Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof

Abstract

To provide solid forms comprising {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions comprising the solid forms, methods of making the solid forms, and methods of their use for the treatment of various diseases and / or disorders.SOLUTION: A crystalline compound (I) has an X-ray powder diffraction pattern comprising peaks at approximately 18.1±0.2, 20.3±0.2, 22.9±0.2, 24.0±0.2, and 26.3±0.2° 2θ, is anhydrous and unsolvated; contains less than 1 wt.% of other crystals of the compound (I) and less than 1 wt.% of amorphous compounds (I), and is at least 99.9% pure as measured by HPLC.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application was filed on November 15, 2013, the entire contents of which are incorporated herein by reference. This application claims the benefit of U.S. Provisional Patent Application No. 61 / 904,803.

[0002] 1. FIELD OF THEINVENTION Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid The present invention relates to compositions comprising one or more solid forms, methods for making the solid forms, and methods for treating various or associated diseases. Methods of their use for the treatment of conditions are provided herein. [Background technology]

[0003] 2. BACKGROUND OF THEINVENTION Given that changes in solid form can affect various physical and chemical properties, The identification and selection of solid forms of pharmaceutical compound (I) is complex and their properties are dependent on other important pharmaceutical properties. Among other things, benefits include processing, maintenance, storage, formulation, stability, and bioavailability. Possible pharmaceutical solids include crystalline solids, amorphous solids, and mixtures thereof. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by a lack of structural order. The desired class of pharmaceutical solids depends on the specific application; amorphous solids may be selected, for example, based on an enhanced dissolution profile, while crystalline A solid can have desirable properties, such as physical or chemical stability (e.g., SR Vippagunta et al. (Adv. Drug. Deliv. Rev., (2001) 48:3-26); L. Yu (Adv. See Drug. Deliv. Rev., (2001) 48:27-42).

[0004] Potential solid forms of the pharmaceutical compound (I), whether crystalline or amorphous, include single-component solids and multi-component solids. A monocomponent solid consists essentially of pharmaceutical compound (I) in the absence of other compounds. The diversity among single-component crystalline materials is such that multiple three-dimensional arrangements exist for a particular pharmaceutical compound. This could potentially arise from the phenomenon of polymorphism (see, for example, SR Byrn et al., "Solid-State Synthesis of Drugs"). "Solid State Chemistry of Drugs," (1999) SSCI, West Lafayette. The importance of discovering the body is that it is an HIV protease inhibitor formulated as a soft gelatin capsule. This was highlighted in the case of the drug ritonavir, which was marketed approximately two years after the product was released. Due to unexpected precipitation of a new polymorph with lower molecular weight, product It became necessary to withdraw it from the market (SR Chemburkar et al., Org. Process Re s. Dev., (2000) 4:413-417)).

[0005] Further diversity among the potential solid forms of a pharmaceutical compound arises from the possibility of multicomponent solids. Crystalline solids containing two or more ionic species are called salts (e.g., "handheld drug salts"). Handbook of Pharmaceutical Salts: Properties, Selection, and Uses (See "Chemical Analysis and Use," edited by PH Stahl and CG Wermuth, (2002), Wiley, Weinheim.) Additional species of multi-component solids that could potentially provide other property enhancements for the pharmaceutical compound or its salts. Classes include, for example, hydrates, solvates, cocrystals, and clathrates, among others (e.g., See, for example, SR Byrn et al., Solid State Chemistry of Drugs. (1999) SSCI, West Lafayette). In addition, multiple component crystal forms are potentially polymorphic. Polymorphism is when a given multicomponent composition exists in two or more three-dimensional crystal arrangements. The discovery of solid forms may aid in the development of safe, effective, stable, and marketable pharmaceutical compounds. This is extremely important in

[0006] A new class of prolyl hydroxylase inhibitors and hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors Their use for treating or preventing diseases ameliorated by modulation of hydroxylase includes No. 7,811,595, which is incorporated herein by reference in its entirety. The synthesis of such prolyl hydroxylase inhibitors is described in U.S. Pat. No. 12 / 0309977, which is incorporated herein by reference in its entirety. Such compounds inhibit HIF prolyl hydroxylases, thereby stabilizing HIFα. Stabilization of HIFα results in increased endogenous erythropoietin (EPO) production. One of the compounds is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino acetic acid ("Compound (I)"), and a method for producing the compound is disclosed in US Pat. No. 6,339,433 filed on Jun. 26, 2007. No. 7,811,595 (particularly Schemes I and II and the accompanying drawings of columns 15-17 and 25) See Synthesis Procedures), and U.S. Patent Application Publication No. 2012-0309977, filed June 5, 2012 ( No. 13 / 488,554 (see, inter alia, paragraphs

[0254] to

[0267] ), Each of these patents is incorporated herein by reference in its entirety. Summary of the Invention

[0007] (3. SUMMARY OF THEINVENTION) {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid ("Compound ( Provided herein is a solid form comprising "I)". In certain embodiments, the solid form comprises , the single component crystalline form of compound (I). In certain alternative embodiments, the solid form is Multi-component crystalline forms of Compound (I), including but not limited to salts, co-crystals, solvates, and hydrates. In other embodiments, the solid form may be a single component amorphous form of the free acid of Compound (I). In other embodiments, the solid form includes, but is not limited to, a salt of Compound (I). The solid form is a multi-component amorphous form that is not defined. anemia secondary to or associated with chronic renal disease, anemia secondary to chronic heart disease, idiopathic anemia of aging, Anemia of chronic disease, myelodysplastic syndromes, myelofibrosis, other aplastic or dysplastic anemias, Chemotherapy-induced anemia (causing chemotherapy to treat cancer, hepatitis C, or to inhibit bone marrow production) anemia resulting from blood loss; anemia resulting from iron deficiency; For the treatment or prevention of anemia resulting from vitamin B12 deficiency (sickle cell disease, or thalassemia) Methods of their use for the preparation of compounds of formula (I) and (II) are also provided herein. Other useful solid forms of Compound (I), including, but not limited to, polymorphs thereof. Certain embodiments are provided herein.

[0008] In certain embodiments, the present invention provides a compound having the X-ray powder diffraction pattern shown in FIG. Form A of substance (I): [ka] In certain embodiments, Form A of Compound (I) has a molecular weight of about 18.1, 20.3, 22.9, 24 having an X-ray powder diffraction pattern containing 1, 2, 3, 4, or 5 peaks at 26.3° 2θ, Crystalline Compound (I) is substantially free of other crystalline forms of Compound (I).

[0009] In certain embodiments, Form A of Compound (I) has a DSC thermogram of about 175.8° C. In certain embodiments, the thermal event at about 175.8° C. is a melting event. In certain embodiments, Form A of Compound (I) melts at about 175.8°C.

[0010] In certain embodiments, Form A of Compound (I) is present in an amount of less than about 15% by weight, less than about 10% by weight, or It contains about 5% by weight of another crystalline compound (I).

[0011] In certain embodiments, the present invention provides Form A of Compound (I): [ka] and having 1, 2, 3, 4, or 5 peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ. The crystalline compound (I) has an X-ray powder diffraction pattern including a crystalline compound (I) having substantially the same structure as the amorphous compound (I). The present invention relates to Form A of compound (I), which does not contain

[0012] In certain embodiments, Form A of Compound (I) has a DSC thermogram of about 175.8° C. In certain embodiments, the thermal event at about 175.8° C. is a melting event. In certain embodiments, the crystalline Compound (I) melts at about 175.8°C.

[0013] In certain embodiments, Form A of Compound (I) is present in an amount of less than about 15% by weight, less than about 10% by weight, or Contains less than about 5% by weight of amorphous compound (I).

[0014] In certain embodiments, the present invention provides crystalline Compound (I), such as Form A of Compound (I): [ka] which is determined by GC / MS to be a compound of formula (II): [ka] The present invention relates to crystalline Compound (I), such as Form A of Compound (I), which is substantially free of wherein the crystalline compound is less than about 100 ppm, less than about 50 ppm, less than about 10 ppm, In certain embodiments, the compound of formula (I) is present in an amount of less than or equal to 1 ppm. Crystalline Compound (I), such as Form A, contains an amount of Formula (II) that is less than detectable by GC / MS.

[0015] In certain embodiments, Form A of Compound (I) has a molecular weight of approximately 18.1, 20.3, 22.9, 24.0, and It has an X-ray powder diffraction pattern containing 1, 2, 3, 4, or 5 peaks at 26.3° 2θ.

[0016] In certain embodiments, Form A of Compound (I) has a DSC thermogram of about 175.8° C. In certain embodiments, the thermal event at about 175.8° C. is a melting event. In certain embodiments, the crystalline Compound (I) melts at about 175.8°C.

[0017] In certain embodiments, the present invention provides a method for the preparation of a pharmaceutical composition that is at least 99.5% pure as measured by HPLC. Form A of compound (I): [ka] Regarding.

[0018] In certain embodiments, Form A of Compound (I) has a molecular weight of approximately 18.1, 20.3, 22.9, 24.0, and It has an X-ray powder diffraction pattern containing 1, 2, 3, 4, or 5 peaks at 26.3° 2θ.

[0019] In certain embodiments, Form A of Compound (I) has a DSC thermogram of 175.8° C. In certain embodiments, the thermal event at about 175.8° C. is a melting event. In certain embodiments, Form A of Compound (I) melts at about 175.8°C.

[0020] In certain embodiments, Form A of Compound (I) is at least about 99.6% pure, at least At least about 99.7% pure, at least about 99.8% pure, or at least about 99.9% pure. In embodiments, purity can be determined, for example, by HPLC.

[0021] In certain embodiments, Form A of compound (I) is a compound of formula (II) as determined by GC / MS. thing: [ka] In certain embodiments, the crystalline compound is substantially free of or less than about 100 ppm, less than about 50 ppm, less than about 10 ppm, or less than 1 ppm of the compound of formula (II). In certain embodiments, Form A of compound (I) is present in an amount that is less than detectable by GC / MS. Contains formula (II).

[0022] In certain embodiments, the present invention provides Form B of compound (I): [ka] In regards to

[0023] It has the X-ray powder diffraction pattern shown in FIG.

[0024] In certain embodiments, the present invention provides Form B of compound (I): [ka] In regards to

[0025] It has the X-ray powder diffraction pattern shown in FIG.

[0026] In certain embodiments, Form A, Form B, and Form C of Compound (I) have the following dipolar ion groups: It exists in the following forms: [ka] .

[0027] Single component crystalline forms, multiple component crystalline forms, single component amorphous forms, and / or multiple component non-crystalline forms of Compound (I) Pharmaceutical compositions comprising the crystalloid form and a pharma- ceutical acceptable diluent, excipient, or carrier are also provided herein. In certain embodiments, the present invention provides Form A, Form B, or Form C of Compound (I). or Form C.

[0028] Further embodiments herein include methods for making, isolating, and / or characterizing the solid forms of the invention. This provides a method for [Brief description of the drawings]

[0029] (4. BRIEF DESCRIPTION OF THE DRAWINGS) [Figure 1] FIG. 1 shows an X-ray powder diffraction (XRPD) analysis of Compound (I), Form A.

[0030] [Diagram 2] FIG. 2 shows a polarized light microscopy (PLM) analysis of Compound (I), Form A.

[0031] [Diagram 3] FIG. 3 shows a thermogravimetric / differential thermal analysis (TG / DTA or TGA) analysis of Compound (I), Form A.

[0032] [Figure 4] FIG. 4 shows a differential scanning calorimetry (DSC) analysis of Compound (I), Form A.

[0033] [Diagram 5] FIG. 5 shows a dynamic vapor sorption (DVS) isotherm plot of Compound (I), Form A.

[0034] [Figure 6] FIG. 6 shows XRPD analysis of Compound (I), Form A, before and after DVS.

[0035] [Figure 7] FIG. 7 shows the particle size analysis of Compound (I), Form A.

[0036] [Figure 8] FIG. 8 shows the 1H NMR spectrum of Compound (I), Form A.

[0037] [Figure 9] FIG. 9 shows the IR spectrum of Compound (I), Form A.

[0038] [Figure 10] FIG. 10 shows the HPLC analysis of Compound (I), Form A.

[0039] [Figure 11] FIG. 11 shows an X-ray powder diffraction (XRPD) analysis of Compound (I), Form B.

[0040] [Figure 12] FIG. 12 shows an X-ray powder diffraction (XRPD) analysis of Compound (I), Form C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] 5. Detailed Description of the Invention (5.1 Definition) As used herein, the term "anemia" is art-recognized and means It is defined by the following hemoglobin thresholds: [Table 1] Anemia can occur due to chronic (e.g., anemia secondary to chronic kidney disease, anemia secondary to chronic heart failure, or due to aging) Idiopathic anemia, anemia due to chronic diseases such as inflammatory bowel disease or rheumatoid arthritis, myelodysplastic syndrome , myelofibrosis, and other aplastic or dysplastic anemias), subacute (e.g., cancer, hepatitis C, or It is induced by chemotherapy, such as chemotherapy to treat other chronic diseases that reduce bone marrow production. anemia induced by), acute (e.g., blood loss from wounds or surgery), nutrition-related (e.g., iron deficiency or Vitamin B12 deficiency), or hemoglobinpathies (e.g., sickle cell The causes of pulmonary embolism may be pulmonary edema, thalassemia, etc. As used herein, the term “Compound (I)” refers to the compound {[5-(3-chlorophenyl)-3- hydroxypyridine-2-carbonyl]amino}acetic acid, and compound (I) has the following structure: R [ka] . In certain embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine- 2-carbonyl]amino}acetic acid, but in certain alternative embodiments, the compound is {[5- Pharmaceutically acceptable (3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In certain alternative embodiments, the compound is {[5-(3-chlorophenyl) Specific alternative examples include solvates of 1-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In an embodiment, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl In certain preferred embodiments, the compound may be a hydrate of its parent compound, As used herein, the term "aromatic" refers to a compound that is in the form of a salt, solvate, or hydrate. As described above, Compound (I) can be used with any zwitterionic species as well as any pharma- ceutically acceptable zwitterionic species. Contains salt.

[0042] As used herein, the terms "prevent," "preventing," and "prevention" refer to It is recognized in the art that conditions, diseases, such as local recurrence, When used in connection with other conditions, such as and reducing the frequency of symptoms of the condition in the subject compared to a subject not receiving the composition. Compounds such as compound (I), or pharma- ceutical acceptable salts thereof, which induce or delay the onset of , solvates, or hydrates.

[0043] As used herein, the terms "treat," "treating," and "treatment" refer to The treatment of pathological conditions, such as those described herein, in a method of improving or stabilizing a subject's condition. The term "treat" refers to the reversal, alleviation, or cessation of symptoms, clinical signs, and underlying pathology. "Treatment" also refers to the eradication or amelioration of a disease or symptoms associated with the disease. In the same manner, such terms refer to Compound (I), or a pharma- ceutically acceptable salt, solvate or the like thereof. the spread or prevalence of such diseases resulting from the administration of the compound or hydrate to patients suffering from such diseases; refers to minimization of exacerbations.

[0044] As used herein, the term "pharmaceutical acceptable salts" refers to salts of inorganic acids and bases, as well as and salts prepared from pharma- ceutically acceptable non-toxic acids or bases, including organic acids and bases. Suitable pharma- ceutically acceptable base addition salts of compound (I) include lithium, calcium , magnesium, zinc, bismuth, ammonium (including alkyl-substituted ammonium), Suitable non-toxic acids include, but are not limited to, acetic acid, glutamic acid, and choline. Alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, Citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, Glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, Pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid Inorganic and organic acids such as carboxylic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Examples of salts include, but are not limited to, acids. Other examples of salts are well known in the art. For example, Remington's Pharmaceutical Sciences, 22nd Edition, Pharmaceuti See Cal Press, (2012).

[0045] As used herein, the term "hydrate" refers to a compound formed by bonding with non-covalent intermolecular forces. 5-(3-chlorophenyl)-3-hydroxypyridine, which further contains stoichiometric or non-stoichiometric amounts of water The term "amino-2-carbonyl" refers to acetic acid or a pharma- ceutical acceptable salt thereof.

[0046] As used herein, the term "solvate" refers to a compound that is bound by non-covalent intermolecular forces. 5-(3-chlorophenyl)-3-phenylpropanediol, further containing stoichiometric or non-stoichiometric amounts of a solvent other than water hydroxypyridine-2-carbonylamino}acetic acid or a pharma- ceutical acceptable salt thereof. do.

[0047] As used herein, the term "HIF prolyl hydroxylase" refers to a gene that is known in the art. HIF prolyl hydroxylases are recognized and may be abbreviated as "PHDs." These are also known as "prolyl hydroxylase domain-containing proteins" that can be used to are referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively. There are also three different PHD isoforms, PHD1, PHD2, and PHD3.

[0048] The terms "solid form," "solid forms," ​​and related terms are used herein to refer to Compound (I). As used herein, a physical substance that contains compound (I) that is not primarily in a liquid or gaseous state. Crystalline and amorphous forms are examples of solid forms. In one embodiment, The solid form is Form A. In another embodiment, the solid form is Form B. In the solid form, Form C.

[0049] The term "crystalline" and related terms used herein refer to a substance, component, product, or form that is When used to describe, the substance, component, or product is physically present as determined by X-ray diffraction. It means that the compound is qualitatively crystalline. For example, Remington's Pharmaceutical Sciences Pharmaceutical Sciences, 22nd ed., Pharmaceutical Press, (2012); United States Pharmacopeia, 30th ed. (2011).

[0050] The terms "crystalline form," "crystalline form," and related terms herein refer to a compound comprising a chemical compound. Refers to crystalline solid forms, polymorphs, solvates, hydrates, or other molecular complexes, salts, and solvates of salts. The present invention includes, but is not limited to, any of the above-mentioned compounds, hydrates of the salts, or other molecular complexes of the salts, or polymorphs thereof. The term "crystal form" may refer to a specific single or multicomponent crystalline form.

[0051] The terms "polymorph," "polymorphic form," and related terms herein refer to the same molecule, multiple molecules, Polymorphs refer to two or more crystalline forms that contain a molecule or ion in the crystal lattice. As a result of the sequence or conformation of the on, for example, the melting temperature, heat of fusion, solubility, Polymorphism may be exhibited by a compound having different physical properties, such as different dissolution rates and / or different vibrational spectra. The differences in physical properties include storage stability, compressibility, and density (important for formulation and product manufacturing), and dissolution This affects pharmaceutical parameters such as release rate (an important factor in bioavailability). Differences in stability may result from chemical reactivity (e.g., if the dosage form consists of a polymorphic form). When the polymorphs are mixed, they change color more quickly than when they are made up of different polymorphs. catalytic oxidation), or mechanical transformation (e.g., a kinetically favored polymorph is thermodynamically favored). tablets disintegrate on storage as the tablet converts to the more stable polymorphic form, or both (e.g. This may be due to the fact that some polymorphic tablets are more susceptible to breakdown in high humidity. As a result, in some extreme cases, polymorphic transformations can result in loss of efficacy, while in other extreme cases In addition, the physical properties of the crystals can be important in processing. For example, some polymorphs may be more prone to forming solvates or may require filtration to wash out impurities. Can be difficult to pour (e.g., particle shape and size distribution can vary between polymorphs) .

[0052] Techniques for characterizing crystalline and amorphous forms include thermogravimetric analysis (TGA), melting point, differential scanning calorimetry (DSC), and NMR. DSC, X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g. infrared ( IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy (e.g. , polarized light microscopy), hot stage optical microscopy, scanning electron microscopy Scanning electron microscopy (SEM), electron crystallography, dynamic vapor sorption (DVS), and quantitative analysis, particle size analysis (PSA), These include, but are not limited to, surface area analysis, solubility testing, and dissolution testing.

[0053] The terms "amorphous", "amorphous form", and related terms used herein are intended to This means that the substance, ingredient, or product is substantially non-crystalline as determined by X-ray diffraction. In certain embodiments, a sample containing an amorphous form of a substance is prepared by mixing other amorphous forms and / or may be substantially free of crystalline form.

[0054] As used herein, and unless otherwise specified, the terms "about" and "approximately" mean the same thing. When used in connection with a dosage, amount, or weight percent of a composition or dosage form ingredient, provides a pharmacological effect equivalent to that obtained from a given dose, amount, or weight percentage. The term "dosage, amount, or weight percent" refers to a dosage, amount, or weight percent that is recognized by those of skill in the art. The terms "about" and "approximately" when used in this context refer to the dosages specified, Within 15%, more specifically within 10%, more specifically within 5% of the amount or weight percent of the Dosages, amounts, or weight percents are contemplated.

[0055] As used herein, and unless otherwise specified, the terms "about" and "approximately" mean the same thing. A numerical value or range of values ​​provided to characterize a particular solid form, e.g., a specific temperature or does not describe a temperature range, e.g., melting, dehydration, desolvation, or glass transition temperature. changes in mass, e.g., changes in mass as a function of temperature or humidity; or the solvent or water content in terms of percentage; or, for example, IR or Raman When used in connection with peak position in an analysis by spectroscopy or XRPD, the value or While the range of values ​​describes a particular solid form, it is understood that the range of values ​​may be reasonable to one of ordinary skill in the art. Specifically, the terms "about" and "approximately" are used in this context. When used, a numerical value or range of values ​​refers, in certain embodiments, to the recited value or range of values. Changes within 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the range For XRPD, the values ​​given are ±0.2° 2-theta.

[0056] As used herein, an "effective amount" refers to an amount that provides a therapeutic effect in treating a disease or is Delay or minimize symptoms associated with any disease or condition described in this document. Compound (I) or a pharma- ceutically acceptable salt, solvate, or hydrate thereof sufficient to limit the Refers to the amount of a compound.

[0057] The terms "subject" and "patient" refer to primates (e.g., humans), bovine, ovine, and / or human mammals, unless otherwise specified. including, but not limited to, cats, rabbits, rats, mice, etc. In a specific embodiment, the term "animal" refers to a mammal, such as a mammalian animal. The subject or patient is a human. In certain embodiments, the patient is a patient suffering from a disease described herein. Having a disease or condition.

[0058] (5.2 Solid form) Certain embodiments of the present invention include a monocomponent compound comprising compound (I) having the chemical structure shown below:

[0023] In one embodiment, the compound is a medicament for the preparation of a pharmaceutical composition comprising: [ka] .

[0059] Compound (I) can be prepared in accordance with the teachings of this specification, including the methods detailed in the Examples below. Compound (I) can be synthesized or obtained by any method apparent to one skilled in the art. U.S. Patent No. 7,811, filed June 26, 2007, which is incorporated herein by reference in its entirety. ,595 (see, in particular, Schemes I and II and the accompanying synthetic procedures in columns 15-17 and 25). and U.S. Patent Application Publication No. 2012-0309977, filed June 5, 2012 (U.S. Patent Application No. 13 / No. 488,554 (see, inter alia, paragraphs

[0254] to

[0267] ). The solid form of compound (I) can then be produced from compound (I) prepared by such a process. It can be manufactured.

[0060] Certain embodiments of the invention are directed to treating anemia (e.g., anemia secondary to or associated with chronic kidney disease, Anemia secondary to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, bone Myelofibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemia (cancer, type C chemotherapy to treat hepatitis or other long-term drug therapies that reduce bone marrow production), Anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency, sickle cell anemia A single solid form of the free acid of compound (I) useful in the treatment or prevention of erythropoietinemia, thalassemia, or thalassemia. Accordingly, a patient suffering from anemia is provided with an effective amount of a solid form of Compound (I). Provided herein are methods for treating anemia, comprising:

[0061] A single component solid form of Compound (I) can be prepared in any manner apparent to one of skill in the art based on the teachings herein. Also, the single component solid form of Compound (I) can be prepared by the method detailed in the Examples below. It can be prepared according to the techniques, including the methods, described herein.

[0062] 5.2.1 Form A of Compound (I) Certain embodiments herein provide Form A crystalline form of Compound (I). Form A of compound (I) can be prepared, for example, as described in U.S. Pat. No. 7,811,523, filed Jun. 26, 2007. No. 95 (see, in particular, Schemes I and II and the accompanying synthetic procedures in columns 15-17 and 25); and U.S. Patent Application Publication No. 2012-0309977, filed June 5, 2012 (U.S. Patent Application No. 13 / 48 No. 8,554) (see, inter alia, paragraphs

[0254] to

[0267] ) The resulting compound (I) is then subjected to a crystallization procedure as described herein below. and can be obtained.

[0063] A representative XRPD pattern of Form A of Compound (I) is provided in Figure 1. In the present invention, Form A of Compound (I) is located at approximately the following positions: 9.8, 11.0, 13.3, 14.6, 14.8, 15. 0, 16.3, 16.4, 16.9, 18.1, 18.6, 19.7, 20.3, 22.0, 22.9, 23.3, 24.0, 24.2, 25.2 , 25.7, 25.9, 26.3, 26.8, 27.6, 28.3, 28.9, 29.6, 29.8, 30.3, 31.3, 32.2, 32.9, 34.1, 34.9, 35.2, 35.7, 36.2, 36.7, 37.2, 37.4, 37.7, 38.3, 38.6, and 38.9° 2θ In certain embodiments, the form of compound (I) is Form A is approximately at the following locations: 15.0, 18.1, 18.6, 19.7, 20.3, 22.9, 24.0, 24.2, 25.2 , 26.3, 26.8, 35.2, and 37.4° 2θ at 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, or 12, or 13. In certain embodiments, Form A of Compound (I) is characterized by an XRPD peak located at: The XRPD pattern included peaks at approximately 18.1, 20.3, 22.9, 24.0, 26.3, 26.8, and 35.2 degrees 2θ. In certain embodiments, Form A of Compound (I) has a molecular weight of approximately 18.1, 20.3, 22.9, or 30. , 24.0, and 26.3 degrees 2θ.

[0064] Representative thermal properties of Form A of Compound (I) are shown in Figures 3 and 4. Representative T The GA / DTA thermogram shows very little weight loss from ambient temperature, followed by approximately 22 Above 0°C, there is a significant weight loss, consistent with decomposition. It exhibits a single sharp endotherm with a offset.

[0065] A representative DSC thermogram shown in FIG. 4 has an onset of about 172.4°C and a peak of about 175.8°C. In certain embodiments, the thermal event at about 175.8° C. In certain embodiments, Form A melts at about 175.8° C. In embodiments, Form A is unsolvated. In certain embodiments, Form A is anhydrous. do.

[0066] Form A of Compound (I) has desirable properties for the synthesis, processing, and manufacture of pharmaceutical products containing Compound (I). For example, in certain embodiments, Form A of Compound (I) exhibits a favorable stability profile. It has excellent mechanical properties, which are important for processing and manufacturing.

[0067] In certain embodiments, Form A of Compound (I) is non-hygroscopic, e.g., can be stored at 90% relative humidity ( For example, in certain embodiments, the water sorption at RH is less than about 0.5%. When added, Form A has a pH of less than about 0.4%, less than about 0.3% when increased from about 0% to about 90% RH. In certain embodiments, Form A exhibits a mass increase of less than about 0.2% at about 0% to about 90% RH. When the moisture content is increased to 100%, the weight of the mixture increases by about 0.13%. ) After sorption analysis, the XRPD pattern of the Form A material does not change substantially. A representative dynamic vapor sorption (DVS) isothermal plot is shown in Figure 5. The moisture sorption analysis utilized an incremental profile from 20-90-20% relative humidity (RH) in 10% increments. At each step, the sample was stirred until a stable weight was achieved (99.5% step completion) or for 1000 min. After the sorption cycle is complete, the same procedure is followed, but The sample can be dried by lowering it completely to about 0% RH and then returning it to the starting point of 20% RH. .

[0068] In certain embodiments, Form A of Compound (I) is a small particle having a majority of particles less than 100 μm. In certain embodiments, Form A of Compound (I) comprises particles having an average diameter of less than 100 μm. A representative particle size analysis is presented in FIG.

[0069] In certain embodiments, Form A of Compound (I) is substantially pure. In the present invention, Form A of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, Both are about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity is can be determined, for example, by HPLC.

[0070] In certain embodiments, Form A of Compound (I) is determined by GC / MS to be a compound of formula (II): [ka] In certain embodiments, the crystalline compound is substantially free of Generally, the concentration is less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, and less than about 5 ppm. less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of the compound of formula (II). In one embodiment, Form A of compound (I) contains an amount of formula (II) that is less than detectable by GC / MS. .

[0071] In certain embodiments, Form A of Compound (I) is present in an amount of less than about 15% by weight, less than about 10% by weight, or Contains less than about 5% by weight of amorphous compound (I).

[0072] In certain embodiments, Form A of Compound (I) is present in an amount of less than 15% by weight, less than 10% by weight, or less than 5% by weight. Contains less than % by weight of other crystalline compound (I).

[0073] 5.2.2 Form B of Compound (I) Certain embodiments herein provide the Form B crystal form of Compound (I). Form B of compound (I) can be prepared, for example, as described in U.S. Pat. No. 7,811,523, filed Jun. 26, 2007. No. 95 (see, in particular, Schemes I and II and the accompanying synthetic procedures in columns 15-17 and 25); and U.S. Patent Application Publication No. 2012-0309977, filed June 5, 2012 (U.S. Patent Application No. 13 / 48 No. 8,554) (see, inter alia, paragraphs

[0254] to

[0267] ) The resulting compound (I) is then subjected to a crystallization procedure as described herein below. and can be obtained.

[0074] A representative XRPD pattern of Form B of Compound (I) is provided in Figure 11. In certain embodiments, Form B of Compound (I) is located at the following approximate positions: 8.6, 15.3, 18.6, 21.3, 22.7, 23.8, 2 The compound is characterized by XRPD peaks located at one or more of: 8.1, 8.1, and 30.0 degrees 2θ. Form B of Compound (I) has one of the following approximate positions: 8.6, 15.3, 22.7, and 28.1° 2θ. , 2, 3, or 4 located XRPD peaks.

[0075] In certain embodiments, Form B of Compound (I) is substantially pure. In the present invention, Form B of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, Both are about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity is can be determined, for example, by HPLC.

[0076] In certain embodiments, Form B of compound (I) is a compound of formula (II) as determined by GC / MS. thing: [ka] In certain embodiments, the crystalline compound is substantially free of Less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm , less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of the compound of formula (II). wherein Form B of compound (I) contains an amount of formula (II) that is less than detectable by GC / MS.

[0077] In certain embodiments, Form B of Compound (I) is less than about 15% by weight, less than about 10% by weight, or Contains less than about 5% by weight of amorphous compound (I).

[0078] In certain embodiments, Form B of Compound (I) is present in an amount of less than 15% by weight, less than 10% by weight, or less than 5% by weight. Contains less than % by weight of other crystalline compound (I).

[0079] 5.2.3 Form C of Compound (I) Certain embodiments herein provide the Form C crystalline form of Compound (I). Form C of compound (I) can be prepared, for example, as described in U.S. Pat. No. 7,811,523, filed Jun. 26, 2007. No. 95 (see, in particular, Schemes I and II and the accompanying synthetic procedures in columns 15-17 and 25); and U.S. Patent Application Publication No. 2012-0309977, filed June 5, 2012 (U.S. Patent Application No. 13 / 48 No. 8,554) (see, inter alia, paragraphs

[0254] to

[0267] ) The resulting compound (I) is then subjected to a crystallization procedure as described herein below. You can get more.

[0080] A representative XRPD pattern of Form C of Compound (I) is provided in Figure 12. In the present invention, Form C of Compound (I) is located at approximately the following positions: 7.2, 9.2, 11.1, 13.7, 14.3, 16.7 ,17.4,18.4,19.1,19.9,20.1,21.6,22.3,22.4,22.4,23.1,24.8,25.3,26.3, 26.6, 27.6, 27.9, 28.3, 28.9, 29.5, 30.3, 31.4, 31.5, 32.5, 33.7, 33.8, 36.0, 37 The compound is characterized by XRPD peaks located at one or more of 37.0, 37.5, 39.1, and 39.5 degrees 2θ. In embodiments, Form C of Compound (I) is present at approximately the following positions: 7.2, 17.4, 22.3, 22.4., XRPD peaks located at 1, 2, 3, 4, 5 or 6, 7, or 8 of 22.4, 28.9, 33.7, and 33.8° 2θ In certain embodiments, Form C of Compound (I) has a molecular weight of approximately 17.4, 22.3, and 22.4° 2θ. Form C of product (I) has an XRPD pattern further including an additional peak at approximately 22.4° 2θ. In certain embodiments, Form C of Compound (I) has a pH of approximately 7.2, 28.9, 33.7, and 33.8°2. It has an XRPD pattern that further includes a peak at θ.

[0081] In certain embodiments, Form C of Compound (I) is substantially pure. In the present invention, Form C of Compound (I) is at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, Both are about 99.8% pure, or at least about 99.9% pure. In certain embodiments, the purity is can be determined, for example, by HPLC.

[0082] In certain embodiments, Form C of compound (I) is a compound of formula (II) as determined by GC / MS. thing: [ka] In certain embodiments, the crystalline compound is substantially free of Less than about 100 ppm, less than about 75 ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm , less than about 3 ppm, less than about 2 ppm, or less than about 1 ppm of the compound of formula (II). In the present invention, Form C of compound (I) contains an amount of formula (II) that is less than detectable by GC / MS.

[0083] In certain embodiments, Form C of Compound (I) is less than about 15% by weight, less than about 10% by weight, or Contains less than about 5% by weight of amorphous compound (I).

[0084] In certain embodiments, Form C of Compound (I) is less than 15% by weight, less than 10% by weight, or less than 5% by weight. Contains less than % by weight of other crystalline compound (I).

[0085] 5.3 Manufacturing Method Certain embodiments herein provide crystalline Compound (I), such as Form A. In such a manner, Form A of compound (I) can be prepared, for example, as described in U.S. Pat. No. 7,811,595 and / or U.S. Pat. Compound (I) prepared according to application Ser. No. 13 / 488,554 is then reacted with the resulting compound (I) [ka] a) preparing a solution of Compound (I) in an organic solvent; b) supersaturating the solution to cause the formation of crystals; and c) isolating the crystals; The method can be obtained by subjecting the compound to a procedure comprising the steps of: wherein the crystalline Compound (I), such as Form A of Compound (I), is less than about 15% by weight, less than about 10% by weight, Forms of Compound (I), such as those containing less than about 5% by weight, or less than 1% by weight, of other crystalline Compound (I). The crystalline compound (I), such as A, is substantially free of other crystalline compounds of formula (I); or Crystalline Compound (I), such as Form A of Compound (I), is present at less than about 100 ppm, about 75 ppm, or less than about 100 ppm, as determined by GC / MS. Less than ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm and / or less than about 1 ppm of the compound of formula (II). Compound (I) was found to be a compound of formula (II) as determined by GC / MS: [ka] Substantially free of; or The crystalline compound (I) is less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, or less than 1% by weight. When the compound (I) is amorphous, the crystalline compound (I), such as Form A of the compound (I), is amorphous. The composition is substantially free of compound (I).

[0086] In certain such embodiments, the crystalline Compound (I) has at least It is at least 99.5% pure.

[0087] In certain such embodiments, the organic solvent is acetone, methyl isobutyl ketone , n-heptane, tetrahydrofuran, methyltetrahydrofuran (e.g. 2-methyltetrahydrofuran), and water, or any combination thereof. In certain such embodiments, the organic solvent is acetone.

[0088] In certain such embodiments, the process further comprises filtering the solution through a charcoal filter. In certain embodiments, such filtration further comprises filtering the compound. This can be done after preparing the organic solvent solution of (I). In certain embodiments, such filtration can be done after preparing the organic solvent solution of (I). Filtration can be carried out prior to making the solution supersaturated.

[0089] In certain embodiments, making the solution supersaturated can be achieved by adding an anti-solvent, cooling the solution, or This may include removing the residue, reducing the volume of the solution, solvent exchange, or any combination thereof. Super-saturation of a solution involves reducing the volume of the solution. In certain such embodiments, the volume reduction is performed by evaporation. In certain such embodiments, the step of reacting comprises the addition of an anti-solvent, the anti-solvent being water or In certain such embodiments, the solution is supersaturated. Methods for reducing the concentration of the solvent include cooling the solution and adding an anti-solvent. In an embodiment, supersaturating the solution includes solvent exchange and cooling the solution.

[0090] In certain embodiments, where the supersaturation of the solution involves a solvent exchange, the solvent exchange may be carried out under reduced pressure. In certain such embodiments, distillative solvent exchange is used. In this manner, acetone is exchanged for methyl isobutyl ketone.

[0091] In certain embodiments, where supersaturating the solution comprises cooling the solution, the solution , from about 19°C to about 25°C, or even from about 0°C to about 5°C.

[0092] In certain embodiments, the method comprises dissolving the solution in a crystalline form of Compound (I), such as Form A of Compound (I). ) seeding the mixture.

[0093] In certain embodiments, the method further comprises washing the crystals. In such an embodiment, the washing is performed with acetone, methyl isobutyl ketone, n-heptane, and and washing the crystals with a liquid selected from the group consisting of water, and any combination thereof. In certain such embodiments, the washing comprises washing with a combination of acetone and water. In certain alternative such embodiments, the washing is with methyl isobutyl ketone. Includes cleaning.

[0094] In certain embodiments, isolating the crystals comprises filtering the crystals. In an embodiment, the method further comprises drying the isolated crystals, optionally at elevated temperature and under reduced pressure. In certain such embodiments, the drying is carried out at a temperature of about 50° C. .

[0095] In a particular embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: a) preparing a solution of Compound (I) in an organic solvent; b) supersaturating the solution, causing the formation of crystals; and c) isolating the crystals; and optionally drying the crystals. A crystalline compound (I), such as Form A of compound (I), produced by a process comprising: [ka] Regarding. Crystalline Compound (I), such as Form A of Compound (I), is substantially free of other crystalline Compound (I); or Iwa Crystalline Compound (I), such as Form A of Compound (I), is a compound of formula (II), as determined by GC / MS: [ka] Substantially free of; or Crystalline Compound (I), such as Form A of Compound (I), is substantially free of amorphous Compound (I).

[0096] In certain such embodiments, the crystalline Compound (I) has at least It is at least 99.5% pure.

[0097] In certain such embodiments, the organic solvent is acetone, methyl isobutyl ketone , n-heptane, and water, or any combination thereof. In some embodiments, the organic solvent is acetone.

[0098] In certain such embodiments, the process comprises passing the solution through a charcoal filter. In certain embodiments, such filtration further comprises filtering the compound (I In certain embodiments, such filtration may be performed after preparing a solution of the organic solvent. This can be done prior to supersaturating the solution.

[0099] In certain embodiments, making the solution supersaturated can be achieved by adding an anti-solvent, cooling the solution, or This may include removing the residue, reducing the volume of the solution, solvent exchange, or any combination thereof. In certain such cases, supersaturating a solution involves reducing the volume of the solution. In an embodiment, the volume reduction is performed by evaporation. In certain such embodiments involving the addition of the anti-solvent, the anti-solvent is water. In one embodiment, supersaturating the solution comprises cooling the solution and adding an anti-solvent. In certain alternative such embodiments, supersaturating the solution includes adding This involves exchanging the medium and cooling the solution.

[0100] In certain embodiments, where the supersaturation of the solution involves a solvent exchange, the solvent exchange can be carried out under reduced pressure. In certain such embodiments, acetone is mixed with methyl isobutene to form a distillation solvent exchange. It is replaced by Chirketone.

[0101] In certain embodiments, supersaturating the solution comprises cooling the solution. is cooled to about 19°C to about 25°C, or even to about 0°C to about 5°C.

[0102] In certain embodiments, the process further comprises: subjecting the solution to a crystallization ( The method further comprises seeding the mixture with compound (I).

[0103] In certain embodiments, the process further comprises washing the crystals. In such an embodiment, washing may be performed by washing the crystals with acetone, methyl isobutyl ketone, n-hexane, or hexanes. and water, or any combination thereof. In certain such embodiments, the washing comprises washing with a combination of acetone and water. In certain alternative such embodiments, the washing comprises methyl isobutyl ketone. This includes cleaning with

[0104] In certain embodiments, isolating the crystals comprises filtering the crystals. In an embodiment, the process further comprises drying the isolated crystals, optionally at elevated temperature and under reduced pressure. In certain such embodiments, the drying is carried out at a temperature of about 50° C. can be.

[0105] In certain embodiments, Form B of Compound (I) can be prepared as described, for example, in U.S. Pat. No. 7,811,595 and / or U.S. Pat. or from compound (I) prepared according to U.S. Patent Application No. 13 / 488,554, and then the resulting compound ( I) [ka] a) preparing a solution of Compound (I) in acetonitrile; and b) evaporating the solvent. The compound can be obtained by subjecting the compound to a procedure including the steps of:

[0106] In certain embodiments, crystalline Compound (I), such as Form B of Compound (I), is less than about 15% by weight. , less than about 10% by weight, less than about 5% by weight, or less than 1% by weight of other crystalline compounds (I), etc. Crystalline Compound (I), such as Form B of Compound (I), is substantially free of other crystalline compounds of formula (I). or Crystalline Compound (I), such as Form B of Compound (I), is present at less than about 100 ppm, about 75 ppm, or less than about 100 ppm, as determined by GC / MS. Less than ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm and / or less than about 1 ppm of the compound of formula (II). Compound (I) was found to be a compound of formula (II) as determined by GC / MS: [ka] Substantially free of; or The crystalline compound (I) is less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, or less than 1% by weight. When the compound (I) is amorphous, the crystalline compound (I), such as form B of the compound (I), is amorphous. The composition is substantially free of compound (I).

[0107] In certain such embodiments, crystalline Compound (I), such as Form B of Compound (I), is prepared by HPL C. It is at least 99.5% pure.

[0108] In certain embodiments, Form C of Compound (I) can be prepared as described, for example, in U.S. Pat. No. 7,811,595 and / or U.S. Pat. or from compound (I) prepared according to U.S. Patent Application No. 13 / 488,554, and then the resulting compound Object (I) [ka] a) preparing a solution of compound (I) in 2-methyltetrahydrofuran; b) adding n-heptane; c) heating the suspension (e.g., to about 40-50° C.); d) cooling the suspension (e.g., to about 0-10° C.); and c) Isolating the crystals The compound can be obtained by subjecting the compound to a procedure including the steps of:

[0109] In certain embodiments, crystalline Compound (I), such as Form C of Compound (I), is less than about 15% by weight. , less than about 10% by weight, less than about 5% by weight, or less than 1% by weight of other crystalline compounds (I), etc. Crystalline Compound (I), such as Form C of Compound (I), is substantially free of other crystalline compounds of formula (I). or Crystalline Compound (I), such as Form C of Compound (I), is present at less than about 100 ppm, about 75 ppm, or less than about 100 ppm, as determined by GC / MS. Less than ppm, less than about 50 ppm, less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm Crystallization, such as Form C of Compound (I), such as containing less than about 1 ppm of the compound of Formula (II). Compound (I) was found to be a compound of formula (II) as determined by GC / MS: [ka] Substantially free of; or The crystalline compound (I) is less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, or less than 1% by weight. When the compound (I) is amorphous, the crystalline compound (I), such as form C of the compound (I), is amorphous. The composition is substantially free of compound (I).

[0110] In certain such embodiments, crystalline Compound (I), such as Form C of Compound (I), is prepared by HPL C. It is at least 99.5% pure.

[0111] In certain embodiments, the addition of n-heptane is for at least 30 minutes (e.g., from about 30 to about 60 minutes). In certain embodiments, the addition of n-heptane is carried over a period of about 40 to 50 minutes. In certain embodiments, the suspension is stirred for at least about 1 hour at 50° C. In certain embodiments, the mixture is heated to about 40 to 50° C. for about 0 to 1 hour (e.g., about 1 to about 2 hours). The suspension cooled to 0° C. is stirred for at least about 1 hour (for example, about 1 to about 2 hours). In certain embodiments, isolating the crystals comprises filtering the crystals. In the same manner, the filtered crystals were dissolved in cold n-heptane / 2-methyltetrahydrofuran (e.g., 6 :1) and dried. In certain such embodiments, drying is performed for about 50 min. The reaction is carried out under vacuum at a temperature below 100° C. (eg, about 50° C.).

[0112] (5.4 How to use) In certain embodiments, the present invention provides methods for treating HIF prolyl hydroxylases (e.g., PHD1, PH and / or PHD3). In accordance with the present invention, the compound ( I), such as Form A, Form B, or Form C, or any other solid form described herein. The present invention relates to a method comprising administering an effective amount of a solid form of Compound (I).

[0113] In certain embodiments, the present invention provides methods for treating HIF prolyl hydroxylases (e.g., PHD1, PH Methods for treating or preventing diseases or disorders that are improved by inhibiting The present invention relates to a method for treating a disease or disorder that is ameliorated by inhibiting HIF prolyl hydroxylase. The method includes administering to a patient suffering from a rheumatoid arthritis an effective amount of a solid form of Compound (I). In certain such embodiments, the present invention provides a method for treating a disease characterized by an improved immune system by inhibiting PHD1. The present invention relates to a method for treating or preventing a disease or disorder, the disease or disorder being improved by inhibiting PHD1. The method comprises administering to a patient having a disease or disorder that is associated with an effective amount of a solid form of Compound (I). In certain such embodiments, the present invention relates to a method for treating cancer by inhibiting PHD2. A method for treating or preventing a disease or disorder ameliorated by inhibiting PHD2, comprising: administering to a patient having a disease or disorder that is ameliorated by administering an effective amount of a solid form of Compound (I). In certain such embodiments, the present invention relates to a method comprising: A method for treating or preventing a disease or disorder that is ameliorated by inhibiting PHD3, comprising: A patient having a disease or disorder that is ameliorated by inhibiting The method further comprises administering a

[0114] In certain embodiments, the present invention provides methods for treating HIFα (e.g., HIF-1α, HIF-2α, and / or HIF A method for treating or preventing a disease or disorder that is ameliorated by stabilizing α-3α. and administering to a patient having a disease or disorder that is ameliorated by stabilizing HIFα an effective amount of the compound. Specific such embodiments include the above methods comprising administering a solid form of compound (I). In the above, the present invention relates to a method for treating a disease or disorder that is improved by stabilizing HIF-1α. The present invention relates to a method for preventing or inhibiting a disease or disorder that is ameliorated by stabilizing HIF-1α. administering to a patient having the disease an effective amount of a solid form of Compound (I). In certain such embodiments, the present invention provides improved HIF-2α signaling by stabilizing HIF-2α. The present invention relates to a method for treating or preventing a disease or disorder caused by inhibiting HIF-2α. administering to a patient having a disease or disorder to be improved an effective amount of a solid form of Compound (I). In certain such embodiments, the present invention relates to a method comprising stabilizing HIF-3α. The present invention relates to a method for treating or preventing a disease or disorder that is improved by stabilizing HIF-3α. and administering to a patient having a disease or disorder that can be ameliorated by the administration of an effective amount of the solid form of Compound (I). The present invention relates to a method comprising administering to a subject the

[0115] In certain embodiments, the present invention relates to reduced endogenous production of erythropoietin (EPO). A method for treating or preventing a disease or condition associated with decreased endogenous production of EPO, comprising administering to said patient a therapeutically effective amount of EPO. The method comprises administering to a patient having a disease or disorder associated with said disease an effective amount of a solid form of Compound (I). This relates to a method of

[0116] In certain embodiments, the present invention provides a method for treating anemia (e.g., secondary to or associated with chronic kidney disease). anemia due to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplasia syndrome, myelofibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemia (Chemotherapy to treat cancer, Hepatitis C, or other long-term drug therapy that reduces bone marrow production anemia due to blood loss, anemia due to iron deficiency, anemia due to vitamin B12 deficiency A method for treating or preventing anemia (anemia, sickle cell disease, or thalassemia), comprising administering to a patient having anemia The method comprises administering to the subject an effective amount of a solid form of Compound (I). In an embodiment, the present invention is a method of treating anemia, such as anemia secondary to chronic kidney disease. The method comprises administering to a patient suffering from anemia an effective amount of a solid form of Compound (I). It concerns the method.

[0117] In certain embodiments, the present invention provides a method for treating anemia in patients with anemia secondary to chronic kidney disease (CKD). and administering to the patient an effective amount of a solid form of Compound (I) for treating or preventing anemia secondary to CKD. In certain embodiments, the CKD is stage 1, 2, 3, 4, or 5 chronic kidney disease. In certain such embodiments, CKD is stage 3, 4, or 5 chronic kidney disease. In certain embodiments, the CKD is stage 1 chronic kidney disease. In certain embodiments, the CKD is stage 2 chronic kidney disease. In certain embodiments, the CKD is stage 3 chronic kidney disease. In certain embodiments, the CKD is stage 4 chronic kidney disease. In certain embodiments, the CKD is stage 5 chronic kidney disease. The patient is a pre-dialysis chronic kidney disease. In certain embodiments, the patient is a dialysis patient, These patients may be referred to as having end stage renal disease (ESRD). For anemia, such as anemia secondary to CKD or ESRD, epoetin alfa and epoetin beta Treatment with erythropoiesis-stimulating agents, including rhEPO products such as darbepoetin, or peginesatide. In certain embodiments, the patient may be refractory to prior treatment for anemia. whereas in certain alternative embodiments, the patient has previously been treated for anemia. Not yet.

[0118] In certain embodiments, the present invention relates to a method for treating or preventing a disease or disorder associated with angiogenesis. The method comprises administering to a patient having an angiogenesis-related disease or disorder an effective amount of compound (I In certain embodiments, the present invention relates to a method comprising administering a solid form of The present invention relates to a method for controlling angiogenesis, comprising administering to a patient an effective amount of a solid form of Compound (I). The method further comprises:

[0119] In certain embodiments, the present invention relates to a disease or condition affected by the levels of VEGF or GAPDH. The present invention relates to a method for treating or preventing a disorder, the method comprising administering to a patient a therapeutically effective amount of VEGF or GADPH. or a patient having a disorder, comprising administering to said patient an effective amount of a solid form of Compound (I). Regarding the law.

[0120] In certain embodiments, the present invention provides a method for promoting wound healing, comprising administering to a subject having a wound. The method comprises administering to the patient an effective amount of a solid form of Compound (I).

[0121] In certain embodiments, the present invention provides a method for increasing revascularization of damaged tissue or improving vasculature. The method for increasing the production of erythropoietin, comprising administering to a patient having damaged tissue an effective amount of compound (I). In certain embodiments, the present invention relates to a method comprising administering a cellular form of A method for vascularizing ischemic tissue, comprising administering to a patient having ischemic tissue an effective amount of a compound The method comprises administering a solid form of (I).

[0122] In certain embodiments, the present invention provides a method for promoting the growth of a skin graft substitute, comprising: administering to a patient having a skin graft an effective amount of a solid form of Compound (I), This relates to a method of writing.

[0123] In certain embodiments, the present invention promotes tissue repair in the context of guided tissue regeneration (GTR). A method comprising administering to a patient an effective amount of a solid form of Compound (I). Regarding.

[0124] In certain embodiments, the present invention relates to reduced endogenous production of erythropoietin (EPO). A method for treating a disease or condition associated with reduced endogenous production of EPO, comprising administering to said patient a In patients with a disease or condition, serum EPO levels are significantly increased compared to baseline serum EPO levels. without a significant increase in hemoglobin levels compared to the patient's baseline hemoglobin levels administering a sufficient number of consecutive doses of a solid form of Compound (I) to elevate the level of The present invention relates to a method comprising:

[0125] In certain embodiments, the present invention relates to reduced endogenous production of erythropoietin (EPO). A method for treating a disease or condition associated with reduced endogenous production of EPO, comprising administering to said patient a In patients with a disease or condition, serum EPO levels are significantly increased compared to baseline serum EPO levels. without a significant increase in hemoglobin levels compared to the patient's baseline hemoglobin levels administering a sufficient number of consecutive doses of a solid form of Compound (I) to elevate the level of The method further comprises:

[0126] In certain embodiments, the present invention relates to reduced endogenous production of erythropoietin (EPO). A method for treating a disease or condition associated with reduced endogenous production of EPO, comprising administering to said patient a In patients with a disease or condition, the patient is administered a steroid to significantly increase serum iron levels compared to baseline serum iron levels. The study was conducted to increase the patient's total iron-binding capacity (TIBC) without adding any additional iron. administering a sufficient number of consecutive doses of a solid form of Compound (I) to Regarding.

[0127] In certain embodiments, the present invention provides a method of treating or preventing anemia in a subject, comprising: a) administering to the subject an amount of an anemia inhibitor or inhibitor of the present invention; and / or b) restore or maintain the diurnal pattern of EPO serum levels; and / or and / or b) significantly increase hepcidin levels; and administering to the subject a medicamentously effective amount of a solid form of Compound (I). The method further comprises:

[0128] In certain embodiments, the present invention provides a method for treating non-severe anemia secondary to chronic kidney disease, congestive heart failure, and chronic kidney disease. and idiopathic anemia of aging. The method includes treating non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, In patients with anemia or age-related idiopathic anemia, the results showed that baseline hepcidin expression levels were significantly higher than baseline levels in the control group. The study improved patients' baseline serum hemoglobin levels without significantly reducing hepcidin expression. A sufficient number of consecutive doses were administered to elevate serum hemoglobin levels compared to the baseline. The method comprises administering a solid form of compound (I).

[0129] In certain embodiments, the present invention relates to a method for treating diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, Sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid artery disease vascular occlusive disease, chronic uveitis / vitreous inflammation, mycobacterial infections, Lyme disease, systemic erythritis Causes include erythematosus, retinopathy of prematurity, Eales' disease, Behcet's disease, retinitis, or choroiditis. ocular infections, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Talgart's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, external ophthalmopathy Atraumatic post-laser complications, diseases associated with rubeosis, and proliferative vitreoretinopathy (vitroe retinopathy), Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis , hemangioma, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid tumors or hematological tumors, acquired immune deficiency syndrome, skeletal and cardiac ischemia, stroke, coronary artery disease, A method for treating or preventing a disease or disorder selected from the group consisting of peripheral vascular disease and coronary artery disease. administering to a patient having such a disease or disorder an effective amount of a solid form of Compound (I). The method relates to the above method, comprising:

[0130] In certain embodiments, the solid form of Compound (I) is a solid form of Compound (I) as described in U.S. Pat. No. 6,393,346, filed on Jun. 13, 2013. Administration can be according to dosing regimens such as those disclosed in application Ser. No. 61 / 834,808.

[0131] 5.5 Combination Therapy In certain embodiments, the present invention provides a method for treating anemia, such as anemia secondary to chronic kidney disease. 1. A method for producing {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, comprising the steps of: The method further comprises administering the acid in combination with another pharmaceutical agent. This method may be achieved by the simultaneous, sequential, or separate dosing of the individual components of the treatment. Additionally, when administered as a component of such combination therapy, {[5-(3-chlorophenyl)-3-phenyl Hydroxypyridine-2-carbonylamino-2-acetic acid may be synergistic with other medicines. As a result, the daily dose of either or both of the components may be adjusted to any amount normally administered as monotherapy. Alternatively, the dosage of the component of such a combination therapy may be reduced compared to that of the component of such a combination therapy. When administered intravenously, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine The effects of benzo[a]acetic acid and other medicinal agents may be additive, so the daily dose of each component should be adjusted accordingly compared to monotherapy. The dosage of either component typically administered in a single dose is similar to or the same as that of either component normally administered in a single dose.

[0132] In certain embodiments, the present invention provides a method for treating anemia, such as anemia secondary to chronic kidney disease. 1. A method for producing {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, comprising the steps of: administering to a patient having anemia a compound which is an acid, wherein Compound (I) may optionally be combined with an iron supplement such as ferrous sulfate, ferrous gluconate, or ferrous fumarate. In certain such embodiments, the iron supplement is administered in combination with the At least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours after administration of the compound or even for at least 6 hours. In certain embodiments, the iron supplement is It is administered in an amount that maintains ferritin at a level of about 50 ng / mL to about 300 ng / mL. In one embodiment, the iron supplement is orally administered in a daily amount of at least about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered orally at a dosage of about 50 mg of elemental iron. In certain embodiments, the iron supplement is administered intravenously. The dose is administered continuously and / or indefinitely, such as for 42 or more consecutive days. In such cases, iron supplements are used to maintain ferritin at levels between about 50 ng / mL and about 300 ng / mL. In certain such embodiments, Compound (I) is administered daily. The amount is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a solid form of Compound (I). In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 6 Such daily doses may be administered once a day, twice a day, or three times a day, preferably once a day, orally. Can be administered orally.

[0133] In certain embodiments, the present invention provides a method for treating anemia, such as anemia secondary to chronic kidney disease. 1. A method for producing {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, comprising the steps of: administering to a patient having anemia a compound which is an acid, wherein Compound (I) may optionally be combined with an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic. In certain such embodiments, the ESA is administered in the presence of epoetin alfa, rhEPO products, including but not limited to erythropoietin beta, darbepoetin, or peginesatide. In certain such embodiments, the ESA is administered as salvage therapy. In an alternative embodiment, the ESA is administered continuously and / or indefinitely, such as for 42 or more consecutive days. In certain such embodiments, the daily dose of Compound (I) is about 150 mg, about 300 mg, or about 150 mg. , about 450 mg, about 600 mg, or about 750 mg of a solid form of Compound (I). In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The daily dose can be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0134] 5.6 Pharmaceutical Compositions The pharmaceutical compositions can be used to prepare individual, single unit dosage forms. The pharmaceutical compositions and dosage forms described herein may comprise any of the compounds provided herein or pharma- ceutical acceptable salts thereof. The present invention also includes, but is not limited to, the above-mentioned salts, solvates, or hydrates of the parent compound. may further contain one or more excipients.

[0135] In certain embodiments, pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. The suitability of a particular excipient for inclusion in a pharmaceutical composition or dosage form is provided. Various methods well known in the art may be used to administer the dosage form to a patient, including, but not limited to, the manner in which the dosage form is administered. For example, oral dosage forms such as tablets are not suitable for use in parenteral dosage forms. The suitability of a particular excipient depends on the specific active ingredient in the dosage form. For example, the decomposition of some active ingredients may be affected by the intake of certain excipients, such as lactose. may be accelerated by exposure to water

[0136] Lactose-free compositions are well known in the art and are described, for example, in the United States Pharmacopeia (USP) 25 In general, lactose-free compositions may contain excipients listed in NF20 (2002). , binders / fillers, and lubricants in pharma- ceutically compatible and pharma-ceutically acceptable amounts. In one embodiment, the lactose-free dosage form comprises the active ingredient, microcrystalline cellulose, pregelatinized denaturant, and / or glycerol. Contains pun and magnesium stearate

[0137] Anhydrous pharmaceutical compositions and dosage forms are also provided since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) may determine characteristics such as the shelf life or stability of a formulation over time. It has gained widespread acceptance in the pharmaceutical industry as a means of simulating long-term storage to determine For example, Jens T. Carstensen's article, Drug Stability: Principles and Practice (Dru g Stability: Principles & Practice), 2nd edition, Marcel Dekker, NY, NY, 1995, pp. See, e.g., 379-80. In fact, water and heat accelerate the decomposition of some compounds. Thus, Moisture and / or humidity are commonly present during the manufacture, handling, packaging, storage, shipping, and use of drug products. As common ingredients are encountered, the effect of water on a formulation can be very significant.

[0138] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Thus, anhydrous compositions, in one embodiment, can be protected from exposure to water. The compositions are packaged using known ingredients so that they can be included in suitable prescription kits. Examples of suitable packaging include hermetically sealed foils, plastics, unit dose containers (e.g., vials), Including, but not limited to, blister packs and strip packs.

[0139] Pharmaceutical compositions and dosage forms are also provided that include one or more compounds that reduce the rate at which an active ingredient decomposes. Such compounds are referred to herein as "stabilizers" and include ascorbic acid. These include, but are not limited to, antioxidants such as, pH buffers, or salt buffers.

[0140] The amounts and specific types of active ingredients in a dosage form, as well as the amounts and types of excipients, can also include, but are not limited to, It may vary depending on factors such as the route by which it is administered to a patient.

[0141] 5.6.1 Oral Dosage Forms Pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets (e.g., chewable tablets), caplets, Individual dosage forms, such as tablets, capsules, suspensions, and liquids (e.g., flavored syrups) Such dosage forms contain predetermined amounts of active ingredients and can be provided in any suitable form, including, but not limited to, pharmaceutical, pharmaceutical, or pharmaceutical compositions, as described herein. Generally, the Remington Science and Practice of Pharmaceutical Preparations is used. 's The Science and Practice of Pharmacy), 21st edition, Lippincott Williams & Wilki See ns (2005).

[0142] The oral dosage forms provided herein may be formulated according to conventional pharmaceutical compounding techniques to incorporate the active ingredient in at least one The formulation is prepared by intimately mixing with one or more excipients. The excipients are used to determine the desired formulation for administration. Depending on the form, a wide variety of forms may be used, e.g., in oral liquid or aerosol dosage forms. Suitable excipients include water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Solid oral dosage forms (e.g., powders, tablets, capsules, and capsules) Examples of excipients suitable for use in tablet formulations include starch, sugars, microcrystalline cellulose, etc. These include, but are not limited to, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0143] In one embodiment, the oral dosage form is a tablet or capsule, in which case the solid excipient is In another embodiment, tablets are coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by any method of pharmacy. The compositions and dosage forms comprise the active ingredients being uniformly and intimately attached to liquid carriers, finely divided solid carriers, or both. The product is prepared by mixing the ingredients thoroughly and then, if necessary, shaping the product into the desired presentation.

[0144] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing or molding powder or granules. The active ingredient in a free-flowing form such as granules, powder, or powdered sugar is optionally mixed with an excipient and compressed in a suitable machine. It can be prepared by

[0145] Examples of excipients that can be used in the oral dosage forms provided herein include binders, fillers, disintegrants, and For use in pharmaceutical compositions and dosage forms, including, but not limited to, disintegrants, and lubricants. Suitable binders include corn starch, potato starch, or other starches. , gelatin, gum acacia, sodium alginate, alginic acid, other alginates, Natural and synthetic rubbers such as powdered ragweed, guar gum, cellulose and its derivatives (e.g. , ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, carbo Sodium hydroxymethylcellulose), polyvinylpyrrolidone, methylcellulose, alpha-deoxycellulose Starch, hydroxypropyl methylcellulose (e.g., No. 2208, 2906, 2910), microcrystalline Examples of suitable cellulose esters include, but are not limited to, cellulose acetate, cellulose esters, cellulose acetate copolymer ...

[0146] Suitable forms of microcrystalline cellulose include AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-58. 1. AVICEL-PH-105 (FMC, American Viscose Division, Avicel Sales (Marx Hook, These include, but are not limited to, substances sold as “chemicals” (available from the European Commission) and mixtures thereof. A specific binder is a microcrystalline cellulose and calcium carbonate binder sold as AVICEL RC-581. A suitable anhydrous or low moisture excipient is a mixture of sodium carboxymethylcellulose and sodium carboxymethylcellulose. Excipients include AVICEL-PH-103™ and Starch 1500 LM. Other microcrystalline celluloses A suitable form is microcrystalline cellulose containing silica, e.g. PROSOLV 50, PROSOLV 90, PROSOLV This includes, but is not limited to, substances sold as HD90, PROSOLV 90 LM, and mixtures thereof. Not determined.

[0147] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include: Talc, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol Examples of such materials include, but are not limited to, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical composition is, in one embodiment, The binder or filler in the pharmaceutical composition is present in an amount of from about 50 to about 99% by weight of the composition or dosage form. In an embodiment, it is present in about 20 to about 30 weight percent of the pharmaceutical composition or dosage form. In another embodiment, the binder or filler in the composition is about 24 parts by weight of the pharmaceutical composition or dosage form. It exists in 10 cents.

[0148] In certain embodiments, the filler is a block copolymer of ethylene oxide and propylene oxide. Such block copolymers include, but are not limited to, poloxamers. Poloxamer 188NF, Poloxamer 237NF, and Pluronic are available. Poloxamer 338NF, Poloxamer 437NF, and mixtures thereof. In certain embodiments, poloxamer 188NF, poloxamer 237NF, poloxamer Poloxamer, including but not limited to poloxamer 338NF, poloxamer 437NF, and mixtures thereof. Mer or Pluronic is a surfactant.

[0149] In certain embodiments, the bulking agent is isomalt, lactose, lactitol, mannitol, may include sorbitol, xylitol, erythritol, and mixtures thereof. , but not limited to these.

[0150] Disintegrants are used in the composition to provide a tablet that disintegrates when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage. Conversely, those that contain too little disintegrant will not disintegrate at a desired rate or under the desired conditions. Therefore, it is important not to use too much or too little, which can adversely alter the release of the active ingredient. A sufficient amount of disintegrant may be used to form a solid oral dosage form without causing any disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In an embodiment, the pharmaceutical composition comprises about 0.5 to about 15% by weight of a disintegrant, or about 5 to about 9% by weight of a disintegrant. or about 1 to about 5% by weight of a disintegrant, or about 1 to about 7% by weight of a disintegrant, or about 7% by weight of a disintegrant Contains:

[0151] Disintegrants that can be used in the pharmaceutical compositions and dosage forms include agar, alginic acid, calcium carbonate. , microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, povidone Lacrilin potassium, sodium starch glycolate, potato or tapioca Starch, other starches, pregelatinized starch, other starches, clay, other algins, etc. Cellulosics, gums, and mixtures thereof.

[0152] Glidants and / or lubricants that can be used in pharmaceutical compositions and dosage forms include Calcium stearate, magnesium stearate, mineral oil, light mineral oil glycerin, sorbitol, mannitol, polyethylene glycol, other glycosyl Stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc Hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, tofu oil, etc.) Corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate Examples of suitable glycerols include, but are not limited to, ethyl laureate, agar, and mixtures thereof. Additional flow enhancers include, for example, siloid silica gel (AEROSIL 200, WR Grace, Inc., Baltimore, MD). (manufactured by Degussa, Plano, TX), synthetic silica coagulation aerosol (commercially available from Degussa, Plano, TX), CAB-O - SIL (a calcined colloidal silicon dioxide product sold by Cabot Corporation, Boston, MA), and Glidants and / or lubricants, if used at all, include mixtures thereof. may be used in an amount of less than about 1 weight percent of the pharmaceutical composition or dosage form into which it is incorporated.

[0153] In certain embodiments, the oral dosage form comprises the compound, silica-containing microcrystalline cellulose, dextran, Sodium starch glycolate, block copolymer of ethylene oxide and propylene oxide Contains sodium stearyl fumarate and colloidal silicon dioxide. In an embodiment, the oral dosage form contains Compound (I) in an amount of about 5% to about 75% by weight of the oral dosage form. Sodium starch glycolate in an amount of about 15% to about 85% about 2% to about 10% of a block copolymer of ethylene oxide and propylene oxide in an amount of about 2% to about 10%, sodium stearyl fumarate in an amount of 0.2% to about 2%, and colophony The silica gel composition contains about 0.2% by weight to about 2% by weight of silica gel.

[0154] In certain embodiments, the oral dosage form comprises the compound, microcrystalline cellulose, isomalt, Sodium Starch Glycolate, Sodium Lauryl Sulfate, Povidone, Colloidal Diacid In certain embodiments, the oral dosage form contains silicon dioxide, silicon carbide, and magnesium stearate. The oral dosage form contains compound (I) in an amount of about 40% to about 50% of the oral dosage form, and microcrystalline cellulose in an amount of about 40% to about 50% of the oral dosage form. 0% isomalt, 0% to about 5% sodium starch glycolate, about 10%, sodium lauryl sulfate in an amount of 0.2% to about 2%, and povidone in an amount of about 2% to about 10 %, colloidal silicon dioxide in an amount of 0.1% to about 1%, and magnesium stearate. The amount of the rubber is about 0.1% by weight to about 1% by weight.

[0155] In certain embodiments, the present invention provides a method for administering a medicament comprising administering from about 100 mg to about 1,200 mg, about 200 mg to about 1,000 mg, about 40 The present invention relates to a unit dosage form comprising from about 0 mg to about 800 mg, or from about 450 mg to about 600 mg of Compound (I).

[0156] In certain embodiments, the present invention provides a method for the preparation of a pharmaceutical composition comprising administering to a patient a dosage of about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150, or even about 1,200 mg of a solid form of Compound (I). In certain such embodiments, the unit dosage form comprises about 40 mg, About 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of a solid form of Compound (I). In certain such embodiments, the unit dosage form is a capsule containing about 15 In certain such embodiments, the single tablet comprises 0.0 mg of a solid form of Compound (I). The dosage form is a tablet containing about 315 mg of the solid form of Compound (I).

[0157] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, liquid Liquid dosage forms include preparations, suspensions, syrups, and elixirs. Inert diluents, solubilizing agents, such as water or other solvents, commonly used in the art. and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol Recalls: Oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, Castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene and mixtures thereof. can.

[0158] Oral compositions can include, in addition to inert diluents, wetting agents, emulsifying and suspending agents, sweetening, flavoring agents, Adjuvants such as colorants, flavors and preservatives may also be included.

[0159] The suspending agent may contain, in addition to the active inhibitor(s), e.g., ethoxylated isostearyl alcohols. Alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose aluminium metahydroxide, bentonite, agar agar and tragacanth, and The composition may contain a suspending agent, such as a mixture of these. EXAMPLES

[0160] 6. Working Examples The following examples are offered by way of illustration and not by way of limitation. The following abbreviations are used in the description and examples: Used for: ACN: Acetonitrile Am: amorphous AS: ID of antisolvent crystallization experiment DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMA: Dimethylacetamide DMF: N,N-dimethylformide DMSO: Dimethyl sulfoxide DSC: Differential scanning calorimetry DTA: Differential Thermal Analysis DVS: Dynamic water vapor sorption EtOH: Ethanol FBRM: Focused Beam Reflectance Measurement HPLC: High-performance liquid chromatography IPA: 2-propanol LCMS: Liquid Chromatography with Mass Spectrometry MEK: Methyl ethyl ketone MeOH: Methanol MiBK: Methyl isobutyl ketone mp: melting point MS: Mass spectrometry MTBE: tert-butyl methyl ether MTBE: Methyl tert-butyl ether NMP: N-methyl-2-pyrrolidone NMP: N-methylpyrrolidinone NMR: nuclear magnetic resonance RH: Relative humidity RT: room temperature S: Solvent SDTA: Single Differential Thermal Analysis SM: starting material TA: Thermal analysis TCP: ID for thermal cycling and reflux experiments TGA: Thermogravimetric analysis THF: tetrahydrofuran TLC: Thin Layer Chromatography XRPD: X-ray powder diffraction

[0161] The following non-limiting example is compound (II): [ka] The present invention provides a method for producing highly pure compound (I) by removing

[0162] Chemical structure names were generated using ChemDraw Ultra (Cambridgesoft, Cambridge, MA). did.

[0163] 6.1 Form A of Compound (I) Compound (I) Form A precursor (10.01 g, 0.033 mol) was placed in a flask equipped with a mechanical stirrer, temperature probe, and nitrogen A 500 ml round bottom flask was placed in a flask equipped with a vacuum line. 50 ml of THF was placed in the 500 ml round bottom flask. The resulting mixture was stirred at room temperature until all solids were dissolved. 50 g of deionized water was added to the 500 1 ml round bottom flask and the mixture was cooled to 0-5°C.

[0164] 6.65 g of 50% by weight aqueous sodium hydroxide solution was mixed with 50 g of water to obtain a sodium hydroxide solution. While maintaining the temperature of the mixture at 0 to 5°C, the prepared sodium hydroxide solution was added. was slowly added to the 500 ml round bottom flask. The pH of the mixture was adjusted using the sodium hydroxide solution prepared. After addition of the ethanol solution, the temperature was 13. The mixture was warmed to 19-25°C and stirred for 1-2 hours (the mixture (You may need to stir longer.)

[0165] While maintaining the temperature of the reaction mixture below 25° C., a 37% by weight concentrated aqueous HCl solution is added to the reaction mixture. About 8.5 g of 37 wt % concentrated aqueous HCl was slowly added to the reaction mixture until the pH reached 5. Liquid was used.

[0166] The mixture was then concentrated to approximately 60 ml (55-65 ml is recommended). An additional 50 g of deionized water was added. was added and the mixture was stirred for about 2 hours.

[0167] The solid was collected from the mixture by filtration and washed with 20 g of deionized water. The solid material was air-dried until the solid mass was 0.001 g. The dried solid weighed 13.4 g. HPLC analysis showed This indicated that the purity of the solid was 99.46% (area %).

[0168] 6.1.1 Hydrothermal Trituration of Form A of Compound (I) The solid material obtained in section 6.1 was stirred in a flask equipped with a mechanical stirrer, temperature probe, and nitrogen line. 70 g of deionized water was added to the 500 ml round bottom flask, and the resulting The mixture was stirred at 70-80° C. for 16 hours. The mixture was cooled to room temperature, and the solid was separated from the mixture by filtration. The solid material was collected from the container and washed with 20 g of deionized water. The solid material was air-dried until mobile. did.

[0169] 6.1.2 Charcoal Treatment and Recrystallization of Form A of Compound (I) The solid material obtained in section 6.1 was stirred in a flask equipped with a mechanical stirrer, temperature probe, and nitrogen line. 130 g of acetone was added to the 500 ml round bottom flask, and the resulting mixture was The mixture was stirred at room temperature until all solids had dissolved (approximately 30 min). If the solids did not completely dissolve, Then, more acetone was added. The resulting solution was treated with activated charcoal. The charcoal was then removed by filtration. The resulting acetone solution was concentrated to approximately 73 ml (70-75 ml is recommended). The solution was heated to reflux. 65 g of water was slowly added while keeping the solution below 50° C. Precipitation of a light-colored solid was observed. The mixture was cooled to 22°C (19-25°C) over approximately 2 hours. The mixture was stirred at 22° C. for about 2 to 3 hours. The solid was collected from the mixture by filtration, and 11.5 g of acetone was added. The solid material was then washed with a mixture of 100 g of ethyl acetate and 15 g of deionized water. The solid material was allowed to air dry for at least 6 hours. The weight of the solid material was 9.2 g. HPLC analysis showed the purity of the solid to be 99.71% (area %). It was shown that...

[0170] 6.2 Solid Form A of Compound (I) 6.2.1 Characterization of Form A of Compound (I) XRPD analysis, illustrated in FIG. 1, indicates that Form A exhibits a peak at up to 40° 2θ on a reasonably flat baseline. It has sharp, well-defined peaks, indicating that it is predominantly crystalline. The peaks range from about 8° to 16° 2θ. The elevated background is a known artifact due to the sample holder. A list of X-ray diffraction peaks for Form A of Compound (I) is provided in Table 1 below.

[0171] Table 1. X-ray diffraction peaks of Form A of Compound (I) [Table 2]

[0172] The PLM analysis, shown in Figure 2, shows some birefringence under polarized light. However, the crystal is very very small and has no clearly defined morphology.

[0173] The TGA analysis, shown in FIG. 3, showed negligible weight loss from ambient temperature, followed by about 22 The DTA analysis, shown in Figure 3, shows a significant weight loss at 171.5 °C above 0 °C, consistent with decomposition. It exhibits a single sharp endotherm with an onset of

[0174] DSC analysis, shown in FIG. 4, shows a single peak with an onset of 172.4° C. and a peak at 175.8° C. It exhibits a sharp endotherm.

[0175] DVS analysis, shown in FIG. 5, showed that the water sorption at 90% RH was 0.13%, indicating that the material is non- The XRPD analysis after DVS, shown in Figure 6, shows no change in morphology. This indicates that:

[0176] The FBRM data shown in FIG. 7 indicates that the material has a majority of 100 as shown in the unweighted distribution. This indicates that it is made up of small particles smaller than 1 μm.

[0177] The solution NMR spectrum, shown in Figure 8, is consistent with the structure of compound (I). The rule is given in Figure 9.

[0178] The HPLC analysis depicted in FIG. 10 indicates the sample purity shown in Table 2.

[0179] Table 2. HPLC Purity of Form A of Compound (I) [Table 3]

[0180] (6.2.2 Solubility Experiments) Approximately 20 mg of Compound (I) Form A was placed into each of 48 vials and diluted in an appropriate solvent system. Five volume aliquots were added to the appropriate vials. Between each addition, the mixture was checked for dissolution. If no dissolution was evident, the mixture was warmed to about 50°C and checked again. This procedure was continued until either 0.01 was observed or 100 volumes of solvent had been added. The degrees are shown in Table 3.

[0181] Table 3. Solvent list for solubility experiments [Table 4] TIFF2025011163000029.tif223170

[0182] (6.2.3 Analysis method) XRPD analysis was performed on a Siemens D5000, scanning the samples from 3 to 50° 2θ. A sample of less than mg (depending on the material) was gently stirred on a glass disk inserted into the XRPD sample holder. The sample was then placed in a Siemens D5000 diffractometer operating in reflection mode, The analysis was performed using the following experimental conditions in Table 4. Calibration check was performed on a Siemens D5000 XRPD for aluminum. This was performed monthly using NaPowder Standard Reference Material 676a.

[0183] Table 4. X-ray powder diffraction (XRPD) experimental conditions [Table 5]

[0184] The peak values ​​in X-ray powder diffraction patterns may vary slightly depending on the instrument or sample. may vary and therefore values ​​quoted should not be construed as absolute. It should be understood that the measurement has acceptable variability, such as ±0.2 degrees 2-theta (e.g., Remington's Pharmaceutical Sciences, 22nd Edition, Pharmaceutical Sciences cal Press, (2012); United States Pharmacopeia, 30th ed., (2011).

[0185] Polarized light microscopy (PLM) was performed using a Motic camera and image capture software (Motic Images Plus 2 All images were taken with an Olympus BX50 polarizing microscope equipped with a 2.0-mm f / 2.0 aperture. All images were taken at 20x magnification unless otherwise noted. The images were recorded using an objective lens.

[0186] Thermogravimetry / differential thermal analysis (TG / DTA) was performed using a simultaneous thermogravimetry / differential thermal analyzer. Accurately weigh the following (depending on the substance) into an open aluminum pan and place in the analyzer. The sample was then heated from 25° C. to 300° C. at a rate of 10° C. / min, during which The change in sample weight was recorded along with the differential thermal events (DTA). Nitrogen was used as the purge gas at 100 cm 3 / min The TGA furnace was then cooled to room temperature before being checked with an indium standard. The samples were cleaned monthly by burn-out. Weight checks were also performed monthly. DSC data was This may vary depending on the scan speed and sample pan geometry.

[0187] Differential scanning calorimetry (DSC) was performed on a Seiko DSC6200 equipped with a cooling device. (depending on the material) was accurately weighed into an aluminum DSC pan and covered with a perforated aluminum lid. The sample pan was then placed in a Seiko DS Once a stable heat flow response was obtained, the samples and standards were loaded into the C6200 at a scan rate of approximately 10°C / min. The specimen was heated to 220°C and the resulting heat flow response was monitored. Monthly temperature checks were performed using an indium standard test. The experiment was carried out using the materials.

[0188] Dynamic Vapor Sorption (DVS) was performed using the DVS-1 Dynamic Vapor Sorption Analyzer from Surface Measurement Systems. Approximately 10-20 mg of sample was placed on the wire mesh water vapor sorption pan of the balance. The samples were subjected to an increasing profile of 20-90% relative humidity (RH) in 10% increments and kept at a stable weight. Samples were added at each step until 99.5% step completion was achieved or 1000 minutes had elapsed. After the sorption cycle was completed, the same procedure was followed, but the temperature was lowered completely to approximately 0% RH and then finally to 20%. The sample was dried using a return to the starting RH. Weight change during the sorption / desorption cycle The hygroscopicity of the sample was determined by plotting the hygroscopicity of the sample. After the DVS analysis, the physical form of the sample changed. The solid was reanalyzed by XRPD to determine if any.

[0189] Focused beam reflectance measurement (FBRM) using a Mettler Toledo D600 probe for particle size analysis The probe was placed in a suspension of the material in approximately 200 ml of acetonitrile and the sample was stirred. While stirring, the chord length distribution by various counting statistics was monitored over several minutes. The performance test was carried out on the FBRM using a PVC standard and a fixed beaker stand. FBRM data may vary depending on solubility in the solvent system used.

[0190] Infrared spectroscopy (IR) was performed on a Bruker ALPHA P spectrometer. Sample materials were and directly from the material (i.e., KBr disk) using the following parameters in Table 5: The IR spectrometer was subjected to internal performance quality checks every month.

[0191] Table 5. Infrared spectroscopy (IR) experimental conditions [Table 6]

[0192] 1 H nuclear magnetic resonance ( 1 H NMR experiments were performed on a Bruker AV400 ( 1 The measurement was performed at a frequency of 400 MHz. 1 H NMR experiments were carried out in DMSO-d6 and samples were prepared at a concentration of approximately 1 mg / mL.

[0193] High performance liquid chromatography (HPLC) was carried out under the conditions in Table 6 and the gradient program in Table 7. did.

[0194] Table 6. High performance liquid chromatography (HPLC) experimental conditions [Table 7]

[0195] Table 7. High-performance liquid chromatography (HPLC) experimental gradient program [Table 8]

[0196] 6.3 Solid Form B of Compound (I) To prepare the solid form B of Compound (I), approximately 600 mg of Compound (I) was weighed into a 100 mL Duran flask. The solution was then poured into a clean 100 mL flask and dissolved in approximately 40 mL of acetonitrile. Filter into a glass beaker and place in a desiccator under vacuum until all solvent has been removed. XRPD analysis, illustrated in FIG. 11, indicates that Form B exhibits sharp, well-defined peaks on a reasonably flat baseline. The peaks are from about 8° to 16° 2θ, indicating that the crystal is predominantly crystalline. The observed background is a known artifact due to the sample holder.

[0197] TGA analysis of Form B showed a small weight loss of 1.2% between 100° C. and 130° C., followed by a 1.2% increase in mass above about 220° C. The DTA showed significant weight loss between 120 and 135°C. The onset at 171.5°C and the peak at 175.7°C were unclear. There was a major sharp endotherm with

[0198] DSC analysis showed a small exotherm with an onset of 109.2°C and a peak of 113.7°C. This was followed by a major sharp endotherm with an onset of 173.4°C and a peak at 176.2°C.

[0199] DVS analysis showed that the water sorption at 90% RH was 0.33%, indicating that the material is non-hygroscopic. XRPD analysis after DVS showed no change in morphology.

[0200] Form B exhibited favorable qualities such as crystallinity and a high melting point in addition to being anhydrous and non-hygroscopic. However, form B is metastable and can convert to form A in a slurry at elevated temperatures.

[0201] 6.4 Solid Form C of Compound (I) A solution of about 22% (g / ml) of compound (I) in 2-methyltetrahydrofuran was added to a small amount of n-heptane. Adding the mixture at 40-50°C for at least 30 minutes results in approximately 7% (g / mL) of 2-methyltetrahydrofuran (TTA) of compound (I). The suspension was stirred at 40-50°C for at least 1 hour, and then followed by slow cooling to 0-10° C. The suspension was stirred at 0-10° C. for at least 1 hour, The wet cake was washed with cold n-heptane / 2-methyltetrahydrofuran (6:1). Upon drying under vacuum at up to 50° C., Form C was formed as white crystals. RPD analysis demonstrated that Form C had a sharp, well-defined peak out to 40° 2θ on a reasonably flat baseline. and is predominantly crystalline.

[0202] 6.5 Pharmaceutical Compositions 6.5.1 40 mg, 200 mg, and 300 mg Capsule Formulations A capsule formulation can be prepared as follows: [Table 9]

[0203] 6.5.2 120 mg, 185 mg, 250 mg, and 315 mg capsule formulations A capsule formulation can be prepared as follows: [Table 10]

[0204] 6.5.3 150 mg tablet formulation A tablet formulation can be prepared as follows: [Table 11] Abbreviations: NF = National Formulary, USP = United States Pharmacopeia 1 Removed during processing

[0205] 6.5.4 315mg tablet formulation A 315 mg tablet formulation can be manufactured using wet granulation as follows: [Table 12]

[0206] 6.5.5 Alternative 315 mg tablet formulation A 315 mg tablet formulation can be manufactured using wet granulation as follows: [Table 13]

[0207] 6.5.6 100 mg tablet formulation A 100 mg tablet formulation can be manufactured using wet granulation as follows: [Table 14] Abbreviations: NF = National Formulary, USP = United States Pharmacopeia 1 Removed during processing

[0208] 6.5.7 250 mg tablet formulation A 250 mg tablet formulation can be manufactured using wet granulation as follows: [Table 15] Abbreviations: NF = National Formulary, USP = United States Pharmacopeia 1Removed during processing

Claims

1. Contains 1, 2, 3, 4, or 5 peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ Crystalline compound (I) having an X-ray powder diffraction pattern: 【Chemistry 1】 The crystalline compound (I) is substantially free of other crystalline compounds (I).

2. The crystalline compound (I) according to claim 1, containing less than 15% by weight of other crystalline compounds (I).

3. The crystalline compound (I) according to claim 2, containing less than 10% by weight of other crystalline compounds (I).

4. The crystalline compound (I) according to claim 3, containing less than 5% by weight of other crystalline compounds (I).

5. Contains 1, 2, 3, 4, or 5 peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ Crystalline compound (I) with X-ray powder diffraction: 【Chemistry 2】 The crystalline compound (I) is substantially free of an amorphous compound (I).

6. 6. The crystalline compound of claim 5, comprising less than 15% by weight of amorphous compound (I).

7. 7. The crystalline compound of claim 6, comprising less than 10% by weight of amorphous compound (I).

8. 8. The crystalline compound of claim 7, comprising less than 5% by weight of amorphous compound (I).

9. Crystalline compound of compound (I): 【Chemistry 3】 which is determined by GC / MS to be a compound of formula (II): 【Chemistry 4】 The crystalline compound of compound (I) is substantially free of

10. Contains 1, 2, 3, 4, or 5 peaks at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ 10. The crystalline compound of claim 9 having an X-ray powder diffraction pattern.

11. 11. The crystalline compound according to claim 9 or 10, comprising less than 100 ppm of the compound of formula (II).

12. 12. The crystalline compound of claim 11, comprising less than 50 ppm of the compound of formula (II).

13. 13. The crystalline compound of claim 12, comprising less than 10 ppm of the compound of formula (II).

14. 14. The crystalline compound of claim 13, comprising less than 1 ppm of the compound of formula (II).

15. Crystalline Compound (I) that is at least 99.5% pure as determined by HPLC: 【Chemistry 5】 。

16. 15. The crystalline compound (I) of claim 14, wherein the crystalline compound (I) is at least 99.6% pure as measured by HPLC. The crystalline compound described herein.

17. 17. The method of claim 16, wherein the crystalline compound (I) is at least 99.7% pure as measured by HPLC. The crystalline compound described herein.

18. 17. The method of claim 16, wherein the crystalline compound (I) is at least 99.8% pure as measured by HPLC. The crystalline compound described herein.

19. 18. The method of claim 17, wherein the crystalline compound (I) is at least 99.9% pure as measured by HPLC. The crystalline compound described herein.

20. As determined by GC / MS, the compound of formula (II): 【Chemistry 6】 The crystalline compound according to any one of claims 15 to 19, which is substantially free of:

21. 21. The crystalline compound of claim 20, comprising less than 100 ppm of the compound of formula (II).

22. 22. The crystalline compound of claim 21, comprising less than 50 ppm of the compound of formula (II).

23. 23. The crystalline compound of claim 22, comprising less than 10 ppm of the compound of formula (II).

24. 24. The crystalline compound of claim 23, comprising less than 1 ppm of the compound of formula (II).

25. 25. The crystalline compound of claim 24, comprising an amount of formula (II) that is less than detectable by GC / MS. 。

26. A pharmaceutical composition comprising the crystalline compound according to any one of claims 1 to 25.

27. 27. The pharmaceutical composition of claim 26, further comprising a pharma- ceutically acceptable carrier.

28. 26. An oral dosage form comprising the crystalline compound of any one of claims 1 to 25.

29. The crystalline compound according to any one of claims 1 to 25 is administered to a patient suffering from anemia. and

30. 28. Treating anemia, comprising administering to a patient suffering from anemia the pharmaceutical composition of claim 27. How to do it.

31. 31. The method of claim 29 or 30, wherein the anemia is anemia of chronic renal disease.

32. Crystalline compound (I) 【Chemistry 7】 A method for producing a) preparing a solution of Compound (I) in an organic solvent; b) supersaturating the solution to cause the formation of crystals; and c) isolating the crystals; Including, the crystalline Compound (I) is substantially free of other crystalline forms of Compound (I); or The crystalline compound (I) is determined by GC / MS to be a compound of formula (II): 【Chemistry 8】 is substantially free of; or The above method, wherein the crystalline compound (I) is substantially free of amorphous compound (I).

33. The crystalline compound (I) has 1, 2, 3, 4 dimers at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ.

33. The method of claim 32, having an X-ray powder diffraction pattern comprising at least one peak, or five peaks.

34. 3. The method of claim 2, wherein the crystalline compound (I) is at least 99.5% pure as measured by HPLC.

3. The method described in claim 3.

35. The organic solvent is selected from the group consisting of acetone, methyl isobutyl ketone, n-heptane, and water, and The method according to any one of claims 32 to 34, wherein the method is selected from any combination of the above.

36. 36. The method of claim 35, wherein the organic solvent is acetone.

37. 3. The method of claim 2, further comprising filtering the solution through a charcoal filter.

7. The method according to any one of claims 6 to 6.

38. The solution is made supersaturated by adding an anti-solvent, cooling the solution, decreasing the volume of the solution, 37. The method of claim 32, further comprising reducing The method according to any one of the preceding claims.

39. 40. The method of claim 38, wherein the volume reduction is performed by evaporation.

40. 39. The method of claim 38, wherein the anti-solvent is water.

41. The step of supersaturating the solution comprises cooling the solution and adding an anti-solvent. Item 41. The method according to item 38 or 40.

42. 4. The method of claim 3, wherein supersaturating the solution comprises solvent exchange and cooling the solution.

8. The method according to claim 8.

43. 43. The method of claim 42, wherein the solvent exchange comprises a distillation solvent exchange under reduced pressure.

44. 44. The method of claim 43, wherein acetone is exchanged for methyl isobutyl ketone.

45. The method of any one of claims 38 to 44, wherein the solution is cooled to about 19°C to about 25°C. Law.

46. 46. ​​The method of claim 45, wherein the solution is further cooled to about 0°C to about 5°C.

47. 47. The method of claim 32, further comprising seeding the solution. How to.

48. The method of any one of claims 32 to 47, further comprising washing the crystals.

49. The washing may be performed with acetone, methyl isobutyl ketone, n-heptane, and water, or any of these.

49. The method of claim 48, comprising washing with liquids selected from any combination.

50. 50. The method of claim 49, wherein the cleaning comprises cleaning with a combination of acetone and water.

51. 50. The method of claim 49, wherein the washing comprises washing with methyl isobutyl ketone.

52. 52. Any of claims 32 to 51, wherein isolating the crystals comprises filtering the crystals. The method described in claim 1.

53. Claims 32-52, further comprising drying the crystals, optionally at elevated temperature and under reduced pressure. The method according to any one of the preceding claims.

54. 54. The method of claim 53, wherein the drying is carried out at a temperature of about 50°C.

55. a) preparing a solution of Compound (I) in an organic solvent; b) supersaturating the solution to cause the formation of crystals; and c) isolating the crystals; A crystalline compound (I) produced by a process comprising: 【Chemistry 9】 And, The crystalline compound (I) is substantially free of other crystalline compounds (I); or The crystalline compound (I) is determined by GC / MS to be a compound of formula (II): 【Chemistry 10】 or The crystalline compound (I), which is substantially free of an amorphous compound (I).

56. The crystalline compound (I) has 1, 2, 3, 4 dimers at approximately 18.1, 20.3, 22.9, 24.0, and 26.3° 2θ.

56. The crystalline compound of claim 55, having an X-ray powder diffraction pattern comprising: 。

57. 6. The method of claim 5, wherein the crystalline compound (I) is at least 99.5% pure as measured by HPLC.

6. The crystalline compound according to claim 5.

58. The organic solvent is selected from the group consisting of acetone, methyl isobutyl ketone, n-heptane, and water, and The crystallization method according to any one of claims 55 to 57, selected from any combination of the following: Compound.

59. 59. The crystalline compound of claim 58, wherein the organic solvent is acetone.

60. 55 - Claims 55 - 56, further comprising filtering the solution through a charcoal filter.

59. The crystalline compound according to any one of claims 59.

61. The solution is made supersaturated by adding an anti-solvent, cooling the solution, decreasing the volume of the solution, 55-60. The method of claim 55, further comprising: The crystalline compound according to any one of claims 1 to 5.

62. 62. The crystalline compound of claim 61, wherein the volume reduction is performed by evaporation.

63. 62. The crystalline compound of claim 61, wherein the antisolvent is water.

64. The step of supersaturating the solution comprises cooling the solution and adding an anti-solvent. Item 64. The crystalline compound according to item 61 or 63.

65. 7. The method of claim 6, wherein supersaturating the solution comprises solvent exchange and cooling the solution.

2. The crystalline compound according to claim 1.

66. 62. The crystalline compound of claim 61, wherein the solvent exchange comprises a distillation solvent exchange under reduced pressure.

67. 67. The crystalline compound of claim 66, wherein acetone is exchanged for methyl isobutyl ketone.

68. The resultant of any one of claims 61 to 67, wherein the solution is cooled to about 19°C to about 25°C. Crystalline compound.

69. 69. The crystalline compound of claim 68, wherein the solution is further cooled to about 0°C to about 5°C.

70. 70. The method of claim 55, further comprising seeding the solution. A crystalline compound.

71. The crystalline form of any one of claims 55 to 70, further comprising washing the crystals. compound.

72. The washing may be performed with acetone, methyl isobutyl ketone, n-heptane, and water, or any of these.

72. The crystalline compound of claim 71, comprising washing with a liquid selected from any combination. 。

73. 73. The crystallization method of claim 72, wherein the washing comprises washing with a combination of acetone and water. Compound.

74. 73. The crystalline compound of claim 72, wherein the washing comprises washing with methyl isobutyl ketone. thing.

75. 75. The method of claim 55, wherein isolating the crystals comprises filtering the crystals.

3. The crystalline compound according to claim 1.

76. 76. The method of claim 55, further comprising drying the crystals, optionally at elevated temperature and under reduced pressure. The crystalline compound according to any one of claims 1 to 5.

77. 77. The crystalline compound of claim 76, wherein the drying is carried out at a temperature of about 50°C.

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