C (corresponding to melting).

[0069] In another embodiment, Form A of the compound of Formula (I) has substantially Figure 3 DSC thermogram shown. It will be appreciated that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on instrument parameters and therefore the same material may have thermograms that appear substantially different from one another when data is generated on two different instruments.

[0070] In another embodiment, Form A of the compound of formula (I) has Figure 4 Thermogravimetric analysis (TGA) graphs showing substantially the same. In the range of about 30°C to about 180°C, the TGA weight loss is about 0.7%.

[0071] In yet another embodiment, Form A is substantially pure.

[0072] In yet another embodiment, Form A is substantially chemically pure.

[0073] In yet another embodiment, Form A is substantially phase pure.

[0074] The present invention further provides a hydrated crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide (H A In one aspect of the foregoing embodiment, the XRPD pattern of Form B may further comprise one, two, three or four representative peaks selected from 12.6 ± 0.2 ° 2θ, 19.3 ± 0.2 ° 2θ, 22.0 ± 0.2 ° 2θ and 25.9 ± 0.2 ° 2θ. In one aspect of the foregoing embodiment, the XRPD pattern of Form B may further comprise an additional representative peak of 10.3 ± 0.2 ° 2θ.

[0075] Hydrate Form H A The XRPD pattern may include one or more (e.g., two, three, four, five or six) representative peaks selected from 18.8 ± 0.2 ° 2θ, 18.6 ± 0.2 ° 2θ, 12.6 ± 0.2 ° 2θ, 19.3 ± 0.2 ° 2θ, 22.0 ± 0.2 ° 2θ, 25.9 ± 0.2 ° 2θ and 10.3 ± 0.2 ° 2θ. A The XRPD pattern of may include one or more (eg, two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 2 and measured at a temperature of about 23°C.

[0076] In another embodiment, the hydrate H A The compound of claim 1 is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 18.8±0.2°2θ, 18.6±0.2°2θ, 12.6±0.2°2θ, 19.3±0.2°2θ, 22.0±0.2°2θ, 25.9±0.2°2θ and 10.3±0.2°2θ measured at a temperature of about 23°C.

[0077] In another embodiment, the hydrate H AThe compound of claim 1 is characterized by an x-ray powder diffraction pattern comprising five or more 2θ values ​​selected from the group consisting of 18.8±0.2°2θ, 18.6±0.2°2θ, 12.6±0.2°2θ, 19.3±0.2°2θ, 22.0±0.2°2θ, 25.9±0.2°2θ and 10.3±0.2°2θ measured at a temperature of about 23°C.

[0078] In yet another embodiment, the hydrated crystalline form H of the compound of formula (I) A Basically Figure 5 XRPD pattern shown.

[0079] 2,4-Dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide hydrate form H A can be thermally characterized.

[0080] In one embodiment, the hydrated crystalline form H of the compound of formula (I) is measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min. A has a thermal profile comprising an endothermic peak starting at about 21°C (attributed to dehydration), an endothermic peak starting at about 142°C (attributed to melting), and an endothermic peak starting at about 184°C (corresponding to hydrate H A The endothermic peak at the beginning of melting of the type.

[0081] In another embodiment, the hydrated crystalline form H of the compound of formula (I) is measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min. A It has a thermal profile including an endothermic peak with an onset at about 17°C (attributable to dehydration) and an endothermic peak with an onset at about 181°C (attributable to melting).

[0082] In another embodiment, the hydrated crystalline form H of the compound of formula (I) A Basically Fig. 6A or Figure 6B DSC thermogram shown.

[0083] It will be appreciated that hydrated forms may produce different thermograms (in terms of peak shape and profile) depending on instrument parameters, and therefore the same material may have thermograms that appear substantially different from one another when the data is generated on two different instruments.

[0084] In another embodiment, the hydrated crystalline form H of the compound of formula (I) A With Fig. 7A or Figure 7B Substantially the same thermogravimetric analysis (TGA) graphs are shown. The TGA weight loss is about 5% in the range of 30°C and 135°C, or 9.5% in the range of 30°C and 150°C.

[0085] In yet another embodiment, the hydrate crystalline form H A It is basically pure.

[0086] In yet another embodiment, the hydrate crystalline form H A It is essentially chemically pure.

[0087] In yet another embodiment, the hydrate crystalline form H A They are basically pure.

[0088] The present invention further provides a hydrated crystalline form of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide (H B In another embodiment, the XRPD pattern further comprises an additional representative peak of 13.0±0.2°2θ. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 6.5±0.2°2θ, 11.2±0.2°2θ, and 12.1±0.2°2θ. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 2.8±0.2°2θ and 16.6±0.2°2θ. In another embodiment, the XRPD pattern further comprises one or more additional representative peaks selected from 10.6±0.2°2θ, 16.1±0.2°2θ, and 18.3±0.2°2θ.

[0089] In one aspect of the aforementioned embodiment, the hydrate crystalline form H B The XRPD pattern may further comprise one, two, three or four representative peaks selected from 2.8±0.2°2θ, 6.5±0.2°2θ, 9.9±0.2°2θ, 10.6±0.2°2θ, 11.2±0.2°2θ, 12.1±0.2°2θ, 13.0±0.2°2θ, 16.1±0.2°2θ, 16.6±0.2°2θ and 18.3±0.2°2θ.

[0090] Hydrate Form H BThe XRPD pattern may comprise one or more (e.g., two, three, four, five or six) representative peaks selected from 2.8±0.2°2θ, 6.5±0.2°2θ, 9.9±0.2°2θ, 10.6±0.2°2θ, 11.2±0.2°2θ, 12.1±0.2°2θ, 13.0±0.2°2θ, 16.1±0.2°2θ, 16.6±0.2°2θ, and 18.3±0.2°2θ.

[0091] Hydrate Form H B The XRPD pattern of may include one or more (eg, two, three, four, five, or six) representative peaks selected from the peaks disclosed in Table 3 and measured at a temperature of about 23°C.

[0092] In another embodiment, the hydrate H B The compound of claim 1 is characterized by an x-ray powder diffraction pattern comprising four or more 2θ values ​​selected from the group consisting of 2.8±0.2°2θ, 6.5±0.2°2θ, 9.9±0.2°2θ, 10.6±0.2°2θ, 11.2±0.2°2θ, 12.1±0.2°2θ, 13.0±0.2°2θ, 16.1±0.2°2θ, 16.6±0.2°2θ and 18.3±0.2°2θ measured at a temperature of about 23°C.

[0093] In another embodiment, the hydrate H B The compound of claim 1 is characterized by an x-ray powder diffraction pattern comprising five or more 2θ values ​​selected from the group consisting of 2.8±0.2°2θ, 6.5±0.2°2θ, 9.9±0.2°2θ, 10.6±0.2°2θ, 11.2±0.2°2θ, 12.1±0.2°2θ, 13.0±0.2°2θ, 16.1±0.2°2θ, 16.6±0.2°2θ and 18.3±0.2°2θ measured at a temperature of about 23°C.

[0094] In yet another embodiment, the hydrated crystalline form H of the compound of formula (I) B Basically Figure 8 XRPD pattern shown.

[0095] 2,4-Dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide hydrate form H B In one embodiment, the hydrated crystalline form H of the compound of formula (I) is measured by DSC at a heating rate of 10°C / min. BThe compound has a differential thermogravimetric curve including an endothermic peak starting at about 19° C. (attributed to dehydration) and an endothermic peak starting at about 143° C. (attributed to melting).

[0096] In another embodiment, the hydrated crystalline form H of the compound of formula (I) B Basically Fig. 9 DSC thermogram shown.

[0097] In another embodiment, the hydrate crystalline form H B With Fig.10 Substantially the same thermogravimetric analysis (TGA) graphs are shown. The TGA weight loss is about 6.3% in the range of about 30°C to about 136°C.

[0098] In yet another embodiment, the hydrate crystalline form H B It is basically pure.

[0099] In yet another embodiment, the hydrate crystalline form H B Are chemically pure.

[0100] In yet another embodiment, the hydrate crystalline form H B They are basically pure.

[0101] Pharmaceutical compositions, dosages and administration

[0102] In one embodiment, the crystalline forms of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide described herein can be used alone or they can be formulated into a pharmaceutical composition, which also contains at least one pharmaceutically acceptable excipient, and usually contains at least two or more pharmaceutically acceptable excipients. Excipients known in the art can be used without departing from the purpose and scope of the present application.

[0103] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, carriers, diluents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents, antioxidants), isotonic agents, absorption delaying agents, salts, drug stabilizers, binders, additives, bulking agents, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It should be understood that unless the conventional excipient is incompatible with the active ingredient, the present application contemplates the use of any conventional excipient in any therapeutic or pharmaceutical composition.

[0104] The pharmaceutical composition can be formulated for specific administration routes, such as topical administration, oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical composition of the present invention can be prepared in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories), or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations (such as sterilization) and / or can contain conventional inert diluents, lubricants, carriers or buffers, and adjuvants (such as solvents, preservatives, stabilizers, wetting agents, emulsifiers and swelling agents, etc.).

[0105] The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.

[0106] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low water content ingredients and low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored so that their anhydrous nature is maintained. Therefore, it is preferred to package anhydrous compositions using materials known to prevent exposure to water so that they can be included in suitable formulation kits.

[0107] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compounds of the present invention as active ingredients decompose. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers, etc.

[0108] For a subject of about 50-70kg, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 1-1000mg one or more active ingredients, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 10-50mg active ingredients. Preferably, the pharmaceutical composition of the present invention or combination can be in a unit dose of about 10mg, about 25mg or about 50mg. The therapeutically effective dose or amount of compound, pharmaceutical composition or combination thereof depends on the species, body weight, age and individual condition, disorder or disease or its severity of the subject. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for prevention, treatment or inhibition of disorder or disease progression.

[0109] The above dosage properties can be demonstrated in in vitro and in vivo tests using advantageous mammals (eg, mice, rats, dogs, monkeys, pigs) or isolated tissues and preparations thereof.

[0110] In the embodiments of the present disclosure, the crystalline form (particularly Form A) of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide can be used to prepare a pharmaceutical composition (particularly a topical composition, such as in the form of a cream) comprising one or more pharmaceutically acceptable excipients.

[0111] combination:

[0112] The crystalline form (particularly Form A) of the compound of formula (I) of the present invention can be used to prepare a drug, which can be administered simultaneously with one or more other therapeutic agents or before or after these therapeutic agents. The drug can be administered alone by the same or different routes of administration, or other agents can be prepared together in the same pharmaceutical composition as the pharmaceutical composition prepared with the crystalline form of the compound of formula (I) of the present invention.

[0113] The other therapeutic agent can be selected from a disease-modifying antirheumatic drug (DMARD); a vitamin D derivative; a steroid; a retinoid; a JAK / TYK inhibitor; salicylic acid; coal tar; anthralin; a calcineurin inhibitor; a lymphocyte recirculation regulator; an mTOR inhibitor; an ascomycin with immunosuppressive properties; an immunosuppressive compound; an adhesion molecule inhibitor; a chemotherapeutic agent; a UV therapy agent; an anti-tumor necrosis factor (TNF) agent; a T-cell signaling inhibitor; a proinflammatory cytokine blocker; a chemokine blocker; a pyrimidine synthesis inhibitor; an antimalarial; a lymphocyte-interacting compound; a sphingosine-1-phosphate (S1P) inhibitor; a nonsteroidal anti-inflammatory drug ("NSAID"); an anti-infective agent; or an acetylsalicylic acid agent (ASA), including aspirin.

[0114] Suitable disease-modifying antirheumatic drugs (DMARDs) for use in combination include, but are not limited to, gold salts, sulfasalazine, antimalarials, methotrexate, D-penicillamine, azathioprine, mycophenolic acid, cyclosporin A, tacrolimus, sirolimus, minocycline, leflunomide, glucocorticoids.

[0115] Suitable JAK / TYK inhibitors for use in combination include, but are not limited to: pan JAK inhibitors or more specifically JAK / TYK2 inhibitors, such as tofacitinib, baricitinib; JAK inhibitors, such as Ruxolitinib.

[0116] Suitable calcineurin inhibitors for use in combination include, but are not limited to, cyclosporin A, FK 506, or FKBP12.

[0117] Suitable lymphocyte recirculation modulators for use in combination include, but are not limited to, FTY720, or an FTY720 analog.

[0118] Suitable mTOR inhibitors for use in combination include, but are not limited to, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin (everolimus, WO 2005 / 052187), sirolimus, temsirolimus (CCI779), ABT578, AP23573, or TAFA-93.

[0119] Suitable ascomycins with immunosuppressive properties for use in combination include, but are not limited to, ABT-281, ASM981, corticosteroids, cyclophosphamide, azathioprine, methotrexate, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, or 15-deoxyspergualin.

[0120] Suitable immunosuppressive compounds for use in combination include, but are not limited to, recombinant binding molecules having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, such as at least an extracellular portion of CTLA4 or a mutant thereof linked to a non-CTLA4 protein sequence, such as CTLA4Ig (e.g., designated ATCC68629) or a mutant thereof (e.g., LEA29Y); corticosteroids; azathioprine; methotrexate; cyclosporine; retinoids; phosphodiesterase type 4 (PDE4) inhibitors, such as apremilast.

[0121] Suitable adhesion molecule inhibitors for use in combination include, but are not limited to, LFA-1 antagonists, ICAM-1 or ICAM-3 antagonists, VCAM-4 antagonists, or VLA-4 antagonists.

[0122] Suitable chemotherapeutic agents for use in combination include, but are not limited to, paclitaxel, gemcitabine, cisplatin, doxorubicin, or 5-fluorouracil.

[0123] Suitable UV therapy agents for use in combination include, but are not limited to: sunlight; or laser.

[0124] Suitable anti-TNF agents for use in combination include, but are not limited to, monoclonal antibodies against TNF, such as infliximab, adalimumab, CDP870; or receptor constructs against TNF-RI or TNF-RII, such as Etanercept, PEG-TNF-RI; or TNF-α blockers, such as adalimumab, infliximab, golimumab.

[0125] Suitable T cell signaling inhibitors for use in combination include, but are not limited to, abatacept, integrin blockers such as Vedolizumab.

[0126] Suitable proinflammatory cytokine blockers for use in combination include, but are not limited to, IL-1 blockers such as canckinumab; IL-1 traps such as AAL160, ACZ 885; IL-6 blockers; IL-1 receptor blockers such as anakinra; IL-12 inhibitors such as ustekinumab; IL-23 inhibitors such as risankizumab; IL-17 inhibitors such as secukinumab or ixekizumab; or IL17R blockers such as brodalumab.

[0127] Suitable chemokine blockers for use in combination include, but are not limited to, for example, inhibitors or activators of proteases (e.g., metalloproteases); anti-IL-15 antibodies; anti-IL-6 antibodies, such as tocilizumab; or anti-CD20 or anti-CD40 antibodies, such as rituximab, iscalimab.

[0128] Suitable pyrimidine synthesis inhibitors for use in combination include, but are not limited to, leflunomide.

[0129] Suitable antimalarials for use in combination include, but are not limited to: chloroquine; or hydroxychloroquine.

[0130] Suitable lymphocyte interactive compounds for use in the combination include, but are not limited to, D-penicillamine.

[0131] Suitable sphingosine-1-phosphate (S1P) inhibitors for use in combination include, but are not limited to: minocycline; or tetracycline.

[0132] Suitable NSAIDs for use in combination include, but are not limited to, aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, alminofen, amfenac, ampiroxicam, antolmetinguacil, anirolac, antrafenin, azapropazone, benolate, bermoprofen, bindarit, bromfenac, buclofen, bucolom, bufenac, bumadizon, butibufen, butixirat, carbasalat calcium, carprofen, choline magnesium trisalicylate ...trisalicylate, celecoxib, Cinmetacin, Cinnoxicam, clidanac, Clobuzarit, Deboxamet, dexibuprofen, Dexketoprofen, diclofenac, diflunisal, droxicam, Eltenac, Enfenamins aure), Etersalat, etodolac, etofenamate, etoricoxib, Feclobuzon, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, fepradinol, feprazone, flobufen, floctafenin e), flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glucametacin, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin farnesate, dometacinfarnesil, indoprofen, Isoxepac, Isoxicam, ketoprofen, ketorolac, lobenzarit, Lonazolac, lornoxicam, Loxoprofen, lumiracoxib, meclofenamic, Meclofen, mefenamicacid, meloxicam, mesalazine, MiroProfen, Mofezolac, nabumetone, naproxen, niflumic acid, olsalazine, oxaprozin, Oxipinac, oxyphenbutazone, parecoxib, phenylbutazone, Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsaure, rofecoxib, Romazarit, salicylamide, salicylic acid, Salmilastan Stein, Salnacedin, salsalate, sulindac, sudoxicam, suprofen, Talniflumate, tenidap, Tenosal, tenoxicam, tepoxalin, tiaprofenic acid, Taramid, Tilnoprofenarbamel, timegadine, Tinoridin, Tiopinac, tolfenamic acid, tolmetin, Ufenamat, valdecoxib, Ximoprofen, zaltoprofen, Zoliprofen, and combinations thereof.

[0133] Suitable acetylsalicylic acid drugs (ASA) for use in combination include, but are not limited to, 5-ASA derivatives such as sulfasalazine.

[0134] Treatment kit

[0135] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a medicament prepared using a crystalline form (particularly Form A) of a compound of formula (I). In one embodiment, the kit comprises a device (such as a container, a separate bottle, or a separate foil packet) for retaining the compositions separately. An example of such a kit is a blister pack, such as is typically used for packaging of tablets, capsules, and the like.

[0136] The kit of the invention can be used for administering different dosage forms (eg, oral and parenteral), for administering the separate compositions at different dosage intervals or for titrating the separate compositions against each other. To aid compliance, the kit of the invention typically comprises instructions for administration.

[0137] abbreviation

[0138] Abbreviations used in the following examples and elsewhere in this document are:

[0139] AC activity control

[0140] aq. Aqueous solution

[0141] AcOH Acetic acid

[0142] BINAP Racemic 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0143] BOC tert-Butyloxycarbonyl

[0144] BP reaction Gene integration reaction between attB and attP sites of cloning gene vector

[0145] br. Broad peak

[0146] d Doublet

[0147] dd double doublet

[0148] DCM Dichloromethane

[0149] DMF N,N-Dimethylformamide

[0150] DMSO Dimethyl sulfoxide

[0151] EtOAc Ethyl acetate

[0152] eq equivalent

[0153] GC-MS Gas chromatography and mass spectrometry

[0154] h hour

[0155] HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyl Urea hexafluorophosphate

[0156] HPLC High Pressure Liquid Chromatography

[0157] Hz Hertz

[0158] IC50 half maximal inhibitory concentration

[0159] J coupling constant

[0160] L / mL / μL Liter / milliliter / microliter

[0161] LC-MS Liquid chromatography and mass spectrometry

[0162] M / mM / μM / nM / pM mole / millimole / micromole / nanomole / picomole

[0163] MeOH Methanol

[0164] mCPBA m-Chloroperoxybenzoic acid

[0165] MS mass spectrometry

[0166] m multiplet

[0167] mg / μg milligram / microgram

[0168] min

[0169] mL milliliters

[0170] mmol millimole

[0171] m / z mass-to-charge ratio

[0172] NMR Nuclear Magnetic Resonance

[0173] ppm parts per million

[0174] Prep HPLC

[0175] Rt retention time

[0176] RT Room temperature

[0177] s Single peak

[0178] sat. saturated SFC Supercritical Fluid Chromatography

[0179] TBME, MTBE methyl tert-butyl ether

[0180] NMR measurements were performed on a Bruker 600 MHz or Bruker 400 MHz NMR spectrometer with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ values) are reported in ppm downfield from tetramethylsilane (TMS), and the 5 modes of spectral splitting are designated as singlet (s), doublet (d), double doublet (dd), double triplet (dt), double quartet (dq), triplet (t), three doublets (td), quartet (q), four doublets (qd), quintet (quint), septet (sep), multiplet, unresolved or overlapping signals (m), broad signals (br). Deuterated solvents are given in brackets and have the chemical shifts of dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR spectral data.

[0181] Mass spectrometry was performed using electrospray, chemical and electron impact ionization methods on LC-MS, SFC-MS or GC-MS systems from a range of instruments configured as follows: Agilent 1100 HPLC system with Agilent 6110 mass spectrometer. [MH]+ refers to the protonated molecular ion of the chemical species.

[0182] MS method:

[0183] Method 1

[0184] column: Express C18 2.7μm; 2.1x 50mm

[0185] Column temperature: 80°C

[0186] Gradient: 1% to 50% B in 1.4 min; 50%-98% B in 0.30 min, flow rate: 1.0 mL / min

[0187] Eluent A: water + 4.76% isopropanol + 0.05% FA + 3.75mM AA

[0188] Eluent B: Isopropanol + 0.05% FA

[0189] Method 2

[0190] Column: Acquity UPLC BEH C18, 1.7μm, 2.1x 50mm

[0191] Column temperature: 80°C

[0192] Eluent A: water + 0.05% FA + 3.75mM AA, B: isopropanol + 0.05% FA Flow rate 0.6mL / min

[0193] Gradient: 5% to 98% B in 1.7 min

[0194] Method 3

[0195] Column: Acquity UPLC BEH C18, 1.7μm, 2.1x 50mm

[0196] Column temperature: 80°C

[0197] Eluent A: water + 0.05% FA + 3.75mM AA, B: isopropanol + 0.05% FA Flow rate 0.4mL / min

[0198] Gradient: 5% to 60% B in 8.4 min, then 60% to 98% B in 1 min

[0199] Preparation of the Amorphous Form of 2,4-Dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide:

[0200] To a solution of 3-(4-((S)-2-amino-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide (Intermediate 3-1; 1.10 g, 2.46 mmol) in DMF (15 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (530 mg, 4.2 mmol), followed by HATU (1.9 g, 4.93 mmol) and finally triethylamine (1.7 mL, 12.3 mmol). After stirring overnight at RT, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3, water (twice) and brine. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography (column: RediSep 80 g; eluent: TBME / MeOH 100:0 to 0:100) to give a pale yellow solid which was triturated with DCM / MeOH 4:1 at 0°C, followed by filtration and washing of the solid with ice-cold isopentane to give the title compound as a colourless solid (771 mg, 62%).

[0201] LC-MS: Rt=4.48 min; MS: m / z=510 [MH]+ (Method 3).

[0202] 1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.95(d,1H),8.20(d,1H),7.83(d,2 H),7.46(d,1H),7.40(d,1H),7.28-7.16(m,3H),7.11-7.05(m,3H),7.05-6 .94(m,1H),4.82(dd,1H),3.90(s,3H),3.38-3.34(m,1H),2.93-2.71(m,2 H),2.23-2-12(br.m,1H),2.09(s,3H),1.97(s,3H),1.85-1.65(m,3H)ppm.

[0203] XRPD spectra were measured at room temperature (about 296 K) on a Bruker D8 Discover instrument using a VANTEC-500 detector. The radiation used to collect the data was The power of the X-ray generator was 40 kV, 40 mA, 1600. The step size and resolution were 60 s per step, 2 steps. The diffraction data were collected in the range of 9 to 36° (2θ values). The scanning time was 120 s.

[0204] The obtained XRPD spectrum is shown in Figure 1 , the figure shows that the obtained compound 4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide is amorphous.

[0205] Intermediate 3-1:

[0206] 3-(4-((S)-2-amino-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide

[0207]

[0208] Step 1: 3-(4-((S)-2-((tert-Butoxycarbonyl)amino)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide

[0209] To a solution of 3-(4-aminophenyl)-2,4-dimethylpyridine 1-oxide (Intermediate 1-1; 1.26 g, 5.89 mmol) in DMF (30 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid (Intermediate 2-1, compound of peak 3; 1.50 g, 4.91 mmol), HATU (2.24 g, 5.89 mmol) and Et3N (2.04 mL, 14.74 mmol) in sequence. The mixture was stirred at RT for 18 h, then diluted with EtOAc and washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried (Na2SO4) and all volatiles were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0% to 25% TBME in MeOH) to give the title compound (1.97 g, 80%) as a light yellow solid.

[0210] LC-MS: Rt=1.08min; MS m / z=502.3[MH]+ (Method 1).

[0211] Step 2: 3-(4-((S)-2-amino-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide

[0212] To a solution of 3-(4-((S)-2-((tert-butoxycarbonyl)amino)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide (1.97 g, 3.93 mmol) in dioxane (40 mL) was added 4M HCl in dioxane (40 mL) dropwise and the solution was stirred at RT for 18 h. All volatiles were removed under reduced pressure. The residue was diluted with 1M aqueous Na2CO3 and extracted three times with DCM / isopropanol 4:1. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (0% to 10% TBME in MeOH) to give the title compound (1.47 g, 91%) as a white foam. LC-MS: Rt=0.62 min; MS m / z=402.2 [MH]+ (Method 1).

[0213] Intermediate 1-1:

[0214] 3-(4-Aminophenyl)-2,4-dimethylpyridine 1-oxide

[0215]

[0216] Step 1: 3-Bromo-2,4-dimethylpyridine 1-oxide

[0217] At 10 ℃-15 ℃, m-CPBA (90g, 0.516mol, 1.2 equivalents) was added to a solution of 3-bromo-2,4-dimethylpyridine (80g, 0.430mol) in DCM (800mL). After stirring for 3 hours at the same temperature, HPLC analysis showed that the starting material was completely converted. The mixture was poured into a 10% Na2SO3 aqueous solution, stirred for 5 minutes, and the layers were separated. The aqueous phase was extracted with DCM (400mL). The organic phases were combined and washed with a 10% Na2CO3 aqueous solution. The aqueous phase was re-extracted with DCM (400mL). The organic phases were combined, washed twice with brine (400mL), dried (Na2SO4) and concentrated to produce the title compound (68g, 78% yield) as an off-white solid.

[0218] 1H NMR (400MHz, DMSO) δ8.22(d,1H),7.30(d,1H),2.57(s,3H),2.34(s,3H)ppm.

[0219] Step 2: 3-(4-aminophenyl)-2,4-dimethylpyridine 1-oxide

[0220] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (91g, 0.416mol), Na2CO3 (110g, 1.038mol), water (140mL) and Pd(dppf)Cl2·DCM complex (12.7g, 0.017mol) were added to a solution of 3-bromo-2,4-dimethylpyridine 1-oxide (70g, 0.346mol) in dioxane (700mL). The reaction mixture was purged with nitrogen and stirred at 100°C for 16 hours. HPLC analysis showed that the starting material was completely converted. The reaction mixture was filtered, the filtrate was concentrated, absorbed with DCM (700mL), and washed with brine (350mL). The aqueous phase was extracted with DCM (350mL x 5). The organic phases were combined, dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography (DCM:MeOH 15:1) to give the title compound as a light brown solid (53.4 g, 72% yield).

[0221] 1H NMR (400MHz, DMSO-d6) δ8.14(d,J=6.6Hz,1H),7.17(d,J=6.6Hz,1H),6.84(d,J =8.3Hz,2H),6.66(d,J=8.3Hz,2H),5.26(s,2H),2.11(s,3H),1.99(s,3H)ppm.

[0222] Intermediate 2-1:

[0223] (S)-2-((tert-Butyloxycarbonyl)amino)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid

[0224]

[0225] To a cooled (0 ° C) mixture of 2-(1,2,3,4-tetrahydronaphthalen-1-yl)glycine (2 g, 9.74 mmol) in a mixture of dioxane (30 mL) and 1 M NaOH aqueous solution (15 mL) was added ditert-butyl dicarbonate (3.4 g, 14.6 mmol). After stirring for 5 h at RT, the mixture was partitioned between EtOAc and 10% KHSO4 aqueous solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was triturated with DCM / methanol 1:1, the resulting solid was filtered and dried in vacuo. The mother liquor was purified by silica gel column chromatography (column: RediSep 40 g; eluted with 5% to 70% EtOAc in heptane). The pure fractions were evaporated and combined with the filtered material to produce a stereoisomeric mixture of the title compound (2.37 g, 76%) as a colorless solid.

[0226] Separation of individual stereoisomers was achieved by: Chiral SFC (column: ChiralPak AY, 300 x 50 mm I.D., 10 μm; 25% ethanol, flow rate: 100 mL / min.

[0227] Analytical chiral SFC (ChiralPak AY, 150×4.6 mm ID, 3 μm, 5%-40% ethanol + 0.05% DEA; flow rate = 2.5 mL / min, T = 35° C.):

[0228] Peak 1: Rt = 2.41 min: 873 mg

[0229] Peak 2: Rt = 2.99 min: 130 mg

[0230] Peak 3: Rt = 3.29 min: 1040 mg

[0231] Peak 4: Rt = 4.71 min: 78 mg

[0232] LC-MS: Rt=5.05 min; MS m / z=304.2 [MH]+ (Method 2).

[0233] The stereochemistry of the compound eluting in peak 3 (designated as intermediate 2-1) was determined to be (S,S) by X-ray crystallography.

[0234] Preparation of 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide in crystalline and hydrated form:

[0235] Crystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spray. Techniques for crystallizing or recrystallizing a crystal form from a solvent or solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent or solvent mixture, seeding the crystal with a supersaturated solvent mixture of the molecule and / or salt, freeze drying the solvent mixture, and adding an antisolvent (counter solvent) to the solvent mixture. Exemplary methods for preparing the crystal forms described herein are listed in detail below.

[0236] Drug crystals (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, SR Byrn, RRP Feiffer and JG Stowell, 2nd ed., SSCI, West Lafayette, IN, USA (1999).

[0237] For crystallization techniques using solvents, the selection of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used, for example, the compound can be dissolved in a first solvent to provide a solution, followed by the addition of an antisolvent to reduce the solubility of the compound in the solution and provide for the formation of crystals. An antisolvent is a solvent in which the compound has a low solubility.

[0238] In one method of preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of a compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and solvent at a given temperature. This may also be referred to as a suspension.

[0239] Seedlings can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a particular polymorph or to control the particle size distribution of the crystallized product. Therefore, the calculation of the required amount of seedlings depends on the size of the available seedlings and the desired size of the average product particles, as described in "Programmed Cooling of Batch Crystallizers", JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seedlings are needed to effectively control the growth of crystals in a batch. Small-sized seedlings can be produced by screening, grinding or micronizing large crystals, or by micronizing a solution. It should be noted that grinding or micronizing of crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., becoming amorphous or another polymorph).

[0240] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as a cold recrystallization solvent), and the separated solid can be dried under a nitrogen purge to provide the desired crystal form. The separated solid can be analyzed by a suitable spectrum or analytical technique, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, etc., to ensure that the preferred crystal form of the product is formed. The resulting crystal form is typically produced in an amount greater than about 70% by weight of the isolated yield, preferably greater than 90% by weight of the isolated yield based on the weight of the compound initially used in the crystallization procedure. If necessary, the product can be co-ground or passed through a mesh screen to debulk the product.

[0241] Alternatively, the crystalline form can be prepared directly from the reaction medium of the final process for preparing 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide. This can be achieved, for example, by using a solvent or solvent mixture in the final process step from which 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide can be crystallized. Furthermore, the crystalline form can be obtained by distillation or solvent addition techniques.

[0242] In addition to the methods briefly discussed below, it will be appreciated that a variety of analytical methods can be used to characterize any of the materials described herein.

[0243] The following non-limiting examples illustrate the present disclosure.

[0244] Examples

[0245] Example 1: Preparation of Form A

[0246] Step 1:

[0247]

[0248] To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (18.341 g, 145.4 mmol) in THF (330 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (63.197 g, 166.2 mmol) followed by N,N-diisopropylethylamine (DIPEA) (53.703 g, 415.5 mmol) at 20-30° C. The mixture was stirred at 20-30° C. for 0.5 h. Thereafter, a solution of 3-(4-((S)-2-amino-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide in THF (166 g, 33.5% w / w, 138.5 mmol) was added to the mixture. The reaction mixture is stirred at 20 ℃ to 30 ℃ for 3h. The reaction is quenched by adding water (330ml) at 20 ℃ to 30 ℃. The solution is then extracted with EtOAc (330ml, 2x). The organic phase is washed with 1N HCl aqueous solution (330ml, 2x), 10% NaHCO aqueous solution (330ml, 2x) and water (330ml), and then concentrated in vacuo. The crude residue is loaded into MTBE (500ml), and then stirred for a while. After filtration, the wet cake is dissolved in DCM (500ml) and MeOH (50ml). The solution is washed with 10% NH.H2O (500ml, 3x) and water (500ml), and then concentrated under vacuum to obtain a crude product. The crude product is purified by slurrying overnight in MeOH (150ml) and MTBE (500ml) at 20 ℃ to 30 ℃. The product was further charged into water (500 ml) and then stirred at 65° C. to 70° C. for 2 h. After filtration and drying, 38.9 g of a light brown solid were obtained.

[0249] Step 2:

[0250] A suspension of 1.5 g of the material obtained according to the above procedure was equilibrated in water at 25° C. for one week. Afterwards, the solid was isolated by filtration and dried under vacuum at 30° C. overnight (about 18 hours). The obtained material was characterized by high-resolution XRPD, TGA and DSC, indicating that Form A was obtained.

[0251] Example 1A: High Resolution Powder X-ray Diffraction of Form A

[0252] The sample material from step 2 of Example 1 was filled into a silicon low-background sample holder for reflection measurement, and the filled holder was placed in the diffractometer. XRPD patterns were collected in reflection mode on a Bruker D8 Advance system equipped with a LynxEye solid-state detector at room temperature (about 296K). The radiation used to collect the data was CuKα (λ=0.15418nm). Diffraction data were collected in the range of 2-40° 2θ, and the diffraction data generated by the CuKα1 radiation were evaluated. The spectrum obtained is shown in Figure 2 The peaks are listed in Table 1.

[0253] Table 1: X-ray powder diffraction data of Form A

[0254]

[0255] The relative intensity of all peaks is ≥ 5%

[0256] Example 1B: Differential Scanning Calorimetry (DSC) of Form A

[0257] DSC thermograms were recorded with a TA Discovery DSC instrument (TA Instruments, USA) using heat flux compensation. The TA Discovery instrument was calibrated for temperature and enthalpy using certified reference materials (such as indium) according to the manufacturer's instructions. About 2 mg of sample material was sealed in a standard pin-punctured aluminum pan and heated from 0°C to 250°C in a DSC at a heating rate of 10°C / min. During the measurement, the DSC apparatus was purged with dry N2 gas at a flow rate of 50 ml / min. The obtained DSC thermograms are shown in Figure 3 Two thermal events were observed:

[0258] First endotherm (attributable to loss of residual water): Tstart = 3.1 °C, ΔH = 13 J / g.

[0259] Second endotherm (attributed to melting): Tonset = 185.6°C, ΔH = 63 J / g.

[0260] Example 1C: Thermogravimetric analysis (TGA) of Form A:

[0261] Thermogravimetric analysis was performed using a TA Discovery TGA instrument (TA Instruments, USA). About 2-10 mg of sample material was sealed in a standard aluminum pan with a perforated lid and heated from 30°C to 300°C in the TGA at a heating rate of 10°C / min. During the measurement, the TGA apparatus was purged with dry N2 gas at a flow rate of 20 ml / min. The obtained graphs are shown in Figure 4The loss on drying between about 30°C and 180°C was 0.7% m / m.

[0262] Example 2: Hydrate H A Preparation of type

[0263] Method 1

[0264] The material obtained from Example 1, Step 1 was stored at room temperature at 92% RH for three days and then directly analyzed by XRPD. As a result of this storage, hydrate H A .

[0265] Method 2

[0266] In a separate experiment, about 50 mg of the material from Example 1, Step 1 was equilibrated in 0.5 mL of a water / acetonitrile mixture containing 7.1% m / m water at 25° C. for two weeks. The solid phase was then separated by filtration and analyzed by XRPD. The XRPD pattern of the wet solid cake showed hydrate H A .

[0267] Example 2A: Hydrate H A High-resolution powder X-ray diffraction

[0268] The sample material was filled into a silicon low-background sample holder for reflection measurements and the filled holder was placed in the diffractometer. XRPD patterns were collected in reflection mode on a Bruker D8 Advance system equipped with a LynxEye solid-state detector at room temperature (about 296K). The radiation used to collect the data was CuKα (λ=0.15418nm). Diffraction data were collected in the range of 2-40° 2θ and the diffraction patterns generated by the CuKα1 radiation were evaluated. The peak produced.

[0269] The spectrum obtained using a sample of material from Method 1 is shown in Figure 5 The peaks are listed in Table 2.

[0270] Table 2: Hydrate Form H A X-ray powder diffraction data of

[0271]

[0272] The relative intensity of all peaks is ≥ 5%

[0273] Example 2B: Hydrate H A Differential Scanning Calorimetry (DSC)

[0274] DSC thermograms were recorded with a TA Discovery DSC instrument (TA Instruments, USA) using heat flux compensation. The TA Discovery instrument was calibrated for temperature and enthalpy using certified reference materials (such as indium) according to the manufacturer's instructions. About 2 mg of sample material was sealed in a standard pin-punctured aluminum pan and heated from 0°C to 250°C in the DSC at a heating rate of 10°C / min. During the measurement, the DSC apparatus was purged with dry N2 gas at a flow rate of 50 ml / min.

[0275] The DSC thermogram obtained using the material from Method 1 is shown in Fig. 6A middle.

[0276] Three thermal events were observed:

[0277] First endotherm (attributable to dehydration): Tonset = 20.8°C, ΔH = 169 J / g.

[0278] Second endotherm (attributed to melting): Tonset = 141.8°C, ΔH = 3 J / g.

[0279] Third endotherm (attributable to melting): Tonset = 183.6°C, ΔH = 44 J / g.

[0280] The DSC thermogram obtained using the material from Method 2 is shown in Figure 6B middle.

[0281] Two thermal events were observed:

[0282] First endotherm (attributable to dehydration): Tonset = 17.0°C, ΔH = 157 J / g.

[0283] Second endotherm (attributed to melting): Tonset = 181.0°C, ΔH = 47 J / g.

[0284] Example 2C: Hydrate H A Thermogravimetric analysis (TGA) of

[0285] Thermogravimetric analysis was performed using a TA Discovery TGA instrument (TA Instruments, USA). About 2-10 mg of sample material was sealed in a standard aluminum pan with a perforated lid and heated in the TGA at a heating rate of 10°C / min from 30°C to at least 250°C. During the measurement, the TGA apparatus was purged with dry N2 gas at a flow rate of 20 ml / min.

[0286] The diagram obtained using material from Method 1 is Fig. 7A The loss on drying between about 30°C and 135°C was 5.12% m / m.

[0287] The diagram obtained using material from Method 2 is Figure 7B The loss on drying between about 30°C and 150°C was 9.46% m / m.

[0288] Separately obtained dynamic vapor sorption (DVS) data (not shown) indicate that the hydrate H A The water content of hydrates is even higher, in the range of 16% to 18%. A The unstable nature at ambient temperature and humidity resulted in rapid water loss during sample handling, and the high water content observed by DVS analysis was not found in DSC or TGA analysis. This water loss behavior is thought to explain the two hydrates H A Different DSC and TGA results of samples.

[0289] Example 3: Hydrate H B Preparation of type

[0290] About 50 mg of the material obtained from Example 1, Step 1 was equilibrated in 0.5 mL of a water / acetonitrile mixture containing 7.1% m / m water at 50° C. for at least one week. Afterwards, the solid phase was separated by filtration, the solid was dried in air for about 10 minutes, and then analyzed by XRPD. The XRPD pattern of the solid cake showed hydrate H B .

[0291] Example 3A: Hydrate H B High-resolution powder X-ray diffraction

[0292] The sample material was filled into a silicon low-background sample holder for reflection measurements and the filled holder was placed in the diffractometer. XRPD patterns were collected in reflection mode on a Bruker D8 Advance system equipped with a LynxEye solid-state detector at room temperature (about 296K). The radiation used to collect the data was CuKα (λ=0.15418nm). Diffraction data were collected in the range of 2-40° 2θ and the diffraction patterns generated by the CuKα1 radiation were evaluated. The peak produced.

[0293] The spectrum obtained using a sample of material from Example 3 is shown in Figure 8 The peaks are listed in Table 3.

[0294] Table 3: Hydrate Form H B X-ray powder diffraction data of

[0295]

[0296] The relative intensity of all peaks is ≥ 5%

[0297] Example 3B: Hydrate H B Differential Scanning Calorimetry (DSC)

[0298] DSC thermograms were recorded with a TA Discovery DSC instrument (TA Instruments, USA) using heat flux compensation. The TA Discovery instrument was calibrated for temperature and enthalpy using certified reference materials (such as indium) according to the manufacturer's instructions. About 2 mg of sample material was sealed in a standard pin-punctured aluminum pan and heated from 0°C to 250°C in the DSC at a heating rate of 10°C / min. During the measurement, the DSC apparatus was purged with dry N2 gas at a flow rate of 50 ml / min.

[0299] The DSC thermogram obtained using the material from Example 3 is shown in Fig. 9 middle.

[0300] Two thermal events were observed:

[0301] First endotherm (attributable to dehydration): Tonset = 19.0°C, ΔH = 182 J / g.

[0302] Second endotherm (attributable to melting): Tonset = 143.4°C, ΔH = 25 J / g.

[0303] Example 3C: Hydrate H B Thermogravimetric analysis (TGA) of

[0304] Thermogravimetric analysis was performed using a TA Discovery TGA instrument (TA Instruments, USA). About 2-10 mg of sample material was sealed in a standard aluminum pan with a perforated lid and heated from 30° C. to 300° C. at a heating rate of 10° C. / min in the TGA. During the measurement, the TGA apparatus was purged with dry N2 gas at a flow rate of 20 ml / min.

[0305] The graph obtained using the material from Example 3 is Fig.10 middle.

[0306] The loss on drying between about 30°C and about 136°C was 6.34% m / m.

Claims

1. A crystalline form of the compound 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide.

2. The crystalline form of the compound 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide according to claim 1, characterized in that The following x-ray powder diffraction pattern, the diffraction pattern comprising a temperature of about 23 ° C and Representative peak expressed in °2θ at 18.8±0.2°2θ measured at an x-ray wavelength λ of 1.34°.

3. The crystalline form of the compound 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide according to claim 1, characterized in that The following x-ray powder diffraction pattern, the diffraction pattern comprising a temperature of about 23 ° C and One or more representative peaks expressed in 2θ selected from the group consisting of 4.9±0.2°2θ, 11.5±0.2°2θ, 12.0±0.2°2θ, 15.5±0.2°2θ, 18.8±0.2°2θ, 19.5±0.2°2θ, 20.5±0.2°2θ, 22.1±0.2°2θ, 23.4±0.2°2θ and 25.9±0.2°2θ measured at an x-ray wavelength λ of 500 nm.

4. The crystalline form according to claim 1, which has an x-ray diffraction spectrum substantially the same as the x-ray powder diffraction spectrum shown in FIG2.

5. The crystal form according to claim 1, characterized in that A differential thermogravimetric curve measured by differential scanning calorimetry (DSC) at a heating rate of 10°C / min includes an endothermic peak starting at about 186°C.

6. The crystalline form according to claim 1, having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in FIG3.

7. The crystalline form of claim 1, having a drying weight loss of about 0.7% as determined by thermogravimetric analysis in the range of about 30°C to about 180°C.

8. The crystalline form according to claim 1, which has a thermogravimetric analysis (TGA) graph substantially the same as that shown in FIG4 .

9. A hydrate having the crystalline form according to claim 1.

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