Arimochromol for treating Gaucher disease

Abstract

Provision of arimochromol for treating Gaucher disease. [Solution] The present invention relates to a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, and more particularly to alimochromol for use in methods of treating Gaucher disease (GD). This specification describes the results of a double-blind, randomized, placebo-controlled, phase 2 dose-finding study in patients with Gaucher disease (GD) types 1 and 3 who were not receiving enzyme and / or substrate replacement therapy.

Description

[Technical Field]

[0001] Technical field The present invention relates to a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts, and more particularly to alimochromol for use in an improved method of treating Gaucher disease (GD). [Background technology]

[0002] background Gaucher disease is an autosomal recessive lysosomal storage disorder (LSD) characterized by a deficiency of the glucocerebrosidase (GBA) enzyme. The enzyme deficiency is caused by a mutation in the GBA1 gene, which leads to the accumulation of glucosylceramide (GlcCer) and its deacylated form, glucosylsphingosine (GlcSph). Glucosylsphingosine accumulates in the brain and is thought to be responsible for the neurological manifestations of GD.

[0003] This disease is characterized by death caused by lysosomal dysfunction, cellular stress, and a significant decrease in enzyme activity. This is most often due to the L444P substitution, which is strongly associated with homozygosity of the GD3 type (GD3). The L444P genotype has previously been shown to respond to several heat shock protein (HSP) induction strategies.

[0004] Gaucher disease has traditionally been classified into three subtypes based on the presence or absence of primary central nervous system (CNS) complications: GD1 (GD1), which is asymptomatic; GD2 (GD2), which involves acute early neurological disease; and GD3, which involves a slower, more chronic neuropathic disorder.

[0005] Clinical onset of GD1 can occur at any age, but when symptoms begin in childhood, the phenotype is typically more severe and the rate of progression is faster. The most frequent signs of the disease are splenomegaly, hepatomegaly, and bone disease, often accompanied by anemia and thrombocytopenia (primarily due to hypersplenism). Signs and symptoms associated with hepatosplenomegaly can range from their absence to abdominal distension, discomfort, or pain. Thrombocytopenia can lead to an increased tendency to bleed and subcutaneously, while anemia can cause stunted growth accompanied by fatigue and low body weight and slow growth. Bone marrow infiltration by Gaucher cells leads to osteopenia, osteonecrosis, and osteosclerosis, sometimes resulting in acute onset of severe pain (bone spasms), chronic bone pain, and pathological fractures that can substantially impact the patient's quality of life.

[0006] Gaucher disease type 3 is characterized as a milder chronic neurological disorder compared to GD2 (acute form). The symptoms begin in late childhood, with or without visceral and bone marrow complications as seen in GD1. The earliest CNS complications can be assessed by detailed ophthalmological examination revealing abnormalities in the onset of horizontal saccades (rapid eye movements), strabismus, and paralysis or paresis of the eyeballs. Neurological progression is characterized by severe hypertonia, rigid arches (opisthotonus), ataxia, dysphagia, and seizures. Visceral disorders in GD3 are often more severe than in GD1. Clinical scoring scales have been developed and validated to assess disease severity and the expected clinical outcomes of treatment in both GD1 and GD3.

[0007] Currently, two types of treatment are available for patients with GD: enzyme replacement therapy (ERT) using recombinant GBA enzyme, and substrate reduction therapy (SRT) which works by inhibiting GlcCer synthase, thereby reducing substrate production. Both types of treatment improve the peripheral characteristics of the disease but do not improve neurological symptoms and are therefore ineffective in treating neuropathic GD.

[0008] The accumulation of GlcCer and GlcSph within lysosomes primarily occurs in mononuclear macrophages, resulting in phagocytic macrophages known as "Gaucher cells." In brain tissue from GD patients with neurological symptoms, neuronal loss and wrinkled, contractile, and atrophic neurons have been reported in the brainstem ganglia and nuclei of the midbrain, the pons and medulla, the cerebellum, the dentate nucleus, and the hypothalamus.

[0009] Chronic stimulation of the immune system is present, attributed to activated macrophages. While there is considerable patient variability, elevated levels of several interleukins ([IL]-1α, IL-1β, IL-1Ra, sIL-2R, IL-6, IL-8, IL-10, IL-18), tumor necrosis factor (TNF)-α, transforming growth factor-β, macrophage colony-stimulating factor, macrophage inflammatory protein-1 (MIP-1), and chemokine (CC motif) ligand 18 have been reported. The most important biomarker, chitotriosidase, is an enzyme produced in large quantities by macrophages and neutrophils. Histochemistry of bone marrow aspirates and spleen sections reveals these storage cells.

[0010] Heat shock (HSR) is a crucial homeostatic system induced under metabolic stress (e.g., protein misfolding and aggregation, nutrient deficiency, oxidative stress, or heat stress). Its main component is HSP (particularly HSP70), which possesses significant cytoprotective properties. Heat shock protein 70 acts as a molecular chaperone, assisting in the folding of newly synthesized damaged proteins, preventing protein aggregation, and targeting severely damaged proteins for degradation. Notably, the cytoprotective effects of HSP70 include protection against lysosomal dysfunction, cell death, and demyelination in mouse studies. Alimochromol is a safe and well-tolerated co-inducer of HSP70 expression that acts via the activation of heat shock factor-1, a major regulator of HSP gene transcription. It is available for oral administration and exhibits the ability to cross the blood-brain barrier. [Overview of the project]

[0011] Abstract A double-blind, randomized, placebo-controlled, phase 2 dose-finding trial was conducted at seven sites in India in patients with Gaucher disease (GD) types 1 and 3 who were not receiving enzyme and / or substrate replacement therapy. A total of 39 patients were randomized in a 1:1:1:1 ratio to receive either placebo or 100 mg, 200 mg, or 400 mg of arimochromol citrate (weight-adjusted) three times daily. The objective of the phase 2 trial was to evaluate the response of three dose levels of arimochromol to various clinical and disease-specific biomarkers over a 6-month treatment period. Overall, 37 patients were included in the analysis set (two patients were excluded due to negative confirmed GD genotype), of which 21 were type 1 GD patients and 16 were type 3 GD patients.

[0012] The data presented herein demonstrate the dose-dependent effects of arimochromol on clinical secondary endpoints associated with specific diseases, including liver and spleen size. Arimochromol also showed a relative decrease in serum chitotriosidase activity, and patients with anemia at baseline showed a time-dependent increase in hemoglobin in the highest dose group.

[0013] This disclosure provides a pharmaceutically active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts for use in methods of treating Gaucher disease (GD), for example Gaucher disease (GD) type 1 (GD1) or GD3 (GD3), for example, the pharmaceutically active ingredient is administered in doses of 100 mg tid, for example 200 mg tid, for example 400 mg tid (equivalent to 300 mg / day, for example 600 mg / day, for example 1200 mg / day), or in corresponding weight-adjusted doses.

[0014] The present disclosure also provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of reducing the size of the liver / treating hepatomegaly, a method of reducing the size of the spleen / treating splenomegaly, and a method of treating hepatosplenomegaly.

[0015] The present disclosure further provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of treating splenomegaly or hepatosplenomegaly associated with anemia and thrombocytopenia, for example, a method of treating anemia and / or thrombocytopenia, for example, a method of increasing hemoglobin.

[0016] The present disclosure further provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of reducing serum chitotriosidase activity and / or a method of increasing glycosylsphingosine (lyso-Gb1).

Brief Description of the Drawings

[0017] [Figure 1] Figure 1 shows the estimated plasma exposure of alimemazine for patients in three alimemazine dose groups. The plasma exposure is estimated using population pharmacokinetic modeling. AUC0-8 (area under the curve from time 0 to 8 hours) is shown for each patient in the three dose groups.

[0018] [Figure 2] Figure 2 shows the relative change in chitotriosidase activity from baseline to placebo for each of the three alimemazine dose groups.

[0019] [Figure 3] Figure 3 shows the relative change in liver size from baseline versus placebo for each of the three arimochromol dose groups.

[0020] [Figure 4] Figure 4 shows the relative change in spleen size from baseline versus placebo for each of the three alimochromol dose groups.

[0021] [Figure 5] Figure 5 shows the mean hemoglobin concentration (g / L) over time for patients with anemia at baseline in the highest dose group (1200 mg / day).

[0022] [Figure 6] Figure 6 shows the change from baseline in plasma glycosylsphingosine (lyso-Gb1) measured at 6 months. [Modes for carrying out the invention]

[0023] Detailed explanation definition In this context, the term “pharmaceutically acceptable derivative” refers to a pharmaceutically acceptable salt that is not harmful to an organism. Such salts include pharmaceutically acceptable basic or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. pharmaceutically acceptable derivatives further include esters and prodrugs of compounds that can be biologically metabolized into active compounds, or other precursors, or crystalline forms of compounds.

[0024] The term "acid addition salt" is intended to include "pharmaceutically acceptable acid addition salts," which refer to salts that are not harmful to organisms. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid. Suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, vimethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977), which are incorporated herein by reference.

[0025] As used herein, the term “therapeutic effective dose” of a compound refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially halt the clinical symptoms of a given disease or disorder and its complications. The amount sufficient to achieve this is defined as the “therapeutic effective dose.” The effective dose for each purpose depends on the severity of the disease or injury, as well as the individual’s weight and overall condition. Determining the appropriate dose can be achieved using routine experimentation by constructing a matrix of values ​​and testing different points within the matrix, and it will be understood that this is all within the normal skill range of a trained physician or veterinarian.

[0026] As used herein, the terms “treatment” and “to treat” refer to the management and care of an individual for the purpose of curing a symptom, disease, or disorder. The term is intended to encompass the entire scope of treatment for a given symptom affecting an individual. The individual being treated is preferably a mammal, particularly a human; however, treatment of animals such as mice, rats, dogs, cats, horses, cattle, sheep, and pigs is also within the scope of this context. The individual being treated may be of various ages.

[0027] Treatment method One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating Gaucher disease (GD).

[0028] One aspect of the present disclosure also provides a method for treating Gaucher disease (GD), comprising one or more steps of administering a pharmacoactive ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts to an individual in need.

[0029] A further aspect of the present disclosure is to provide the use of a medicinal active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts in the manufacture of a medicinal product for treating Gaucher disease (GD).

[0030] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of treating Gaucher disease (GD) type 1 (GD1) or type 3 (GD3).

[0031] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method for treating Gaucher disease (GD) type 1 (GD1) or type 3 (GD3) accompanied by a deficiency of GBA enzyme activity below the lower limit of normal levels.

[0032] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method for treating Gaucher disease (GD) type 1 (GD1).

[0033] In some embodiments, the above-mentioned active pharmaceutical ingredients are intended for use in methods of treating signs of cerebral complications, such as Gaucher disease type 1 (GD1) accompanied by nonclinical signs of cerebral complications.

[0034] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method for treating Gaucher disease (GD) type 3 (GD3).

[0035] In some embodiments, the above-mentioned active pharmaceutical ingredients are intended for use in methods of treating signs of cerebral complications, such as Gaucher disease (GD) type 3 (GD3) accompanied by clinical signs of cerebral complications.

[0036] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method of treating Gaucher disease (GD) type 3 (GD3) accompanied by at least one neurological symptom.

[0037] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of reducing the clinical composite scale of Gaucher disease type 1.

[0038] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method for reducing the clinical GD1 severity score.

[0039] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method of treating Gaucher disease (GD) in patients aged 4 to 60 years.

[0040] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method of treating Gaucher disease (GD) in patients aged 4 to 6 years, for example 6 to 8 years, for example 8 to 10 years, for example 10 to 12 years, for example 12 to 14 years, for example 14 to 16 years, for example 16 to 18 years.

[0041] In some embodiments, the above-mentioned active pharmaceutical ingredient is intended for use in a method of treating Gaucher disease (GD) in patients weighing 10 kg or more.

[0042] One aspect of the present disclosure provides a pharmaceutically active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of treating Gaucher disease (GD), wherein the pharmaceutically active ingredient is administered at doses of 100 mg tid, e.g., 200 mg tid, e.g., 400 mg tid.

[0043] One aspect of the present disclosure provides a pharmaceutically active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of treating Gaucher disease (GD), wherein the pharmaceutically active ingredient is administered at doses of 300 mg / day, for example, 600 mg / day, or for example, 1200 mg / day.

[0044] In some embodiments, the above-mentioned active pharmaceutical ingredient is administered in a 100 mg tid equivalent to 300 mg / day ("low dose").

[0045] In some embodiments, the above-mentioned active pharmaceutical ingredient is administered in a 200 mg tid (tidi) dose, which corresponds to 600 mg / day ("moderate dose").

[0046] In some embodiments, the above-mentioned active pharmaceutical ingredient is administered at a dose of 400 mg tid, which corresponds to 1200 mg / day ("high dose").

[0047] In some embodiments, the above-mentioned active pharmaceutical ingredient is administered in weight-adjusted doses, correlated with the patient's body weight, in low, medium, and high doses. The correlation between weight bands and doses is shown herein below.

[0048] One aspect of the present disclosure also provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of reducing liver size.

[0049] In one embodiment, the above method for reducing liver size is a method for reducing liver size in patients with Gaucher disease.

[0050] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating hepatomegaly.

[0051] In one embodiment, the above method for treating hepatomegaly is a method for treating hepatomegaly in patients with Gaucher disease.

[0052] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of reducing spleen size.

[0053] In one embodiment, the above method for reducing the size of the spleen is a method for reducing the size of the spleen in patients with Gaucher disease.

[0054] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating splenomegaly.

[0055] In one embodiment, the above method for treating splenomegaly is a method for treating splenomegaly in patients with Gaucher disease.

[0056] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods for reducing the size of the spleen and liver.

[0057] In one embodiment, the above method for reducing the size of the spleen and liver is a method for reducing the size of the spleen and liver in patients with Gaucher disease.

[0058] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating hepatosplenomegaly.

[0059] In one embodiment, the above method for treating hepatosplenomegaly is a method for treating hepatosplenomegaly in patients with Gaucher disease.

[0060] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts for use in methods of treating splenomegaly with anemia and thrombocytopenia, or hepatosplenomegaly with anemia and thrombocytopenia.

[0061] In one embodiment, the above method for treating splenomegaly accompanied by anemia and thrombocytopenia, or hepatosplenomegaly accompanied by anemia and thrombocytopenia, is a method for treating splenomegaly accompanied by anemia and thrombocytopenia, or hepatosplenomegaly accompanied by anemia and thrombocytopenia, in patients with Gaucher disease.

[0062] One aspect of the present disclosure is to provide a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of treating anemia and / or thrombocytopenia.

[0063] In one embodiment, the above method for treating anemia and / or thrombocytopenia is a method for treating anemia and / or thrombocytopenia in patients with Gaucher disease.

[0064] In one embodiment, the patient with Gaucher disease is anemic.

[0065] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of increasing hemoglobin.

[0066] In one embodiment, the above method for increasing hemoglobin is a method for increasing hemoglobin in patients with Gaucher disease.

[0067] In one embodiment, the above method for increasing hemoglobin is a method for increasing hemoglobin in patients with Gaucher disease, who are anemic.

[0068] In one embodiment, the above method for increasing hemoglobin is a method for increasing hemoglobin in an anemic patient with Gaucher disease.

[0069] In one embodiment, the above treatment increases hemoglobin at a dose of 600 mg / day (200 mg tid) or more, for example, 600-900 mg / day (200-300 mg tid) or 900-1200 mg / day (300-400 mg tid), for example, increasing hemoglobin at a dose of 600 mg / day (200 mg tid) or 1200 mg / day (400 mg tid).

[0070] In one embodiment, the above treatment increases hemoglobin at a dose of 600 mg / day (200 mg tid) or more, for example, 600-900 mg / day (200-300 mg tid) or 900-1200 mg / day (300-400 mg tid), and the above dose is adjusted for body weight (see other parts of this specification).

[0071] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of reducing serum chitotriosidase activity.

[0072] In one embodiment, the above method for reducing serum chitotriosidase activity is a method for reducing serum chitotriosidase activity in patients with Gaucher disease.

[0073] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of increasing glycosylsphingosine (lyso-Gb1).

[0074] In one embodiment, the above method for increasing glycosylsphingosine (lyso-Gb1) is a method for increasing glycosylsphingosine (lyso-Gb1) in patients with Gaucher disease.

[0075] In one embodiment, the Gaucher disease (GD) is of type GD1 (GD1) or type GD3 (GD3).

[0076] In one embodiment, the Gaucher disease (GD) is of type GD1 (GD1).

[0077] In one embodiment, the Gaucher disease (GD) is of type GD3 (GD3).

[0078] In one embodiment, the above treatment reduces liver size in a dose-dependent manner.

[0079] In one embodiment, the above treatment reduces the size of the spleen in a dose-dependent manner.

[0080] In one embodiment, the above treatment reduces chitotriosidase activity in a dose-dependent manner.

[0081] In one embodiment, the above treatment increases hemoglobin in a time-dependent manner.

[0082] One aspect of the present disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts for use in a method of treating Gaucher disease (GD), with a maximum predicted AUC 0~8時間(High dose) shows an AUC of 6 to 9 μg·h / mL after a single dose administration. 0~8時間 It falls within the range of approximately 80.00% to 125.00%.

[0083] In some embodiments, the maximum predicted AUC 0~8時間 (High dose) AUC of 6 to 9 μg·h / mL after single dose administration, e.g., approximately 6 to 6.5, e.g., approximately 6.5 to 7, e.g., approximately 7 to 7.5, e.g., approximately 7.5 to 8, e.g., approximately 8 to 8.5, e.g., approximately 8.5 to 9 μg·h / mL 0~8時間 It falls within the range of approximately 80.00% to 125.00%.

[0084] In some embodiments, the maximum predicted AUC 0~8時間 (High dose) AUC of 6 to 9 μg·h / mL after single dose administration, e.g., approximately 6 to 6.5, e.g., approximately 6.5 to 7, e.g., approximately 7 to 7.5, e.g., approximately 7.5 to 8, e.g., approximately 8 to 8.5, e.g., approximately 8.5 to 9 μg·h / mL 0~8時間 This is within the range of approximately 80.00% to approximately 125.00%, and the above single dose is 100 mg for patients weighing between 10 kg and 30 kg, and / or The above single dose is 200 mg for patients weighing between 30 kg and 50 kg, and / or The above single dose is 300 mg for patients weighing between 50 kg and 70 kg, and / or The above single dose is 400 mg for patients weighing 70 kg or more.

[0085] In some embodiments, a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts is provided for use in a method of treating Gaucher disease (GD), and after administration of 300 mg / day, AUC 0~8時間、定常状態 It has an AUC of approximately 1000 h·ng / mL. 0~8時間、定常状態 It falls within the range of approximately 80.00% to 125.00%.

[0086] In some embodiments, the AUC 0~8時間、定常状態 is within the range of about 80.00% to about 125.00% of the AUC0-8 of about 700 to 1300 h·ng / mL, such as about 800 to 1200 h·ng / mL, such as about 900 to 1100 h·ng / mL after administration of 300 mg / day. 時間、定常状態

[0087] In some embodiments, there is provided a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and its acid addition salts for use in a method of treating Gaucher's disease (GD). After administration of 600 mg / day, the AUC 0~8時間、定常状態 is within the range of about 80.00% to about 125.00% of the AUC 0~8時間、定常状態 of about 2000 h·ng / mL.

[0088] In some embodiments, the AUC 0~8時間、定常状態 is within the range of about 80.00% to about 125.00% of the AUC0-8 of about 1700 to 2300 h·ng / mL, such as about 1800 to 2200 h·ng / mL, such as about 1900 to 2100 h·ng / mL after administration of 600 mg / day. 時間、定常状態

[0089] In some embodiments, there is provided a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and its acid addition salts for use in a method of treating Gaucher's disease (GD). The AUC 0~8時間、定常状態 is within the range of about 80.00% to about 125.00% of the AUC 0~8時間、定常状態 of about 5100 h·ng / mL after administration of 1200 mg / day.

[0090] In some embodiments, the AUC 0~8時間、定常状態 ​​After administration of 1200 mg / day, the AUC is approximately 4500 to 5700 h·ng / mL, for example 4500 to 4600 h·ng / mL, for example 4600 to 4700 h·ng / mL, for example 4700 to 4800 h·ng / mL, for example 4800 to 4900 h·ng / mL, for example 4900 to 5000 h·ng / mL, for example 5000 to 5100 h·ng / mL, for example 5100 to 5200 h·ng / mL, for example 5200 to 5300 h·ng / mL, for example 5300 to 5400 h·ng / mL, for example 5400 to 5500 h·ng / mL, for example 5500 to 5600 h·ng / mL, for example 5600 to 5700 h·ng / mL. 0~8時間、定常状態 It falls within the range of approximately 80.00% to 125.00%.

[0091] In one embodiment, the treatment is preventive, curative, or corrective. In a particular embodiment, the treatment is preventive. In another embodiment, the treatment is curative. In yet another embodiment, the treatment is corrective.

[0092] In some embodiments, the individual has been previously treated for Gaucher disease by enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. In some embodiments, the individual has been previously treated by enzyme replacement therapy and / or substrate replacement therapy. In some embodiments, the individual has not been treated for Gaucher disease by enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. within four months prior to the start of treatment, for example, within three months, for example, within two months, for example, within one month. In some embodiments, the individual has not been treated by enzyme replacement therapy and / or substrate replacement therapy within four months prior to the start of treatment, for example, within three months, for example, within two months, for example, within one month. In some embodiments, the individual has never been treated for Gaucher disease by enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. In some embodiments, the individual has never been treated by enzyme replacement therapy and / or substrate replacement therapy.

[0093] The individuals treated are preferably mammals, particularly humans. However, the treatment of animals such as mice, rats, dogs, cats, horses, cattle, sheep, and pigs is also within the scope of this disclosure. The individuals treated may be of various ages, including infants, children, adolescents, and adults. In preferred embodiments, the individuals used herein are human beings of any age, male or female.

[0094] "An individual in need of it" refers to a diseased individual who can benefit from this disclosure, and such disease is Gaucher disease. A patient is considered an individual in need of it, and a patient with Gaucher disease is considered a patient in need of it. The terms "individual" and "patient" may be used interchangeably herein.

[0095] Arimokromor For the purposes described herein, this disclosure provides a pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and their acid addition salts.

[0096] In some embodiments, the active pharmaceutical ingredient is a racemic mixture of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0097] In some embodiments, the active pharmaceutical ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0098] In some embodiments, the active pharmaceutical ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0099] In some embodiments, the pharmacoactive ingredient is selected from the group consisting of (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0100] In some embodiments, the pharmacoactive ingredient is selected from the group consisting of (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0101] In some embodiments, the active pharmaceutical ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride.

[0102] In some embodiments, the pharmacoactive ingredient is selected from the group consisting of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate.

[0103] In some embodiments, the pharmacoactive ingredient is selected from the group consisting of (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate.

[0104] In some embodiments, the active pharmaceutical ingredient is (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate The following are selected from the group consisting of (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate.

[0105] In some embodiments, the active pharmaceutical ingredient is alimochromol.

[0106] In some embodiments, the active pharmaceutical ingredient is alimochromol (free base), (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. Alimochromol and its preparations are disclosed, for example, in International Publications 97 / 16439, 00 / 050403 and 01 / 79174. In some embodiments, alimochromol is a citrate preparation of the free base, namely (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (also known as BRX-345). The free base of alimochromol has a structure as shown in formula I: [ka]

[0107] Usage / Dosage A composition containing a pharmaceutical active ingredient or one as defined herein is administered in some embodiments to an individual in need in a pharmaceutically effective dose or therapeutically effective dose.

[0108] In some embodiments, the active pharmaceutical ingredient is administered once or several times a day, for example, one to three times a day, one to two times a day, or two to three times a day.

[0109] In some embodiments, the active pharmaceutical ingredient is administered daily, for example, once a day, for example twice a day, or for example three times a day (tid).

[0110] In a preferred embodiment, the active pharmaceutical ingredient is administered three times a day (tid).

[0111] In some embodiments, the active pharmaceutical ingredient is administered over a period of time, such as one week, for example, more than one week, for example, two weeks or more than two weeks, for example, three weeks or more than three weeks, for example, four weeks or more than four weeks, for example, one month or more than one month, for example, two months or more than two months, for example, three months or more than three months, for example, four months or more than four months, for example, five months or more than five months, for example, six months or more than six months, for example, seven months or more than seven months, for example, eight months or more than eight months, for example, nine months or more than nine months, for example, ten months or more than ten months, for example, eleven months or more than eleven months, or for example, one year or more than one year.

[0112] In some embodiments, the active pharmaceutical ingredient is administered for at least 6 months. In some embodiments, the active pharmaceutical ingredient is administered for at least 9 months, for example, at least 1 year, for example, at least 18 months, for example, at least 2 years, for example, at least 30 months, for example, at least 3 years, for example, at least 4 years, for example, at least 5 years, for example, at least 6 years, for example, at least 7 years, for example, at least 8 years, for example, at least 9 years, for example, at least 10 years or longer.

[0113] In some embodiments, the dose is calculated based on the free base of alimochromol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride).

[0114] In some embodiments, the dose is calculated based on alimochromol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate).

[0115] Unless otherwise specified, the dosages of the active pharmaceutical ingredients disclosed herein are given as citrates, and the conversion scheme between citrates and free bases is as follows:

[0116] [Table A]

[0117] In some embodiments, the active pharmaceutical ingredient is alimochromol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate).

[0118] In some embodiments, the active pharmaceutical ingredient is administered in doses ranging from about 25 mg to about 800 mg per dose, for example, from about 100 mg to about 800 mg. In some embodiments, the active pharmaceutical ingredient is administered in doses ranging from about 25 mg to about 50 mg per dose, for example, from about 50 mg to about 75 mg, for example, from about 75 mg to about 100 mg, for example, from about 100 mg to about 150 mg, for example, from about 150 mg to about 200 mg, for example, from about 200 mg to about 300 mg, for example, from about 300 mg to about 400 mg, for example, from about 400 mg to about 500 mg, for example, from about 500 mg to about 600 mg, for example, from about 600 mg to about 700 mg, for example, from about 700 mg to about 800 mg, preferably the active pharmaceutical ingredient is administered three times a day.

[0119] In some embodiments, the active pharmaceutical ingredient is administered in doses of approximately 25 mg, for example, approximately 50 mg, for example, approximately 75 mg, for example, approximately 100 mg, for example, approximately 150 mg, for example, approximately 200 mg, for example, 300 mg, for example, 400 mg, for example, 500 mg, for example, 600 mg, for example, 700 mg, for example, 800 mg per dose, and preferably the active pharmaceutical ingredient is administered three times a day.

[0120] In some embodiments, the active pharmaceutical ingredient is administered in doses of approximately 100 mg, for example, approximately 200 mg, for example, approximately 400 mg per dose, preferably the first active pharmaceutical ingredient is administered three times a day. In some embodiments, the above dose per dose is adjusted for body weight.

[0121] In some embodiments, the active pharmaceutical ingredient is administered in doses of 100 mg tid, for example, 200 mg tid, for example, 400 mg tid. In some embodiments, the above dose is adjusted for body weight.

[0122] In some embodiments, the active pharmaceutical ingredient is administered in a daily dose of approximately 100 mg / day to approximately 200 mg / day, for example, approximately 200 mg / day to approximately 300 mg / day, for example, approximately 300 mg / day to approximately 400 mg / day, for example, approximately 400 mg / day to approximately 500 mg / day, for example, approximately 500 mg / day to approximately 600 mg / day, for example, approximately 700 mg / day to approximately 800 mg / day, for example, approximately 800 mg / day to approximately 900 mg / day, for example, approximately 900 mg / day to approximately 1000 mg / day, for example, approximately 1000 mg / day to approximately 1100 mg / day, for example, approximately 1100 mg / day to approximately 1200 mg / day.

[0123] In a preferred embodiment, the active pharmaceutical ingredient is administered in a daily dose of 300 mg / day, for example, 600 mg / day, or for example, 1200 mg / day.

[0124] In preferred embodiments, the active pharmaceutical ingredient is administered orally. In some embodiments, the active pharmaceutical ingredient is administered via a gastric tube.

[0125] In some embodiments, the active pharmaceutical ingredient is administered in hard capsules of 25 mg, 50 mg, or 100 mg.

[0126] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients who weigh 10 kg or more.

[0127] In some embodiments, the active pharmaceutical ingredient is administered to patients with Gaucher disease in a dose based on the patient's body weight.

[0128] In some embodiments, the active pharmaceutical ingredient is administered to patients with Gaucher disease in a weight-adjusted dose.

[0129] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 100 mg tid, which corresponds to a 300 mg / day dose. This is also referred to as a “low” dose.

[0130] In some embodiments, the active pharmaceutical ingredient is administered at a 200 mg tid (tid) dose, which corresponds to a 400 mg / day dose. This is also referred to as a “moderate” dose.

[0131] In some embodiments, the active pharmaceutical ingredient is administered at a 400 mg tid (t1) dose, which corresponds to a 1200 mg / day dose. This is also referred to as a “high” dose.

[0132] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 10 kg and 30 kg.

[0133] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 25 mg tid ("low dose"), equivalent to a 75 mg / day dose, to patients with Gaucher disease weighing between 10 kg and 30 kg.

[0134] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 50 mg tid ("medium dose"), which corresponds to a 150 mg / day dose, to Gaucher disease patients weighing between 10 kg and 30 kg.

[0135] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 100 mg tid ("high dose"), which corresponds to a 300 mg / day dose for Gaucher disease patients weighing between 10 kg and 30 kg.

[0136] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 30 kg and 50 kg.

[0137] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 50 mg tid ("low dose"), which corresponds to a 150 mg / day dose, to Gaucher disease patients weighing between 30 kg and 50 kg.

[0138] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 100 mg tid ("medium dose"), which corresponds to a 300 mg / day dose for Gaucher disease patients weighing between 30 kg and 50 kg.

[0139] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 200 mg tid ("high dose"), which corresponds to a 600 mg / day dose, to Gaucher disease patients weighing between 30 kg and 50 kg.

[0140] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 50 kg and 70 kg.

[0141] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 75 mg tid ("low dose"), which corresponds to a 225 mg / day dose, to patients with Gaucher disease weighing between 50 kg and 70 kg.

[0142] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 150 mg tid ("medium dose"), which corresponds to a 450 mg / day dose, to Gaucher disease patients weighing between 50 kg and 70 kg.

[0143] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 300 mg tid ("high dose"), which corresponds to a dose of 900 mg / day, to patients with Gaucher disease weighing between 50 kg and 70 kg.

[0144] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients weighing 70 kg or more.

[0145] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 100 mg tid ("low dose"), which corresponds to a 300 mg / day dose for Gaucher disease patients weighing 70 kg or more.

[0146] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 200 mg tid ("medium dose"), which corresponds to a dose of 600 mg / day for Gaucher disease patients weighing 70 kg or more.

[0147] In some embodiments, the active pharmaceutical ingredient is administered at a dose of 400 mg tid ("high dose"), which corresponds to a dose of 1200 mg / day, to patients with Gaucher disease weighing 70 kg or more.

[0148] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients aged between 4 and 60 years.

[0149] In some embodiments, the active pharmaceutical ingredient is administered to patients with Gaucher disease in an age-based dose.

[0150] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients over 18 years of age at a dose of 100 mg tid, which corresponds to a daily dose of 300 mg.

[0151] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients over 18 years of age at a dose of 200 mg tid, which corresponds to a daily dose of 600 mg.

[0152] In some embodiments, the active pharmaceutical ingredient is administered to Gaucher disease patients over 18 years of age at a dose of 400 mg tid, which corresponds to a daily dose of 1200 mg.

[0153] In some embodiments, the active pharmaceutical ingredient is arimochromol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate). In some embodiments, the dose of the active pharmaceutical ingredient is calculated based on arimochromol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate).

[0154] formulation While it is possible to administer pharmaceutical active ingredients as untreated chemicals, in some embodiments it is preferable to provide them in the form of pharmaceutical formulations. Accordingly, compositions containing pharmaceutical active ingredients as defined herein, such as pharmaceutical compositions, i.e., pharmaceutically safe compositions, are also provided herein. Compositions in some embodiments further comprise one or more pharmaceutically and / or physiologically acceptable diluents, carriers, and / or excipients.

[0155] In some embodiments, the composition is formulated for oral administration, for example, in the form of tablets or capsules, or as an oral powder, for example, an oral powder suitable for suspension in a liquid, or for example, as an oral suspension.

[0156] Pharmaceutical compositions containing the active pharmaceutical ingredients of this disclosure can be prepared by conventional techniques. [Examples]

[0157] Example 1 - A multicenter, double-blind, randomized, placebo-controlled trial of arimochromol in patients diagnosed with Gaucher disease type 1 or 3. material and method Method / Test Design This is a placebo-controlled, randomized, double-blind trial evaluating the response of arimochromol at three dose levels to various pharmacodynamic (PD) biomarkers in blood and cerebrospinal fluid (CSF) as an indicator of enhancement of glucocerebrosidase (GBA) enzyme activity in GD1 and GD3.

[0158] The objective of this study was to evaluate whether arimochromol could dose-dependently increase GBA enzyme activity in GD patients. Changes in serum levels of well-established biomarkers related to GBA enzyme activity, as well as changes in hemoglobin and platelet counts, were evaluated over a double-blind 6-month period and compared to placebo. Since both GD1 and GD3 patients have signs of cerebral complications (although non-clinical in GD1 patients), the same biomarker group was evaluated in CSF of GD1 and GD3 patients.

[0159] Eligible GD1 and GD3 patients were randomized in a 1:1:1:1 basis to one of four groups: arimochromol 300 mg / day, arimochromol 600 mg / day, arimochromol 1200 mg / day, or placebo (administered three times daily [tid]).

[0160] Pediatric patients were administered a corresponding dose based on body weight (kilograms). Adult patients randomized to the trial before the protocol's implementation date received a fixed dose, while adult patients randomized to the trial after the protocol's implementation date received an IMP dose based on body weight. Patients were stratified according to GDtype (type 1 or type 3). Patients randomized to receive placebo were further randomized on a 1:1:1 basis to receive arimochromol at 300 mg / day, 600 mg / day, or 1200 mg / day (if there were no safety concerns) in the open-label extension phase of the trial.

[0161] If an unacceptable adverse event (AE) occurred in the judgment of the principal investigator, the patient was administered a reduced dose of the investigational drug (IMP) until the third visit. The patient continued to receive the reduced dose for the remainder of the experiment.

[0162] All patients received a single dose of arimochromol (100 mg in the 300 mg / day treatment group, 200 mg in the 600 mg / day treatment group, 400 mg in the 1200 mg / day treatment group, or the corresponding dose per kg for pediatric patients) prior to the day of implementation of this protocol. Single-dose pharmacokinetics (PK) were performed at the corresponding dose per kg for all patients randomized after the day of implementation of this protocol. Pharmacokinetic (PK) evaluation was performed at the second visit after randomization to confirm the suitability of the dose selected in this study (in terms of the target investigational drug (AUC0~8 - area under the curve from 0 to 8 hours [AUC][AUC0~8])). Blood samples for PK analysis were collected before administration and at 0.5, 1, 2, 4, and 8 hours after administration. Patients randomized to the placebo group received the dose for the extension phase. To verify AUC0–8, corresponding data were evaluated by independent assessors. Patients then immediately began continuous administration of IMP in accordance with the randomization of the trial. IMP was administered three times daily (tid).

[0163] If the AUC exceeded the target, or if an unexpected profile was obtained that could affect patient safety and the patient required dose reduction, the patient received a reduced dose of IMP (blinded) on the third visit. Dose levels were recommended by an independent assessor. Additional blood samples for quantitative population PK analysis of arimochromol were collected before administration and 0.5 hours after administration on the fifth visit, and before administration and 1.5 hours after administration on the seventh visit.

[0164] Cerebrospinal fluid samples for quantitative population PK analysis of arimochromol were collected pre-administration on the 5th visit and after the first day of administration on the 7th visit. The results of population PK analysis and PK / PD modeling were reported separately. Following the proof-of-concept phase, all patients were given the opportunity to continue to an open-label extension phase, during which patients participated in site visits one month after the end of visits in the blinded phase and every six months after the end of visits in the blinded phase. During this open-label extension phase, patients who received arimochromol during the proof-of-concept phase of the trial continued on the same dose of arimochromol assigned to them, while patients who received placebo were given arimochromol 300 mg / day, 600 mg / day, or 1200 mg / day (adult patients), or a corresponding weight-adjusted dose (pediatric patients). All patients randomized after the implementation date of this protocol received an IMP dose based on body weight.

[0165] Study population and number of patients The study population consisted of male and female patients aged 4 to 60 years with a diagnosis of GD (either type 1 or type 3). Forty patients were expected to be enrolled / randomized to the study.

[0166] Total randomized patient population: All patients who completed the screening procedure and were randomly assigned to a treatment group.

[0167] Intention-to-Treat (ITT) population: All randomized patients who received at least one dose of IMP and had effective serum chitotriosidase activity (primary endpoint) at baseline and on any post-baseline visit.

[0168] Per-protocol (PP) population: All randomized patients who received at least 80% of IMP during the treatment phase, had at least one chitotriosidase (CLS) measurement at baseline (first or second visit) and 6 months (fifth visit), whose plasma or serum chitotriosidase activity exceeded 3 times the normal upper limit applicable to local laboratory testing procedures (medical history data were acceptable), and who were identified as GD1 or GD3 in genetic analysis at the fourth visit.

[0169] Blood / CSF population: All randomized patients whose blood and CSF were measured on their 5th and 7th visits, and whose arimochromol concentrations in blood and CSF were correlated with chitotriosidase activity.

[0170] All patient treatment set: All patients who received at least one dose of IMP.

[0171] Efficacy was analyzed using the ITT and PP populations, and safety was analyzed using the entire patient treatment set (unless otherwise specified).

[0172] Diagnostic and primary trial patient eligibility criteria: The following were the main criteria for patients to be included in the study. 1. The patient or their legal representative is able to read and understand the informed consent form. 2. The patient or their legal representative has signed the informed consent form. 3. Please note that the results of local laboratory tests for type 1 or type 3 GD accompanied by a deficiency of GBA enzyme activity below the lower limit of normal were used when selecting subjects for the study. 4. Regarding GD3, at least one neurological symptom 5. The person must be between 4 and 60 years old at the time of registration. 6. The medical history data for plasma or serum chitotriosidase activity is within acceptable limits, exceeding three times the normal upper limit applicable to local laboratory testing procedures. 7. You have never received a GD treatment, or have not received a GD treatment (such as enzyme replacement therapy or substrate reduction therapy, which have been investigated or approved / authorized, and which include procedures such as blood transfusions and splenectomy) within the four months prior to enrollment in the study. 8. Ability to adhere to the procedures / assessments specified in the protocol and the scheduled hospital visit date (lumbar puncture was not performed if the platelet count was less than 50,000 per microliter of circulating blood). 9. Ability to repeatedly visit the trial site for evaluation and follow-up (screening, baseline, 1, 3, 6, 7, 9, and 12 months, and then every 6 months for the remainder of the extension). 10. All sexually active female patients of childbearing age (post-menarche) must use highly effective contraception during the study and for one week after the last dose of IMP. Highly effective contraception includes combination hormonal contraception (oral, vaginal, or transdermal) that suppresses ovulation (containing estrogen and progestogen), progestogen-only hormonal contraception that suppresses ovulation (oral, injectable, or implantable), intrauterine devices, intrauterine hormone-releasing systems, bilateral fallopian tube blockage, and vasectomy of the partner. All sexually active male patients with a female partner of childbearing age (post-menarche) must use condoms, with or without spermicide, in addition to contraception used by their partner, during the study and for three months after the last dose of IMP.

[0173] Exclusion criteria The following were the main exclusion criteria. 1. Liver transplant recipients or recipients scheduled for liver transplantation during the trial period. 2. Splenectomy within 4 months of trial registration or splenectomy planned during the trial. 3. Aspartate aminotransferase and / or alanine aminotransferase levels exceeding three times the upper limit of normal values ​​for age and sex [Central Laboratory Assessment] 4. Serum creatinine level exceeding 1.5 times the upper limit of normal (assessed by the central laboratory). 5. The patient had received IMP within 30 days prior to trial enrollment (note that, according to enrollment criterion No. 7, IMP for GD should not have been taken within the past 4 months prior to enrollment). 6. The patient is pregnant and / or breastfeeding. 7. In the opinion of the principal investigator, the patient has a clinical condition that makes him or she unsuitable for the requirements of this protocol, e.g., a history of serious adverse reactions to sedation or anesthesia (if sedation is required for lumbar puncture), uncontrolled severe epileptic seizures, and / or severe malnutrition. Weight less than 8.10 kg

[0174] Test product, dosage, and dosage form Alimochromol was administered in the form of 25 mg, 50 mg, and 100 mg hard capsules.

[0175] Reference therapy, dosage, and dosage form Placebo: Placebo capsules were visually indistinguishable from arimochromol capsules in size and appearance. Placebos were supplied in identical white hard capsules containing the same weight of capsule filler, packaged and labeled as described for arimochromol. To conceal which capsule was the active capsule (arimochromol), the placebo's excipient composition, texture, appearance, solubility, odor, and flavor were carefully matched.

[0176] IMP (alimochromol and placebo) was transported to the center at temperatures ranging from 2°C to 25°C and stored at temperatures below 30°C.

[0177] Route of administration IMP (alimochromol or placebo) was administered orally three times daily. If necessary, IMP may be dispersed in 20 mL (i.e., 2 tablespoons) of liquid (apple juice, water, or milk) or 1 tablespoon of soft food (yogurt or applesauce). In the dispersed form, IMP may also be administered via a nasogastric tube (if applicable). For complete administration, the tube was rinsed with 5 mL of water.

[0178] Dosage and regimen For patients randomized before the implementation date of this protocol, a dose of mg units was administered three times daily based on the patient's body weight (see Table 1 below). For pediatric patients, the dose was administered according to body weight as shown in Table 1 below. Adult patients (18 years and older) were given a fixed dose as shown in Table 1 below.

[0179] [Table 1]

[0180] All patients, including adult patients randomized to the trial after the implementation date of this protocol, received an IMP dose based on body weight, as shown in Table 2 below.

[0181] [Table 2]

[0182] Evaluation of effectiveness Primary endpoints The primary efficacy endpoint of the study was the percentage change in serum chitotriosidase activity (a marker of macrophage activation) from baseline to 6 months, with baseline defined as the mean value on the pre-treatment visit days (first and second visits).

[0183] Secondary endpoint Measurement of growth and maturity Patients under 18 years of age: • Changes in weight / height curves at 6 months and every other year until the end of the trial. • Age at the onset of puberty (Tanner stage II) for patients who had not reached puberty at the time of screening. • Tanner stages (Tanner stages I to IV) at baseline, 6 months, and at least every 12 months thereafter until the end of the study. For adult patients aged 18 and over, the criteria for evaluating clinical effectiveness were as follows: • Change from baseline in weight at 6 months and at least every 12 months thereafter until the end of the study.

[0184] Imaging endpoints The imaging efficacy endpoint consisted of changes in liver and spleen size (in centimeters) (assessed by ultrasound) at 6 months and every other year until the end of the study.

[0185] Clinical GD severity endpoint (all patients): • Gaucher disease type 1 disease severity scoring system (GD1-DS3) • Modified Severity Scoring Tool (mSST)

[0186] exploratory endpoints Other exploratory endpoints included blood and CSF biomarker analysis, as well as patient acceptability / preference for IMP.

[0187] The endpoints for exploratory biomarkers measured in the blood included: • Changes in plasma glucosylsphingosine (GlcSph) levels at 6 months and every 6 months until the end of the study. * • Changes in hemoglobin, ferritin, and platelet levels at 6 months and every 6 months until the end of the study. * • Changes in GBA enzyme activity (white blood cells) at 6 months and every 6 months until the end of the study. * • Changes in serum macrophage inflammatory protein-1b (MIP-1β, cytokine for bone complications) at 6 months and every 6 months until the end of the study. * * Change from baseline (baseline is defined as the mean value of the pre-treatment visit dates (first and second visit dates)).

[0188] The endpoints for exploratory biomarkers measured by CSF included the following: • Changes in nontransferable glycoprotein B at 6 and 12 months ** • Changes in GlcSph levels at 6 and 12 months ** Changes in chitotriosidase activity (marker of macrophage activation) at 6 and 12 months. ** • Changes in GBA enzyme activity levels at 6 and 12 months ** • Changes in heat shock protein 70 levels at 6 months and 12 months ** ** Changes from the second visit to 6 or 12 months after the second visit.

[0189] Pharmacokinetics Blood samples were collected at the following time points after the initial administration (on the second visit): 0.5, 1, 2, 4, and 8 hours after administration. The AUC0-8 after the initial administration was used to assess whether the exposure level was acceptable. Additional blood samples for quantitative population PK analysis of alimochromol plasma concentrations were collected before administration and 0.5 hours after administration on the fifth visit, and before administration and 1.5 hours after administration on the seventh visit.

[0190] Cerebrospinal fluid samples for quantitative population PK analysis of arimochromol CSF concentration were collected before administration on the 5th visit and after the first day of administration on the 7th visit.

[0191] statistical methods The primary efficacy endpoint was analyzed for the ITT population using an analysis of covariance (ANCOVA) model. Logs of chitotriosidase activity were used for analysis. The response variable in the ANCOVA model was the log of chitotriosidase activity at 6 months, and the independent variables included, as continuous variables, the randomized IMP dose (300 mg / day, 600 mg / day, 1200 mg / day, and 0 mg / day [for placebo]), GD type, and the log of baseline chitotriosidase. A supplementary analysis was performed using the same model, but with the dose actually administered on the third visit after medication adjustments based on possible PK assessments on the second visit.

[0192] The following ANCOVA model was used to correlate logs of drug concentrations in blood and CSF with chitotriosidase activity at 6 months in the blood / CSF population. ANCOVA model for log of chitotriosidase activity using log of drug concentration in CSF measured on the 5th visit, GD type, and baseline chitotriosidase log as covariates. ANCOVA model for log of chitotriosidase activity using logs of drug concentration in the blood measured on the 5th visit, GD type, and baseline chitotriosidase as covariates.

[0193] Secondary efficacy endpoints, including changes in body weight and height, liver size, spleen size, and biomarkers (blood and CSF) relative to baseline (where appropriate), were analyzed using an ANCOVA model with treatment group (the dose actually administered at the third visit after possible medication adjustments based on PK assessment at the second visit, or placebo) and corresponding baseline values ​​as covariates. Appropriate data transformations were performed before statistical analysis as needed for biomarker analysis.

[0194] Descriptive statistics regarding age at the onset of puberty and Tanner stage were provided for each treatment group. No speculative analysis was performed.

[0195] Safety assessments included the following endpoints: incidence and severity of AEs (or AEs occurring under treatment [TEAEs]), C-SSRS, mean values, changes from baseline, and clinically important clinical safety laboratory and vital sign data. Formal statistical analysis of safety data was not performed.

[0196] Plasma and CSF concentrations of arimochromol were summarized using descriptive statistics, categorized by visit date and time. AUC0–8 after the first dose (second visit) was evaluated using a non-compartmental method. The estimated AUC0–8 for each patient was listed.

[0197] The relationship between alimolomolar plasma and CSF concentrations and biomarkers was investigated. All plasma and CSF alimolomolar concentration and administration data were integrated with PK sampling dates and times and used to create a population PK input file for use in population PK modeling analysis. Furthermore, the relationship between alimolomolar PK (plasma / CSF) and biomarkers was also examined using a population PK / PD modeling approach.

[0198] Treatment period The proof-of-concept phase of the trial lasted six months. The open-label extension phase will continue until Alimochromol receives marketing authorization (MA) in India, or until the analysis of data from the proof-of-concept period of this trial or information from the development program ceases to be necessary, whichever comes first.

[0199] The period during which patients participate in the trial Randomization (second visit) was performed 7 to 35 days after screening (first visit). During the proof-of-concept, double-blind, placebo-controlled period of the trial, patients visited the trial one month (third visit), three months (fourth visit), and six months (fifth visit [end of blinding period]) after the second visit. During the open-label extension phase of the trial, patients visited the trial one month (sixth visit), three months (6.1st visit), six months (seventh visit), and thereafter every six months until the end of the trial. The total duration of patient participation in the trial depends on the date MA was granted in India or the availability of relevant data from the development program.

[0200] result Treatment group and key baseline characteristics Thirty-nine subjects were randomized to an intention-to-treat (ITT) population, but two patients were excluded from the ITT set because their confirmatory GD genotyping (post-hoc) analysis was negative. The ITT analysis set consisted of 31 children and 6 adults.

[0201] The number of patients in each treatment group and their baseline characteristics are summarized in Table 3 below.

[0202] [Table 3]

[0203] Dose-dependent plasma exposure to alimochromol Plasma exposure (AUC) was estimated for each patient using population PK modeling. A dose-dependent increase in plasma exposure was observed after administration of arimochromol (see Figure 1).

[0204] Clinical findings Primary endpoints Chitotriosidase activity increased across all treatment groups, although the increase was lower in the arimochromol group compared to placebo. Although statistical significance was not achieved (p=0.4), a relative decrease in chitotriosidase activity from baseline was observed in all dose groups compared to placebo (see Figure 2).

[0205] Secondary clinical endpoints Compared to placebo, clinically significant dose-dependent reductions were observed in liver size (dose-trend effect, p<0.05) and spleen size (dose-trend analysis, p<0.10) (see Figures 3 and 4). The strong correlation between liver and spleen size and treatment (correlation coefficient: 0.53) supports the consistency of the effect.

[0206] Patients with baseline anemia in the higher-dose group showed a time-dependent increase in hemoglobin (time trend analysis p<0.05) (see Figure 5).

[0207] A dose-dependent reduction in the validated clinical composite scale ("Clinical GD1 Severity Score") was also observed in Gaucher disease type 1, but statistical significance was not achieved.

[0208] Other exploratory biomarkers: A dose-dependent increase in glycosylsphingosine (lyso-Gb1) was observed (see Figure 6), but statistical significance was not achieved. In certain embodiments, for example, the following are provided: (Item 1) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of treating Gaucher disease (GD). (Item 2) A medicinal active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating Gaucher disease (GD), administered at doses of 100 mg tid, e.g., 200 mg tid, e.g., 400 mg tid. (Item 3) A medicinal active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and its acid addition salts, for use in a method of treating Gaucher disease (GD), administered at a dose of 300 mg / day, for example, 600 mg / day, for example, 1200 mg / day. (Item 4) The pharmacopoeial active ingredient for use as described in any one of the preceding items, wherein the Gaucher disease (GD) is of type GD1 (GD1) or type GD3 (GD3). (Item 5) The pharmacovigilant active ingredient for use as described in any one of the preceding items, wherein the Gaucher disease (GD) is of the GD1 type (GD1) or GD3 type (GD3) type, characterized by a deficiency of GBA enzyme activity below the lower limit of normal. (Item 6) The pharmacopoeial active ingredient for use as described in any one of the preceding items, wherein the Gaucher disease (GD) is of type GD1 (GD1). (Item 7) The Gaucher disease (GD) is type GD1 (GD1) with signs of cerebral complications, for example, nonclinical signs of cerebral complications, as described in any one of the preceding items. (Item 8) The pharmacopoeial active ingredient for use as described in any one of the preceding items, wherein the Gaucher disease (GD) is of type GD3 (GD3). (Item 9) The Gaucher disease (GD) described above is type GD3 (GD3) with signs of cerebral complications, for example, clinical signs of cerebral complications, and is an active pharmaceutical ingredient for use as described in any one of the preceding items. (Item 10) The pharmacopoeial active ingredient for use as described in any one of the preceding items, wherein the Gaucher disease (GD) is of type GD3 (GD3) with at least one neurological symptom. (Item 11) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods to treat hepatomegaly and / or reduce liver size. (Item 12) A medicinal active ingredient for use as described in any one of the preceding items, wherein the method is for treating hepatomegaly in patients with Gaucher disease and / or for reducing the size of the liver. (Item 13) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods to treat splenomegaly and / or reduce the size of the spleen. (Item 14) The medicinal active ingredient for use as described in any one of the preceding paragraphs, wherein the method described above is for treating splenomegaly in patients with Gaucher disease and / or for reducing the size of the spleen. (Item 15) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods to treat hepatosplenomegaly and / or reduce the size of the liver and decrease the size of the spleen. (Item 16) The pharmacovigilant active ingredient for use as described in any one of the preceding items, wherein the method is for treating hepatosplenomegaly and / or reducing the size of the liver and / or the size of the spleen in patients with Gaucher disease. (Item 17) The splenomegaly is splenomegaly accompanied by anemia and thrombocytopenia, and is a medicinal active ingredient for use as described in any one of the preceding items. (Item 18) The active pharmaceutical ingredient for use as described in any one of the preceding items, wherein the hepatosplenomegaly is hepatosplenomegaly accompanied by anemia and thrombocytopenia. (Item 19) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of treating anemia and / or thrombocytopenia. (Item 20) The pharmacopoeial active ingredient for use as described in any one of the preceding items, wherein the method described above is for treating anemia and / or thrombocytopenia in patients with Gaucher disease. (Item 21) The aforementioned Gaucher disease patient is anemic, and the active pharmaceutical ingredient for use described in any one of the preceding items. (Item 22) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of increasing hemoglobin. (Item 23) The aforementioned method is for increasing hemoglobin in patients with Gaucher disease, and the active pharmaceutical ingredient for use as described in any one of the preceding items. (Item 24) The method described above is for increasing hemoglobin, and includes administering the active pharmaceutical ingredient in a dose of 600 mg / day (200 mg tid) or more, for example, 600-900 mg / day (200-300 mg tid) or 900-1200 mg / day (300-400 mg tid), as described in any one of the preceding paragraphs. (Item 25) The pharmacovigilant active ingredient for use as described in any one of the preceding items, wherein the method is for increasing hemoglobin, and includes administering the pharmacovigilant active ingredient in a dose of 600 mg / day (200 mg tid) or 1200 mg / day (400 mg tid). (Item 26) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and their acid addition salts, for use in methods to reduce serum chitotriosidase activity. (Item 27) The above method is for reducing serum chitotriosidase activity in patients with Gaucher disease, and is a medicinal active ingredient for use as described in any one of the preceding items. (Item 28) A pharmaceutical active ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts, for use in methods of increasing glycosylsphingosine (lyso-Gb1). (Item 29) The above method is for increasing glycosylsphingosine (lyso-Gb1) in patients with Gaucher disease, and is a medicinal active ingredient for use as described in any one of the preceding items. (Item 30) A medicinal active ingredient for use as described in any one of the preceding items, wherein the treatment dose-dependently reduces the size of the liver. (Item 31) A medicinal active ingredient for use as described in any one of the preceding items, wherein the treatment dose-dependently reduces the size of the spleen. (Item 32) A medicinal active ingredient for use as described in any one of the preceding items, wherein the treatment dose-dependently reduces chitotriosidase activity. (Item 33) A medicinal active ingredient for use as described in any one of the preceding items, wherein the treatment increases hemoglobin in a time-dependent manner. (Item 34) The individual has not been treated for Gaucher disease by enzyme replacement therapy and / or substrate replacement therapy, etc., within the past four months, or the individual to be treated has not been previously treated for Gaucher disease by enzyme replacement therapy and / or substrate replacement therapy, etc., for example, the individual to be treated has never been treated by enzyme replacement therapy and / or substrate replacement therapy, the active pharmaceutical ingredient for use as described in any one of the preceding items. (Item 35) A medicinal active ingredient for use as described in any one of the preceding items, wherein the treatment is preventive, curative, or ameliorative. (Item 36) The pharmacovigilant active ingredient for use as described in any one of the preceding items, wherein the pharmacovigilant active ingredient is a racemic mixture of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride. (Item 37) The pharmacoactive ingredient for use as described in any one of the preceding items, wherein the pharmacoactive ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride. (Item 38) The pharmacoactive ingredient for use as described in any one of the preceding items, wherein the pharmacoactive ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride. (Item 39) The aforementioned active pharmaceutical ingredient, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride A pharmaceutical active ingredient for use as described in any one of the preceding items, selected from the group consisting of the following. (Item 40) The aforementioned active pharmaceutical ingredient, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxyimidoyl chloride, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride A pharmaceutical active ingredient for use as described in any one of the preceding items, selected from the group consisting of the following. (Item 41) The pharmacoactive ingredient for use as described in any one of the preceding items, wherein the pharmacoactive ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride. (Item 42) The aforementioned active pharmaceutical ingredient, N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoylchloride maleate A pharmaceutical active ingredient for use as described in any one of the preceding items, selected from the group consisting of the following. (Item 43) The aforementioned active pharmaceutical ingredient, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxyimidoyl chloride maleate, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoylchloride maleate A pharmaceutical active ingredient for use as described in any one of the preceding items, selected from the group consisting of the following. (Item 44) The aforementioned active pharmaceutical ingredient, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboxyimidoyl chloride citrate, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride maleate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride maleate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate A pharmaceutical active ingredient for use according to any one of the preceding items, selected from the group consisting of. (Item 45) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is alimemol. (Item 46) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is alimemol citrate. (Item 47) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered orally. (Item 48) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is formulated for oral administration, for example, in the form of tablets or capsules, or an oral powder suitable for suspension in a liquid, or a suspension for oral administration, for example. (Item 49) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered daily, for example, once a day, for example, twice a day, for example, three times a day. (Item 50) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered three times a day (t.i.d.). (Item 51) A pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered at a dose of about 100 mg to about 400 mg per administration, for example, about 100 mg, 200 mg or 400 mg. (Item 52) The aforementioned active pharmaceutical ingredient is administered in doses of 100 mg tid, for example, 200 mg tid, for example, 400 mg tid, for example, the active pharmaceutical ingredient for use as described in any one of the preceding items. (Item 53) The aforementioned active pharmaceutical ingredient is administered at a dose of 200 mg tid, for use as described in any one of the preceding items. (Item 54) The aforementioned active pharmaceutical ingredient for use as described in any one of the preceding items, wherein the active pharmaceutical ingredient is administered at a dose of 100 mg tid. (Item 55) The aforementioned active pharmaceutical ingredient for use as described in any one of the preceding items, wherein the active pharmaceutical ingredient is administered at a dose of 400 mg tid. (Item 56) The aforementioned active pharmaceutical ingredient for use as described in any one of the preceding items, administered in a daily dose of approximately 100 mg / day to approximately 200 mg / day, for example, approximately 200 mg / day to approximately 300 mg / day, for example, approximately 300 mg / day to approximately 400 mg / day, for example, approximately 400 mg / day to approximately 500 mg / day, for example, approximately 500 mg / day to approximately 600 mg / day, for example, approximately 700 mg / day to approximately 800 mg / day, for example, approximately 800 mg / day to approximately 900 mg / day, for example, approximately 900 mg / day to approximately 1000 mg / day, for example, approximately 1000 mg / day to approximately 1100 mg / day, for example, approximately 1100 mg / day to approximately 1200 mg / day. (Item 57) The aforementioned active pharmaceutical ingredient is administered in a daily dose of 300 mg / day, for example, 600 mg / day, for example, 1200 mg / day, for example, the active pharmaceutical ingredient for use as described in any one of the preceding items. (Item 58) The aforementioned active pharmaceutical ingredient is administered in a daily dose of 300 mg / day, for use as described in any one of the preceding items. (Item 59) The aforementioned active pharmaceutical ingredient is administered in a daily dose of 600 mg / day, for use as described in any one of the preceding items. (Item 60) The aforementioned active pharmaceutical ingredient is administered in a daily dose of 1200 mg / day, as described in any one of the preceding items. (Item 61) The aforementioned active pharmaceutical ingredient for use as described in any one of the preceding items, administered in hard capsules of 25 mg, 50 mg, and 100 mg. (Item 62) The aforementioned active pharmaceutical ingredient is an active pharmaceutical ingredient for use as described in any one of the preceding items, administered to patients with Gaucher disease weighing 10 kg or more. (Item 63) The aforementioned active pharmaceutical ingredient is used for the purposes described in any one of the preceding items, administered to patients with Gaucher disease in a weight-adjusted dose. (Item 64) The aforementioned active pharmaceutical ingredient is an active pharmaceutical ingredient for use as described in any one of the preceding items, administered to patients with Gaucher disease weighing between 10 kg and 30 kg. (Item 65) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 10 kg to 30 kg at a dose of 25 mg tid, which corresponds to a daily dose of 75 mg, for use as described in any one of the preceding items. (Item 66) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 10 kg and 30 kg at a dose of 50 mg tid, which corresponds to a daily dose of 150 mg, for use as described in any one of the preceding items. (Item 67) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 10 kg and 30 kg at a dose of 100 mg tid, which corresponds to a daily dose of 300 mg, for use as described in any one of the preceding items. (Item 68) The aforementioned active pharmaceutical ingredient is an active pharmaceutical ingredient for use as described in any one of the preceding items, administered to Gaucher disease patients weighing between 30 kg and 50 kg. (Item 69) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 30 kg to 50 kg or less in a dose of 50 mg tid, which corresponds to a daily dose of 150 mg, for use as described in any one of the preceding items. (Item 70) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing between 30 kg and 50 kg in a dose of 100 mg tid, which corresponds to a daily dose of 300 mg, for use as described in any one of the preceding items. (Item 71) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 30 kg to 50 kg or less in a dose of 200 mg tid, which corresponds to a daily dose of 600 mg, for use as described in any one of the preceding items. (Item 72) The aforementioned active pharmaceutical ingredient is an active pharmaceutical ingredient for use as described in any one of the preceding items, administered to patients with Gaucher disease weighing between 50 kg and 70 kg. (Item 73) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 50 kg to 70 kg or less in a dose of 75 mg tid, which corresponds to a daily dose of 225 mg, for use as described in any one of the preceding items. (Item 74) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 50 kg to 70 kg or less in a dose of 150 mg tid, which corresponds to a dose of 450 mg / day, for use as described in any one of the preceding items. (Item 75) The aforementioned active pharmaceutical ingredient is administered to Gaucher disease patients weighing 50 kg to 70 kg or less in a dose of 300 mg tid, which corresponds to a daily dose of 900 mg, for use as described in any one of the preceding items. (Item 76) The aforementioned active pharmaceutical ingredient is an active pharmaceutical ingredient for use as described in any one of the preceding items, administered to patients with Gaucher disease weighing 70 kg or more. (Item 77) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient weighing 70 kg or more at a dose of 100 mg t.i.d. corresponding to a dose of 300 mg / day. (Item 78) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient weighing 70 kg or more at a dose of 200 mg t.i.d. corresponding to a dose of 600 mg / day. (Item 79) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient weighing 70 kg or more at a dose of 400 mg t.i.d. corresponding to a dose of 1200 mg / day. (Item 80) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the Gaucher disease patient is 4 years old or older and 60 years old or younger. (Item 81) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the Gaucher disease patient is 4 to 6 years old, for example 6 to 8 years old, for example 8 to 10 years old, for example 10 to 12 years old, for example 12 to 14 years old, for example 14 to 16 years old, for example 16 to 18 years old. (Item 82) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient at an age-adjusted dose. (Item 83) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient over 18 years old. (Item 84) The pharmaceutical active ingredient for use according to any one of the preceding items, wherein the pharmaceutical active ingredient is administered to a Gaucher disease patient over 18 years old at a dose of 100 mg t.i.d. corresponding to a dose of 300 mg / day. (Item 85) The aforementioned active pharmaceutical ingredient is administered to patients with Gaucher disease aged over 18 years of age in a dose of 200 mg tid, which corresponds to a dose of 600 mg / day, as described in any one of the preceding items. (Item 86) The aforementioned active pharmaceutical ingredient is administered to patients with Gaucher disease aged over 18 years of age in a dose of 400 mg tid, which corresponds to a dose of 1200 mg / day, as described in any one of the preceding items. (Item 87) Maximum Predicted AUC 0~8時間 (High dose) AUC of 6 to 9 μg·h / mL after single dose administration, for example, approximately 6 to 6.5, approximately 6.5 to 7, approximately 7 to 7.5, approximately 7.5 to 8, approximately 8 to 8.5, and approximately 8.5 to 9 μg·h / mL after single dose administration. 0~8時間 A pharmaceutical active ingredient for use as described in any one of the preceding items, within the range of approximately 80.00% to approximately 125.00%. (Item 88) AUC 0~8時間、定常状態 However, after administration of 300 mg / day, the AUC was approximately 1000 h·ng / mL. 0~8時間、定常状態 The active pharmaceutical ingredient for use as described in any one of the preceding items, which is within the range of approximately 80.00% to approximately 125.00%, for example, approximately 700 to 1300 h·ng / mL after administration of 300 mg / day, for example, approximately 800 to 1200 h·ng / mL, for example, approximately 900 to 1100 h·ng / mL. (Item 89) AUC 0~8時間、定常状態 However, after administration of 600 mg / day, the AUC was approximately 2000 h·ng / mL. 0~8時間、定常状態 The active pharmaceutical ingredient for use as described in any one of the preceding items, which is within the range of approximately 80.00% to approximately 125.00%, for example, within the range of approximately 80.00% to approximately 125.00% of approximately 1700 to 2300 h·ng / mL, for example, approximately 1800 to 2200 h·ng / mL, for example, approximately 1900 to 2100 h·ng / mL after administration of 600 mg / day. (Item 90) AUC 0~8時間、定常状態However, after administration of 1200 mg / day, the AUC was approximately 5100 h·ng / mL. 0~8時間、定常状態 The range is approximately 80.00% to approximately 125.00%, and after administration of 1200 mg / day, for example, approximately 4500 to 5700 h·ng / mL, for example, 4500 to 4600 h·ng / mL, for example, 4600 to 4700 h·ng / mL, for example, 4700 to 4800 h·ng / mL, for example, 4800 to 4900 h·ng / mL, for example, 4900 to 5000 h·ng / mL, for example, 5000 to 5100 h·ng / A medicinal active ingredient for use as described in any one of the preceding items, in a range of approximately 80.00% to approximately 125.00% of mL, for example, 5100 to 5200 h·ng / mL, for example, 5200 to 5300 h·ng / mL, for example, 5300 to 5400 h·ng / mL, for example, 5400 to 5500 h·ng / mL, for example, 5500 to 5600 h·ng / mL, for example, 5600 to 5700 h·ng / mL. (Item 91) The aforementioned active pharmaceutical ingredient is used for one week, for example, more than one week, for example, two weeks or more than two weeks, for example, three weeks or more than three weeks, For example, 4 weeks or more than 4 weeks, for example, 1 month or more than 1 month, for example, 2 months or more than 2 months, for example, 3 months or more than 3 months, for example, 4 months or more than 4 months, for example, 5 months or more than 5 months, for example, 6 months or more than 6 months, Alternatively, for example, a medicinal active ingredient for use as described in any one of the preceding items, administered over a period of one year or more than one year. (Item 92) The pharmacoactive ingredient for use as described in any one of the preceding items, which is administered for at least six months, for example, at least nine months, for example, at least one year, for example, at least eighteen months, for example, at least two years, for example, at least three years, for example, at least four years, for example, at least five years or longer. (Item 93) A method for treating Gaucher disease (GD), comprising one or more steps of administering a pharmacoactive ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxyimidoyl chloride, its stereoisomers, and its acid addition salts to an individual in need.

Claims

[Claim 1] The invention described in the specification.

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