Pharmaceutical formulations for the treatment of diseases mediated by KDM1A

Abstract

Provided are pharmaceutical compositions comprising N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazol-1-yl)benzamide (Compound A) or a pharmaceutically acceptable salt thereof and at least one stabilizer, pharmaceutical formulations thereof, and methods for treating diseases or disorders associated with KDM1A activity.

Description

Technical Field

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 086,353, filed Oct. 1, 2020, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] Inhibition of the enzyme KDM1A (also known as lysine-specific demethylase 1, LSD1, flavin-containing amine oxidase domain-containing protein, AOF2, BRAF35-HDAC complex protein BHC110, FAD-binding protein BRAF35-HDAC complex) can sufficiently alter gene expression in cells to restore its proper physiological function or the physiological function of tissues, organs or the patient as a whole. This can be achieved by enhancing the transcription of one or more genes that are pathologically silenced, for example, as in some cancer cells and hereditary diseases, or by reducing the transcription of one or more genes involved in the pathological condition. Thus, inhibition of KDM1A may be useful in the treatment of diseases such as cancer and hereditary diseases such as Wilson's disease, cardiomyopathy and abnormal hemoglobinopathy.

[0003] Many therapeutic agents have been identified that alter the state of chromatin, and generally have effects that alter gene expression by directly or indirectly acting on enzymes. While the precise mechanisms of action are not all fully elucidated, these mechanisms can be inferred from our understanding of protein complexes involved in the activation of specific gene expression. These agents include 5'-azacitadine and 5'-aza-2'deoxycytidine (decitabine), which inhibit DNMT1, or other DNA methyltransferases known to be present in and active at promoter sites of silence genes such as the γ-globin promoter; vorinostat and panobinostat or other inhibitors of histone deacetylase (HDAC) enzymes; hydroxyurea (HU), valproic acid, and sodium butyrate, and their analogues, each of which can interfere with the activity of orphan nuclear receptors. All of these agents have benefited from some clinical use, primarily in the management of neoplastic diseases. While the clinical utility of some of these agents for other disease conditions has been demonstrated, they are not widely applied due to their relatively low therapeutic efficacy and toxicity.

[0004] The use of agents that inhibit the enzymatic activity of protein complexes bound to gene promoters may disrupt the repression of γ-globin gene expression, potentially resulting in increased levels of fetal hemoglobin, also known as hemoglobin F (HbF). Such targets include specific protein-protein contact interfaces, e.g., the NuRD complex and KDM1A; e.g., the DNA-binding recognition domains of NR2C1 and NR2C2; e.g., the ligand-binding domains of NR2C1 and NR2C2; enzymatic activity such as lysine demethylase, e.g., KDM1A; histone deacetylases (HDACs), e.g., HDAC1, 2, or 3; and DNA methyltransferases, e.g., DNMT1. [Overview of the project] [Problems that the invention aims to solve]

[0005] For example, in the case of cancer, there is still a need for compositions and methods that alter the pathological phenotype of cells, tissues, organs, or organisms by sufficiently altering gene expression in cells and tissues to restore cells or tissues to normal physiological functions, such as appropriate apoptosis, or by sufficiently inducing the expression of one or more genes to suppress the pathological condition. [Means for solving the problem]

[0006] The compound N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide, referred to herein as compound A or Cpd A, showed activity in inhibiting KDM1A.

[0007] A pharmaceutically acceptable salt of compound A was prepared and examined. The ditosylate salt of compound A, N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide ditosylate, referred herein as compound B or Cpd B, showed activity in inhibiting KDM1A.

[0008] Accordingly, the present inventors disclose novel formulations and methods for treating diseases associated with KDM1A activity.

[0009] N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A) or an pharmaceutically acceptable salt thereof, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, A pharmaceutical composition containing the following is provided.

[0010] A drug-acceptable salt of compound A, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0011] The tosylate salt of compound A, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0012] N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide ditosylate (compound B), At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0013] Pharmaceutical formulations including the formulations described herein are also provided.

[0014] A method for treating a disease or disorder associated with KDM1A activity in a patient in need thereof is also provided, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation described herein to the patient in need thereof.

[0015] A method for inhibiting KDM1A is also provided, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation described herein to a patient in need thereof.

[0016] A method for suppressing the proliferation of malignant myeloid cells in a patient who requires such suppression is also provided, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation described herein to the patient who requires such suppression.

[0017] These and other objects of the present invention are described in the following paragraphs. These objects should not be considered as limiting the scope of the present invention.

Brief Description of the Drawings

[0018] [Figure 1] Shows the manufacturing process of a 5 mg capsule of Compound B described in this specification. [Figure 2] Shows the manufacturing process of a 50 mg capsule of Compound B described in this specification. [Figure 3] Shows the tendency of impurities (vertical axis) over 20 weeks for a 5 mg formulation of Compound B in (a) white opaque capsules and (b) COLORISTA® capsules. [Figure 4] Shows the tendency of impurities (vertical axis) over 20 weeks for a 50 mg formulation of Compound B in (a) white opaque capsules and (b) COLORISTA® capsules. [Figure 5] Shows the release % (vertical axis) as a function of time (minutes, horizontal axis) for a 5 mg dose of Compound A in (a) white capsules containing crospovidone, white capsules without crospovidone, (c) COLORISTA® capsules containing crospovidone, and (d) COLORISTA® capsules without crospovidone. [Figure 6] Shows the manufacturing process of a 5 mg capsule of Compound B described in this specification.

Modes for Carrying Out the Invention

[0019] This detailed description is intended only to inform those skilled in the art regarding the present invention, its principles, and its practical applications so that they can adapt and apply the present invention in many forms so that they may be most suitable for the conditions of a particular use. This specification and its specific examples are shown for illustrative purposes only. Therefore, the present invention is not limited to the embodiments described in this patent application and can be variously modified.

[0020] Definitions Unless otherwise specified, the following terms used in this specification and the appended claims have the meanings set forth below.

[0021] As used herein, the term "API" means "active pharmaceutical ingredient." The APIs disclosed herein are N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A) or a pharmaceutically acceptable salt thereof.

[0022] As used herein, the term “pharmaceutical composition” means a composition comprising compound A or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0023] The term "pharmaceutically acceptable" is used adjectivally, meaning that the modified noun is suitable for use as a medicine or as part of a medicine for use in humans.

[0024] The term "subject" includes humans and other primates, as well as other mammals. In some embodiments, the subject is human.

[0025] The term "therapeutic dose" means the amount of an API or pharmaceutical composition in a reasonable benefit / risk ratio applicable to any medical treatment that is sufficient to treat a medical condition, disorder, or disease.

[0026] The terms “to treat,” “to treat,” and “treatment” mean methods of reducing or suppressing a medical condition, disorder, or disease and / or its associated symptoms.

[0027] "C max The term "peak concentration" refers to the peak concentration of a drug, particularly the maximum plasma / serum concentration measurement.

[0028] "T maxThe term "peak concentration" refers to the time it takes to reach the peak concentration.

[0029] AUC t The term "times" refers to the area under the plasma concentration-time curve, where t is the time point of the last measurable plasma concentration in the study.

[0030] AUC ∞ The term "times" refers to the area under the plasma concentration-time curve from time zero to infinity after a single dose.

[0031] The term “immediate-release” pharmaceutical formulation encompasses any formulation in which the rate of drug release and / or drug absorption from the formulation is not deliberately or intentionally slowed by galenic manipulation. Therefore, the term excludes formulations to which the drug is applied to provide a “modified,” “controlled,” “sustained,” “long-lasting,” “extended,” or “delayed” release. In this context, the term “release” encompasses the delivery (or presentation) of the drug from the formulation into the gastrointestinal tract, into the body's tissues, and / or into the systemic circulation.

[0032] As used herein, "approximately" means ±20% of the specified value, and more specifically, includes values ​​of ±10%, ±5%, ±2%, and ±1% of the specified value.

[0033] B. Active Ingredients (DRUG SUBSTANCE) The pharmaceutical compositions disclosed herein contain at least one pharmaceutically active ingredient: N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A or Cpd A) or a pharmaceutically acceptable salt thereof.

[0034] Compound A is given by the following formula: [ka] It holds.

[0035] Methods for producing compound A and its pharmaceutically acceptable salts are described in U.S. Patent No. 9,981,922, which is incorporated herein by reference.

[0036] Compound A may be present in pharmaceutical compositions in the form of an acid addition salt. Acid addition salts of free amino compounds can be prepared by methods well known in the art and may be formed from organic and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, p-toluenesulfonic acid, and benzenesulfonic acid. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Therefore, "pharmaceutically acceptable salts" of compound A are intended to encompass any and all acceptable salt forms.

[0037] The specific pharmaceutical compositions disclosed herein include compound A, and the ditosylate salt of N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide ditosylate (compound B or Cpd B).

[0038] Compound B is given by the following formula: [ka] It holds.

[0039] Where there is no specific mention of a particular pharmaceutically acceptable salt of compound A used herein, the dosage, whether expressed in milligrams, weight percent, or as a ratio with another component, should be interpreted as being based on the amount of compound A. For example, the reference to "20 mg of compound A or a pharmaceutically acceptable salt thereof" means the amount of compound A or a pharmaceutically acceptable salt thereof that provides the same amount of compound A as 20 mg of free compound A.

[0040] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is the free base of compound A.

[0041] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of compound A.

[0042] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is a tosylate salt of compound A. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is a ditosylate salt of compound A, i.e., compound B.

[0043] In some embodiments, the amount of compound A or its pharmaceutically acceptable salt is about 2 mg to about 100 mg. In some embodiments, the amount of compound A is about 2.5, about 5, about 10, about 20, about 30, about 40, or about 50 mg. In some embodiments, the amount of compound A is about 2.5, about 5, about 10, or about 20 mg. In some embodiments, the amount of compound A is about 2.5 mg. In some embodiments, the amount of compound A is about 5 mg. In some embodiments, the amount of compound A is about 10 mg. In some embodiments, the amount of compound A is about 20 mg. In some embodiments, the amount of compound A is about 30 mg. In some embodiments, the amount of compound A is about 40 mg. In some embodiments, the amount of compound A is about 50 mg. In some embodiments, the amount of compound A is about 60 mg. In some embodiments, the amount of compound A is about 70 mg. In some embodiments, the amount of compound A is about 80 mg. In some embodiments, the amount of compound A is about 90 mg. In some embodiments, the amount of compound A is about 100 mg.

[0044] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in an amount of about 2 to about 10% by weight as measured as free base. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in an amount of about 5% by weight as measured as free base.

[0045] In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in an amount of about 20–30% by weight as measured as free base. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in an amount of about 25% by weight as measured as free base.

[0046] Pharmaceutical composition This disclosure relates to providing compound A or a pharmaceutically acceptable salt thereof in a pharmaceutical composition that is pharmacologically effective and biocompatible. The pharmaceutical compositions disclosed herein are intended for pharmaceutical use in human subjects.

[0047] N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A) or a pharmaceutically acceptable salt thereof, and at least one stabilizer selected from citric acid, fumaric acid and tartaric acid. A pharmaceutical composition containing the following is provided.

[0048] A drug-acceptable salt of compound A, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0049] The tosylate salt of compound A, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0050] N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide ditosylate (compound B), At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, Pharmaceutical compositions containing the above are also provided.

[0051] In some embodiments, at least one stabilizer is present in an amount of about 2 to about 10% by weight. In some embodiments, at least one stabilizer is present in an amount of about 5% by weight.

[0052] In some embodiments, at least one stabilizer is present in an amount of about 20 to about 30% by weight. In some embodiments, at least one stabilizer is present in an amount of about 25% by weight.

[0053] In some embodiments, the composition comprises one or more fillers. In some embodiments, the one or more fillers are selected from silicified microcrystalline cellulose (PROSOLV® SMCC HD90), AVICEL® dry granulation excipient (AVICEL® DG), mannitol (PEARLITOL® 200), anhydrous lactose, and pregelatinized starch (STARCH® 1500).

[0054] In some embodiments, the filler is anhydrous lactose.

[0055] In some embodiments, the filler is AVICEL® DG.

[0056] In some embodiments, the filler is Starch 1500.

[0057] In some embodiments, the filler is a mixture of anhydrous lactose and AVICEL® DG.

[0058] In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 75 to about 90%. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 85%.

[0059] In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 35 to about 50%. In some embodiments, the filler is present in the pharmaceutical composition in an amount of about 45%.

[0060] In some embodiments, the composition comprises one or more disintegrants. In some embodiments, the one or more disintegrants are selected from croscarmellose sodium (AC-DI-SOL®), crospovidone XL (Polyplasdone® XL), and sodium starch glycolate (EXPLOTAB®). In some embodiments, the one or more disintegrants are POLYPLASDONE® XL (crospovidone).

[0061] In some embodiments, one or more of the disintegrants are present in the pharmaceutical composition in an amount of about 2 to about 10%. In some embodiments, one or more of the disintegrants are present in the pharmaceutical composition in an amount of about 5%.

[0062] In some embodiments, the composition comprises one or more lubricants. In certain further embodiments, the one or more lubricants are selected from magnesium stearate (HYQUAL®), sodium stearyl fumarate (PRUV®), and stearic acid (GENAR® Vegetable Grade 50). In some embodiments, the one or more lubricants are magnesium stearate.

[0063] In some embodiments, one or more of the lubricants are present in the pharmaceutical composition in an amount of about 0.1 to about 1%. In some embodiments, one or more of the lubricants are present in the pharmaceutical composition in an amount of about 0.5%.

[0064] In some embodiments, the composition comprises one or more binders. In certain further embodiments, the one or more binders are selected from hypromellose (Methocel® E3 Premium LV) and povidone K-30 (KOLLIDON® 30).

[0065] In some embodiments, the composition comprises one or more fluidizing agents. In certain further embodiments, the one or more fluidizing agents are selected from colloidal silicon dioxide (CAB-O-SIL®) and talc (Pharma 400 USP).

[0066] In some embodiments, the composition includes a coating. In certain further embodiments, the coating is polyvinyl alcohol, a partially hydrolyzed polymer system (OPADRY® Amb II).

[0067] In some embodiments, the composition is formulated by direct blending. In some embodiments, the composition is formulated by wet granulation blending.

[0068] In some embodiments, the composition includes the following:

[0069] [Table 1]

[0070] Compound A is measured as a free base.

[0071] In some embodiments, the composition includes the following:

[0072] [Table 2]

[0073] Compound A is measured as a free base.

[0074] In some embodiments, the composition includes the following:

[0075] [Table 3]

[0076] Compound A is measured as a free base.

[0077] In some embodiments, the composition includes the following:

[0078] [Table 4]

[0079] Compound A is measured as a free base.

[0080] In some embodiments, the composition includes the following:

[0081] [Table 5]

[0082] Compound A is measured as a free base.

[0083] In some embodiments, the composition includes the following:

[0084] [Table 6]

[0085] Compound A is measured as a free base.

[0086] In some embodiments, the composition includes the following:

[0087] [Table 7]

[0088] Compound A is measured as a free base.

[0089] In some embodiments, the composition includes the following:

[0090] [Table 8]

[0091] Compound A is measured as a free base.

[0092] In some embodiments, the pharmaceutical compositions disclosed herein are stable, for example, during storage, dispensing, and throughout the product's shelf life (e.g., up to two years at room temperature / ambient conditions). Stable pharmaceutical compositions may exhibit, for example, less degradation of the API and / or less degradation products. Degradation products that occur during storage of the active ingredient and / or pharmaceutical are undesirable and, in extreme cases, may even be harmful to patients treated with such pharmaceutical. Therefore, it is desirable to control degradation products in pharmaceuticals, particularly impurities that may be harmful.

[0093] Assays of pharmaceutical compositions and determination of degradation products may be performed using HPLC with UV detection. Assays of pharmaceutical compositions and determination of degradation products may be performed using GC or GC / MS detection.

[0094] The pharmaceutical composition may be evaluated for degradation products after storage for at least two weeks, at least one month, at least two months, at least three months, at least six months, at least twelve months, at least eighteen months, or at least twenty-four months. In particular, degradation products may be evaluated at time intervals of 1, 3, 6, 9, 12, 18, 24, 36, and / or 48 months. Storage conditions may be long-term, intermediate, or accelerated. In particular, storage conditions may be, for example, 25℃±2℃ / 40% relative humidity (RH)±5%RH, 25℃±2℃ / 60%RH±5%RH, 30℃±2℃ / 35%RH±5%RH, 30℃±2℃ / 65%RH±5%RH, 40℃±2℃ / 25%RH±5%RH, 40℃±2℃ / 75%RH±5%RH, 50℃±2℃ / 75%RH±5%RH, 60℃±2℃ / 5%RH±5%RH, 60℃±2℃ / 40%RH±5%RH, 70℃±2℃ / 5%RH±5%RH, 70℃±2℃ / 75%RH±5%RH, and / or 80℃±2℃ / 40%RH±5%RH.

[0095] Pharmaceutical preparations While it may be possible to administer the compounds disclosed herein as unprocessed chemical substances, it is also possible to provide them as pharmaceutical formulations.

[0096] Pharmaceutical formulations including the formulations disclosed herein are provided.

[0097] In some embodiments, the pharmaceutical formulation is a tablet. In some embodiments, the pharmaceutical formulation is a capsule. In some embodiments, the capsule is a COLORISTA® capsule.

[0098] Pharmaceutical formulations for oral administration include tablets, gelatin capsules, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be manufactured by compression or molding with one or more auxiliary components as optional. Compressed tablets may be manufactured by compressing an active ingredient in a readily flowable form such as powder or granules in a suitable machine and may be mixed as optional with a binder, an inert diluent or smoothing agent, a surfactant or dispersant. Molded tablets may be manufactured by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. Tablets may be optionally coated or scored and formulated to provide delayed, gradual or controlled release or absorption of the active ingredient therein. Compositions may further contain agents that enhance solubility or dispersibility. All formulations for oral administration should be in a dosage appropriate for such administration. Push-in capsules may contain the active ingredient in a mixture of a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added. The core of a sugar-coated pill is coated with a suitable coating. For this purpose, a concentrated sugar solution may be used and may optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated pill coating to identify or characterize various combinations of doses of the active compound.

[0099] How to use A method for treating a disease or disorder associated with KDM1A activity is provided herein, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient in need thereof.

[0100] In some embodiments, the disease or disorder is cancer.

[0101] In some embodiments, the disease is an inflammatory disease. In certain further embodiments, the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, or systemic lupus erythematosus.

[0102] In some embodiments, the disease or disorder is selected from sickle cell disease, thalassemia major, and other β-abnormal hemoglobin disorders.

[0103] In some embodiments, the disease or disorder is a globin-mediated disease.

[0104] In some embodiments, the disease or disorder is a myeloproliferative neoplasm. In certain further embodiments, the myeloproliferative neoplasm is selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). In certain further embodiments, myelofibrosis is selected from primary myelofibrosis and post-PV / ET myelofibrosis (PPV-MF and PET-MF).

[0105] A method for treating or preventing myeloproliferative neoplasms in a person in need thereof is provided herein, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient in need thereof.

[0106] A method for suppressing the proliferation of malignant myeloid cells in a subject requiring such suppression is further provided herein, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such suppression.

[0107] A method for reducing reticulin and collagen myelofibrosis in a subject requiring such reduction is also provided, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0108] A method for reducing the plasma levels of one or more inflammatory cytokines in a subject requiring such reduction is also provided, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0109] A method for reducing the mass of malignant myeloid cells in a subject requiring such reduction is also provided, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0110] A method for reducing an abnormal spleen size or volume in a person requiring such reduction is also provided, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0111] A method for reducing the amount of extramedullary hematopoiesis in a person requiring such reduction is also provided, which includes administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0112] A method for reducing systemic symptoms of myelofibrosis, as measured by patient-reported surveys, in a target group requiring such reduction, is also provided, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0113] A method for reducing platelet count in a subject requiring such reduction is also provided, which includes administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0114] A method is also provided for reducing myeloid cells to age-adjusted normal cells having less than 5% blast cells in a subject requiring such reduction, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient requiring such reduction.

[0115] a) a method for reducing hemoglobin levels to less than 160 g / L in PV patients, or b) a method for reducing red cell clumps in PV patients, wherein the reduction is inferred from a hemoglobin level Hb of less than 160 g / L, and the method also includes administering a pharmaceutical composition or pharmaceutical preparation described herein to a patient in need thereof.

[0116] A method is also provided for increasing hemoglobin levels in MF patients to a value greater than 100 g / L, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein. A method is also provided for increasing hemoglobin levels to a value greater than 100 g / L and below the upper limit of age- and sex-adjusted normal values ​​in patients who require such an increase, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein to such patients.

[0117] A method for achieving an effect in a patient, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein, wherein the effect is an increase in red blood cell count, an increase in the number of red blood cells containing fetal hemoglobin, an increase in the total concentration of fetal hemoglobin in red blood cells, an increase in the total concentration of fetal hemoglobin in reticulocytes, an increase in the transcription of the gamma globin gene in bone marrow-derived red blood cell precursors, such as proerythroblasts, a reduction in the number of sickle cell crises in the patient's experience over a unit period, such as in the heart, spleen, brain or kidneys caused by sickle cell transformation of cells. Methods are also provided that are selected from stopping or preventing tissue damage, reducing the percentage of red blood cells undergoing sickle cell formation under physiological conditions of relative hypoxia as measured using patient blood in an in vitro assay, increasing the amount of histone 3-lysine methylation at lysine position 4 (H3K4me1 and H3K4me2), and / or reducing the amount of histone 3-methylation near or at the gamma globin promoter at lysine position 9 (H3K9me1 or H3K4me2), as assayed by ChIP using cells derived from the patient being treated.

[0118] A method for inhibiting KDM1A is also provided, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical formulation disclosed herein to a patient in need thereof.

[0119] A method for inhibiting at least one KDM1A function, comprising administering a pharmaceutical composition or pharmaceutical preparation described herein, wherein the inhibition is measured by the phenotype of cultured or in vivo erythrocytes or their precursors, the proliferative capacity of cancer cells, the expression of specific genes known to be regulated by KDM1A activity such as γ-globin, changes in histone methylation status, changes in the methylation status of proteins known to be demethylated by KDM1A, such as G9a or SUV39H1, the expression of KDM1A regulatory genes, or the binding of KDM1A to a natural binding partner such as CoREST, DNMT1, or HDAC, in humans, mice, or genetically modified mice containing the human β-globin locus or a part thereof.

[0120] Abbreviation API = Active pharmaceutical ingredient; HDAC = Histone deacetylase; KDM1A = LC = Loading capacity; LSD1 = Lysine-specific demethylase 1; RRT = Relative retention time; RS = Related substance [Examples]

[0121] Example 1. Initial study of excipients / stabilizers Phase 1 of the compound B drug development began with excipient compatibility studies, identifying excipients that are physically and chemically compatible with compound B API. Excipients commonly used in oral solid dosage forms, such as fillers, binders, disintegrants, fluidizers, lubricants, and organic acid stabilizers, were evaluated for this study.

[0122] [Table 9]

[0123] [Table 10]

[0124] Samples were prepared using a two-component mixture of compound B from Table 1 and an excipient. Briefly, each excipient and API was weighed individually, filled into vials, and then glass beads were added. Since sample preparation was carried out over 10 days, the samples were sealed, vortexed, and refrigerated at 2–8°C before the start of the study. All vials were removed from the refrigerator, equilibrated to room temperature, then opened at the same time point t=0, and stored under the specified storage conditions.

[0125] Samples of compound B API and excipients were stored as a two-component mixture in open vials under conditions of 50°C / 11%RH and 50°C / 75%RH, and evaluated for appearance, assay, and RS at t=0, week 1, and week 2.

[0126] The stability data for each composition is shown in Tables 2-21. Table 22 shows a list of the LC% of compound B in various formulations.

[0127] Table 11

[0128] Table 12

[0129] Table 13

[0130] Table 14

[0131] Table 15

[0132] Table 16

[0133] Table 17

[0134] Table 18

[0135] Table 19

[0136] Table 20

[0137] Table 21

[0138] Table 22

[0139] Table 23

[0140] Table 24

[0141] Table 25

[0142] Table 26

[0143] Table 27

[0144] Table 28

[0145] Table 29

[0146] Table 30

[0147] Table 31

[0148] Example 2. Study of formulations. Excipient compatibility studies evaluated each excipient as a two-component mixture with compound B. In Phase 2 of development, data from excipient compatibility was used to evaluate the synergistic effect of the most stable excipients combined with three levels of stabilizers on the total RS with respect to compound B. Fumaric acid, citric acid, and tartaric acid were evaluated as stabilizers in blends simulated to deliver 5 mg / dose of compound B and 50 mg / dose of compound B, with data between the lowest and highest doses in parentheses. Each stabilizer was evaluated at 1x and 5x ratios with compound B at a 5 mg dose, and at 0.1x ratios with compound B at a 50 mg dose. Control formulations using the same excipients without stabilizers were also set up to evaluate the effectiveness of stabilizers on excipients.

[0149] For each blend formulation shown in Table 23, the required amounts of excipients and APIs were individually dispensed by weight and separated using a 20-mesh sieve. The separated materials were transferred to glass vials of appropriate size and blended manually for 5 minutes. Blend preparation included the addition of three glass beads and vortexing of the sealed vial to ensure thorough mixing, and the components were mixed for 30–60 seconds. Each blend formulation was prepared in 5g batch sizes, with each of the five vials filled. The vials of each blend were stored under 50°C / 11%RH and 50°C / 75%RH conditions and sampled at t=0, week 1, and week 2. The blends were tested at each time point for assays and RS.

[0150] [Table 32]

[0151] Example 3. Blend with fumaric acid. Blends containing compound B base and fumaric acid in ratios of 1:1 (1×), 1:5 (5×), and 10:1 (0.1×) showed an increase in RS-1 ranging from approximately 0.05% at t=0 to approximately 0.15% at t=2 weeks, with a total RS of 0.05% at t=0 to 0.3% at t=2 weeks under each stability condition (Tables 24-26). Compared to formulations manufactured without any acid stabilizers, the total RS values ​​of these blends were relatively low (Table 27). It was noteworthy that all blends containing fumaric acid reacted similarly in terms of degradation, and there was a surprising trend in the data, with samples stored at 50°C / 75%RH showing relatively lower levels of degradation products compared to samples stored at 50°C / 11%RH.

[0152] The following related substances (RS): RS-1 RS-2 RS-3 It was identified.

[0153] [Table 33]

[0154] [Table 34]

[0155] [Table 35]

[0156] [Table 36]

[0157] Example 4. Blend with citric acid. Blends containing compound B base and citric acid in ratios of 1:1 (1×), 1:5 (5×), and 10:1 (0.1×) showed an increase in RS-1 ranging from approximately 0.05% at t=0 to approximately 0.17% at t=2 weeks, with a total RS of 0.05% at t=0 to 5.2% at t=2 weeks under each stability condition (Tables 28-30).

[0158] [Table 37]

[0159] [Table 38]

[0160] [Table 39]

[0161] Example 5. Blend with tartaric acid. Blends containing compound B base and tartaric acid in ratios of 1:1 (1×), 1:5 (5×), and 10:1 (0.1×) showed an increase in RS-1 ranging from approximately 0.05% at t=0 to approximately 0.11% at t=2 weeks, with a total RS of 0.05% at t=0 to 2.5% at t=2 weeks under each stability condition (Tables 31-33).

[0162] [Table 40]

[0163] [Table 41]

[0164] [Table 42]

[0165] Example 6. Manufacturing process and dosage form. Using the results from the blend evaluation study, the following set of experiments was designed for manufacturing process selection and dosage form selection. Tablet and capsule delivery systems were evaluated using direct blending and wet granulation approaches for the dose range of 5 mg to 50 mg. The qualitative composition of the blends was maintained as it was in the blend study.

[0166] In addition, a control formulation was designed without using fumarate and by replacing Polyplasdone® XL with Starch 1500®.

[0167] A series of 13 experiments were designed to evaluate the effects of the manufacturing process and dosage form. Experiments 1-3 were designed as a single general direct blend divided into three parts and formulated as dose-proportional formulations at doses of 5 mg and 10 mg. The first part was used to produce 5 mg Compound B tablets, the second part to produce 10 mg Compound B tablets, and the third part to produce 5 mg Compound B capsules. Similarly, Experiments 4-6 were designed as a single general wet granulation blend divided into three parts. The first part was used to produce 5 mg Compound B tablets, the second part to produce 10 mg Compound B tablets, and the third part to produce 5 mg Compound B capsules. 35 mg and 50 mg tablets and capsules were designed to have similar dosage formulations at a blend weight of 200 mg / dose. The blend was weighed individually for each tablet, manually loaded into a die, and the tablets were compressed using a single punch on a rotary press. The encapsulation was performed manually on a chemical balance. The dosage and manufacturing process for each of the 13 experiments are shown below.

[0168] [Table 43]

[0169] [Table 44]

[0170] [Table 45]

[0171] [Table 46]

[0172] Ten units of the finished product (tablets or capsules) were packaged into 30cc bottles from each or 13 batches, induction sealed, and sealed with a screw-on 28mm cap. A total of seven bottles were packaged for each batch, and their stability was evaluated under two accelerated conditions: 50°C / 75%RH and 50°C / 11%RH. For assay / RS, samples were evaluated at t=0, 1 week, 2 weeks, and 5 weeks.

[0173] Bottle used: 30cc wide-mouthed, round, white medicine bottle Drug Plastics and Closures Inc. Product Number 0030GAX101.

[0174] Cap used: 28mm SecuRx RbTx white FS M1 w / .035 Pulp Prt'SFYP'wht Drug Plastics and Closures Inc., Product Number 28CRG11101.

[0175] The results of this study were quite surprising and very clear. All tablet formulations manufactured with or without fumaric acid, via direct blending or wet granulation, were found to be highly unstable compared to data confirmed in excipient compatibility and blend stability studies.

[0176] Direct Blending: A standard blend of compound B was prepared via direct blending and used to produce tablets (5 mg and 10 mg) and capsules (5 mg). The total RS of the 5 mg tablets increased from 0.12% at t=0 to 0.92% at t=5 weeks for samples stored at 50°C / 75% RH (Table 37). Similarly, the total RS of the 10 mg tablets increased from 0.11% at t=0 to 0.71% at t=5 weeks for samples stored at 50°C / 75% RH (Table 38). The capsules (5 mg) were relatively more stable than the tablets. The total RS of the capsules was 0.11% at t=0 and increased to 0.17% after 5 weeks of storage at 50°C / 75% RH (Table 39).

[0177] Both the 35 mg tablets and 50 mg capsules were manufactured using a direct blending process. The total RS of the 35 mg tablets increased from 0.12% at t=0 to 0.44% at t=2 weeks at 50°C / 75%RH and to 0.39% at t=5 weeks at 50°C / 75%RH (Table 43). The 50 mg capsules were relatively more stable than the 35 mg tablets. The total RS of the 50 mg capsules was 0.11% at t=0, increased to 0.17% at t=2 weeks at 50°C / 75%RH and to 0.12% at 5 weeks at 50°C / 75%RH (Table 45).

[0178] Wet Granulation: A standard blend of compound B was prepared via wet granulation to produce tablets (5 mg and 10 mg) and capsules (5 mg). The total RS of the 5 mg tablets increased from 0.10% at t=0 to 1.76% at t=5 weeks for samples stored at 50°C / 75%RH (Table 40). The total RS of the 10 mg tablets increased from 0.10% at t=0 to 1.51% at t=5 weeks for samples stored at 50°C / 75%RH (Table 41). The total RS of the capsules (5 mg) increased from 0.10% at t=0 to 0.78% at t=5 weeks for samples stored at 50°C / 75%RH (Table 42).

[0179] Both tablets (35 mg) and capsules (50 mg) were manufactured after wet granulation. The total RS in the tablets (35 mg) increased from 0.10% at t=0 to 0.64% after 5 weeks of storage at 50°C / 75%RH (Table 44). The total RS in the capsules increased from 0.11% at t=0 to 0.26% after 5 weeks of storage at 50°C / 75%RH (Table 46).

[0180] The data from wet granulation tended to be similar to those observed with direct blending, and compound B capsules were relatively more stable than tablets produced by wet granulation. However, the increase in total RS for capsules produced by wet granulation was higher than that observed for capsules produced by direct blending.

[0181] Three control formulations, manufactured without fumarate and crospovidone and with the addition of Starch 1500®, showed the highest RS (Tables 47, 48, and 49 for 5 mg, 10 mg, and 35 mg tablets, respectively). These were not further evaluated.

[0182] All tablets and capsules produced through the specified manufacturing process are generated from conventional blends, thus eliminating bias in elucidating the results. Overall, capsules of compound B are significantly more stable than tablets of compound B. Capsules produced by the direct blend manufacturing process exhibit superior stability compared to capsules produced by wet granulation. This was surprising, as compressed tablets are conventionally assumed to be more stable than capsules due to the presence of moisture in the capsule shell. The inventors hypothesize that the compressive force used in tablet production affects the crystalline structure of the active ingredient, thereby accelerating degradation. Capsule formulations produced using the direct blend process are similar to the blend stability data obtained in Section 3, further suggesting that the compressive force in tablet production may have an effect on stability. The HPMC capsules used in this formulation are designed to be suitable for hygroscopic blends that are susceptible to moisture, and therefore, it is presumed that moisture in these capsules is tightly bound and cannot be utilized for hydrolysis.

[0183] [Table 47]

[0184] [Table 48]

[0185] [Table 49]

[0186] [Table 50]

[0187] [Table 51]

[0188]

Table 52

[0189]

Table 53

[0190]

Table 54

Table 55

[0192]

Table 56

[0193]

Table 57

[0194]

Table 58

[0195] <00①0893>

Table 59

[0196] Example 7. Scale-up: 1 kg. The direct blend and encapsulation processes and formulations identified in the above section were processed in about 500 g blend splits to create multiple strengths. The blends were hand-filled into the capsules used for the stability testing, and thus the next step was to scale up the blends and evaluate them on an automatic encapsulation device. This was carried out in a two-step approach. First, to bracket all strengths, 1 kg blends were produced for 5 mg and 50 mg doses according to the formulations listed in Table 50.

[0197]

Table 60

[0198] The manufacturing processes for both blends were similar and are shown in Figures 1 and 2. Briefly, for the 5 mg blend, at 250 rotations, Compound B was blended with half of the fumaric acid, Avicel DG, Polyplasdone XL, and lactose anhydrous DT. The remaining half of the lactose anhydrous DT was added to this blend and mixed for a further 250 rotations, followed by blending with magnesium stearate for 100 rotations. The 50 mg blend was manufactured similarly, except that the lactose was added in one portion with the fumaric acid, Avicel DG, and Polyplasdone XL at 250 rotations. Magnesium stearate was blended for 100 rotations. The physical properties of both blends are shown in Table 51.

[0199]

Table 61

[0200] Both blends were encapsulated using an MG Flexalab automated encapsulation machine. The filling weight range for the 5 mg blend was 100 mg ± 5%, equivalent to 95–105 mg, and for the 50 mg blend, it was 200 mg ± 5%, equivalent to 190–210 mg. The average weight of two empty capsules was measured at 59.0 mg; therefore, the target weight for the 5 mg capsules was 159 mg (154–164 mg), and the target weight for the 50 mg capsules was 259 mg (149–169 mg).

[0201] The capsules were processed using a weight sorter, and the resulting data was processed to eliminate rejections due to errors caused by the performance of the encapsulation equipment. The acceptance rate for 5 mg capsules exceeded 94%, and for 50 mg capsules it exceeded 99%. Therefore, the blend appears to be applicable to processing with a high-speed encapsulation equipment. Capsules recovered at the beginning, middle, and end of encapsulation were tested for content uniformity. The 5 mg capsules had an acceptance value of 4.5–6, and the 50 mg capsules had an acceptance value of 1.9–3.5; the data are shown in Table 52. The encapsulation processing parameters are shown in Table 53.

[0202] [Table 62]

[0203] [Table 63]

[0204] Example 8. Scale-up: 2 kg. The initial scale-up to 1 kg was considered successful based on the confirmed AV values ​​for the 5 mg and 50 mg doses. The second stage of scale-up was performed on a 2 kg scale for the 5 mg and 50 mg doses. Each blend was encapsulated in size 2 white opaque capsules and COLORISTA® all-color capsules. The formulation details are shown in Table 50, and the manufacturing process is shown in Figures 1, 2, and 6. The encapsulation parameters are shown in Table 53.

[0205] Each formulation was kept stable for up to 16 weeks at 25°C / 60%RH and 50°C / 75%RH. The fundamental reason for this was to evaluate the stability of the encapsulated blends after processing them through the complete manufacturing process and comparing the RS trends between the white capsules and the COLORISTA® capsules.

[0206] The white and COLORISTA® capsules formulated with compound B in 5 mg or 50 mg contain the following components: Bottle contains 5mg capsules (white, opaque); 20 capsules per bottle. 5mg capsules (white, opaque) in a blister pack; 6 capsules per blister pack. Bottle contains 5mg capsules (COLORISTA®); 20 capsules per bottle 5mg capsules (COLORISTA® registered trademark) in a blister pack; 6 capsules / blister pack Bottle contains 50mg capsules (white, opaque); 20 capsules per bottle. 50mg capsules (white, opaque) in a blister pack; 6 capsules per blister pack. Bottle contains 50mg capsules (COLORISTA®); 20 capsules per bottle 50mg capsules (COLORISTA® registered trademark) in a blister pack; 6 capsules / blister pack The samples were then packaged in bottles and blisters and stored stably for 16 weeks at 25°C / 60%RH and 50°C / 75%RH.

[0207] The following packaging materials were used: Bottle: 30cc HDPE bottle, wide-mouth pharmaceutical round white bottle Cap: 28mm SecuRx RbTx white FSM1 w / .035 pupl Prt‘SFYP’Wht Blister material: ALU-ALU blister.

[0208] For the capsules recovered throughout the encapsulation process, a stratified content uniformity test was conducted. The individual capsule assay values of Compound A, 5mg capsule dosage form were in the range of 96.6 - 108.9% (Table 55). This data was verified with the composite sample recovered at the end of the implementation. The results of blend uniformity are shown in Table 56, which is in the range of 100.5 - 103.8%. Compared with blend uniformity, the higher variability in content uniformity was attributed to the variability confirmed with the empty capsule shell weight. The average weight of empty size 2 white opaque VCaps plus was reported to be approximately 59mg with a distribution of 50 - 65mg (Table 57). The fill weight of 5mg capsule dosage form is shown as 100mg with a range of 95 - 105mg. Therefore, the empty capsule weight can vary up to 15mg, and the filled capsule weight needs to be maintained within 10mg. The solution proposed for future batches is to use a smaller capsule size and potentially weight-sort the empty capsules into a narrow weight range to avoid such high variability in the content uniformity test. The results of content uniformity of 50 capsules are shown in Table 54. These show significantly low variability within the individual capsule assay values and acceptable variability within the blend due to the high fill weight.

[0209]

Table 64

[0210]

Table 65

[0211]

Table 66

[0212] [Table 67]

[0213] Assay values ​​for the 5 mg capsules showed significant variation at each time point tested. This is expected to be due to the variance observed in individual capsule assay values ​​during the content uniformity test. Assay values ​​for the 50 mg capsules were within the expected variance during the 16-week stability test. RS-1 was maintained within the range of 0.06–0.07% throughout the 16 weeks for all tested formulations. Results from all samples are shown in Tables 58–73.

[0214] The total RS appears to deviate from the trend in both intensities during this study. From this data, it is suggested that the total RS initially decreased from approximately 0.20–0.25% to approximately 0.16–0.17% at t=1 week and maintained that level until approximately 4 weeks in all tested samples and temperature conditions. It is noteworthy that the individual RSs in this study were aggregated at levels above LOD but below LOQ to capture the trend of whether they actually increased or disappeared over time. The peak at approximately RRT 1.922 is below LOQ and disappears after t=0, thereby explaining the decreasing trend in RS. However, new RSs were observed in each formulation and packaging composition at t=12 weeks, which contributes to the higher total RS. This higher level of RS was observed at relatively similar levels under both 25°C / 60%RH and 50°C / 75%RH conditions and maintained until 16 weeks. Packaging composition did not affect the total RS during the duration of this study. It is noteworthy that in all cases, known RS-1 values ​​are relatively unaffected by exposure to time and temperature. The trend of total RS over time is shown in Figure 3.

[0215] [Table 68]

[0216] Table 69

[0217] Table 70

[0218] Table 71

[0219] Table 72

[0220] Table 73

[0221] Table 74

[0222] Table 75

[0223] Table 76

[0224] Table 77

[0225] Table 78

[0226] [Table 79]

[0227] [Table 80]

[0228] [Table 81]

[0229] [Table 82]

[0230] [Table 83]

[0231] Example 9. Crospovidone-free composition Compound B capsules (5 mg) were prepared in batch size 300 g without using crospovidone in the formulation. The final blend was manually encapsulated in size 2 CS Vcaps plus COLORISTA® capsules, and n=6 capsules were evaluated for dissolution testing. Table 74 shows the formulation information. Capsules were prepared using either CAPSUGEL® size 2 CS VCaps plus white opaque capsules or CAPSUGEL® size 2 CS VCaps plus COLORISTA® capsules. Table 75 shows dissolution information for 5 mg opaque capsules containing and without crospovidone, and Table 76 shows dissolution information for 5 mg opaque COLORISTA® capsules. Further dissolution information for the white capsules and COLORISTA® capsules is shown in Tables 77 and 78, and illustrated in Figure 5, respectively.

[0232] [Table 84]

[0233] [Table 85]

[0234] [Table 86]

[0235] [Table 87]

[0236] [Table 88]

[0237] The pharmaceutical compositions, methods, and uses described herein are included as illustrations of the present invention and will be better understood by referring to the following exemplary embodiments and examples, which do not limit the scope of the invention.

[0238] The above detailed description and accompanying examples are merely illustrative and should not be construed as limiting the scope of the invention as defined solely by the appended claims and equivalents. Various modifications and alterations to the embodiments disclosed will be apparent to those skilled in the art. Such modifications and alterations, including but not limited to modifications and alterations of chemical structure, substituents, derivatives, intermediates, synthesis, formulation or method, or any combination of such modifications and alterations to the use of the invention, may be made without departing from the spirit and scope thereof.

[0239] All of the above references (patents and non-patent literature) are incorporated into this patent application by reference. The descriptions of those references are intended merely to summarize the claims of their authors. No reference (or any part thereof) is acknowledged to be (or possibly to be) relevant prior art. The applicant reserves the right to challenge the accuracy and validity of the references listed. This specification includes the following disclosures: (Note 1) N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A) or an pharmaceutically acceptable salt thereof, At least one stabilizer selected from citric acid, fumaric acid, and tartaric acid, A pharmaceutical composition containing the following: (Note 2) The pharmaceutical composition described in Appendix 1, wherein compound A or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of compound A. (Note 3) The pharmaceutical composition described in Appendix 2, wherein compound A or a pharmaceutically acceptable salt thereof is a tosylate salt of compound A. (Note 4) The pharmaceutical composition described in Appendix 3, wherein compound A or a pharmaceutically acceptable salt thereof is the ditosylate salt of compound A. (Note 5) The pharmaceutical composition described in Appendix 1, wherein compound A or a pharmaceutically acceptable salt thereof is compound A. (Note 6) The pharmaceutical composition according to any one of the appendices 1 to 5, wherein compound A or the pharmaceutically acceptable salt thereof is present in an amount of about 2 to about 10% by weight as measured as a free base. (Note 7) The pharmaceutical composition as described in Appendix 6, wherein compound A or the pharmaceutically acceptable salt thereof is present in an amount of approximately 5% by weight as measured as a free base. (Note 8) The pharmaceutical composition according to any one of the appendices 1 to 5, wherein compound A or the pharmaceutically acceptable salt thereof is present in an amount of about 20 to about 30% by weight as measured as a free base. (Note 9) The pharmaceutical composition as described in Appendix 8, wherein compound A or the pharmaceutically acceptable salt thereof is present in an amount of about 25% by weight as measured as a free base. (Note 10) A pharmaceutical composition according to any one of the appendices 1 to 9, wherein at least one stabilizer is citric acid. (Note 11) A pharmaceutical composition according to any one of the appendices 1 to 9, wherein at least one stabilizer is fumaric acid. (Note 12) A pharmaceutical composition according to any one of the appendices 1 to 9, wherein at least one stabilizer is tartaric acid. (Note 13) The pharmaceutical composition according to any one of the appendices 1 to 7, wherein at least one stabilizer is present in an amount of about 2 to about 10% by weight. (Note 14) The pharmaceutical composition according to Appendix 13, wherein at least one of the aforementioned stabilizers is present in an amount of about 5% by weight. (Note 15) A pharmaceutical composition according to any one of the appendices 1 to 5, 8, or 9, wherein at least one stabilizer is present in an amount of about 20 to about 30% by weight. (Note 16) The pharmaceutical composition according to Appendix 15, wherein at least one stabilizer is present in an amount of about 25% by weight. (Note 17) A pharmaceutical composition according to any one of the appendices 1 to 16, comprising one or more fillers. (Note 18) The one or more fillers mentioned above are silicified microcrystalline cellulose (PROSOLV® SMCC). A pharmaceutical composition as described in Appendix 17, selected from HD90), AVICEL® dry granulation excipient (AVICEL® DG), mannitol (PEARLITOL® 200), anhydrous lactose, and pregelatinized starch (STARCH® 1500). (Note 19) The pharmaceutical composition described in Appendix 18, wherein the filler is anhydrous lactose. (Note 20) The aforementioned filler is AVICEL® DG, as described in Appendix 18 of the pharmaceutical composition. (Note 21) The aforementioned filler is Starch The pharmaceutical composition described in Appendix 18, which is 1500. (Note 22) The pharmaceutical composition described in Appendix 18, wherein the filler is a mixture of anhydrous lactose and AVICEL® DG. (Note 23) The pharmaceutical composition according to any one of the appendices 17 to 22, wherein the filler is present in the pharmaceutical composition in an amount of approximately 75 to approximately 90%. (Note 24) The pharmaceutical composition according to any one of the appendices 17 to 22, wherein the filler is present in the pharmaceutical composition in an amount of approximately 35 to approximately 50%. (Note 25) A pharmaceutical composition according to any one of the appendices 1 to 24, comprising one or more disintegrants. (Note 26) The pharmaceutical composition described in Appendix 25, wherein the one or more disintegrants are selected from croscarmellose sodium (AC-DI-SOL®), crospovidone XL (Polyplasdone® XL), and sodium starch glycolate (EXPLOTAB®). (Note 27) The pharmaceutical composition as described in Appendix 26, wherein the one or more disintegrants are POLYPLASDONE®XL (crospovidone). (Note 28) The pharmaceutical composition according to any one of the above-mentioned one or more disintegrants, wherein the pharmaceutical composition is present in an amount of about 2 to about 10%. (Note 29) The pharmaceutical composition according to Appendix 28, wherein one or more of the disintegrants are present in the pharmaceutical composition in an amount of approximately 5%. (Note 30) A pharmaceutical composition according to any one of the appendices 1 to 29, comprising one or more lubricants. (Note 31) The aforementioned one or more lubricants include magnesium stearate (HYQUAL®), sodium stearyl fumarate (PRUV®), and stearic acid (GENAR® Vegetable). A pharmaceutical composition selected from Grade 50) as described in Appendix 30. (Note 32) The pharmaceutical composition according to Appendix 31, wherein the one or more lubricants are magnesium stearate. (Note 33) The pharmaceutical composition according to any one of the appendices 30 to 32, wherein the one or more lubricants are present in the pharmaceutical composition in an amount of about 0.1 to about 1%. (Note 34) The pharmaceutical composition according to Appendix 33, wherein the one or more lubricants are present in the pharmaceutical composition in an amount of approximately 0.5%. (Note 35) A pharmaceutical composition described in any one of the appendices 1 to 34, which is formulated by direct blending. (Note 36) A pharmaceutical composition described in any one of the appendices 1 to 34, formulated by wet granulation blending. (Note 37) The pharmaceutical composition described in Appendix 1, comprising the following, wherein compound A is measured as a free base. Table 89 (Note 38) The pharmaceutical composition described in Appendix 1, comprising the following, wherein compound A is measured as a free base. Table 90 (Note 39) A pharmaceutical preparation containing any one of the compounds described in Appendix 1 to 38. (Note 40) A tablet, the pharmaceutical preparation described in Appendix 39. (Note 41) A pharmaceutical preparation described in Appendix 39, which is in capsule form. (Note 42) The aforementioned capsule is a COLORISTA® capsule, as described in Appendix 41. (Note 43) A method for treating a disease or disorder associated with KDM1A activity in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition described in any one of Appendix 1 to 38 or a pharmaceutical preparation described in any one of Appendix 39 to 42 to the patient in need thereof. (Note 44) The disease or disorder associated with KDM1A activity is cancer, as described in Appendix 43. (Note 45) The cancer is selected from Ewing's sarcoma, multiple myeloma, T-cell leukemia, Wilms' tumor, small cell lung cancer, bladder cancer, prostate cancer, breast cancer, head / neck cancer, colon cancer, and ovarian cancer, as described in Appendix 44. (Note 46) The disease or disorder associated with KDM1A activity is a myeloproliferative neoplasm, as described in Appendix 43. (Note 47) The myeloproliferative neoplasm is selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML), as described in Appendix 45. (Note 48) The myeloproliferative neoplasm is myelofibrosis, as described in Appendix 47. (Note 49) The myelofibrosis described above is selected from primary myelofibrosis (PMF) and post-PV / ET myelofibrosis (MF), as described in Appendix 48. (Note 50) The myelofibrosis is post-PV / ET myelofibrosis (MF), as described in Appendix 49. (Note 51) The disease or disorder associated with KDM1A activity is an inflammatory disease, as described in Appendix 43. (Note 52) The inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, or systemic lupus erythematosus, according to the method described in Appendix 51. (Note 53) A method for inhibiting KDM1A, comprising administering a therapeutically effective amount of a pharmaceutical composition described in any one of Appendix 1 to 38 or a pharmaceutical preparation described in any one of Appendix 39 to 42 to a patient in need thereof. (Note 54) A method for suppressing the proliferation of malignant myeloid cells in a subject requiring such suppression, comprising administering a therapeutically effective amount of a pharmaceutical composition described in any one of Appendix 1 to 38 or a pharmaceutical preparation described in any one of Appendix 39 to 42 to the patient requiring such suppression. (Note 55) The malignant myeloid cells have mutations in one or more genes selected from the group consisting of Janus kinase 2 (JAK2), myeloproliferative leukemia virus oncogene (MPL), and calreticulin (CALR), as described in Appendix 54.

Claims

1. N-((S)-5-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)-1-(4-methylpiperazine-1-yl)-1-oxopentan-2-yl)-4-(1H-1,2,3-triazole-1-yl)benzamide (compound A) or an pharmaceutically acceptable salt thereof, The stabilizer is fumaric acid, AVICEL® dry granulation excipient, one or more fillers selected from mannitol and anhydrous lactose, Crospovidone is the disintegrant, One or more lubricants selected from magnesium stearate, sodium stearyl fumarate, and stearic acid, A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of compound A.

3. The pharmaceutical composition according to claim 2, wherein compound A or a pharmaceutically acceptable salt thereof is a tosylate salt of compound A.

4. The pharmaceutical composition according to claim 3, wherein compound A or a pharmaceutically acceptable salt thereof is a ditosylate salt of compound A.

5. The pharmaceutical composition according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is compound A.

6. Compound A or the salt thereof that is acceptable as a drug is present in an amount of about 2 to about 10% by weight as a free base. The aforementioned stabilizer is present in an amount of approximately 2 to approximately 10% by weight. The aforementioned one or more fillers are present in an amount of approximately 75 to approximately 90% by weight. The aforementioned disintegrant is present in an amount of approximately 2 to approximately 10% by weight. The aforementioned one or more lubricants are present in an amount of approximately 0.1 to approximately 1% by weight. A pharmaceutical composition according to any one of claims 1 to 5.

7. Compound A or the salt thereof that is acceptable as a drug is present in an amount of approximately 5% by weight as a free base, The aforementioned stabilizer is present in an amount of approximately 5% by weight. The aforementioned one or more fillers are present in an amount of approximately 85% by weight. The aforementioned disintegrant is present in an amount of approximately 5% by weight. The aforementioned one or more lubricants are present in an amount of approximately 0.5% by weight. The pharmaceutical composition according to claim 6.

8. Compound A or the acceptable salt thereof is present in an amount of approximately 20 to approximately 30% by weight as a free base. The aforementioned stabilizer is present in an amount of approximately 20 to approximately 30% by weight. The aforementioned one or more fillers are present in an amount of approximately 35 to approximately 50% by weight. The aforementioned disintegrant is present in an amount of approximately 2 to approximately 10% by weight. The aforementioned one or more lubricants are present in an amount of approximately 0.1 to approximately 1% by weight. A pharmaceutical composition according to any one of claims 1 to 5.

9. Compound A or the salt thereof that is acceptable as a drug is present in an amount of approximately 25% by weight as a free base. The aforementioned stabilizer is present in an amount of approximately 25% by weight. The aforementioned one or more fillers are present in an amount of approximately 45% by weight. The aforementioned disintegrant is present in an amount of approximately 5% by weight. The aforementioned one or more lubricants are present in an amount of approximately 0.5% by weight. The pharmaceutical composition according to claim 8.

10. The pharmaceutical composition according to claims 1 to 9, wherein the one or more fillers are selected from AVICEL® DG, PEARLITOL® 200, and anhydrous lactose.

11. The pharmaceutical composition according to claim 10, wherein the filler is anhydrous lactose.

12. The pharmaceutical composition according to claim 10, wherein the filler is AVICEL® DG.

13. The pharmaceutical composition according to claim 10, wherein the filler is a mixture of anhydrous lactose and AVICEL® DG.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the disintegrant is POLYPLASDONE (trademark) XL.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the one or more lubricants are selected from HYQUAL®, PRUV®, and GENAR® Vegetable Grade, 50.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the one or more lubricants is magnesium stearate.

17. The pharmaceutical composition according to claim 1, comprising the following, wherein compound A is measured as a free base. Table 1

18. The pharmaceutical composition according to claim 1, comprising the following, wherein compound A is measured as a free base. Table 2

19. A pharmaceutical preparation comprising the compound described in any one of claims 1 to 18.

20. The pharmaceutical preparation according to claim 19, which is a tablet.

21. The pharmaceutical preparation according to claim 19, which is a capsule.

Images