(5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione solid form

Abstract

The present invention provides compounds for the prevention and / or treatment of inflammatory conditions, muscle diseases, fibrous diseases, viral infections, and / or diseases involving cartilage degradation and / or disruption of cartilage homeostasis, particularly osteoarthritis. [Solution] A solid form of (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione represented by the following formula, a pharmaceutical preparation containing the same, a method for producing the same, and the solid form or preparation are provided. TIFF2026168117000020.tif34170

Description

[Technical Field]

[0001] (Field of Invention) In this specification, in particular, the solid form of the present invention, and pharmaceutical compositions containing the same and their production. Methods for treating inflammatory conditions, muscle diseases, fibrous diseases, viral infections, and / or cartilage For the prevention and / or treatment of diseases involving disruption of cartilage homeostasis Use of the solid form or composition is provided. [Background technology]

[0002] (Background of the invention) ADAMTS-5 was identified in 1999 (Abbaszade et al., 1999). In 2005, two independent studies were identified. The group identified ADAMTS-5 as the major aggrecanase in mouse cartilage (Gla (Sson et al., 2005; Stanton et al., 2005). Aggrecan protein by ADAMTS-5. Degradation occurs at various sites; however, at the Glu373-Ala374 linkage (agrecan IGD) The severance of this joint is extremely detrimental to the integrity and function of the cartilage due to the loss of integrity at this joint. This leads to the loss of the entire aggrecan molecule, which is a pathological condition of osteoarthritis and inflammatory arthritis. It appears to be of high importance in development (Little et al., 2007).

[0003] Studies in genetically modified mouse models (GeMMs) have shown that disruption of ADAMTS-5 leads to internal Cartilage damage and aggrecan loss following induction of osteoarthritis due to surgical instability of the meniscus (DMM). It has been shown to have a protective effect against (Glasson et al., 2005). Furthermore, the DMM model in which ADAMTS-5 knockout mice show reduced changes in subchondral bone (Botter et al. li terature, 2009) and do not develop osteoarthritis-associated mechanical allodynia (Malfait et al., 2 010). In addition to preclinical evidence, clinical evidence also demonstrates the importance of and interest in ADAMTS-5 as a target for osteoarthritis . In recent years, studies using antibodies targeting ADAMTS-5 (Chiusaroli et al., 2013) have been reported. ELISAs that allow measurement of aggrecanase-derived cartilage neoepitope levels in synovial fluid and blood from rodents to humans have been develo ped. This method reveals increased levels of ADAMTS-5-inducible neoepitope levels in the joints of rats in which cartilage degradation is induced by meniscal tear and in the joints of patie nts with osteoarthritis, thereby providing further translational evidence for the importance of this protease in the pathogenesis of osteoart hritis (Chockalingam et al., 2011; Larsson et al., 2014).

[0004] These findings provide strong evidence for the central role of ADAMTS-5 in the pathology of osteoarthritis as a key target, and ADAMTS-5 inhibitors that can reach sufficient levels in articular cartilage are expected to exert a protective effect on cartilage in osteoarthrit is patients.

[0005] More recently, the role of ADAMTS5 has been studied in muscle disorders (Addinsall et al., 2020), liver fibrosis (Bauters et al., 2018, 2016), renal fibrosis (Collins and Wann, 2020; Taylor et al., 20 END ​​​​20) pulmonary fibrosis such as IPF (Pardo et al., 2008), and / or viruses such as influenza It has been confirmed in other diseases, including staghorn infections (McMahon et al., 2016).

[0006] In this context, a new drug is under development, and in particular, a compound according to formula (I) (5S )-Cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine-1-I [Lu]-3-oxo-propyl]imidazolidine-2,4-dione or GLPG1972 or S201086 or aldehyde yumasutat: [ka] However, it is still under development.

[0007] Formula (I) (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methylpipe [Radin-1-yl]-3-oxopropyl]imidazolidine-2,4-dione is open to WO2016 / 102347. It has been shown that this is an ADAMTS-5 inhibitor, and it is also used for inflammatory conditions, muscle diseases, and fibrosis. Disease, viral infection, and / or cartilage breakdown and / or disruption of cartilage homeostasis It may be useful in the prevention and / or treatment of diseases involving it, particularly osteoarthritis.

[0008] Various physiologically active substances (for example, but not limited to, pharmaceuticals that are usually referred to as drugs) A key characteristic of pharmaceuticals, medicines, and biocides is their "bio" "Availability" or a form that can be absorbed and utilized by a target organ or organism. This is the activity concentration at which the drug is active. In many cases, bioavailability is related to the solubility of the drug in water. Consequently, this can depend on many parameters, such as acid-basicity and / or polymorphism.

[0009] Drugs in free base form may be poorly soluble in water, but acidic sites (e.g., carboxylic acids) The presence of a phenol, sulfonic acid, or basic site (e.g., amino group, basic nitrogen center). By conveniently utilizing this, a salt of the drug can be produced. The resulting ionic Due to its ionic properties and reduced solubility, the compound is much more soluble in water. It becomes soluble, and therefore its bioavailability can be improved. A guideline of 50 μg / mL has been provided by Lipinski et al. (Lipinski et al. literature) (2001).

[0010] Numerous salt-forming agents are available, and the selection of salts must be carefully considered. The purpose of salt selection is to identify the best salt form suitable for development, mainly of four main types. Key criteria: water solubility across various pH levels, high crystallinity, low hygroscopicity, and optimal chemical stability. It is sex-based (Stahl et al., 2011).

[0011] Polymorphism is a property of the solid state of some molecules (and molecular complexes), and here we are referring to a single molecule. However, the melting point, thermal behavior using thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC), and X-ray patterns are also important. Diffraction (XRPD), infrared absorption fingerprinting, and / or solid-state ( 13 C) Determine the NMR spectrum. Diverse and distinct crystal structures with different physical properties whose characteristics can be revealed by doing so. This causes [something].

[0012] If a preferred solid form of the drug or its salt, such as a crystalline or polymorphic form, can be identified. Further investigations will be conducted, both qualitatively and quantitatively, to identify alternative solid forms. It is possible. The availability of such solid forms is highly unpredictable and intuitionless. This may require a combination of meticulous empirical design, perseverance, and serendipity. In addition to the challenges related to finding one or more distinct solid forms, this The properties of any form discovered so far, one or more of these, are actually used in drug development. It is necessary to carefully evaluate whether it is suitable for development. In fact, the first In terms of physical and mechanical properties, the crystallinity of a drug is particularly important, as is its solubility and dissolution. This may affect the velocity, fluidity, hardness, compressibility, and / or melting point. Secondly, In some cases, the crystalline form may have advantages compared to the amorphous form, for example. This could potentially make the purification process to the high purity required by most regulatory authorities more efficient. Therefore, the cost may be lower in the crystalline form than in the amorphous solid form. In addition, the handling of the crystalline form may be, for example, oily or sticky. It may be improved compared to amorphous forms, and in practice, well defined Drying crystalline materials that have a drying or desolvation temperature may, in some cases, involve contact with organic solvents. In the case of amorphous solids, which may have higher affinity and a more variable drying temperature than amorphous solids. It can be easily controlled. Finally, downstream processing of crystalline drugs is possible in some cases. Therefore, it may be possible to improve process control. In the third aspect, physical and Furthermore, the chemical stability and / or shelf life are better in the crystalline form compared to the amorphous form. It has the potential to improve.

[0013] Further pharmacokinetic and pharmacodynamic properties of a drug may depend on its specific solid or crystalline structural form. There is a possibility of a connection, and manufacturing the same form and maintaining it from manufacturing to administration to the patient is the most important thing. This will also be important. Therefore, obtaining salts and / or crystalline forms that are superior to amorphous materials is important. This is strongly desired (Hilfiker et al., 2006).

[0014] For example, drug compounds having improved stability, solubility, shelf life, and in vivo pharmacology. Because there is a consistent demand for new or purer solid forms of existing drug molecules, They continue to be criticized. [Overview of the project]

[0015] (Summary of the invention) In this specification, in particular, the solid form of the present invention, the pharmaceutical composition containing the same, and the production thereof Methods, as well as inflammatory conditions, muscle diseases, fibrous diseases, viral infections, and / or cartilage breakdown. and / or diseases involving disruption of cartilage homeostasis, particularly the prevention of osteoarthritis and Use of the solid form or composition for the purpose of treatment or therapy is provided.

[0016] Therefore, in the first embodiment, in particular, the solid form of the present invention having formula (I) - hereinafter referred to as compound 1: Formula (I) (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-pipera [Zin-1-yl]-3-oxopropyl]imidazolidined-2,4-dione: [ka] It will be provided.

[0017] In the first embodiment, the solid form of the present invention is a crystalline form. In a more specific embodiment... In another embodiment, the solid form of the present invention is anhydrous. In another embodiment, the solid form is solvated.

[0018] In another embodiment, the solid form of the present invention is amorphous. The solid form is solvated. In another aspect, the solid form is not solvated. .

[0019] In certain cases, particularly in inflammatory conditions, muscle diseases, fibrous diseases, viral infections, and / or prevention of diseases involving cartilage breakdown and / or disruption of cartilage homeostasis and / or The present invention provides a solid form for use in therapeutic applications.

[0020] Furthermore, unexpectedly, the solid state of the present invention is compared to other solid state states of compound 1. It has also been shown to show improved exposure.

[0021] In a further embodiment, in particular, the solid form of the present invention, and pharmaceutical carriers, excipients, or diluents A pharmaceutical composition comprising is provided. In a particular embodiment, the pharmaceutical composition further comprises the present invention. It may contain further therapeutic active ingredients suitable for use in combination with the solid form. In this embodiment, the further therapeutic active ingredient is used for inflammatory conditions, muscle diseases, fibrous diseases, and viral infections. Prevention of diseases involving infection and / or cartilage degradation and / or disruption of cartilage homeostasis It is a drug for the purpose of treating / or a disease.

[0022] Furthermore, the solid form of the present invention useful in pharmaceutical compositions and therapeutic methods provided herein The condition is acceptable as a pharmaceutical product at the time of preparation and use.

[0023] In further embodiments, in particular those listed herein, in particular inflammatory conditions, muscle diseases, Fibrous diseases, viral infections, and / or cartilage breakdown and / or cartilage homeostasis To treat mammals suffering from diseases selected from among those involving disruption, particularly humans. A method for obtaining an effective amount of the pharmaceutical composition or solid form of the present invention as described herein. A method is provided which includes administering the following.

[0024] In this specification, in particular, the solid form of the present invention and suitable medical use Pharmaceutical compositions comprising drug carriers, excipients, or diluents are also provided. In certain embodiments, the pharmaceutical The drug composition is used for inflammatory conditions, muscle diseases, fibrous diseases, viral infections, and / or cartilage breakdown. and / or use in the prevention and / or treatment of diseases involving disruption of cartilage homeostasis It is for practical use.

[0025] In additional embodiments, the following embodiments disclosed herein, in particular: A method for synthesizing the solid form of the present invention is provided using a typical synthesis protocol and pathway. It will be done. Other purposes and advantages will become apparent to those skilled in the art from consideration of the following detailed description. [Brief explanation of the drawing]

[0026] (Drawing description) [Figure 1] Figure 1: Powder X-ray diffraction profile of crystal morphology I [Figure 2] Figure 2: Powder X-ray diffraction profile of crystal morphology II [Figure 3] Figure 3: DSC profile of crystal morphology I [Figure 4] Figure 4: DSC profile of crystal morphology II [Figure 5]Figure 5: TGA profile of crystal morphology I [Figure 6] Figure 6: TGA profile of crystal morphology II [Figure 7] Figure 7: IR spectrum of crystal morphology I [Figure 8] Figure 8: IR spectrum of crystal morphology II [Figure 9] Figure 9: 13C solid-state NMR spectrum of crystal morphology I [Figure 10] Figure 10: 13C solid-state NMR spectrum of crystal morphology II [Figure 11] Figure 11: 15N solid-state NMR spectrum of crystal morphology I [Figure 12] Figure 12: 15N solid-state NMR spectrum of crystal morphology II [Figure 13] Figure 13: DVS profile of crystal morphology I [Figure 14] Figure 14: DVS profile of crystal morphology II [Figure 15] Figure 15: Powder X-ray diffraction profile of crystal morphology III [Figure 16] Figure 16: DSC profile of crystal morphology III [Figure 17] Figure 17: TGA profile of crystal morphology III [Figure 18] Figure 18: Powder X-ray diffraction profile of amorphous compound 1 [Figure 19] Figure 19: TGA profile of amorphous compound 1 [Figure 20] Figure 20: DSC profile of amorphous compound 1 [Figure 21] Figure 21: Urinary protein / creatinine ratios for compound 1 (group A, black circles), vehicle (group B, black squares), lisinopril (group C, upward-pointing black triangles), and sham (group D, downward-pointing black triangles). [Figure 22]Figure 22: Muscle grip strength (g / g) corrected for body weight - y-axis - Before treatment, during treatment, and at the end of treatment in a Duchenne dystrophy model (mouse MDX assay) - x-axis - For each group: vehicle (black circle), compound 1 (black square), prednisolone (upward-pointing black triangle), and compound 1 + prednisolone (downward-pointing black triangle) [Figure 23] Figure 23: Post-treatment bone volume fraction (bone volume / tissue volume, %, y axis) for the vehicle group (A), compound 1 group (B), prednisolone group (C), and prednisolone + compound 1 combination (D) (x axis) in a Duchenne dystrophy model (mouse mdx assay). [Modes for carrying out the invention]

[0027] (Detailed description of the invention) (definition) The following terms are intended to have the meanings presented below, along with the meanings presented below. This is useful in understanding the description and intended scope of the present invention.

[0028] Compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions When describing the present invention, which may encompass methods of use, the following terms, if present, are not specifically noted. Unless otherwise specified, the following meanings apply. Where used herein, the following parts are defined as The displacement can also be substituted with various substituents, and the definition of each of these substituents is that such a substituted part It should also be understood that it is intended to include within the scope shown below. Yes. Unless otherwise specified, the term “replaced” is defined as follows: The terms "base" and "radical" are interchangeable as used herein. It should be further understood that it can be considered a target.

[0029] The articles "a" and "an" in this specification refer to one or the grammatical object of the article. It can be used to refer to more than one (i.e., at least one). For example, "similar" "An analogue" means one similar thing or more similar things.

[0030] "Acceptable as a medicine" means that the use in animals, and more specifically in humans, is approved by the federal government. Approved by a regulatory authority of a prefectural or state government, or by a corresponding regulatory authority in a country other than the United States. Or it may be approved, or it may be listed in the United States Pharmacopeia or other generally accepted pharmacopoeias. It means that they are there.

[0031] A "medically acceptable salt" is one that is medically acceptable and possesses the desired pharmacological activity of the parent compound. This refers to a salt of the compound of the present invention having the following characteristics. Specifically, such a salt is non-toxic and inorganic or These can be organic acid addition salts and base addition salts. Specifically, such salts include: (1) hydrochloric acid, Formed with inorganic acids such as hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with acetic acid, propionic acid, and Xanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, Succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-Hydro) Roxybenzoyl benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid ethanolic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid , 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, can Farsulfonic acid, 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucohep Tonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, Gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucon Acid addition salts formed with organic acids such as acids; or (2) acid protons present in the parent compound , metal ions, for example alkali metal ions, alkaline earth ions, or aluminum Substituted with mu ions; or ethanolamine, diethanolamine, trie Salts formed when coordinating with organic bases such as tanolamine and N-methylglucamine. It includes, but only as an example, sodium, potassium, calcium, Magnesium, ammonium, tetraalkylammonium, etc.; and compounds with basic functional properties If it contains a substance, use hydrochloride, hydrobromide, tartrate, mesylate, acetate, or Murray Contains salts of non-toxic organic or inorganic acids such as phosphates and oxalates. "Acceptable as a medicine" The term "acceptable cation" refers to the cationic counterion of an acidic functional group. Such cations include sodium, potassium, calcium, magnesium, and ammonium. Examples include tetraalkylammonium cations.

[0032] A "pharmaceutically acceptable vehicle" is a dilution in which the compound of the present invention is administered. This refers to an agent, adjuvant, excipient, or carrier.

[0033] The terms "inert solid diluent" or "solid diluent" or "diluent" apply to tablets and / or It is used to produce capsules with appropriate dosage size, performance, and processability. It refers to a material that is used to fill. Inert solid diluents are sometimes called fillers or filler materials. Specific examples of diluents include powdered cellulose, silicified microcrystalline cellulose acetate, and pressure Condensable sugar, powdered sugar, corn starch and pregelatinized starch, dextrose, dextrose String, glucose, erythritol, ethylcellulose, fructose, fumaric acid, Glycerin lumitostearate, inhaled lactose, isomalt, kaolin, lactitol Anhydrous lactose, lactose monohydrate, and corn starch, spray-dried monohydrate Substances and microcrystalline cellulose, maltodextrin, maltose, mannitol, medium-chain triglycerides Glycerides, microcrystalline cellulose, polydextrose, polymethacrylate, simetic acid Ingredients: corn, sorbitol, pregelatinized starch, sterilizable corn, sucrose, sugar globules (sug ar sphere), sulfobutyl ether, β-cyclodextrin, talc, tragacanth, tre Examples of diluents include halos or xylitol. More specific examples of diluents include powdered sediment. Lurose, silicified microcrystalline cellulose acetate, compressible sugar, corn starch and aluminum Pre-fermented starch, glucose, fructose, glyceryl palmitostearate, anhydrous, 1 Hydrate and corn starch, spray-dried monohydrate and microcrystalline cellulose, maltodextrin Chistrin, maltose, mannitol, medium-chain triglycerides, microcrystalline cellulose, po Lidextrose, sorbitol, starch, gelatinized, sucrose, sugar globules, trehalose Examples include ce or xylitol.

[0034] "Lubricants" are prone to their components clumping together and agglomerating, and are also problematic when used in tablet presses or capsule filling machines. It refers to a material that prevents sticking. Also, lubricants ensure low solid and mold adhesion. The formation and ejection of tablets occur with friction between them and the wall. A specific example of a lubricant is... In addition, canola oil, hydrogenated castor oil, cottonseed oil, glyceryl behenate, glyceryl monostearate Lyceryl, Glyceryl Palmitostearate, Magnesium Stearate, Medium-Chain Triglycerides Ceridopropyl alcohol, mineral oil, light mineral oil, octyldodecanol, poloxamer, polyethylene glyco Polyoxyethylene stearate, polyvinyl alcohol, starch, or hardened plant Oils are one example. More specific examples of lubricants include magnesium stearate and behenic acid. Examples include glyceryl, glyceryl monostearate, or hydrogenated vegetable oil.

[0035] The "disintegrant" dissolves when wet, breaking down the tablet in the digestive tract for absorption. This refers to the material that releases the active ingredient. This means that when the tablet comes into contact with water, it disintegrates rapidly. This ensures that the material breaks down into smaller fragments, making dissolution easier. Specific examples of disintegrants These include alginic acid, powdered cellulose, chitosan, colloidal silicon dioxide, and corn. Locoside starch and pregelatinized starch, crospovidone, glycine, guar gum, low-lying starch Hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, croscarmellose Examples include melose sodium or povidone.

[0036] The term "coloring agent" refers to a chemical used to give color to a preparation. Specific examples of coloring agents include: Iron oxides, or synthetic organic dyes (US Food and Drug Administration, Federal The Code of Federal Regulations (Title 21 CFR Part 73, Subpart B) is one example. .

[0037] The terms "plasticizing agent" or "plasticizer" are used in the context of plasticization. This refers to a chemical additive used to improve the flexibility of a film or coating; a plasticizer. Specific examples include polyethylene glycol or propylene glycol.

[0038] The term "pigment" refers to an insoluble coloring agent.

[0039] "Film coating agent," "coating agent," or "coating material" The term refers to a drug used to produce a decorative or functional layer on the outer surface of a dosage form. Specific examples of film coating agents include glucose syrup and maltodextrin. Examples include ammonium compounds, alginates, or carrageenans.

[0040] A "flow enhancer" promotes the flow of powder by reducing friction and cohesive forces between particles. It refers to the material used for propulsion. This has the ability to reduce friction on the mold walls. Therefore, it is used in combination with a lubricant. Specific examples of flow promoters include powdered se Lurose, colloidal silicon dioxide, hydrophobic colloidal silica, silicon dioxide, or talc Examples include colloidal silicon dioxide, which is hydrophobic. More specific examples of flow accelerators include colloidal silicon dioxide. Examples include colloidal silica, silicon dioxide, or talc.

[0041] "Flavoring agents" mask the unpleasant taste of active ingredients, allowing patients to complete the course of drug therapy. It refers to materials that can be used to improve the acceptability of something. Fragrances are natural. This can be natural (for example, fruit extract) or artificial. Non-exclusive examples of flavorings. Examples include mint, cherry, anise, peach, apricot, licorice, raspberry, Alternatively, vanilla is another option.

[0042] A "prodrug" is a drug that has a cleavable group and can be cleaved by solvolysis or under physiological conditions. Therefore, a derivative of the compound of the present invention, which is active as a pharmaceutical in vivo, This refers to compounds containing choline esters. Such examples include, but are not limited to, choline ester compounds. Examples include conductors and N-alkylmorpholine esters.

[0043] A "solvate" is a compound that has been obtained in a form associated with a solvent through a solvolysis reaction. This refers to a physical association that includes hydrogen bonding. Common solvents include water, ethanol, and acetic acid. Examples include the compounds of the present invention, which can be prepared, for example, in crystalline form and solvated or hydrated. It is possible. Suitable solvates include pharmaceutically acceptable solvates such as hydrates, and Furthermore, it includes both stoichiometric solvates and non-stoichiometric solvates. In one example, Solvates are, for example, compounds in which one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. In that case, it may be possible to isolate it. "Solvate" encompasses both the solution phase and the isolateable solvate. Representative solvates include hydrates, ethanolates, and methanolates.

[0044] Where used herein, “solid form of the present invention” and equivalent expressions mean amorphous or This is intended to encompass crystalline compounds of the formula(s) described herein, and the expression Where circumstances permit, pharmaceutically acceptable salts and solvates, such as hydrates, and the It includes solvates of salts that are pharmaceutically acceptable. Similarly, references to intermediates are themselves patentable. Whether requested or not, if circumstances permit, include its salts and solvates. It is intended to do so.

[0045] As used herein, the terms “polymorph” or “polymorphic form” refer to multiple forms of the same molecule. It refers to the number of crystalline forms. Different polymorphic forms of a molecule refer to the arrangement or configuration of the molecule within the crystal lattice. As a result of the arrangement, they have different physical properties. Some of the different properties of the crystals include the melting temperature. Examples include heat of fusion, solubility, dissolution rate, and / or vibrational spectrum of a particular compound. The physical form is particularly important when the compound is used in a pharmaceutical formulation. This is because the different solid forms of the compound result in different properties of the drug product.

[0046] Molecular polymorphism can occur through processes such as melt-recrystallization, melt-cooling, solvent-recrystallization, solvent removal, and rapid evaporation. Many methods as demonstrated in this art, such as rapid cooling, slow cooling, vapor diffusion, and sublimation, are used. It can be obtained by law. Techniques for characterizing polymorphisms include powder X-ray diffraction (XR PD), single-crystal X-ray diffraction (XRD), differential scanning calorimetry (DSC), vibrational spectroscopy (e.g., IR and Raman). Spectroscopy, solid-state nuclear magnetic resonance (ssNMR), hot-stage optical microscopy, scanning electron microscopy (SEM) ), electron beam crystal structure analysis and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility test, and dissolution The solution test can be cited.

[0047] The term "hydrate" refers to a chemical substance formed by the interaction of water with another compound. do.

[0048] As used herein, the term “dihydrate” means a mixture of two water molecules per molecule of substrate. It refers to the hydrated substance it contains.

[0049] As used herein, the term "crystalline" means that the constituent atoms, molecules, or ions are This refers to a solid arranged in a regular, orderly, repeating pattern in three dimensions.

[0050] This specification and the claims are defined as "selected from... and..." and "is... or..." This includes a list of species that use the expression "ru". In general, unless otherwise specified, it refers to the group as a whole, or any single member thereof. It is intended to include, or any subgroup thereof. The use of this phrasing is simply an abbreviation. This is for the purpose described above and does not restrict the removal of individual elements or subgroups as needed. There was no intention behind it.

[0051] Where a scope is referred to herein, the reference to the scope refers to each member of that scope. It should be considered to be such.

[0052] "Subject" includes human beings. The terms "human being," "patient," and "subject" are defined herein. It is used interchangeably in [location].

[0053] "Effective dose" is the amount administered to a subject to treat a disease. "Effective amount" means the amount of the compound of the present invention that is sufficient to bring about the treatment of [condition]. This can vary depending on the disease and its severity, as well as the age, weight, etc. of the person being treated. ru.

[0054] "Prevention" or "prevention" means reducing the risk of acquiring or developing a disease or disability. In other words, they may be exposed to substances that cause disease, or they may have a predisposition to contract disease. This refers to preventing the development of at least one clinical symptom of the disease before the onset of the disease in the subject. vinegar.

[0055] The term "prophylaxis" is related to "prevention" and its purpose. However, measures or It refers to a treatment. Non-limited examples of preventive measures include the administration of vaccines; for example, immobility. Administration of low molecular weight heparin to hospitalized patients at risk of thrombosis due to malaria; and Prior to visiting geographical areas where local diseases are prevalent or where there is a high risk of contracting malaria, chlorocy One example is the administration of antimalarial drugs such as [specific example].

[0056] "To treat" or "treatment" of any disease or disorder is, in one embodiment, disease To improve the illness or disorder (i.e., to stop the disease or its clinical symptoms) This refers to reducing at least one sign, extent, or severity. In another embodiment, In this context, "to treat" or "treatment" is at least one that cannot be recognized by the object. This refers to improving the physical parameters of. In another embodiment, it means "to treat "To treat" or "to treat" a disease or disorder by physically adjusting it (for example, the recognizable symptoms of Stabilization) or physiological regulation (e.g., stabilization of physical parameters), It refers to both. In a further embodiment, “to treat” or “treatment” refers to the treatment of a disease. Regarding slowing down the progress.

[0057] As used herein, the term "inflammatory disease" includes rheumatoid arthritis, deformities, and other similar conditions. Idiopathic arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic respiratory diseases (for example, Asthma, rhinitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colon disease) Inflammation), conditions driven by endotoxins (e.g., complications after bypass surgery or, for example, chronic conditions) Chronic endotoxin states, which contribute to heart failure, and related diseases involving cartilage, such as joint diseases. It refers to a group of conditions that include rheumatoid arthritis, osteoarthritis, and allergies. This refers to respiratory tract diseases (e.g., asthma), chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. More specifically, the term refers to rheumatoid arthritis and osteoarthritis (OA). In this context, the term refers to osteoarthritis (OA).

[0058] As used herein, the term “muscle disease” means that an abnormal gene (mutation) is present in healthy muscles. Progressive weakness and loss of muscle mass, which hinders the production of proteins necessary for forming meat. It refers to a group of diseases that cause loss. In particular, this term refers to muscular dystrophy. More specifically, the term refers to Duchenne muscular dystrophy, Becker muscular dystrophy. Myotonic dystrophy, facioscapulohumeral dystrophy, congenital dystrophy , and / or limb-girdle dystrophy. Most specifically, the term means Duchess This refers to muscular dystrophy of the Nnu type.

[0059] As used herein, the term “fibrous disease” refers to an excess of extracellular matrix. Characterized by excessive scarring due to the production, deposition, and contraction of cells and / or fibron This is associated with abnormal accumulation of cutin and / or collagen, and / or increased fibroblast recruitment. It refers to a disease affecting, for example, the heart, kidneys, liver, joints, lungs, and pleural tissue. Fibrosis of individual organs or tissues such as peritoneal tissue, skin, cornea, retina, musculoskeletal system, and digestive tract. This means that. In particular, the term fibrotic disease refers to pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF)), Progressive fibrotic morphology of interstitial lung disease (PF-ILD), progressive nodular fibrosis (PMF), and / or cystic fibrosis. Fibrosis (CF, etc.), iatrogenic drug-induced fibrosis, occupation-induced fibrosis and / or environmentally induced fibrosis Other diffuse parenchymal lung diseases with various etiologies, including vascular diseases, granulomatous diseases (sarcoidosis, Hypersensitivity pneumonitis, collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphatic vascular disease Myomatosis, genetic disorders (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibroma) Diseases, metabolic storage disorders, familial interstitial lung disease; radiation-induced fibrosis; chronic obstructive pulmonary disease (COPD) ); Scleroderma; Bleomycin-induced pulmonary fibrosis; Chronic asthma; Silicosis; Asbestos-induced pulmonary fibrosis; Acute respiratory distress syndrome (ARDS); renal fibrosis; polycystic disease (PKD), autosomal dominant polycystic kidney disease (AD) PKD, tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy, membranous nephropathy; hypertension Hypertension; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; toxin / drug induction Hepatic fibrosis; hemochromatosis; non-alcoholic steatohepatitis (NASH); bile duct injury; primary bile duct Cirrhotic cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autoimmune hepatitis; corneal scarring Transformation; hypertrophic scarring; Dupuytren's disease, keloids, dermatofibrosis; scleroderma; systemic sclerosis Spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis; arteriosclerosis; Weghe Nørner granulomatosis; Peyronie's disease, or chronic lymphocytic disease. More specifically, the term These include idiopathic pulmonary fibrosis (IPF), progressive fibrotic interstitial lung disease (PF-ILD), IgA nephropathy, and membranous kidney disease. Focal segmental glomerulosclerosis, autosomal dominant polycystic kidney disease (ADPKD), and / or non-alcoholic glomerulosclerosis. This refers to non-alcoholic steatohepatitis (NASH).

[0060] As used herein, the term “viral infection” refers to infection caused by a virus. It refers to an infection that occurs within the body. In particular, this term is used for influenza (the fl It means u)).

[0061] As used herein, "involvement of cartilage breakdown and / or disruption of cartilage homeostasis" The term "diseases that cause" includes osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, and gouty arthritis. Arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy Painful osteodystrophy, achondroplasia, Paget's disease, Tietze syndrome, or costochondritis, Fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, Amylosis, hydarthrosis, periodic disease, Endemic forms of arthritis such as rheumatic spondylitis and endemic osteoarthritis, as well as Museren's disease and Handicap disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, This includes conditions such as scleroderma and ankylosing spondylitis. More specifically, the term refers to degenerative conditions. It means osteoarthritis (OA).

[0062] "The compound(s) of the present invention" and equivalent expressions refer to the compound(s) of the formula(s) described herein. This expression, meaning to include a compound, is acceptable in medical contexts. This includes salts and solvates, such as hydrates, and pharmaceutically acceptable solvates of salts. Similarly, references to intermediates are included regardless of whether they themselves are claimed. This means, where permissible in the context, to include their salts and solvates.

[0063] In this specification, for example, but not limited to, C 1-8 The range of alkyl groups is Where applicable, a citation of a scope should be considered an indication of each member of that scope.

[0064] Other derivatives of the compound of the present invention are active in both their acid and acid derivative forms, However, acid-sensitive forms are often soluble, histocompatibility, or delayed-release in mammals. This offers the advantage of (Bundgard, H., literature (1985)). Prodrugs are, for example, preferably with a hydrophilic acid. Esters prepared by reaction with alcohols, or substituted or unsubstituted with hydrophilic compounds. Amides, or acid anhydrides, or mixed anhydrides, prepared by reaction with amines, It includes acid derivatives well known to experts in the field. Derived from the acidic group attached to the compound of the present invention. Simple aliphatic or aromatic esters, amides, and anhydrides are particularly useful prodrugs. Yes. In some cases, (acyloxy)alkyl ester or ((alkoxycarbonyl) It is desirable to prepare a biester-type prodrug such as an oxy)alkyl ester. . Certain such prodrugs are C of the compound of the present invention. 1-8 Alkyl, C 2-8 Alkenil , arbitrarily substituted C 6-10 Aryl, and (C 6-10 Ariel)-(C 1-4 Alkyl ester ru.

[0065] The present disclosure provides that (i) all atoms of a given atomic number are in a form having the mass number (or multiple predominant in nature (referred to herein as "natural isotope form"), or ( ii) one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of the atoms predominant in nature (referred to herein as "non-natural variant isotope form"), includes all isotope forms of the compounds of the present invention provided herein. It is recognized that an atom may naturally exist as a mixture of multiple mass numbers. The term "non-natural variant isotope form" also refers to atoms of a given atomic number that have a less common mass number in nature (referred to herein as "uncommon isotope") is understood. Furthermore, the term "non-natural variant isotope form" refers to the ratio of atoms of a given atomic number having a mass number that is not more common in nature (herein, referred to as "uncommon isotope") is understood. In addition, the term "non-natural variant isotope form" means that the ratio of uncommon isotopes, compared to that occurring in nature, is increased, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% by the number of atoms of that atomic number atoms of a given atomic number that have a mass number not commonly found in nature (referred to herein as "uncommon isotope") referred to as) is increased compared to that occurring in nature, for example, by the number of atoms of that atomic number increased to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the embodiments including the forms (the latter embodiment is referred to as "isotopically enriched variant form"). Also, the term "non-natural variant isotope form" also includes embodiments in which the ratio of uncommon isotopes is reduced compared to that occurring in nature. Isotope forms can include radioactive forms (i.e., which incorporate radioisotopes) and non-radioactive forms. Radioactive embodiments in which the content is reduced compared to that existing in nature are also included. Isotope forms may include radioactive forms (namely, which incorporate radioisotopes) and non-radioactive forms. Radioactive that is, which incorporates radioisotopes, and non-radioactive forms. Radioactive the active form is usually an isotopically enriched variant form.

[0066] Accordingly, non-natural variant isotope forms of the compounds include, at one or more atoms, one or more deuterium( 2 H or D), carbon-11( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15 ( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), salt Element-36( 36 Cl), Chlorine-37( 37 Cl), Fluorine-18( 18 F), Iodine-123( 123 I) Iodine-125 125 I) Na It may contain any artificial or uncommon isotope, or in one or more atoms The product may contain the isotope in a ratio that is increased compared to the ratio that is dominant in nature.

[0067] Non-natural variant isotopic forms containing radioactive isotopes are, for example, those of drugs and / or substrates. It can be used in tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14 That is to say 14 C considers that their acquisition is easy and that detection means are available. Therefore, it is particularly useful for this purpose. Deuterium, that is, 2 Non-H or D Natural variant isotope forms exhibit higher metabolic stability, for example, an increased in vivo half-life. Alternatively, it may result in certain therapeutic benefits arising from a reduced required dose, and therefore, in some cases, In some cases, this can even be advantageous. Furthermore, 11 C, 18 F, 15 O, and 13 Positron-emitting isotopes such as N The incorporated non-natural variant isotope form may be prepared, which increases the substrate receptor occupancy. In positron emission topography (PET) tests used for investigation It will be useful.

[0068] They have the same molecular formula, but the properties or arrangement of the bonds between their atoms, or the relationship between their atoms It should also be understood that compounds with different spatial arrangements are called "isomers." Isomers that have different arrangements of atoms in space are called "stereoisomers."

[0069] Stereoisomers that are not mirror images of each other are called "diastereomers," and their superposition is also called diastereomers. Stereoisomers, which are mirror images that cannot be mirrored, are called "enantiomers." If it has a center, for example, if it is bonded to four different bases, then it is a set of enantioms. Omers are possible. Enantiomers are characterized by the absolute configuration of their chiral centers. This can be done and is described by the R- and S-order rules of Kahn and Prelogue, or the numerator The plane of polarization rotates in a manner that is either dextrorotatory or levorotatory (i.e., (+) or (+) respectively). A can be named and characterized as a (-)-isomer. Chiral compounds are characterized by their individual enantivities. They can exist as omers or as mixtures thereof. Enantiomers in the same proportion The mixture it contains is called a "racemic mixture."

[0070] A "tautomer" is an interchangeable form of a specific compound structure, and involves the substitution of hydrogen atoms and electrons. This refers to compounds that differ in terms of position. Therefore, the two structures differ in the transfer of π electrons and atoms (usually H). Equilibrium can be reached through dynamics. For example, enols and ketones can be either acidic or base. Because it is rapidly interconverted by processing, it is a tautomer. Other examples of tautomerism These are the acid and nitro forms of phenylnitromethane, and these can be treated with an acid or a base. It is formed similarly by principle.

[0071] Tautomeristic forms may be related to achieving optimal chemical reactivity and biological activity of the target compound. ru.

[0072] The compounds of the present invention may have one or more chiral centers; therefore, such compounds They can be produced as individual (R)- or (S)-stereoisomers, or as mixtures thereof.

[0073] Unless otherwise indicated, the description or description of specific compounds in this specification and claims is not accurate. The names refer to the individual enantiomers and their mixtures, whether racemic or not. It is intended to include both of the following: for determining stereochemistry and separating stereoisomers. The law is well known in this field.

[0074] It is recognized that the compound of the present invention can be metabolized to produce biologically active metabolites. It is likely.

[0075] (This invention) In this specification, in particular, (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluor [Lopenyl)-3-methylpiperazine-1-yl]-3-oxopropyl]imidazolidine-2,4-di The solid form of ON, as well as pharmaceutical compositions containing the same and methods for producing the same, and inflammatory conditions, muscle diseases Diseases, fibrous diseases, viral infections, and / or cartilage breakdown and / or cartilage homeostasis For the prevention and / or treatment of diseases involving cis disruption, particularly osteoarthritis, the solid form Use of a state or composition is provided. [ka]

[0076] In one embodiment, the solid form of the present invention is amorphous.

[0077] In one embodiment, the solid form of the present invention is a crystalline form.

[0078] In one embodiment, the solid form of the present invention is a solvate. In a specific embodiment... The solid form of the present invention is a hydrate or a dihydrate. In a more specific embodiment, the present invention The solid form of Ming is a dihydrate.

[0079] In one embodiment, the solid form of the present invention is not solvated. In a specific embodiment... Furthermore, the solid form of the present invention is anhydrous.

[0080] In one embodiment, the solid form of the present invention is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5- [Difluorophenyl)-3-methyl-piperazine-1-yl]-3-oxopropyl]imidazolidine This is the dihydrate form (form I) of -2,4-zion. In the most specific embodiment, the solid form of the present invention The morphology is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-p Crystalline dihydrate form of perazin-1-yl-3-oxopropyl-imidazolidin-2,4-dione (Form I)

[0081] In another embodiment, the solid form of the present invention is (5S)-cyclopropyl-5-[3-[(3S)-4-(3, 5-Difluorophenyl)-3-methylpiperazine-1-yl]-3-oxopropyl]imidazolid This is the anhydrous form (form II) of n-2,4-dione. In the most specific embodiment, the present invention is solid The morphology is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-p Perazine-1-yl-3-oxopropyl-imidazolidin-2,4-dione in crystalline anhydrous form (form This is state II.

[0082] (Amorphous form) In one embodiment, the solid form of the present invention is amorphous. The solid form of the present invention is characterized by a powder X-ray diffraction pattern substantially consistent with that shown in Figure 18.

[0083] In one embodiment, the solid form of the present invention is amorphous and substantially the same as Figure 20. The resulting DSC curve is a further distinguishing feature.

[0084] In one embodiment, the solid form of the present invention is amorphous and substantially the same as Figure 18. It features a powder X-ray diffraction pattern that matches and a DSC curve that substantially matches Figure 20.

[0085] (polymorphic form I) Provided herein, in particular, is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluor [Lopenyl)-3-methylpiperazine-1-yl]-3-oxopropyl]imidazolidine-2,4-di It is the dihydrate solid form of ON. In another embodiment, the solid form of the present invention is crystalline. There is (Form I). In yet another embodiment, the solid form of the present invention is crystalline (Form I) and characterized by one or more of the parameters described in more detail below. It is possible.

[0086] In one embodiment, the solid form of the present invention is polymorphic form I, and the following positions: 6.2, 1 2.5, 14.1, 14.6, 15.6, 15.7, 17.8, 18.0, 18.8, 19.1, 19.7, 20.8, 21.4, 22.4, 25. Powder X-ray diffraction patterns having one or more peaks at 2, 26.4, 28.9, or 29.0 ± 0.2° 2θ This can be considered a characteristic.

[0087] In the most specific embodiment, the solid form of the present invention is polymorphic form I, and the following Position: 6.2, 12.5, 14.1, 14.6, 15.6, 15.7, 17.8, 18.0, 18.8, 19.1, 19.7, 20.8, 21.4 Powder X-rays with one or more peaks at 22.4, 25.2, 26.4, 28.9, or 29.0 ± 0.2° 2θ It may be characterized by a folding pattern and a powder X-ray diffraction pattern substantially as shown in Figure 1.

[0088] In a particular embodiment, the solid form of the present invention is polymorph I, and is located at position 6. 2, 12.5, 14.1, 14.6, 15.6, 15.7, 17.8, 18.0, 18.8, 19.1, 19.7, 20.8, 21.4, 22.4 , 25.2, 26.4, 28.9, or 29.0 ± 0.2° 2θ at least 1, 5, 10, 15 or more It may be characterized by a powder X-ray diffraction pattern having a peak.

[0089] In a particular embodiment, the solid form of the present invention is polymorph I, and is at position 6. Powder X-ray diffraction pattern with peaks at 2, 12.5, 15.7, 19.1, 25.2, and 26.4 ± 0.2° 2θ It can be characterized by [something].

[0090] In a particular embodiment, the solid form of the present invention is polymorph I, and is at position 6. It has peaks at 2, 12.5, 14.1, 15.7, 19.1, 21.4, 22.4, 25.2, and 26.4 ± 0.2° 2θ. The powder X-ray diffraction pattern can be used as a characteristic feature.

[0091] In a particular embodiment, the solid form of the present invention is polymorph I, and is at position 6. 2, 12.5, 14.1, 14.6, 15.6, 15.7, 17.8, 18.0, 18.8, 19.1, 19.7, 20.8, 21.4, 22.4 It is characterized by a powder X-ray diffraction pattern having peaks at 25.2, 26.4, 28.9, and 29.0 ± 0.2° 2θ. It is possible.

[0092] In one embodiment, the solid form of the present invention is polymorphic form I, and is substantially shown in Figure 1. The present invention may be characterized by a powder X-ray diffraction pattern such as the one described above. In certain embodiments, the present invention The solid form is polymorphic form I, further characterized by the DSC profile shown in Figure 3. In this embodiment, the solid form of the present invention is polymorphic form I, and the TGA profile of Figure 5 It will be a further feature.

[0093] (polymorphic form II) Provided herein, in particular, is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluor [Lopenyl)-3-methylpiperazine-1-yl]-3-oxopropyl]imidazolidine-2,4-di It is an anhydrous solid form of ON. In another embodiment, the solid form of the present invention is crystalline. (Form II). In yet another embodiment, the solid form of the present invention is crystalline (Form I). I) and characterized by one or more of the parameters described in more detail below. It is possible.

[0094] In one embodiment, the solid form of the present invention is polymorphic form II, and the following position: 8.5, 10.3, 12.6, 13.2, 13.6, 14.7, 15.3, 15.7, 16.7, 18.3, 18.6, 20.3, 20.8, 22.9, 24 The powder X-ray diffraction pattern is characterized by having one or more peaks at 0.5, 27.2, or 30.4±0.2° 2θ. It is possible.

[0095] In one embodiment, the solid form of the present invention is polymorphic form II, and the following position: 8.5, 10.3, 12.6, 13.2, 13.6, 14.7, 15.3, 15.7, 16.7, 18.3, 18.6, 20.3, 20.8, 22.9, 24 At 0.5, 27.2, or 30.4±0.2° 2θ, there are at least 1, 5, 10, 15 or more peaks. It may be characterized by a powder X-ray diffraction pattern having the following characteristics.

[0096] In one embodiment, the solid form of the present invention is polymorphic form II, and the following position: 10.3 It is characterized by a powder X-ray diffraction pattern with peaks at 15.3, 15.7, 16.7, and 18.6±0.2° 2θ. obtain.

[0097] In one embodiment, the solid form of the present invention is polymorphic form II, and the following position: 10.3 Powder X-ray diffraction pattern with peaks at 15.3, 15.7, 16.7, 18.6, 24.5, and 30.4±0.2° 2θ It can be characterized by [something].

[0098] In one embodiment, the solid form of the present invention is polymorphic form II, and the following position: 8.5, 10.3, 12.6, 13.2, 13.6, 14.7, 15.3, 15.7, 16.7, 18.3, 18.6, 20.3, 20.8, 22.9, 24 The powder X-ray diffraction pattern may be characterized by peaks at 0.5, 27.2, and 30.4, ±0.2° 2θ. .

[0099] In one embodiment, the solid form of the present invention is polymorphic form II, and is substantially shown in Figure 2. The present invention may be characterized by a powder X-ray diffraction pattern such as the one described above. In certain embodiments, the present invention The solid form is polymorphic form II, further characterized by the DSC profile shown in Figure 4. In a particular embodiment, the solid form of the present invention is polymorphic form II, and the TGA form shown in Figure 6 This adds another feature to the rofile.

[0100] (polymorphic form III) Provided herein, in particular, is (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluor [Lopenyl)-3-methylpiperazine-1-yl]-3-oxopropyl]imidazolidine-2,4-di It is an ON solid form. In another embodiment, the solid form of the present invention is crystalline ( (Form III). In yet another embodiment, the solid form of the present invention is crystalline (Form III). ), and characterized by one or more of the parameters described in more detail below can.

[0101] In one embodiment, the solid form of the present invention is polymorphic form III, and the position is as follows: 9.0 , 11.0, 11.4, 14.2, 15.0, 16.4, 16.6, 17.5, 18.1, 18.6, 18.8, 19.3, 20.0, 20.5, It has one or more peaks at 21.7, 22.4, 23.4, 23.8, 26.2, 26.6, or 27.8±0.2° 2θ. The powder X-ray diffraction pattern can be used as a characteristic feature.

[0102] In a particular embodiment, the solid form of the present invention is polymorphic form III, and in the following positions: 9.0, 11.0, 11.4, 14.2, 15.0, 16.4, 16.6, 17.5, 18.1, 18.6, 18.8, 19.3, 20.0, 20. 5, 21.7, 22.4, 23.4, 23.8, 26.2, 26.6, or 27.8±0.2° 2θ at least 1, 5, 10, The powder X-ray diffraction pattern may be characterized by having 15 or more peaks.

[0103] In a particular embodiment, the solid form of the present invention is polymorphic form III, and in the following positions: Powder X-ray diffraction pattern with peaks at 11.0, 16.6, 17.5, 18.8, 20.5, and 22.4 ± 0.2° 2θ It can be characterized by its design.

[0104] In a particular embodiment, the solid form of the present invention is polymorphic form III, and in the following positions: 9.0, 11.0, 14.2, 16.4, 16.6, 17.5, 18.6, 18.8, 20.5, 22.4, 23.4, and 26.2, ±0.2 The powder X-ray diffraction pattern may be characterized by a peak at ° 2θ.

[0105] In a particular embodiment, the solid form of the present invention is polymorphic form III, and in the following positions: 9.0, 11.0, 11.4, 14.2, 15.0, 16.4, 16.6, 17.5, 18.1, 18.6, 18.8, 19.3, 20.0, 20. Powder X has peaks at 5, 21.7, 22.4, 23.4, 23.8, 26.2, 26.6, and 27.8±0.2° 2θ. It can be characterized by its linear diffraction pattern.

[0106] In one embodiment, the solid form of the present invention is polymorphic form III, and is substantially as shown in Figure 15. The powder X-ray diffraction pattern may be characterized as shown. In a particular embodiment, the original The solid form of Akira is polymorphic form III, and is further characterized by the DSC profile shown in Figure 16. In a more specific embodiment, the solid form of the present invention is polymorphic form III, and T in Figure 17. It is further characterized by a GA profile.

[0107] (Pharmaceutical Composition) In some embodiments, the solid forms disclosed herein can be contained in a solid dosage form such as a tablet . For example, in some embodiments, the solid forms disclosed herein can be provided in a tablet in an amount ranging from 50 mg to 1000 mg. In some embodiments, a tablet comprising 50 mg to 1000 mg of polymorph Form I is provided. In some em bodiments, a tablet comprising 50 mg to 1000 mg of polymorph Form II is provided. In some embod iments, a tablet comprising 50 mg to 1000 mg of polymorph Form III is provided. In some embod iments, a tablet comprising 50 mg to 1000 mg of an amorphous form is provided.

[0108] In one embodiment, there is provided herein, in particular, a pharmaceutical composition comprising the solid form of the present invention and an inert solid diluent . In certain embodiments, there is provided herein, in particular, a pharmaceutical composition comprising 29 to 31 wt% of polymorph Form I and 42 to 43 wt% of an inert solid diluent. In certain embodiments, the solid form of the present invention is polymorph Form I or polymorph Form II. In another specific embodiment, the inert solid diluent is lactose monohydrate. .

[0109] In one embodiment, there is provided herein, in particular, a pharmaceutical composition comprising the solid form of the present invention, a first inert solid diluent, and a second inert solid diluent. In certain embodiments , there is provided herein, in particular, 29 to 31 wt% of polymorph Form I, 42 to 43 wt% of the first inert A pharmaceutical composition is provided comprising a solid diluent and a second inert diluent in an amount of 19.5 to 20.5 wt%. In certain embodiments, the solid form of the present invention is polymorphic form I or polymorphic form II. In a particular embodiment, the first inert solid diluent is lactose monohydrate. In another, more specific embodiment, the first inert solid diluent is corn starch It is.

[0110] In one embodiment, as described herein, in particular, the solid form of the present invention, the first inert solid A pharmaceutical composition comprising a diluent and a second inert solid diluent is provided. In a particular embodiment, In this specification, in particular, 29-31 wt% of polymorph I and 42-43 wt% of the first inert form It contains a solid diluent, 19.5-20.5 wt% of a second inert diluent, and 6.5-7.5 wt% of a disintegrant. A pharmaceutical composition is provided. In a particular embodiment, the solid form of the present invention is polymorphic form I or polymorphic form II. In a more specific embodiment, the first inert solid diluent is It is cotose monohydrate. In another, more specific embodiment, the first inert solid dilution The agent is corn starch. In yet another, more specific embodiment, the disintegrant It is povidone.

[0111] In one embodiment, as described herein, in particular, the solid form of the present invention, the first inert solid A pharmaceutical composition comprising a diluent and a second inert solid diluent is provided. In a particular embodiment, In this specification, in particular, 29-31 wt% of polymorph I and 42-43 wt% of the first inert form Solid diluent, 19.5-20.5 wt% second inert diluent, 6.5-7.5 wt% disintegrant, and 0.15 A pharmaceutical composition comprising up to ~0.25 wt% of a glidant is provided. In certain embodiments, the solid form of the present invention is polymorph Form I or polymorph Form II. In more specific embodiments, the first inert solid diluent is lactose monohydrate. In another more specific embodiment , the first inert solid diluent is corn starch. In yet another more specif ic embodiment, the disintegrant is povidone. In yet another more specific embodiment , the glidant is colloidal silicon dioxide.

[0112] In certain embodiments, herein, in particular, by weight: 1) 29 to 31 wt% of the solid form of the present invention 2) 42 to 43 wt% of lactose monohydrate 3) 19.5 to 20.5 wt% of corn starch 4) 6.5 to 7.5 wt% of povidone 5) 0.15 to 0.25 wt% of colloidal silicon dioxide 6) 0.4 to 0.6 wt% of magnesium stearate A pharmaceutical composition comprising the above is provided.

[0113] In certain embodiments, herein, in particular, by weight: 1) About 30 wt% of the solid form of the present invention 2) About 42.3 wt% of lactose monohydrate 3) About 20 wt% of corn starch 4) About 7 wt% of povidone 5) About 0.2 wt% of colloidal silicon dioxide 6) About 0.5 wt% of magnesium stearate A pharmaceutical composition comprising the above is provided.

[0114] In certain embodiments, herein, in particular, by weight: 1) Polymorph II of 29-31 wt% 2) 42-43 wt% lactose monohydrate 3) 19.5-20.5 wt% corn starch 4) 6.5-7.5 wt% povidone 5) 0.15-0.25 wt% colloidal silicon dioxide 6) 0.4-0.6 wt% magnesium stearate A pharmaceutical composition containing the following is provided.

[0115] In a particular embodiment, as described herein, in particular, by weight: 1) Polymorph II, approximately 30 wt% 2) Approximately 42.3 wt% lactose monohydrate 3) Approximately 20 wt% corn starch 4) Approximately 7 wt% povidone 5) Approximately 0.2 wt% colloidal silicon dioxide 6) Approximately 0.5 wt% magnesium stearate A pharmaceutical composition containing the following is provided.

[0116] In one embodiment, as described herein, the solid form and inert solid dilution of the present invention are particularly discussed. A pharmaceutical composition containing an agent is provided. In particular, in this embodiment, A pharmaceutical composition is provided comprising 49-51 wt% of polymorph I and 22-23 wt% of an inert solid diluent. In a particular embodiment, the solid form of the present invention is polymorphic form I or polymorphic form II. In another specific embodiment, the inert solid diluent is lactose monohydrate. .

[0117] In one embodiment, as described herein, in particular, the solid form of the present invention, the first inert solid A pharmaceutical composition comprising a diluent and a second inert solid diluent is provided. In a particular embodiment, In this specification, in particular, 49-51 wt% of polymorph I and 22-23 wt% of the first inert A pharmaceutical composition is provided comprising a solid diluent and a second inert diluent in an amount of 19.5 to 20.5 wt%. In certain embodiments, the solid form of the present invention is polymorphic form I or polymorphic form II. In a particular embodiment, the first inert solid diluent is lactose monohydrate. In another, more specific embodiment, the first inert solid diluent is corn starch It is.

[0118] In one embodiment, as described herein, in particular, the solid form of the present invention, the first inert solid A pharmaceutical composition comprising a diluent and a second inert solid diluent is provided. In a particular embodiment, In this specification, in particular, 49-51 wt% of polymorph I and 22-23 wt% of the first inert It contains a solid diluent, 19.5-20.5 wt% of a second inert diluent, and 6.5-7.5 wt% of a disintegrant. A pharmaceutical composition is provided. In a particular embodiment, the solid form of the present invention is polymorphic form I or polymorphic form II. In a more specific embodiment, the first inert solid diluent is It is cotose monohydrate. In another, more specific embodiment, the first inert solid dilution The agent is corn starch. In yet another, more specific embodiment, the disintegrant It is povidone.

[0119] In one embodiment, as described herein, in particular, the solid form of the present invention, the first inert solid A pharmaceutical composition comprising a diluent and a second inert solid diluent is provided. In a particular embodiment, In this specification, in particular, 49-51 wt% of polymorph I and 22-23 wt% of the first inert Solid diluent, 19.5-20.5 wt% second inert diluent, 6.5-7.5 wt% disintegrant, and 0.15 A pharmaceutical composition containing ~0.25 wt% of a flow promoter is provided. In a particular embodiment, The solid form of the present invention is polymorphic form I or polymorphic form II. In a more specific embodiment, The first inert solid diluent is lactose monohydrate. In another, more specific embodiment... In this case, the first inert solid diluent is corn starch. Furthermore, another more specific In one particular embodiment, the disintegrant is povidone. In yet another, more specific embodiment... In this case, the flow accelerator is colloidal silicon dioxide.

[0120] In a particular embodiment, as described herein, in particular, by weight: 1) Solid form of the present invention at 49-51 wt% 2) 22-23 wt% lactose monohydrate (diluent) 3) 19.5-20.5 wt% corn starch (diluent) 4) 6.5-7.5 wt% povidone (disintegrant) 5) 0.15-0.25 wt% colloidal silicon dioxide (flow enhancer) 6) 0.4-0.6 wt% magnesium stearate (lubricant) A pharmaceutical composition containing the following is provided.

[0121] In a particular embodiment, as described herein, in particular, by weight: 1) The solid form of the present invention at approximately 50 wt% 2) Approximately 22.3 wt% lactose monohydrate 3) Approximately 20 wt% corn starch 4) Approximately 7 wt% povidone 5) Approximately 0.2 wt% colloidal silicon dioxide 6) Approximately 0.5 wt% magnesium stearate A pharmaceutical composition containing the following is provided.

[0122] In a particular embodiment, as described herein, in particular, by weight: 1) Polymorph II of 49-51 wt% 2) 22-23 wt% lactose monohydrate (diluent) 3) 19.5-20.5 wt% corn starch (diluent) 4) 6.5-7.5 wt% povidone (disintegrant) 5) 0.15-0.25 wt% colloidal silicon dioxide (flow enhancer) 6) 0.4-0.6 wt% magnesium stearate (lubricant) A pharmaceutical composition containing the following is provided.

[0123] In a particular embodiment, as described herein, in particular, by weight: 1) Polymorph II, approximately 50 wt% 2) Approximately 22.3 wt% lactose monohydrate 3) Approximately 20 wt% corn starch 4) Approximately 7 wt% povidone 5) Approximately 0.2 wt% colloidal silicon dioxide 6) Approximately 0.5 wt% magnesium stearate A pharmaceutical composition containing the following is provided.

[0124] When used as a pharmaceutical, the compounds of the present invention are usually administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical field, and less than the amount of formula I Each may contain one active compound of the present invention. Typically, the compounds of the present invention are used as pharmaceuticals. It is administered in an effective amount. The amount of the compound of the present invention actually administered is typically the amount used to treat. The state in which it occurs, the selected route of administration, the actual compound of the present invention administered, and the individual patient's age. The decision will be made by a physician, taking into consideration relevant circumstances including age, weight, response, and the severity of the patient's symptoms. It is determined.

[0125] The pharmaceutical compositions of the present invention can be administered orally, rectally, transdermally, subcutaneously, intra-articularly, intravenously, intramuscularly, and nasally. It can be administered via various routes, including internally. Depending on the intended delivery route, this product The compounds are preferably used as injection or oral compositions, or entirely for transdermal administration. It is formulated as an ointment, lotion, or patch.

[0126] Compositions for oral administration may take the form of a bulk liquid solution or suspension, or a bulk powder. It is possible. However, more generally, the composition facilitates accurate medication administration. It is provided in unit dosage form for human and other mammalian use. The term "unit dosage form" is used for human and other mammalian use. This refers to physically distinct units suitable as unit dosages, where each unit is a suitable pharmaceutical excipient. A predetermined amount of active ingredients, calculated to produce the desired therapeutic effect, associated with the vehicle or carrier. Contains properties material. Typical unit dosage forms include pre-filled and pre-measured liquid compositions. Examples include ampoules or syringes, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound of the present invention according to formula I is usually less The components are (approximately 0.1 to 50 wt%, or preferably about 1 to 40 wt%), and the remainder is various vehicles Alternatively, it serves as a carrier and a processing aid that helps form the desired drug delivery form.

[0127] A liquid form suitable for oral administration contains buffers, suspenders and dispersants, colorants, flavorings, etc. It may contain a suitable aqueous or non-aqueous vehicle. The solid form may consist of, for example, the following components: Binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, For example, starch or lactose, disintegrants, such as alginic acid, Primogel, etc. or corn starch; lubricants, for example, magnesium stearate; flow promoters, For example, colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or A flavoring agent, for example, either peppermint or orange flavoring, or a similar flavoring. The compounds of the present invention may contain the properties of the present invention.

[0128] The injectable composition is typically a sterile saline solution or phosphate buffer known in the art for injection. Based on physiological saline or other injectable carriers. As described above, the composition of formula I in such a composition The active compound of the present invention typically contains fewer components, often in the form of about 0.05 to 10 wt%. The rest are things like injection carriers.

[0129] The transdermal composition typically contains the active ingredient in an amount of about 0.01 to about 20 wt%, preferably about 0.1 Approximately 20 wt%, preferably in the range of approximately 0.1 to approximately 10 wt%, more preferably in the range of approximately 0.5 to approximately 15 wt%. It is formulated as a topical ointment or cream containing the amount of [amount]. In such cases, the active ingredient is usually combined with either a paraffinic ointment base or a water-miscible ointment base. They are combined. Alternatively, the active ingredient is, for example, in the cream together with an oil-in-water cream base. It can be formulated as such. Such transdermal formulations are well known in the art and are usually active Includes additional ingredients that enhance the skin penetration or stability of the ingredient or formulation. All such publicly known The transdermal preparations and components are included within the scope of the present invention.

[0130] The compound of the present invention can also be administered by a transdermal device. Therefore, transdermal administration is possible. This can be achieved using a patch agent of either a storage tank type, a porous membrane type, or a solid matrix type. It is possible.

[0131] The above components for orally administered, injectable, or topically administered compositions are representative. This is merely a general description. Other materials and processing techniques are incorporated herein by reference. This is included in Remington's Pharmaceutical Sciences, 17th edition, 198. 5. It is listed in Part 8 of Mack Publishing Company, Easton, Pennsylvania.

[0132] The compounds of the present invention can also be administered in a sustained-release form or via a sustained-release drug delivery system. A typical explanation of sustained-release materials can be found in Remington's Pharmaceutica. It can be found in (L Sciences).

[0133] The following examples illustrate typical pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0134] (Formulation 1 - Tablets) The compound of the present invention according to formula I, as a dry powder, is mixed with a dry gelatin binder in a weight ratio of approximately 1:2. It can be mixed. A small amount of magnesium stearate can be added as a lubricant. Yes, it is possible. The mixture can be compressed into 240-270 mg tablets (75 mg of the activated compound of the present invention according to Formula I per tablet) using a tablet press. It can be molded into an object.

[0135] (Formulation 2 - Capsule) The compound of the present invention according to formula I is mixed with a starch diluent in a dry powder form at a weight ratio of approximately 1:1. This can be done. The mixture can be taken into 250 mg capsules (125 mg per capsule according to Formula I of the present invention). It can be filled into the active compound.

[0136] (Formulation 3 - Liquid formulation) The compound of the present invention according to formula I (125 mg) is mixed with sucrose (1.75 g) and xanthan gum (4 mg). This can be done, and the resulting mixture can be blended into a No. 10 mesh US sieve. After passing through, the previously prepared microcrystalline cellulose and carboxymethylcellulose are added. It can be mixed with an aqueous solution of sodium (11:89, 50 mg). Sodium benzoate (10 mg) Fragrances and colorants can be diluted with water and added while stirring. After that, sufficient Water can be added while stirring. Then, add more water to make 5 mL It can generate total capacity.

[0137] (Formulation 4 - Tablets) The compound of the present invention according to formula I, as a dry powder, is mixed with a dry gelatin binder in a weight ratio of approximately 1:2. It can be mixed. A small amount of magnesium stearate can be added as a lubricant. Yes, it is possible. The mixture can be compressed into 450-900 mg tablets (150-300 mg of the active compound according to Formula I of the present invention) using a tablet press. It can be molded into this form.

[0138] (Example - Tablets) Compound 1 (50g), lactose monohydrate (22.5g), microcrystalline cellulose (23g), colloidal Weigh out 0.5g of anhydrous silica and 3g of croscarmellose sodium, and then apply a suitable amount to the following containers. Transfer to a bowl and mix.

[0139] The resulting powder is dry-granulated using roller compression. The granules are then sieved through a 500 μm sieve. Next, add magnesium stearate (0.5g) and mix.

[0140] Next, the final mixture is compressed into tablets using a tablet press with a force of ±20N.

[0141] (Formulation 5 - Injectable) The compound of the present invention according to Formula I is added to an aqueous injection medium of buffered sterile physiological saline at a concentration of approximately 5 mg / mL. It can be dissolved or suspended down to a certain degree.

[0142] (Formulation 6 - Topical Agent) Stearyl alcohol (250g) and white petrolatum (250g) can be melted at approximately 75°C. Subsequently, the compound of the present invention according to formula I (50g) and methylparaben (0.2g) were dissolved in water (approximately 370g). 5g), propylparaben (0.15g), sodium lauryl sulfate (10g), and propylene glyco You can add the mixture (120g) and stir the resulting mixture until it solidifies. It is possible.

[0143] (Treatment methods) In one embodiment, the present invention is for use in the prevention and / or treatment of inflammatory diseases. The present invention provides a compound of the present invention, or a pharmaceutical composition containing a compound of the present invention. In particular, the term is Rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing vertebra Inflammation, allergic respiratory diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease Diseases (e.g., Crohn's disease, ulcerative colitis), conditions driven by endotoxins (e.g., bipolar disorder) Postoperative complications or, for example, chronic endotoxin conditions that contribute to chronic heart failure, and joint problems It refers to diseases and related conditions involving cartilage. More specifically, the term refers to rheumatoid arthritis. Malignant arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease (e.g., chlorosis). This refers to ulcerative colitis.

[0144] In another embodiment, the present invention relates to the production of pharmaceuticals for the prevention and / or treatment of inflammatory diseases. The present invention provides for the use of the compound of the present invention, or a pharmaceutical composition containing the compound of the present invention. The term in question refers to rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis. Ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD) , inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), endotoxin-driven conditions (e.g.) For example, complications after bypass surgery or, for instance, a chronic endotoxin state that contributes to chronic heart failure. This refers to cartilage-related diseases, such as joint disorders. More specifically, the term This includes rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. For example, it refers to Crohn's disease, ulcerative colitis, etc.

[0145] In an additional method of treatment, the present invention relates to the prevention of mammals suffering from inflammatory diseases. and / or a method of treatment comprising an effective amount of the compound of the present invention for the treatment or prevention of the disease. The method provides comprising administering one or more substances or pharmaceutical compositions described herein. In particular, the term refers to rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, and dysplasia. Atherosclerotic arthritis, ankylosing spondylitis, allergic respiratory diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease Diseases (COPD), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), and endotoxins are driven by Conditions that cause chronic heart failure (for example, complications after bypass surgery or chronic heart failure) This refers to toxin-related conditions, and related diseases involving cartilage, such as joint disorders. More specifically, The term refers to rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), and inflammation. It refers to intestinal diseases (for example, Crohn's disease, ulcerative colitis).

[0146] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Provided. In a particular embodiment, the other therapeutic agent is an inflammatory disease treatment agent. The term in question is used in relation to rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, and psoriatic arthritis. Inflammation, ankylosing spondylitis, allergic airway diseases (e.g., asthma, rhinitis), chronic obstructive pulmonary disease (COPD) D), inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), pathological conditions driven by endotoxins ( For example, complications after bypass surgery, or, for example, a chronic endotoxin state that contributes to chronic heart failure. ), and related diseases involving cartilage, such as joint diseases. More specifically, the use The term refers to rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease (COPD), and inflammatory bowel disease. This refers to conditions such as Crohn's disease and ulcerative colitis.

[0147] In one embodiment, the present invention relates to the use of in the prevention and / or treatment of muscle diseases. The present invention provides a compound of the present invention, or a pharmaceutical composition containing the compound of the present invention. In particular, the term refers to muscle It means dystrophy. More specifically, the term refers to Duchenne muscular dystrophy. Becker muscular dystrophy, myotonic dystrophy, facioscapulohumeral dystrophy This refers to congenital dystrophy and / or limb-girdle dystrophy. In this context, the term refers to Duchenne muscular dystrophy.

[0148] In another embodiment, the present invention relates to the production of pharmaceuticals for the prevention and / or treatment of muscle diseases. The present invention provides the use of the compound of the present invention, or a pharmaceutical composition containing the compound of the present invention. In particular, The term refers to muscular dystrophy. More specifically, the term refers to Duchenne muscular dystrophy. Muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, facioscapulohumeral dystrophy This refers to type dystrophy, congenital dystrophy, and / or limb-girdle dystrophy. Most specifically, the term refers to Duchenne muscular dystrophy.

[0149] In an additional method of treatment, the present invention relates to the prevention of muscular diseases in mammals and / or a method of treatment, comprising an effective amount of the compound of the present invention for the treatment or prevention of the disease. This provides the method comprising administering one or more of the pharmaceutical compositions described herein. In particular, the term refers to muscular dystrophy. More specifically, the term refers to du Chenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, face Facescapulohumeral dystrophy, congenital dystrophy, and / or limb-girdle dystrophy It means that. Most specifically, the term means Duchenne muscular dystrophy. .

[0150] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. To provide. In a particular embodiment, the other therapeutic agent is a treatment for muscle diseases. In particular, The term refers to muscular dystrophy. More specifically, the term refers to Duchenne muscular dystrophy. Muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, facioscapular dystrophy This refers to arm dystrophy, congenital dystrophy, and / or limb-girdle dystrophy. Most specifically, the term refers to Duchenne muscular dystrophy.

[0151] In one embodiment, the present invention is for use in the prevention and / or treatment of fibrous diseases. The present invention provides a compound of the present invention, or a pharmaceutical composition containing a compound of the present invention. In particular, the term is , heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and It refers to fibrosis of individual organs or tissues, such as the digestive tract. In particular, the term fibrotic disease refers to Pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), progressive mass fibrosis (PMF), and / or cystic fibrosis) Fibrosis (CF, etc.), iatrogenic drug-induced fibrosis, occupation-induced fibrosis and / or environmentally induced fibrosis Other diffuse parenchymal lung diseases with various etiologies, including sarcoidosis, hyperpulmonary diseases, granulomatous diseases (sarcoidosis, hyperpulmonary diseases) Sensitivity pneumonitis, collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleus muscle Tumors, genetic disorders (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis) Metabolic storage disorders, familial interstitial lung disease; radiation-induced fibrosis; chronic obstructive pulmonary disease (COPD); Scleroderma; Bleomycin-induced pulmonary fibrosis; Chronic asthma; Silicosis; Asbestos-induced pulmonary fibrosis; Acute Respiratory distress syndrome (ARDS); renal fibrosis; polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPK) D) Tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy, membranous nephropathy; hypertension Disease; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; toxic / drug-induced Hepatic fibrosis; hemochromatosis; non-alcoholic steatohepatitis (NASH); bile duct injury; primary biliary hepatitis Cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autoimmune hepatitis; corneal scarring Hypertrophic scarring; Dupuytren's disease, keloids, dermatofibrosis; scleroderma; systemic sclerosis. Spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis; arteriosclerosis; Wegener - Granulomatous disease; Peyronie's disease, or chronic lymphocytic disease. More specifically, idiopathic lung cancer. The term IPF (intracellular filamentous nephropathy) includes IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, and autosomal dominant polysomnitis. This refers to polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH). The term idiopathic pulmonary fibrosis (IPF) is used in relation to IgA nephropathy and autosomal dominant polycystic kidney disease (ADPKD). , and / or non-alcoholic steatohepatitis (NASH).

[0152] In another embodiment, the present invention relates to the production of pharmaceuticals for the prevention and / or treatment of fibrous diseases. The present invention provides for the use of the compound of the present invention, or a pharmaceutical composition containing the compound of the present invention. The term in question refers to the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, It refers to fibrosis of individual organs or tissues, such as the musculoskeletal system and the digestive tract. In particular, fibrous diseases and The term pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), progressive mass fibrosis (PMF), and / or This includes cystic fibrosis (CF), iatrogenic drug-induced fibrosis, occupation-induced fibrosis and / or ring fibrosis. Other diffuse parenchymal lung diseases with various etiologies, including border-induced fibrosis, and granulomatous diseases (sarcoid). Dosis, hypersensitivity pneumonitis, collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, Lymphangioleiomyomatosis, genetic disorders (Hermanski-Pudlak syndrome, tuberous sclerosis, Neurofibromatosis, metabolic storage disorders, familial interstitial lung disease; radiation-induced fibrosis; chronic obstructive pulmonary disease Lung disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced Pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; polycystic venous disease (PKD), autosomal dominant polycystic fibrosis Polycystic kidney disease (ADPKD), tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy, membrane Alcohol-induced nephropathy; hypertension; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; poison Drug-induced hepatic fibrosis; hemochromatosis; non-alcoholic steatohepatitis (NASH); bile duct injury Primary biliary cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autoimmune hepatic fibrosis Inflammation; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, dermatofibrosis; scleroderma; Systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis; arteries Sclerosis; Wegener's granulomatosis; Peyronie's disease; or chronic lymphocytic disease. More specifically The term idiopathic pulmonary fibrosis (IPF) is a combination of IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, and This refers to autosomal dominant polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH). Most specifically, the term idiopathic pulmonary fibrosis (IPF) is used to describe IgA nephropathy, autosomal dominant polyfibrosis. This refers to polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH).

[0153] In an additional method of treatment, the present invention relates to the prevention of mammals suffering from fibrous diseases. and / or a method of treatment comprising an effective amount of the compound of the present invention for the treatment or prevention of the disease. The method provides comprising administering one or more substances or pharmaceutical compositions described herein. In particular, the term applies to the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, and horns. It refers to fibrosis of individual organs or tissues such as membranes, the retina, the musculoskeletal system, and the digestive tract. In particular, The term fibrotic disease includes pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF) and progressive nodular fibrosis (PMF)). ), and / or cystic fibrosis (CF), iatrogenic drug-induced fibrosis, occupation-induced fibrosis and / Alternatively, other diffuse parenchymal lung diseases and granulomatous diseases with various etiologies, including environmentally induced fibrosis. (Sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, alveolar proteinosis, Langerhans cell musculoblast Blastomatosis, lymphangioleiomyomatosis, genetic disorders (Hermanskiy-Pudlak syndrome, nodular Sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease; radiation-induced fibrosis; chronic Obstructive pulmonary disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos Stoichiometric pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; polycystic venous disease (PKD); autosomal chromosome Polycystic kidney disease dominant (ADPKD), tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA Nephropathy, membranous nephropathy; hypertension; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic gland disease Fibrosis; Toxic / drug-induced hepatic fibrosis; Hemochromatosis; Non-alcoholic steatohepatitis (NASH); Bile duct injury; primary biliary cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autologous Immunotherapy; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, dermatofibrosis; skin Scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis This refers to conditions such as arteriosclerosis, Wegener's granulomatosis, Peyronie's disease, or chronic lymphocytic disease. Specifically, the term idiopathic pulmonary fibrosis (IPF) includes IgA nephropathy, membranous nephropathy, and focal segmental glomeruli. Sclerosis, autosomal dominant polycystic kidney disease (ADPKD), and / or non-alcoholic steatohepatitis (NASH) This means, most specifically, that the term idiopathic pulmonary fibrosis (IPF) is an autosomal dominant form of IgA nephropathy. This refers to polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH).

[0154] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Provided. In a particular embodiment, the other therapeutic agent is a therapeutic agent for fibrotic diseases. Furthermore, the term in question applies to the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, and retina. This refers to fibrosis of individual organs or tissues, such as the musculoskeletal system and the digestive tract. In particular, fibrous diseases. The term refers to pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), progressive mass fibrosis (PMF), and / or or cystic fibrosis (CF), iatrogenic drug-induced fibrosis, occupation-induced fibrosis and / or Other diffuse parenchymal lung diseases with various etiologies, including environmentally induced fibrosis, and granulomatous diseases (sarco). Idosis, hypersensitivity pneumonitis, collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis Lymphangioleiomyomatosis, genetic disorders (Hermanskie-Pudlak syndrome, tuberous sclerosis) Neurofibromatosis, metabolic storage disorders, familial interstitial lung disease; radiation-induced fibrosis; chronic obstruction Pulmonary pulmonary disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced lung disease Pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; polycystic venereal disease (PKD), autosomal dominant polycystic fibrosis Polycystic kidney disease (ADPKD), tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy Membranous nephropathy; hypertension; Alport; intestinal fibrosis; hepatic fibrosis; cirrhosis; alcohol-induced hepatic fibrosis; Toxic / drug-induced hepatic fibrosis; hemochromatosis; non-alcoholic steatohepatitis (NASH); bile duct injury Scars; primary biliary cirrhosis; infection-induced hepatic fibrosis; virus-induced hepatic fibrosis; and autoimmune Hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, dermatofibrosis; cutaneous scleroderma Systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; restenosis; atherosclerosis; arteries Sclerosis; Wegener's granulomatosis; Peyronie's disease; or chronic lymphocytic disease. More specifically The term idiopathic pulmonary fibrosis (IPF) is a combination of IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, and This refers to autosomal dominant polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH). Most specifically, the term idiopathic pulmonary fibrosis (IPF) is used to describe IgA nephropathy, autosomal dominant polyfibrosis. This refers to polycystic kidney disease (ADPKD) and / or non-alcoholic steatohepatitis (NASH).

[0155] In one embodiment, the present invention relates to the use in the prevention and / or treatment of viral infections. The present invention provides a compound for the use of the present invention, or a pharmaceutical composition containing the compound for the use of the present invention. The word means influenza or flu.

[0156] In another embodiment, the present invention relates to a pharmaceutical product for the prevention and / or treatment of viral infections. The present invention provides the use of the compound of the present invention, or a pharmaceutical composition containing the compound of the present invention, in production. In particular, the term refers to influenza or the flu.

[0157] In an additional method of treatment, the present invention relates to a mammal suffering from a viral infection. A method for prevention and / or treatment of the disease, comprising an effective amount of the present invention for the treatment or prevention of the disease. The method comprising administering one or more compounds or pharmaceutical compositions described herein. provide.

[0158] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. To provide. In a particular embodiment, the other therapeutic agent is a treatment for viral infections. .

[0159] In certain embodiments, the present invention relates to the degradation of cartilage and / or the disruption of cartilage homeostasis. The compounds of the present invention for use in the prevention and / or treatment of diseases involving, or the present invention A pharmaceutical composition containing the compound is provided. In a particular embodiment, cartilage degradation and / or Diseases involving disruption of cartilage homeostasis include osteoarthritis, psoriatic arthritis, and juvenile arthritis. Rheumatism, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic nerve Transsexual dystrophy, painful osteotrophy, achondroplasia, Paget's disease, Tietze syndrome Or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, Sarcoidosis, amylosis, hydarthrosis, periodic diseases, rheumatoid spinal disease Inflammation, endemic forms of arthritis such as endemic osteoarthritis, Muserenian disease and handicap Diseases of the disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and Selected from ankylosing spondylitis. More specifically, the breakdown of the cartilage and / or cartilage homeostasis. One disease involving stasis disruption is osteoarthritis (OA).

[0160] In another embodiment, the present invention relates to the breakdown of cartilage and / or disruption of cartilage homeostasis. The compound of the present invention in the production of pharmaceuticals for the prevention and / or treatment of diseases involved, or the present invention The present invention provides the use of a pharmaceutical composition containing the compound of the present invention. In a particular embodiment, the cartilage is Diseases involving disruption of resorption and / or cartilage homeostasis include osteoarthritis and psoriatic arthritis. Juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, Reflex sympathetic dystrophy, painful osteoatrophy, achondroplasia, Paget's disease, T Otze syndrome or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic joints Inflammation, arthropathy, sarcoidosis, amylosis, joint effusion (hydarthrosis), periodic diseases, Endemic forms of arthritis such as rheumatic spondylitis and endemic osteoarthritis, as well as Museren's disease and Handicap disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, Selected from scleroderma and ankylosing spondylitis. More specifically, the breakdown of the cartilage and / or One disease involving disruption of cartilage homeostasis is osteoarthritis (OA).

[0161] In an additional method of treatment, the present invention relates to the decomposition of cartilage and / or cartilage homeostasis A method for the prevention and / or treatment of a mammal suffering from a disease involving a disturbance of the For the treatment or prevention of disease, an effective amount of the compound of the present invention or the pharmaceutical combination described herein The present invention provides the method comprising administering one or more of the products. Decomposition of cartilage and / or cartilage homeolysis A disease involving disruption of ostasis. In certain embodiments, the breakdown and / or of the cartilage. Diseases involving disruption of cartilage homeostasis include osteoarthritis, psoriatic arthritis, and juvenile arthritis. Rheumatism, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic nerve Transsexual dystrophy, painful osteotrophy, achondroplasia, Paget's disease, Tietze syndrome Or costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, Sarcoidosis, amylosis, hydarthrosis, periodic diseases, rheumatoid spinal disease Inflammation, endemic forms of arthritis such as endemic osteoarthritis, Muserenian disease and handicap Diseases of the disease; degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and Selected from ankylosing spondylitis. More specifically, the breakdown of the cartilage and / or cartilage homeostasis. One disease involving stasis disruption is osteoarthritis (OA).

[0162] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Provided. In a particular embodiment, the other therapeutic agent breaks down cartilage and / or cartilage A drug for the treatment of diseases involving disruption of meostasis, and the method of treatment is the treatment of the disease For the treatment or prevention of the disease, an effective amount of the compound of the present invention or a pharmaceutical composition described herein This includes the administration of one or more of the following. In certain embodiments, the cartilage is broken down and / or the cartilage is restored. Diseases involving disruption of ostasis include osteoarthritis, psoriatic arthritis, and juvenile rheumatoid arthritis. Gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy Trophy, painful osteodystrophy, achondroplasia, Paget's disease, Tietze syndrome or Costochondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, sarcoid Dosis, amylosis, hydarthrosis, periodic disease, rheumatoid spondylitis, regional Endemic forms of arthritis such as pathological osteoarthritis, Muserenian disease, and Handygod's disease ; Degeneration caused by fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing Selected from spondylitis. More specifically, the breakdown of the cartilage and / or cartilage homeostasis. One disease involving disruption of this system is osteoarthritis (OA).

[0163] For the prevention and / or treatment of long-term conditions such as degenerative states, the therapeutic regimen is Oral administration is typically performed over several months or years, and therefore for the convenience and tolerability of the patient. Preferred. When administered orally, the usual dose is 1 to 4 times a day (1 to 4), especially 1 to 3 times a day (1 to 3). Dosage, typically a regular dose of once or twice a day (1-2), and most typically once a day (1) The dosage is a typical regimen. Alternatively, for long-acting drugs, in the case of oral administration... Typical regimens include once every two weeks, once a week, and once a day. Specifically, medication The regimen is every 1 to 14 days, more specifically every 1 to 10 days, and even more specifically every 1 to 7 days. And, more specifically, it could be every 1 to 3 days.

[0164] Using these dosing patterns, each dose provides approximately 1 to 1000 mg of the compound of the present invention. The product is provided in doses ranging from approximately 10 to 500 mg, with a particular emphasis on providing approximately 30 to 250 mg. .

[0165] Transdermal doses typically achieve blood levels similar to or lower than those achieved with injectable doses. Selected to provide the service.

[0166] The injection dose levels are all approximately 0.1 mg / kg / , with a duration of approximately 1 to 120 hours, and especially between 24 and 96 hours. The range is at least 10 mg / kg / hour. To achieve an appropriate steady-state level, approximately 0. A preloading bolus of 1 mg / kg to approximately 10 mg / kg or more may be administered. The maximum total dose is not expected to exceed approximately 1 g / day for human patients weighing 40-80 kg.

[0167] When used to prevent the onset of a disease, the compounds of the present invention are used to prevent the onset of the disease. For patients with the condition, typically under the advice and supervision of a physician, the above-mentioned dosage levels may be used. It will be administered as follows. Patients at risk of developing certain conditions will usually be given the treatment for those conditions. Individuals with a family history of the condition, or those who have developed the condition through genetic testing or screening. This includes individuals who have been confirmed to be prone to this condition.

[0168] The compounds of the present invention may be administered as the sole active agent, or they may be the same or of the same type. It has been shown to exhibit similar therapeutic activity and to be safe and effective in such combination administration. It may be administered in combination with other therapeutic agents, including other compounds of the present invention. Specific implementation In this configuration, co-administration of two (or more) drugs, in a significantly lower dose of each drug. This allows for the use of [the substance], thereby reducing the observed side effects.

[0169] In one embodiment, the compound of the present invention or a pharmaceutical composition containing the compound of the present invention is a pharmaceutical It is administered as such. In a specific embodiment, the pharmaceutical composition further contains an active ingredient It also includes.

[0170] In one embodiment, the compound of the present invention is used for the treatment and / or prevention of inflammatory diseases. It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, immunomodulatory agents. Drugs, for example, azathioprine, corticosteroids (for example, prednisolone or dexamethoxazole) Metasone, cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate Fetil, Muromonab-CD3 (OKT3, e.g., Orthoclone®), ATG, Aspirin Examples include acetaminophen, ibuprofen, naproxen, and piroxicam. ru.

[0171] In one embodiment, the compound of the present invention is used for the treatment of arthritis (e.g., rheumatoid arthritis) and / Alternatively, it may be administered in combination with another therapeutic agent for prevention, and specific agents may include, but are not limited to, these. However, painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, synthetic DMARDs (for example, limited It is not something that is done, but methotrexate, leflunomide, sulfasalazine, aurano Fin, sodium aurthiomalate, penicillamine, chloroquine, hydroxychloroquine azathioprine, tofacitinib, baricitinib, hostamatinib, and cyclosporine ), as well as biological DMARDs (for example, but not limited to, infliximab, etc.) Examples include tanercept, adalimumab, rituximab, and abatacept.

[0172] In one embodiment, the compound of the present invention is used for the treatment and / or prevention of proliferative disorders. It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, methotrexate. Leucovorin, Adriamycin, Prednisone, Bleomycin, Cyclophosph Amid, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinbron Rustin, vinorelbine, doxorubicin, tamoxifen, toremifene, meges acid Trol, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g., Herse Butin (trademark), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa (trademark)), (Registered trademark), Tarceva (trademark), Elbitax (trademark), VEGF inhibitors (e.g., Avastin (trademark) Proteasome inhibitors (e.g., Velcade®), Gleevec®, and HS Examples include p90 inhibitors (e.g., 17-AAG). Furthermore, the compounds of the present invention according to formula I are radioactive. It may be administered in combination with other therapies, including but not limited to therapeutic or surgical procedures. In a specific embodiment, the proliferative disorder is selected from cancer, myeloproliferative disorder, or leukemia. It will be selected.

[0173] In one embodiment, the compounds of the present invention are for the treatment and / or prevention of autoimmune diseases. It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, glucocor Thicoids, cell proliferation inhibitors (e.g., purine analogs), alkylating agents (e.g., nitrites) En mustard (cyclophosphamide), nitrosourea, the platinum compound of the present invention, and so Other than those listed above, antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine) , cytotoxic antibiotics (e.g., dactinomycin, anthracyclines, mitomeycin) (e.g., C, bleomycin, and mitramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3) (OTK3) monoclonal antibody, AtoGum® and Thymoglobulin®), Crossporine, tacrolimus, rapamycin (sirolimus), interferon (for example, I FN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalim) Examples include mab, mycophenolate, fingolimod, and myriocin.

[0174] In one embodiment, the compound of the present invention is for the treatment and / or prevention of transplant rejection. It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, calcinu -phosphoric acid inhibitors (e.g., cyclosporine or tacrolimus (FK506)), mTOR inhibitors (e.g., Sirolimus, everolimus), antiproliferative agents (e.g., azathioprine, mycophenolic acid), Adrenocortical steroids (e.g., prednisolone, hydrocortisone), antibodies (e.g., mono Clonal anti-IL-2Rα receptor antibodies (baziliximab, daclizumab), polyclonal anti-T Examples include cell antibodies (e.g., anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)). ru.

[0175] In one embodiment, the compound of the present invention is used for the treatment of asthma and / or rhinitis and / or COPD and / or administered in combination with another therapeutic agent for prevention, and the specific drugs are not limited to these. However, β2-adrenergic receptor agonists (e.g., salbutamol, revalbuterol, Terbutaline and bitolterol), epinephrine (inhalant or tablet), anticholinergics (e.g.) For example, ipratropium bromide, glucocorticoids (oral or inhaled), long-acting. β2-agonists (e.g., salmeterol, formoterol, vanbuterol, and sustained-release agonists) Oral albuterol, combination of inhaled corticosteroids and long-acting bronchodilators (for example, Fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthetic inhibitors (e.g., montelukast, zafirlukast and diloiton), media IgE release inhibitors (e.g., cromoglycates and ketotifen), biological regulators of the IgE response Children (e.g., omalizumab), antihistamines (e.g., ceterizine, cinnabar) Lysine, fexofenadine) and vasoconstrictors (e.g., oxymetazoline, xylometazolone) Examples include zoline, naphazoline, and tramazoline.

[0176] Furthermore, the compounds of the present invention may be administered in combination with emergency treatment for asthma and / or COPD. Such treatments include oxygen or heliox administration, or nebulized salbutamol or terbex. Tallinn (optionally combined with anticholinergics (e.g., ipratropium)), systemic s Theroid (oral or intravenous, e.g., prednisone, prednisolone, methylprednisolone) (Lon, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific β-agonist Animal drugs, for injection or inhalation (e.g., epinephrine, isoethaline, isoproterenol, Metaproterenol), anticholinergic agents (intravenous injection or spray, e.g., glycopyrrolate, Atropine, ipratropium), methylxanthine (theophylline, aminophylline, ba Mifilin), inhaled anesthetics with bronchodilating effects (e.g., isoflurane, halothane, etc.) Examples include flurane, ketamine, and intravenous magnesium sulfate.

[0177] In one embodiment, the compound of the present invention is used for the treatment and / or prevention of inflammatory bowel disease (IBD). It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, gluconol. Corticoids (e.g., prednisone, budesonide), synthetic disease-modifying immunomodulators (e.g., Methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporine) and immunomodulatory agents that modify the body's disease (inflix) Examples include mab, adalimumab, rituximab, and abatacept.

[0178] In one embodiment, the compound of the present invention is another therapeutic agent for the treatment and / or prevention of SLE. It is administered in combination with, and specific drugs include, but are not limited to, human monoclonal antimicrobial agents. Body (belimumab (Benlysta)), antimalarial drugs (e.g., Plaquenil, hydroxychloroquine) Disease-modifying antirheumatic drugs (DMARDs) such as (e.g., methotrexate and Azathioprine, cyclophosphamide and mycophenolic acid, nonsteroidal anti-inflammatory drugs Immunosuppressants and analgesics such as, opioids (e.g., dextropropoxyfen and co Codamole), opioids (e.g., hydrocodone, oxycodone, MS-Contin, or meta) Examples include DON and fentanyl duragesic transdermal patches.

[0179] In one embodiment, the compound of the present invention is used for another treatment for the treatment and / or prevention of psoriasis. It is administered in combination with other drugs, and specific drugs include, but are not limited to, coal tar, ditoxin. Lanol ​​(antraline), corticosteroid-like desoximethasone (Topicort®) fluocinonide, vitamin D3 analogs (e.g., calcipotriol), argan oil, and Bath solutions, moisturizers, and medicines containing retinoids (etretinate, acitretin, tazarotene) Topical treatments such as creams and ointments, methotrexate, cyclosporine, retinoids D, thioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil Systemic drugs such as azathioprine, tacrolimus, fumarate esters, or amevib ( (Trademark), Enbrel (Trademark), Humira (Trademark), Remicade (Trademark), Laputiva (Trademark) and This includes biological agents such as ustekinumab (an IL-12 and IL-23 antagonist). Furthermore, the present invention The combination includes phototherapy or photochemotherapy (e.g., psoralen and ultraviolet A therapy (PUVA)), but These may be administered in combination with other therapies, but are not limited to these.

[0180] In one embodiment, the compound of the present invention is used for the treatment and / or prevention of allergic reactions. It is administered in combination with other therapeutic agents, and specific drugs include, but are not limited to, antihistamines. Min drugs (for example, cetirizine, diphenhydramine, fexofenadine, levocetirizine) (e.g., prednisone, betamethasone, beclomethasone, dextrin) Samethasone), epinephrine, theophylline, or anti-leukotriene agents (e.g., montelucine) Examples include sto or zafirlukast, anticholinergics, and decongestants.

[0181] As will be apparent to those skilled in the art, co-administration allows two or more therapeutic agents to be administered in the same treatment regimen. This includes all means of delivery to the patient as part of the treatment. The two or more drugs are a single It may be administered simultaneously in a formulation, i.e., as a single pharmaceutical composition, but this is not essential. The drug may be administered in different formulations and at different times. [Examples]

[0182] (Experiment Section) (General method) Powder X-ray diffraction data was obtained using a PANalytical Empyrean diffractometer equipped with an X'cellerator detector. The samples were collected using a PANalytical (Amlelo, Netherlands) device. The radiation used was CuKα (1.54A). The voltage and current were set to 45kV and 40mA, respectively. The data was collected at room temperature with a step size of [number missing]. The samples were collected at angles from 3° to 40° 2θ, with a 0.013° 2θ. The samples were then placed on a disc-shaped holder and collected using Mylar (registered trademark). The film is prepared between the layers, and the diffraction profile is recorded in transmission mode while the sample is rotated. did.

[0183] Differential scanning calorimetry (DSC) data is obtained from a DSC Q1000 (or DSC Q2000) differential scanning calorimeter (TA Ins Data was collected using Truments (Newcastle, DE, USA). Data was collected at a heating rate of 10°C / min from 25°C~ The samples were collected over a temperature range of 250°C. Analysis was performed under nitrogen, and the samples were prepared using a standard perforated filter. The luminium dish was filled with the solution. Indium was used as the calibration standard.

[0184] Thermogravimetric analysis (TGA) data was obtained using a TGA Q5000 thermogravimetric analyzer (TA Instruments, Newcastle, DE The data was collected using (USA). The data covers a temperature range of 25°C to 250°C at a heating rate of 10°C / min. The samples were collected. The analysis was performed under nitrogen, and the samples were packed into standard lidless aluminum dishes. Nickel was used as a temperature calibration standard using the Curie point method.

[0185] Infrared spectra were obtained using a Bruker ALPHA II infrared spectrophotometer (Bruker, Wissembourg, France). The data was recorded using [a specific method / tool]. The data was recorded in ATR mode at room temperature for 2 cm. -1 24 scans at this resolution The data was collected after averaging.

[0186] solid 13 The 13C NMR spectrum was obtained at ambient temperature using a Bruker SB Avance III HD 500 spectrometer. Using a 4mm CP / MAS SB VTN probe, the following: -Frequency: 125.76MHz, - Spectral width: 37kHz, -Magic angle rotation speed: 10kHz, - Pulse program: Cross-polarization using SPINAL64 decoupling -Recycling delay: 10s, -Acquisition time: 46ms, -Contact time: 4ms, Total count: 4096 It was recorded under these conditions. Before the FT, 5 Hz line-broadening was applied. The result obtained in this way The spectrum is shown for comparison with the adamantane sample (high-frequency peaks of adamantane). (The concentration was set to 38.5 ppm.)

[0187] solid 15 N NMR spectra were obtained at ambient temperature using a Bruker SB Avance III HD 500 spectrometer. Using a 4mm CP / MAS SB VTN probe, the following: -Frequency: 50.68MHz, - Spectral width: 25kHz, -Magic angle rotation speed: 5kHz, - Pulse program: Cross-polarization using SPINAL64 decoupling -Recycling delay: 30s, -Acquisition time: 40ms, -Contact time: 4ms, - Total count: 8192 It was recorded under these conditions.

[0188] Before the Fourier transform (FT), a 5 Hz linewidth expansion was applied. The resulting spectrum was then processed. 15 N is Do The results are shown for comparison with the glycine sample (the frequency is between the two peaks of glycine). (And, within the reference frame corresponding to 0 ppm ± 0.2 ppm, the ammonia level was set to 33.4 ppm.)

[0189] Water sorption / desorption profiles are measured by the Dynamic Vapor Sorption System, DVS (Surface Measuring). Recorded at ement Systems, London, UK. Approximately 5-10 mg of the sample substance was subjected to controlled conditions at 25°C. The DVS device, operating under high humidity, was placed in a dish. The program details the mass fluctuations below. Recorded as a function of relative humidity: - Allow the sample to rest at 50% RH until the mass fluctuation is less than 0.002% per minute within the 6-hour time limit. It was scaled down. - The relative humidity was increased from 50%RH to 90%RH at a rate of 10% per hour. - Allow the sample to rest at 90% RH until the mass fluctuation is less than 0.002% per minute within the 6-hour time limit. It was scaled down. - The relative humidity was reduced from 90%RH to 0%RH at a rate of 10% per hour. - Allow the sample to settle at 0% RH until the mass fluctuation is less than 0.002% per minute within the 6-hour time limit. It was scaled down. - The relative humidity was increased from 0%RH to 50%RH at a rate of 10% per hour. (abbreviation) [Table 1] TIFF2026168117000005.tif108170

[0190] (Example 1. Preparation by synthesis of the solid form of the present invention) (1.1. Amorphous (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3- Preparation of methylpiperazine-1-yl]-3-oxopropyl]imidazolidined-2,4-dione) The amorphous material is prepared according to the procedure for the preparation of compound 1 described in WO2016 / 102347. Alternatively, it can be obtained by heating polymorph I to 100°C under vacuum.

[0191] The amorphous morphology was characterized by XRPD as shown in Figure 18.

[0192] The amorphous morphology was characterized by a DSC substantially as shown in Figure 20.

[0193] The amorphous morphology was characterized by thermogravimetric analysis (TGA) as substantially shown in Figure 19. .

[0194] (1.2. (5S)-Cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-pipera Preparation of polymorph I of din-1-yl]-3-oxo-propyl]imidazolidinedione-2,4-dione) (1.2.1. Morphology I - Protocol 1) (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine- 1-Il-3-oxo-propyl]imidazolidined-2,4-dione and IPA (3.93 kg / kg MSM) are used in 20 The reactor is filled at °C. When the suspension is heated to 40°C, a solution is formed, and this solution is then used at this temperature. Maintain for 15 minutes. Then, clarify the solution by filtering it through a PALL filter.

[0195] The first load of water (5 kg / kg MSM) is added at 40°C over 30 minutes. This solution is then mixed over 15 minutes. Cool to 5°C (gradient = -0.3°C / min), then crystalline (5S)-cyclopropyl-5-[3-[(3S)-4-( 3,5-difluorophenyl)-3-methyl-piperazine-1-yl]-3-oxopropyl]imidazoly Add a seed crystal of Zin-2,4-Zion. After 15 minutes, cool the suspension to 5°C in 100 minutes (gradient = -0.3℃ / min).

[0196] The second load of water (2.5 kg / kg MSM) was added at 5°C for 15 minutes, and the medium was stirred at 5°C for a short time. At the very least, maintain the mixture for 10 hours, then filter it through a 20 μm filter.

[0197] Wash the cake twice with pre-cooled (5°C) water (2 × 2.50 kg / kg MSM). The resulting solid is then processed. Dry in a well-ventilated oven at 40°C.

[0198] (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine- Polymorph I of 1-yl]-3-oxopropyl]imidazolidin-2,4-dione was obtained in 81% yield. It can be done.

[0199] Polymorph I was characterized by XRPD (Figure 1).

[0200] Polymorph I is essentially characterized by a DSC as shown in Figure 3, and is approximately 75-85°C (vertical It exhibits an endothermic transition (upward temperature rise), and more specifically, morphology I is converted at a rate of approximately 25°C / min. When heating from °C, an endothermic transition occurs to approximately 80°C when heated in a perforated aluminum dish. It indicated that.

[0201] Polymorph I exhibits a weight loss in the range of approximately 8%, as substantially shown in Figure 5, through thermogravimetric analysis. It was characterized by TGA. This weight loss was due to water, according to Karl Fischer (KF) analysis. This was determined. KF analysis indicates that the water content may be approximately 8%, corresponding to the dihydrate.

[0202] Polymorph I is located at the following positions: 3488.5, 1751.3, 1719.0, 1598.4, 1586.0, 1484.5, 1458.0 , 1439.3, 1410.5, 1252.7, 1199.9, 1113.1, 1051.7, 1026.5, 992.2, 835.2, 807.5, and 675.7cm -1 It featured infrared spectroscopy (IR), which is essentially shown in Figure 7, where a peak is observed. .

[0203] Polymorph I is located at the following positions: -3.7, -2.2, 1.2, 2.5, 8.7, 13.7, 14.3, 27.7, 29.2, 31. 4, 31.8, 40.7, 42.2, 45.8, 46.3, 48.0, 50.4, 53.5, 64.1, 90.9, 91.7, 94.0, 96.6 , 100.9, 152.4, 153.0, 159.1, 163.2, 164.1, 165.1, 166.1, 173.0, 174.8, 178.8ppm As shown in Figure 9, which shows a peak 13 It was characterized by 13C solid-state NMR.

[0204] Polymorph I is located at the following positions: 75.0, 76.8, 93.6, 94.9, 111.5, 115.1, 148.0, and 149.1 ppm. As shown in Figure 11, which shows a peak 15 It was characterized by N solid-state NMR.

[0205] (1.2.2. Morphology I - Protocol 2) Amorphous compound 1 (approximately 50 mg) is dissolved in acetone and heated in a sealed glass vial for 3 minutes. After stirring for 0 minutes, a clear solution was obtained. Next, water (0.5 mL to 1.5 mL) was added while stirring. Upon addition, compound 1 precipitated as form I.

[0206] (1.3. (5S)-Cyclopropyl-5-[3-[(3S)-4-(3,5-Difluorophenyl)-3-methyl-pipera Preparation of polymorph II of din-1-yl]-3-oxo-propyl]imidazolidinedione-2,4-dione) (1.3.1. Morphology II - Protocol 1) (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine- 1-Il-3-oxo-propyl]imidazolidined-2,4-dione and IPA (3.93 kg / kg MSM) are used in 20 The reactor is filled at °C. When the suspension is heated to 40°C, a solution is formed, and this solution is then used at this temperature. Maintain for 30 minutes. Then, clarify the solution by filtering it through a PALL filter. Crystalline (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazi Using 1-yl-3-oxopropyl imidazolidin-2,4-dione (0.01 kg / kg MSM) as the seed crystal Add it.

[0207] After 15 minutes, the medium was cooled to 25°C in 150 minutes (gradient = -0.1°C / min), and maintained at this temperature for 60 minutes. do.

[0208] A methylcyclohexane load (8.18 kg / kg MSM) was applied at 25°C for 90 minutes. Add it. Maintain the mixture at this temperature for 60 minutes, then cool it down to 5°C over 200 minutes (gradient). Maintain this temperature (-0.1°C / min) while stirring for 12 hours, then filter through a 20 μm filter. ru.

[0209] The cake is washed with pre-cooled (5°C) MCH (2.40 kg / kg MSM). The resulting solid is then vacuum-sealed. Dry at -40-50°C.

[0210] (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine- Polymorph II of 1-yl]-3-oxopropyl]imidazolidin-2,4-dione was produced in a yield of 65.6%. It can be obtained.

[0211] Residual solvent: MCH (0.8%), IPA (<0.1%)

[0212] (1.4. Morphology II - Protocol 2) (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazine- 1-Iyl]-3-oxopropyl]imidazolidine-2,4-dione and methyl isobutyl ketone (5k The suspension (g / kg MSM) is packed into the reactor at 20°C. When the suspension is heated to 60°C, a solution is formed, and Maintain this temperature for 15 minutes. Then, filter the solution using a PALL filter. Clarify the solution. Add the first load of DIPE (5 kg / kg MSM) at 60°C for 45 minutes. Then dissolve In the liquid, crystalline (5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl- Piperazine-1-yl-3-oxopropyl-imidazolidine-2,4-dione (0.025 kg / kg MSM) Add seed crystals. After 15 minutes, add a further load of DIPE (5 kg / kg MSM) over 30 minutes. The following protocol: - Cooling to 50°C in 30 minutes (gradient = -0.3°C / min), contact time at 50°C for 60 minutes. - Cooling to 40°C in 30 minutes (gradient = -0.3°C / min), contact time at 40°C for 120 minutes. - Cooling to 30°C in 30 minutes (gradient = -0.3°C / min), contact time at 30°C for 120 minutes. - Cooling to 20°C in 30 minutes (gradient = -0.3°C / min), contact time at 20°C for 120 minutes. - Cooling to 10°C in 30 minutes (gradient = -0.3°C / min), contact time at 10°C for 120 minutes. - Cooling to 0°C in 30 minutes (gradient = -0.3°C / min), contact time at 0°C for 120 minutes. It is cooled to 0°C.

[0213] Filter the medium through a 20 μm filter.

[0214] The cake is washed with pre-cooled (0°C) DIPE (5 kg / kg MSM). The resulting solid is then subjected to a vacuum for 4 minutes. Dry at 0-50°C.

[0215] Polymorphic form II was characterized by an XRPD as shown in Figure 2.

[0216] Polymorph II is characterized by a DSC substantially as shown in Figure 4, at approximately 155-162°C. (Initial phase) shows an endothermic transition, and more specifically, morphology II is perforated aluminum When heating in a dish, if heating at a rate of 10°C / min from approximately 25°C, the temperature will absorb heat and rise to approximately 159°C. It indicated movement.

[0217] Polymorph II was characterized by thermogravimetric analysis (TGA) as substantially shown in Figure 6.

[0218] Polymorphic form II is located at the following positions: 1717.8, 1624.6, 1584.8, 1447.1, 1193.0, 1556.0, and 1111. 4, 1022.8, 987.4, 823.3, 765.1, and 672.7 cm -1 This is substantially shown in Figure 7, which shows a peak. It featured infrared spectroscopy (IR) techniques.

[0219] Polymorphic form II is located at the following positions: -0.9, 0.3, 2.1, 10.0, 12.3, 17.0, 29.1, 30.1, 34.4, 4 2.4, 45.7, 46.8, 49.1, 52.9, 65.6, 68.3, 91.7, 96.1, 97.5, 98.6, 102.3, 153.0, 1 Figure 9 substantially shows peaks at 53.9, 158.3, 163.6, 165.1, 170.0, 174.8, and 180.9 ppm. so 13 It was characterized by 13C solid-state NMR.

[0220] Polymorph II is found at the following locations: 70.3, 80.4, 89.9, 97.4, 106.0, 108.9, 145.3, and 146.5 ppm. As shown in Figure 11, which shows a peak 15 It was characterized by N solid-state NMR.

[0221] (1.4.1. Morphology II - Protocol 3) [ka] (4R)-4-methyl-2,5- In a suspension of dioxo-4-imidazolidinepropanoic acid (standard mass 1 wt, CAS 1957994-69-2), While stirring, the first batch of N,N-DIPEA (0.6 wt / wt equivalent) was added over 60 minutes, followed by... Next, the second batch of N,N-DIPEA (1.5 wt / wt equivalent) is added over 60 minutes.

[0222] Next, (2S)-1-(3,5-difluorophenyl)-2-methylpiperazine (2.0 wt / wt equivalent, CAS Add (845740-76-3) over approximately 70 minutes while maintaining the temperature at 20-25°C, followed by methyl TH 50% propanephosphonic anhydride in F (3.6 wt / wt equivalent) while maintaining a temperature in the range of 20-25°C. Add it after approximately 2.5 hours.

[0223] Maintain the reaction mixture at 20-25°C for 45 minutes while stirring, then increase the batch temperature by 3 minutes per hour. The temperature was raised to 8-42°C, maintained for 2 hours and 15 minutes, and then cooled to 20-30°C.

[0224] Add purified water (4.9 wt / wt equivalent) to the reaction mixture and allow to stand for 70 minutes while maintaining the temperature in the range of 20-30°C. The mixture was added and kept at that temperature for another 15 minutes while stirring. Stirring was stopped and the phases were separated. A batch of a solution of 32% hydrochloric acid (0.3 wt / wt equivalent) in purified water (4.9 wt / wt equivalent) is added to the organic layer. The substance was added over 30 minutes while maintaining a temperature of 20-25°C during the addition process.

[0225] The batch is continuously stirred, then the stirring device is stopped, the phase is separated, and 5 wt% ammonium chloride is added. A nium aqueous solution (4.9 wt / wt equivalent) was added, and the batch was stirred at 20-25°C. Then, stirring was performed. The apparatus was stopped and the phases were separated. A 5 wt% ammonium chloride aqueous solution (4.9 wt / wt equivalent) was added again. The mixture was added, and the batch was stirred at 20-25°C. Then, the stirring device was stopped, and the phases were separated. The phase was washed again with purified water (4.9 wt / wt equivalent) to separate the organic phase, first at atmospheric pressure, then... Then, under vacuum, the mixture was distilled until the internal temperature reached a value higher than 101°C.

[0226] Next, the residue was diluted in methyl isobutyl ketone (1.4 wt / wt equivalent) and stirred for approximately 17 minutes for approximately 60 minutes. The mixture was heated to °C and then cooled to 20-25°C. The batch was filtered through a 0.5 μm cartridge. The cartridge was rinsed with methyl isobutyl ketone (1.4 wt / wt equivalent).

[0227] The resulting solution is heated to 58-62°C, and the batch is maintained at 58-62°C for 25 minutes. Then, diisopropyl ether (11.7 wt / wt equivalent) was added. Seed crystals were added to the solution, and diisopropyl Ropil ether was added three more times (2.6 wt / wt equivalents, 2.6 wt / wt equivalents, and 8.9 wt / wt equivalents). Then, the resulting suspension was cooled to 0-5°C over 14 hours. The resulting suspension was then left to cool for approximately 2 hours. The temperature is maintained, and then the solid is separated by centrifugation, and the pre-cooled diisopropyl alcohol is used. The compound was washed with ruether (8.9 wt / wt equivalent) and dried at 48°C for 20 hours to obtain the title compound.

[0228] (1.4.2. Morphology II - Protocol 4) Amorphous compound 1 (approximately 50 mg) is dissolved in methanol or ethanol, and the cap is closed. The solution was stirred in a vial for 30 minutes to obtain a clear solution. Then, while stirring, water (0.5 mL to 1 mL) was added. 5 mL was added, and compound 1 was precipitated as form II.

[0229] (1.4.3. Morphology II - Protocol 5) Amorphous compound 1 (498 mg) and 5 mL of MTBE were stirred until a clear solution was obtained, and then Then, the mixture was stirred for another 3 hours to precipitate compound 1 as form II, which was then separated by filtration. And finally, it was dried.

[0230] (1.5. (5S)-Cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-pipera Preparation of polymorph III of din-1-yl]-3-oxo-propyl]imidazolidinedione-2,4-dione) Amorphous material (200 mg) is slurryed in MTBE (400 μL) at room temperature. Crystals of form 3 are obtained. To accelerate the transformation, seed crystals of form 3 may be added to the mixture after 2 hours of stirring. After 3 days, The solid is air-dried and analyzed by XPRD, TGA, and DSC.

[0231] Polymorphic form III was characterized by an XRPD as shown in Figure 15.

[0232] Polymorph III shows a transition at approximately 111-170°C (initial temperature), and more specifically, at 10°C / When heating from approximately 25°C at a rate of minutes, form III is heated in a perforated aluminum dish. It was characterized by a DSC that exhibited a transition to approximately 140°C, as substantially shown in Figure 16.

[0233] Polymorph III was characterized by thermogravimetric analysis (TGA) as substantially shown in Figure 17.

[0234] (Example 2. Stability test of the solid form of the present invention) The stability of the solid form of compound 1 as amorphous, form I, and form II is determined under various conditions. The evaluation was conducted as follows. The results are reported below. All three morphologies were shown to be stable. ru. [Table 2]

[0235] (Biological data) (Example 3. Pharmaceutical composition) (3.1. PK testing in humans) Tablets containing 30% or 50% of the drug in crystalline form I and crystalline form II, for healthy male subjects (Group 1) After a single oral administration of 300 mg of compound 1 under fasting and / or feeding conditions to 18 subjects (per subject) The concentration of compound 1 in human plasma was determined by the protein precipitation extraction method. Determined by liquid chromatography using tandem mass spectrometry (LC-MS / MS) detection. did.

[0236] The limit of quantification was 1 ng / mL. In each analysis, two QC samples were used along with the test sample. We analyzed it.

[0237] At various points in time, a blood sample (2 mL) was treated with lithium heparin to determine compound 1 in the plasma. The blood was collected in a tube and immediately cooled (ice bath). Within 30 minutes of blood collection, the cooled centrifugation was performed. Plasma was separated in the aircraft at 4°C for 10 minutes, yielding approximately 1,500g.

[0238] Pre-administration PK samples were collected within 15 minutes prior to administration, and then measured at the following time points: 0.5 hours, 1 hour, and 1.5 hours. Interval, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 4 Samples were collected at 8 hours and 72 hours. For all PK samples between 0.5 hours and 16 hours, a win rate of ±5 minutes was used. Dough was allowed; a window of ±30 minutes was permitted for samples between 24 and 72 hours.

[0239] All statistical analyses are performed using SAS® version 9.4 (or later) (SAS Institute, Ca). This is done using ry, NC, USA and / or Phoenix WinNonLin (version 8 or later) software. Ta.

[0240] All relevant data was documented using summary tables, figures, and target data lists.

[0241] The summary table includes, for continuous variables, the number of non-missing observations, the arithmetic mean, and the standard deviation of the arithmetic mean. (SD) and / or standard error (as applicable), median, minimum, and maximum values, and categorical data. For this, the number and percentage for each category are shown. For PK data, if the limit of quantification exceeds... The number of data points (applicable only to concentration), coefficient of variation (CV%), geometric mean, and Geometric CV% is also shown. In addition to the descriptive statistics summarized in the table, data is represented graphically. The data has been compiled. Unless otherwise noted, estimated statistics were interpreted at a two-sided 5% significance level. (Table I. PK measurement parameters for morphology I and morphology II) [Table 3]

[0242] When tested using this protocol, there was no difference in the median tmax for any of the tablets. However, compared to polymorphism I, an increase in plasma peak exposure (Cmax) was observed in polymorphism II. It was observed (under fasting conditions, for 30% and 50% content tablets, the results were 34% and 40%, respectively).

[0243] (Example 4. In vivo model) (4.1. Protein overload model, Nephrectomy model) This animal model evaluates the efficacy of the compounds of the present invention in kidney diseases, including renal fibrosis. This makes it possible.

[0244] (4.1.1. Materials) This study was conducted using Balb / c mice (Charles River).

[0245] All mice were raised under standardized conditions of a 12-hour day / 12-hour night light cycle. , standard solid feed (https: / / insights.envigo.com / hubfs / resources / data-sheets / 201 They were given "8-datasheet-0915.pdf" and had free access to water.

[0246] The animals were allowed to acclimate for at least a week before the procedure began.

[0247] In mice, a unilateral left-sided nephrectomy was performed via a short lateral incision under anesthesia.

[0248] Siamese control mice underwent only incisions. The mice were allowed to recover from surgery for 7 days.

[0249] (4.1.2. Experimental Protocol) Drug treatment was started one day before the protein overload was initiated.

[0250] Each mouse was administered 240 mg / twice daily (at 8:00 AM and 3:30 PM) by forced oral administration. Compound 1 kg / day or 10 mg / kg / day of lisinopril (lisinopril once, plus vehicle 1 Either (2 times) or vehicle alone (0.5% methylcellulose containing 2% Tween 80 - 2 times) They were given the right to do so.

[0251] Siamese mice were given the vehicle alone. Protein overload was administered at 2 mg / g body weight on day 1. Start with [amount] and increase to 15 mg / g on day 7, following the schedule below, with sterile filtration until day 14. Daily intraperitoneal injection of 450 mg / ml BSA solution in physiological saline (Sigma catalog A4919: low endotoxin). It was initiated by a shot: (Table II. Medication schedule for protein overload model and nephrectomy model) [Table 4]

[0252] The Siamese mice were given an equal volume of saline solution. After the last injection, the mice were kept for 24 hours. They were placed in metabolic cages for intermittent urine collection.

[0253] Next, the mice were anesthetized and then slaughtered. Blood samples were collected. The remaining right kidney... The sample was then perfused with PBS (Sigma 806552) + 10 mM EDTA (Invitrogen 15575-02-Stock 0.5M), and After that, it was excised and then incised laterally.

[0254] Half of it will be used for immunohistochemistry, as preparation for paraffin blocking. Place in phosphorus, lightly tap and dry the remaining half, and use liquid nitrogen for later proteomics analysis. I added it to the pot. I also removed the spleen and cut it in half for FFPE and proteomics.

[0255] (4.1.3. Statistical analysis method) All data were expressed as mean ± SEM. The results were analyzed using GraphPad Prism 8. For datasets > 8, the D'Agostino-Pearson Omnibus Normality Test is used. -The Pearson omnibus normality tests were performed to assess normality, and the Shapiro-Wilk test was performed. The analysis was performed on a dataset of <8. For multiple comparisons, Tukey's post-hoc correction was used. Parametric ANOVA or Kruskal-Wallis test with Dunn's post-hoc test ( Nonparametric data were used. The ELISA standard curve was used, where x is the logarithm of the standard concentration. The plots were generated using Gumoid4PL fit. Relative mRNA expression levels were expressed as 2-ΔCt using Livak. The calculation was performed using an equation. A confidence interval of 0.95, p ≤ 0.05, was applied to all statistical tests.

[0256] The following evaluation criteria: -Urine protein concentration mg / mL -Urinary protein / mg creatinine (mg / mg) - Serum protein concentration (mg / mL) - Urinary creatinine concentration (mg / dL) (mg / mL) - Serum creatinine concentration (mg / dL) -Serum urea concentration (mg / dL) - Versikine, NITEGE, ARGS dot blot - Immunohistochemistry: ADAMTS5, collagen I, collagen IV, fibronectin, CD45, complement C 3. F4 / 80 We measured it. (4.1.4. Results) When the above protocol was implemented, the following values ​​were measured on the 14th day (see Figure 21). (i) As shown in the table below, compound 1 showed statistically significant protein differences compared to the vehicle group. It showed improvement in leukemia (p<0.05, *): (Table III. Proteinuria in individual subjects - Figure 21) [Table 5] TIFF2026168117000011.tif80170 (Table IV. Statistical Analysis: Proteinuria - Figure 21) [Table 6]

[0257] (4.2. Duchenne muscular dystrophy MDX model) (4.2.1. Background) Male mdx mice are most commonly used in preclinical Duchenne muscular dystrophy (DMD) research. This is an animal model (McGreevy et al., 2015).

[0258] (4.2.2. Protocol Overview) A 5-week-old mdx mouse (Animal Resource Centre; Perth, WA, Australia) was placed in a 1 After a week of acclimatization, one of the four treatment groups or no treatment group is selected as shown in the table below. The animals were randomly assigned to one of two groups (15 animals per group). At the start of the study, these groups were divided into two groups. We matched the weight of the mussels. (Table V. Mdx Model Group Allocation) [Table 7]

[0259] After one week of acclimatization, i.e., at approximately 6 weeks of age, the following baseline measurements were performed: -TREAT-NMD Guidelines (https: / / treat-nmd.org / wp-content / uploads / 2016 / 08 / MDX-D Preclinical Duchenne muscular dystrophy research described in "MD_M.2.2.001.pdf" (nd) Grip strength according to standard operating procedures for use -Body composition analysis using an EchoMRI scanner - Spontaneous physical activity and whole body using the Promethion system to record respiratory gases (O2 and CO2) Metabolism was controlled in all treated mice (compound 1, prednisolone, or compound 1 + pre A decision was made regarding donisolone (or vehicle).

[0260] These measurements were taken during the treatment (approximately 10 weeks of age, i.e., at the 4-week mark of treatment) and at the end of the trial. At that time (approximately 15 weeks of age, i.e., at the 9-week treatment stage), the MDX mouse dystrophy was repeated. Evaluate the effects of compound 1, prednisolone, or compound 1 + prednisolone on pathological conditions. The long-term functional evaluation of muscle pathology in MDX mice was assessed, and drug treatment was found to be effective in treating dystrophy. We determined whether these physiological markers of muscle pathology altered their trajectories.

[0261] Untreated control mdx mice were restrained from the beginning to the end of the study. After a one-week acclimatization period, the group was... These mice also undergo baseline measurements of grip strength and body composition at approximately 10 weeks and 15 weeks of age. This was repeated at a certain age. In addition, these mice were regularly weighed and their urine was approximately Samples were collected at 6 weeks of age, approximately 10 weeks of age, and approximately 15 weeks of age.

[0262] At approximately 11-13 weeks of age (and 5-7 weeks after treatment), the pharmacokinetics of serum concentrations of compound 1 were measured. For analysis, 200 μL of blood was treated with compound 1 or compound 1 + prednisolone. It was taken from a mouse.

[0263] At this point, for each of the two treatment groups (compound 1 and compound 1 + prednisolone) , blood samples, at the following time points: - 0 hours (before administration, N=4 mice) - 0.25 hours after administration (N = 4 mice) - 2 hours after administration (N = 4 mice) - 6 hours after administration (N = 3 mice) It was collected there.

[0264] ECM remodeling (e.g., proteins that are substrates for ADAMTS-5 ECM proteins such as versican) Evaluate the effects of compound 1 or compound 1 + prednisolone on cleavage (Stupka et al., 2013). To evaluate, urine samples were collected three times at approximately 6 weeks of age, 10 weeks of age, and 15 weeks of age, i.e., treatment. Before, during, and after the procedure, matricine (degradation fragments of extracellular matrix proteins) It was collected for analysis.

[0265] After 9 weeks of treatment, MDX mice (n=3-4 per day) were subjected to a study on contractile function (hind limb (anterior tibia) and lateral movement). The study focused on the diaphragmatic muscles. The mice were treated with staggered timings, starting each week of the study. This was done with n=3-4 mice per treatment group.

[0266] (4.2.3. Contraction function test) The procedure for testing the contraction function of the anterior tibial and diaphragmatic muscles is described below. A standard procedure existed for the experiment.

[0267] To evaluate the contractile function of the tibialis anterior muscle in situ, mice were anesthetized and the tibialis anterior (TA) muscle was... The distal portion of the muscle and its tendons were exposed.

[0268] The tendon is tied with a top and bottom knot using a needle-attached suture, and then the distal tendon is cut. Furthermore, the distal portion of the TA muscle was cut so that it was free from the surrounding tissue. The sciatic nerve was then cut to the knee joint. It was then exposed from above. Next, the mouse was fixed proximal to a heated platform of the contraction device. The distal end of the TA is connected to an equal-force transducer (i) which is connected to a computer that records the output. It was securely attached to the lever arm mounted on the sometric force transducer. Throughout the entire duration of the performance test protocol, warmed saline solution was applied to the exposed muscles and nerve tissues. It is to be applied to the weave. Electrical pulses are applied to the sciatic nerve, which causes the TA muscle to contract, as well as this The contraction was measured and recorded using a force transducer.

[0269] Finally, the mice were sacrificed after the in situ contraction function test. The left and right TA muscles and extensor digitorum longus (E) muscles were examined. DL), soleus muscle, and quadriceps muscle were subjected to histological analysis, immunohistochemical analysis, and biochemical analysis. It was collected for analysis.

[0270] Blood samples were also collected to evaluate biomarkers for dystrophy muscle pathology.

[0271] In addition, the diaphragm and heart were also collected, and the diaphragm was subjected to a carbochemical test for ex vivo contraction function. The organisms were placed in organ cisterna that were bubbling with 5% CO2 and 95% O2.

[0272] Finally, long bones (femur and tibia) and vertebrae were also collected for further analysis.

[0273] (4.2.4. Biomarkers) Matricaine levels were measured in urine collected before, during, and after the procedure.

[0274] Plasma samples were also analyzed.

[0275] RNA-seq and muscle gene expression were evaluated in diaphragm and TA muscle samples collected using RNA-later.

[0276] (4.2.5. Skeletal muscle) This includes laminin (basement membrane marker) immunohistochemistry and quantitative imaging analysis, as well as muscle fiber size and The percentage of central nucleus muscle fibers (markers of damage and regeneration) was also analyzed.

[0277] Muscle progenitor cells and newly regenerated muscle fibers were also analyzed using desmin immunohistochemistry and quantitative imaging. It was evaluated by analysis.

[0278] Inflammatory markers such as CD68 (monocyte and panmacrophage marker) are analyzed using immunohistochemistry and terminating methods. The results were evaluated using quantitative image analysis.

[0279] For fibrosis markers, Sirius Red was used for collagen, and for ECM complex carbohydrates, F Luorecein isothiocyanate - wheat germ lectin (FITC-WGA), and collagen content Therefore, quantitative image analysis; histological examination using hydroxyproline assay It was analyzed.

[0280] Intramuscular adipocytes were evaluated as an initial assessment on muscle sections stained with hematoxylin and eosin (H&E). I counted them manually.

[0281] (4.2.6. Bones) Bone strength was evaluated by three-point flexion of the tibia.

[0282] The bone structure was evaluated by microctimetric CT analysis of the cortical and trabecular bone of the femur.

[0283] The structure of the epiphyseal cartilage plate was examined using hematoxylin and eosin (H&E) staining (femur) and quantitative imaging. The results were evaluated through analysis. GC treatment has detrimental effects on the epiphyseal cartilage.

[0284] Thigh tissue morphometry was performed on bone marrow adipose tissue (von Kossa); osteoblasts (ALP); and osteoclasts (TRAP). I went.

[0285] The vertebral structure was evaluated using μCT analysis.

[0286] (4.2.7. Results) When the above protocol was implemented, compound 1 showed statistically significant differences compared to the control group. This showed an improvement in muscular grip strength (Figure 22).

[0287] Furthermore, Duchenne dystrophy is associated with bone loss (Novotny et al., 2012). In contrast to the prednisolone treatment group, which is the standard treatment, statistically significant bone and tissue The volume was maintained (Figure 23). (Table VI. Grip strength results - Figure 22 (Vehicle (black circle), Compound 1 (black square), Prednisolone (upward black)) (Triangle), and compound 1 + prednisolone (downward black triangle)) [Table 8] Av g / g BW: Average power output per gram of body weight SD: standard deviation SEM: Standard error of the mean (Table VII. Measurement of bone loss - Figure 23) [Table 9]

[0288] (4.3. Rat CDHFD model) (4.3.1. Overview) A choline-deficient L-amino acid-limited high-fat diet model (CDHFD) exhibits fatty liver similar to that of the MCD diet. It is a model that develops inflammation, hepatic fibrosis, and hepatic cancer formation (Santhekadur et al., 2017). This is used to evaluate the compounds of the present invention.

[0289] (4.3.2. Animals) Upon introduction, the 8 animals are reared at 22°C ± 2°C and 55% ± 10% humidity using a 12-hour dark / light cycle. Male Wistar Han rats (Charles River, France), 1 week old, were given a standard solid feed diet (A124550K R, Research Diet, USA) or high-fat (45%) containing 0.1% methionine and 1% cholesterol. The subjects were fed a choline-deficient (CDHF) diet (A16092003, Research Diet, USA) for 12 weeks. All animals have access to filtered drinking water.

[0290] (4.3.3. Examination) Six weeks after introduction, the animals were assigned to either the control group or the test group. Homogeneous assignment To ensure this, rats were measured by their body weight, serum bilirubin and transaminase levels. The animals were randomly assigned to treatment groups by Bell. The test group animals received 50 mg / kg of the test compound. The patient was administered orally twice daily with 0.5% methylcellulose. The control group received a vehicle of similar volume. 10 mL / kg), i.e., standard feed for control group 1 (C1), and CD for control group 2 (C2, 12 weeks). HF feed and positive controls formulated in CDHF feed + 0.5% methylcellulose + 98.9% water. It is given (compound C, 12 weeks).

[0291] After slaughter (week 12), the activity of the test compound against the development of NASH was measured in plasma alanine aminotran. Spherase levels (ALT), serum alkaline phosphatase levels (ALP), and asparagus Evaluated by ginate aminotransferase (AST) levels, improved liver fibrosis (ELF) bio Evaluation is performed by quantitative marker analysis, and in the liver, histopathological examination of fibrosis and fatty liver is performed. Inspection (Sirius Red, Oil Red O), and lipid levels (triglycerides, non-esterified lipids). It is evaluated by the content of fatty acids (NEFAs, cholesterol), as well as the expression of fibrosis and inflammatory genes. Ta.

[0292] (4.3.4. Results) When this protocol was implemented, the dosage was 50 mg / kg, orally, twice daily, with 0.5% methylcellulose. The test compound administered during the procedure showed a decrease in serum AST (-27%) and α2-cell activity compared to the vehicle group. Consolidated levels of chloroglobulin (-63%), procollagen (-48%), and hyaluronan (-65%) A statistically significant decrease was observed. In the liver, the test compound showed a statistically significant decrease in liver fiber. The number of cases decreased by 48%.

[0293] (4.4. Graft-versus-host (cGvhD) lung model) (4.4.1. Overview) In this cGvHD model, fibrosis is defined as B10.D2(H2 d ) Donor mouse (Minor HLA mismatch) Allogeneic transplantation of bone marrow cells and spleen cells derived from (C) leads to BALB / c(H2 d ) Guided the mouse. Recipe Ent mice exhibit inflammation-driven skin and inflammatory diathesis similar to that seen in patients with rapidly progressive diffuse systemic sclerosis cutaneous disease. It can lead to the development of pulmonary fibrosis (Zerr et al., 2012).

[0294] Treatment was performed only after the onset of the initial clinical symptoms of scleroderma-associated cGvHD.

[0295] (4.4.2. Test Group) The following groups, each containing eight mice, were used in this study. - Syngeneic transplant placebo-treated control group: Syngeneic bone marrow and splenocyte transplantation (BALB / c(H2 d )→BALB / c(H2 d )) From the 21st to the 56th day after transplantation, methyaluronic acid Administration of 0.5% cellulose. - Vehicle-treated fibrosis group: Allogeneic bone marrow and splenocyte transplantation (B10.D2(H2) d )→BALB / c(H2 d )) From day 21 to day 56 after transplantation Then, 0.5% methylcellulose was administered. - A control group to evaluate the pre-treatment level of fibrosis induced by allograft: Allogeneic bone marrow and splenocyte transplantation (B10.D2(H2) d )→BALB / c(H2 d )) . After being slaughtered on the 21st, other Treatment was initiated in groups. - Treatment group: Allogeneic bone marrow and splenocyte transplantation (B10.D2(H2) d)→BALB / c(H2 d )) From day 21 to day 56 after transplantation Administration of the test compound of the present invention. - Positive control group: Allogeneic bone marrow and splenocyte transplantation (B10.D2(H2) d )→BALB / c(H2 d )) From day 21 to day 56 after transplantation Nintedanib is administered once daily at a dose of 50 mg / kg.

[0296] (4.4.3. Steady-state PK) For the group given the test compound on D20, the following was observed using the anticoagulant Li-heparin: Time points: Blood was collected from the tail veins of two animals at each time point before administration, and at 1, 3, and 6 hours.

[0297] The blood sample was stored on ice and centrifuged at approximately 3500 x g for 10 minutes at +4°C within one hour of collection. The plasma was transferred to a polypropylene tube and stored at -20°C.

[0298] (4.4.4. Sampling and Analysis) The animals were slaughtered two hours after the final dose, and samples were taken from the skin (3mm punch biopsy), lungs, spleen, and blood. Samples were collected for histological examination and gene expression analysis.

[0299] (4.4.5. Main Readouts) The anti-fibrotic effect on the skin determines skin thickness and damaged collagen (lesional collag). The analysis was performed by quantitative determination of (en) and staining of myofibroblasts.

[0300] If there is a positive effect on cutaneous fibrosis, then the effect on pulmonary fibrosis is considered to be Ashcroft Scotch. Collagen-coated surface using Alling, hydroxyproline content, and Sirius Red staining. The analysis was performed by quantifying the product.

[0301] (4.4.6. Analysis) Based on the raw data of individual animals, the mean for each group is determined, and the percentage from the disease control is calculated. The rate change was calculated. The treatment group was determined using Dunnett's measured (parametric) data. One-way ANOVA with post-hoc analysis, or scored (non-parametric) For the data (including the 'c' data), we used the Kruskal-Wallis test with Dunn's post-hoc analysis to study disease It was compared to a control group.

[0302] (4.4.7. Results) When this protocol was implemented, the dosage was 120 mg / kg, administered orally twice daily, with Tween 80 / methylcellulose. Compound 1 administered in 0.5% (2 / 98) rose phosphate resulted in a statistically insignificant reduction in skin thickness. However, a statistically significant decrease in myofibroblast count (-35%) and hydroxyprolyx in the skin was observed. It showed a decrease in n content (-8.3%).

[0303] In the lungs, compound 1 showed statistically significant differences compared to the vehicle group in Ashcroft. The study showed a decrease in the score (-1.3 times) and a decrease in collagen-covered lung area (-1.2 times).

[0304] (Conclusion) The foregoing description is illustrative and descriptive in nature, and does not describe the present invention or its preferred applications. Those skilled in the art will understand that this is intended to describe the method of application. Through the experiments, those skilled in the art will be able to see obvious modifications and You will recognize the changes. All such modifications that fall within the scope of the attached claims are , and is intended to be included therein. Therefore, the present invention is as described above. Furthermore, it is intended to be defined by the following claims and equivalents. Yes, they are. (References) [Table 10] TIFF2026168117000017.tif246170TIFF2026168117000018.tif63170

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.

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