Pharmaceutical composition for preventing or treating gaucher disease

Abstract

The present disclosure relates to a pharmaceutical composition for preventing or treating Gaucher disease.

Description

PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING GAUCHER DISEASE

[0001] The present disclosure relates to a pharmaceutical composition for preventing or treating Gaucher disease.

[0002] Gaucher disease (GD) is a genetic disorder in which glucosylceramide (GL1) abnormally accumulates in various organs, including the central nervous system (CNS), due to mutations in the glucocerebrosidase (GBA) gene. For types 2 and 3 Gaucher disease, known as neuronopathic forms of the disease, currently approved drugs are not effective in controlling central neurological symptoms due to poor drug distribution into the brain.

[0003] Clinically, two major categories of Gaucher disease have been recognized: non-neuronopathic and neuronopathic. These can be further subdivided into three types. Type 1 Gaucher disease is the most common form of the disease and includes non-neuronopathic Gaucher disease. Types 2 and 3 Gaucher disease include acute and chronic neuronopathic Gaucher disease. In patients with neuronopathic Gaucher disease, pathogenesis in the central nervous system is related to neuronal death and dropout, which is propagated　by the toxic effects of glucosylceramide. However, little is known about the molecular events leading to this neuronal death.

[0004] Current therapies for Gaucher disease are enzyme replacement therapies such as Cerezyme, a recombinant form of GBA, which are intravenously injected for treatment. However, these protein drugs have several disadvantages in that they have a short half-life in the blood, produce antibodies against the protein, which reduce the drug's effectiveness, have difficulty in delivering the protein to lysosomes, and cannot be used for the treatment of neuronopathic Gaucher disease.

[0005] Recently, it has been known that derivatives having a 2,3-dihydro-1H-indene or 2,3-dihydrobenzofuran moiety, which are compounds having inhibitory activity against glucosylceramide synthase (GCS), are effective in treating Gaucher disease and other diseases (Korean Patent Application Publication No. 10-2021-0059632).

[0006] An object of the present disclosure is to provide a therapy that allows a dimethyl-2,3-dihydro-1H-indene derivative or a pharmaceutically acceptable salt thereof to be safely and effectively administered to a patient with Gaucher disease, and a pharmaceutical composition that may be used therefor.

[0007] However, objects to be achieved by the present disclosure are not limited to the object mentioned above, and other objects not mentioned will be clearly understood by those skilled in the art from the following description.

[0008] Hereinafter, various embodiments described herein will be described with reference to figures. In the following description, numerous specific details are set forth, such as specific configurations, compositions, and processes, etc., in order to provide a thorough understanding of the present disclosure. However, certain embodiments may be practiced without one or more of these specific details, or in combination with other known methods and configurations. In other instances, known processes and preparation techniques have not been described in particular detail in order to not unnecessarily obscure the present disclosure. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrase "in one embodiment" or "an embodiment" in various places throughout this specification are not necessarily referring to the same embodiment of the present disclosure. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0009] In the present disclosure, the term "treating" or "alleviating" may include, without limitation, any action that alleviates or beneficially changes a disease using the composition of the present disclosure.

[0010] In the present disclosure, the term "preventing" may include, without limitation, any action that blocks, suppresses, or delays the symptoms of a disease using the composition of the present disclosure.

[0011] Unless otherwise stated in the specification,　all the scientific and technical terms used in the specification　have the same meanings as commonly understood　by those skilled in the technical field to which the present disclosure pertains.

[0012] The present disclosure relates to an administration method a pharmaceutical composition for preventing or treating Gaucher disease (GD), containing, as an active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0013] [Formula 1]

[0014]

[0015] The quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate compound may have an asymmetric carbon center, and thus may exist as an R or S isomer or a racemic compound, and all of these optical isomers and mixtures may be included in the scope of the present disclosure.

[0016] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 2 below, without being limited thereto:

[0017] [Formula 2]

[0018]

[0019] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 3 below, without being limited thereto:

[0020] [Formula 3]

[0021]

[0022] The pharmaceutical composition may also contain a pharmaceutically acceptable salt of the compound as the active ingredient. The term "pharmaceutically acceptable salt" refers to such salts which are usually considered by those skilled in the art to be suitable for medical applications, e.g., because they are not harmful to subjects which may be treated with the salts, or which give rise to side effects which are tolerable within the respective treatment.　Usually, the pharmaceutically acceptable salts are such salts which are considered as acceptable by the regulatory authorities, such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Japanese Ministry of Health, Labor and Welfare Pharmaceuticals and Medical Devices Agency (PMDA). However, the present disclosure in principle also encompasses salts of the compounds according to the present disclosure which are as such not pharmaceutically acceptable, e.g., as intermediates in the production of the compounds according to the present disclosure or physiologically functional derivatives thereof, or as intermediates in the production of pharmaceutically acceptable salts of the compounds according to the present disclosure or physiologically functional derivatives thereof. Said salts include water-insoluble salts and, particularly, water-soluble salts.

[0023] In each case, those skilled in the art can readily determine whether a certain compound according to the present disclosure or a physiologically functional derivative thereof can form a salt, i.e., whether said compound according to the present disclosure or a physiologically functional derivative thereof has a group which may carry a charge, such as, for example, an amino group, a carboxylic acid group, etc.

[0024] Exemplary salts of the compounds are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy, which are either water insoluble or, particularly, water-soluble acid addition salts. Salts with bases may, depending on the substituents of the compounds of the present disclosure, also be suitable. Acid addition salts may, for example, be formed by mixing a solution of a compound of the present disclosure with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Likewise, pharmaceutically acceptable base addition salts may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate, and the like.

[0025] Salts, which are not pharmaceutically acceptable and which can be obtained, for example, as process products during the production of the compounds according to the present disclosure on an industrial scale, are also encompassed by the present disclosure and, if desired, may be converted into pharmaceutically acceptable salts by processes known to those skilled in the art.

[0026] The pharmaceutical composition may contain camphorsulfonic acid salts of the compounds as the active ingredient, without being limited thereto.

[0027] The pharmaceutical composition may contain (1S)-(+)-10-camphorsulfonic acid salts of the compounds as the active ingredient, without being limited thereto.

[0028] The pharmaceutical composition may contain, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 4 below, without being limited thereto:

[0029] [Formula 4]

[0030]

[0031] In the present disclosure, the term "subject" refers to an individual that has Gaucher disease or is likely to develop Gaucher disease. Here, the term "individual" refers to an animal (e.g., a mammal or a non-mammal), and may be, for example, a human or a non-human primate. As another example, the individual may be a laboratory mammal (e.g., a mouse, a rat, a rabbit, a hamster, etc.). As another example, the individual may be a farm animal (e.g., a horse, a sheep, a cow, a pig, a camel, etc.) or a domestic animal (e.g., a dog, a cat, etc.). Preferably, the individual may be a human.

[0032] In the present disclosure, the term "Gaucher disease (GD)" refers to an autosomal recessive lysosomal storage disorder (LSD) characterized by a deficiency of the enzyme glucocerebrosidase (GBA). The glucocerebrosidase enzyme functions in the lysosomes of cells to break down the lipid glucocerebroside. This enzyme deficiency is caused by mutations in the GBA1 gene, leading to the accumulation of glucosylceramide (GlcCer, also known as GL1) and its deacylated form, glucosylsphingosine (GlcSph). Such glucosylceramide accumulates in the lysosomes of macrophages, resulting in abnormalities in the liver, spleen, and bone marrow, and causing blood disorders (anemia, thrombocytopenia, leukopenia), hepatosplenomegaly, bone destruction, and central nervous system damage. Gaucher disease is classified into the most common non-neuropathic form (type 1 Gaucher disease) and the neuropathic forms, namely acute neuropathic Gaucher disease (type 2 Gaucher disease) and chronic neuropathic Gaucher disease (type 3 Gaucher disease). In neuropathic Gaucher disease, the toxic effects of glucosylceramide can lead to neuronal necrosis and detachment in the nervous system. The Gaucher disease targeted for prevention, amelioration, or treatment in the present invention includes, without limitation, type 1 Gaucher disease, type 2 Gaucher disease, or type 3 Gaucher disease.

[0033] The present invention is characterized in that the active ingredient is administered to the subject at a dose of about 5 mg / kg (mpk) or more, preferably about 10 mg / kg or more.

[0034] In this disclosure, the term "about" is intended to refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurements.　For example, the degree of error can be indicated by the number of significant figures provided for the measurement, as is understood in the art, and includes but is not limited to a variation of ±1 in the most precise significant figure reported for the measurement. Typical exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, and particularly in biological systems, the terms "about" and "approximately" can mean values that are within an order of magnitude, preferably within 5-fold and more preferably within 2-fold of a given value. Numerical quantities given in the present specification are approximate unless stated otherwise, meaning that the term "about" or "approximately" can be inferred when not expressly stated. They include, but are not limited to, all numerical values within an identical or similar range. In this disclosure, when "about" is stated before a numerical range, the expression "about a to b" may be understood to mean "about a to about b."

[0035] The dose of the pharmaceutical composition, which is to be described below in the present specification, may refer to the dose for all mammals, including humans. As an example, the dose in units of "mg / kg" may indicate a desirable dose for non-human mammals as subjects, without being limited thereto. For example, the dose in units of "mg" may refer to the dose for mammals including humans, and in particular, may refer to the optimal dose for humans, without being limited thereto.

[0036] Furthermore, in this disclosure, the doses of the active ingredients described below refer to the amounts of the compounds of Chemical Formulas 1, 2, or 3, excluding salts. Therefore, even when the aforementioned compounds are administered in the form of pharmaceutically acceptable salts, the doses specified herein are calculated based on the active ingredient after the dissociation of the salts in vivo. Alternatively, the doses of the active ingredients may refer to the amounts in the form of pharmaceutically acceptable salts of these compounds.

[0037] In the present disclosure, the active ingredient may be administered to the subject at a dose of about 5 mg / kg to 90 mg / kg, about 10 mg / kg to 90 mg / kg, about 15 mg / kg to 90 mg / kg, about 20 mg / kg to 90 mg / kg, about 25 mg / kg to 90 mg / kg, about 30 mg / kg to 90 mg / kg, about 35 mg / kg to 90 mg / kg, about 40 mg / kg to 90 mg / kg, about 45 mg / kg to 90 mg / kg, about 50 mg / kg to 90 mg / kg, about 55 mg / kg to 90 mg / kg, about 60 mg / kg to 90 mg / kg, about 5 mg / kg to 60 mg / kg, about 10 mg / kg to 60 mg / kg, about 15 mg / kg to 60 mg / kg, about 20 mg / kg to 60 mg / kg, about 25 mg / kg to 60 mg / kg, about 30 mg / kg to 60 mg / kg, about 35 mg / kg to 60 mg / kg, about 40 mg / kg to 60 mg / kg, about 45 mg / kg to 60 mg / kg, about 50 mg / kg to 60 mg / kg, about 55 mg / kg to 60 mg / kg, about 5 mg / kg to 30 mg / kg, about 10 mg / kg to 30 mg / kg, about 15 mg / kg to 30 mg / kg, about 20 mg / kg to 30 mg / kg, or about 25 mg / kg to 30 mg / kg, without being limited thereto.

[0038] The active ingredient may be administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, or about 90 mg / kg, without being limited thereto.

[0039] In addition, the active ingredient may be administered to the subject at a dose of about 1 mg to 540 mg, or about 3 mg to 480 mg. Preferably, the active ingredient may be administered to the subject at a dose of about 1 mg to 100 mg, about 2 mg to 100 mg, about 2.5 mg to 100 mg, about 3 mg to 100 mg, about 5 mg to 100 mg, about 6 mg to 100 mg, about 7 mg to 100 mg, about 7.5 mg to 100 mg, about 8 mg to 100 mg, about 9 mg to 100 mg, about 10 mg to 100 mg, about 15 mg to 100 mg, about 20 mg to 100 mg, about 25 mg to 100 mg, about 30 mg to 100 mg, about 40 mg to 100 mg, about 50 mg to 100 mg, about 60 mg to 100 mg, about 70 mg to 100 mg, about 80 mg to 100 mg, about 90 mg to 100 mg, about 1 mg to 90 mg, about 2 mg to 90 mg, about 2.5 mg to 90 mg, about 3 mg to 90 mg, about 5 mg to 90 mg, about 6 mg to 90 mg, about 7 mg to 90 mg, about 7.5 mg to 90 mg, about 8 mg to 90 mg, about 9 mg to 90 mg, about 10 mg to 90 mg, about 15 mg to 90 mg, about 20 mg to 90 mg, about 25 mg to 90 mg, about 30 mg to 90 mg, about 40 mg to 90 mg, about 50 mg to 90 mg, about 60 mg to 90 mg, about 70 mg to 90 mg, about 80 mg to 90 mg, about 1 mg to 70 mg, about 2 mg to 70 mg, about 2.5 mg to 70 mg, about 3 mg to 70 mg, about 5 mg to 70 mg, about 6 mg to 70 mg, about 7 mg to 70 mg, about 7.5 mg to 70 mg, about 8 mg to 70 mg, about 9 mg to 70 mg, about 10 mg to 70 mg, about 15 mg to 70 mg, about 20 mg to 70 mg, about 25 mg to 70 mg, about 30 mg to 70 mg, about 40 mg to 70 mg, about 50 mg to 70 mg, about 60 mg to 70 mg, about 1 mg to 50 mg, about 2 mg to 50 mg, about 2.5 mg to 50 mg, about 3 mg to 50 mg, about 5 mg to 50 mg, about 6 mg to 50 mg, about 7 mg to 50 mg, about 7.5 mg to 50 mg, about 8 mg to 50 mg, about 9 mg to 50 mg, about 10 mg to 50 mg, about 15 mg to 50 mg, about 20 mg to 50 mg, about 25 mg to 50 mg, about 30 mg to 50 mg, about 40 mg to 50 mg, about 1 mg to 30 mg, about 2 mg to 30 mg, about 2.5 mg to 30 mg, about 3 mg to 30 mg, about 5 mg to 30 mg, about 6 mg to 30 mg, about 7 mg to 30 mg, about 7.5 mg to 30 mg, about 8 mg to 30 mg, about 9 mg to 30 mg, about 10 mg to 30 mg, about 15 mg to 30 mg, about 20 mg to 30 mg, or about 25 mg to 30 mg without being limited thereto.

[0040] In addition, the active ingredient may be administered to the subject at a dose of about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, or about 90 mg, without being limited thereto.

[0041] The above-described dose may be a single dose, without being limited thereto.

[0042] As an example, the single dose of the active ingredient may be about 2.5 mg to 90 mg, about 2.5 mg to 67.5 mg, about 2.5 mg to 45 mg, about 2.5 mg to 22.5 mg, about 5 mg to 90 mg, about 5 mg to 67.5 mg, about 5 mg to 45 mg, about 7.5 mg to 90 mg, about 7.5 mg to 67.5 mg, or about 10 mg to 90 mg, without being limited thereto.

[0043] As an example, the single dose of the active ingredient may be about 3 mg, about 5 mg, about 10 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, or about 90 mg, without being limited thereto.

[0044] In the present invention, the a forementioned dosage may represent an effective amount of the active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof. Furthermore, the compound in the pharmaceutical composition, may be included in an amount corresponding to the described dosage to ensure that the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate compound is administered in vivo in the specified dosage.

[0045] The pharmaceutical composition may be administered on a schedule of once every 1 to 12 weeks. Specifically, the pharmaceutical composition may be administered to a subject on a schedule selected from the group consisting of once every week (i.e., QW), once every 2 weeks (i.e., Q2W), once every 3 weeks (i.e., Q3W), once every 4 weeks (i.e., Q4W), once every 8 weeks (i.e., Q8W), and once every 12 weeks (i.e., Q12W).

[0046] As a specific example, the pharmaceutical composition may be administered on a schedule of once every week (QW).

[0047] As a specific example, the pharmaceutical composition may be administered on a schedule of once every 2 weeks (Q2W).

[0048] As a specific example, the pharmaceutical composition may be administered on a schedule of once every 3 weeks (Q3W).

[0049] As a specific example, the pharmaceutical composition may be administered on a schedule of once every 4 weeks (Q4W).

[0050] As a specific example, the active ingredient may be administered at a dose of about 2.5 mg to 90 mg on a schedule of once every 1, 2, 3, or 4 weeks. As a specific example, the active ingredient may be administered at a dose of about 2.5 mg to 67.5 mg on a schedule of once every 1, 2, or 3 weeks. As a specific example, the active ingredient may be administered at a dose of about 2.5 mg to 45 mg on a schedule of once every 1 or 2 weeks. As a specific example, the active ingredient may be administered at a dose of about 5 mg to 90 mg on a schedule of once every 2, 3, or 4 weeks. As a specific example, the active ingredient may be administered at a dose of about 5 mg to 67.5 mg on a schedule of once every 2 or 3 weeks. As a specific example, the active ingredient may be administered at a dose of about 7.5 mg to 90 mg on a schedule of once every 3 or 4 weeks.

[0051] As a specific example, the active ingredient may be administered to a subject at a dose of about 1 mg to 90 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 90 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 67.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 45 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 22.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 20 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 15 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 10 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg to 5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 22.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 20 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 15 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 10 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 22.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 20 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 15 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 22.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 20 mg on a schedule of once every week (QW).

[0052] As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg, about 3 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, or about 22.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 2.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 3 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 12.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 17.5 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg on a schedule of once every week (QW). As a specific example, the active ingredient may be administered to a subject at a dose of about 22.5 mg on a schedule of once every week (QW).

[0053] As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 90 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 67.5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 45 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 40 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 35 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 30 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 25 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 20 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 15 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg to 10 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 45 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 40 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 35 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 30 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 25 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 20 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 15 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 45 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 40 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 35 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 30 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 45 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 40 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 35 mg on a schedule of once every 2 weeks (Q2W).

[0054] As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, or about 45 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 12.5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 17.5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 22.5 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 25 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 35 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 40 mg on a schedule of once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to a subject at a dose of about 45 mg on a schedule of once every 2 weeks (Q2W).

[0055] As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 90 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 67.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 60 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 50 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 40 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 30 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 20 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg to 15 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 67.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 60 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 50 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 40 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 30 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg to 20 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 67.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 60 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 50 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 40 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 30 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 67.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 60 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 50 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 40 mg on a schedule of once every 3 weeks (Q3W).

[0056] As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 37.5 mg, about 40 mg, about 45 mg, about 50 mg, about 52.5 mg, about 55 mg, about 60 mg, about 65 mg, or about 67.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 7.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 17.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 22.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 25 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 35 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 37.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 40 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 45 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 50 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 52.5 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 55 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 60 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 65 mg on a schedule of once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to a subject at a dose of about 67.5 mg on a schedule of once every 3 weeks (Q3W).

[0057] As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 90 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 80 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 70 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 60 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 50 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 40 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 30 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg to 20 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 90 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 80 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 70 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 60 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 50 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 40 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg to 30 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 90 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 80 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 70 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 60 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 50 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg to 40 mg on a schedule of once every 4 weeks (Q4W).

[0058] As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 10 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 15 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 20 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 25 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 30 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 35 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 40 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 45 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 50 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 55 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 60 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 65 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 70 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 75 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 80 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 85 mg on a schedule of once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to a subject at a dose of about 90 mg on a schedule of once every 4 weeks (Q4W).

[0059] The period during which the pharmaceutical composition is administered may be 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or more, 8 weeks or more, 12 weeks or more, 20 weeks or more, 24 weeks or more, 28 weeks or more, 36 weeks or more, 48 weeks or more, or the like, but the pharmaceutical composition may be administered without limitation on the period as long as the symptoms of Gaucher disease in the subject are alleviated.

[0060] The administration route of the pharmaceutical composition may include oral or parenteral administration, but is preferably oral administration. Here, parenteral administration may include intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal administration.

[0061] The compound included as an active ingredient in the pharmaceutical composition may be used to modulate plasma GL1 levels in a subject. As a specific example, the compound may be used to reduce plasma GL1 levels from abnormally high levels or even from normal levels. As a specific example, plasma GL1 levels may be reduced by at least about 10% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 20% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 30% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 40% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 50% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 60% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 70% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by at least about 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by about 50% to 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by about 60% to 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels may be reduced by about 70% to 80% compared to pre-treatment levels.

[0062] As a specific example, plasma GL1 levels may be reduced by at least about 50% compared to pre-treatment plasma GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0063] As a specific example, plasma GL1 levels may be reduced by at least about 60% compared to pre-treatment plasma GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0064] As a specific example, plasma GL1 levels may be reduced by at least about 70% compared to pre-treatment plasma GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0065] As a specific example, plasma GL1 levels may be reduced by at least about 80% compared to pre-treatment plasma GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0066] As a specific example, plasma GL1 levels may be reduced by about 70% to 80% compared to pre-treatment plasma GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0067] The compound included as an active ingredient in the pharmaceutical composition may cross the blood-brain barrier (BBB) of a subject and be used to regulate GL1 levels in the brain. As a specific example, the compound may be used to reduce GL1 levels in the brain from abnormally high levels or even from normal levels. As a specific example, GL1 levels in the brain may be reduced by at least about 5% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 10% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 20% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 30% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 40% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 50% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 60% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 70% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by at least about 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by about 30% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by about 40% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by about 50% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by about 60% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain may be reduced by about 70% to 80% compared to pre-treatment levels.

[0068] As a specific example, GL1 levels in the brain may be reduced by at least about 30% compared to pre-treatment brain GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0069] As a specific example, GL1 levels in the brain may be reduced by at least about 40% compared to pre-treatment brain GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0070] As a specific example, GL1 levels in the brain may be reduced by at least about 50% compared to pre-treatment brain GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0071] As a specific example, GL1 levels in the brain may be reduced by about 50% to 80% compared to pre-treatment brain GL1 levels, and such a reduction may persist for at least about 3 days, at least about 5 days, at least about 7 days, at least about 10 days, at least about 14 days, at least about 21 days, at least about 25 days, at least about 28 days, at least about 31 days, at least about 33 days, or at least about 36 days compared to pre-treatment levels.

[0072] In the present disclosure, the "pharmaceutical composition" may be in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition may be for administration to animals, specifically humans.

[0073] For use, the pharmaceutical composition of the present disclosure may be formulated in the form of oral preparations such as powders, granules, capsules, tablets, and aqueous suspensions, preparations for external use, suppositories, and sterile injectable solutions, according to the respective conventional methods, without being limited thereto. The pharmaceutical composition of the present disclosure may contain pharmaceutically acceptable carriers. As the pharmaceutically acceptable carriers, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a colorant, a flavoring agent, and the like may be used for oral administration; a buffer, a preservative, a pain-relieving agent, a solubilizer, an isotonic agent, a stabilizer, and the like may be used for injection; and a base, an excipient, a lubricant, a preservative, and the like may be used for topical administration. The pharmaceutical composition of the present disclosure may be prepared in various dosage forms by being mixed with the pharmaceutically acceptable carriers as described above. For example, for oral administration, the pharmaceutical composition may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or the like. For injection, the pharmaceutical composition may be prepared in the form of unit dosage ampoules or in multiple-dosage forms. In addition, the pharmaceutical composition may be formulated into solutions, suspensions, tablets, capsules, sustained-release preparations, or the like.

[0074] Meanwhile, examples of carriers, excipients and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. In addition, the pharmaceutical composition of the present disclosure may further contain a filler, an anticoagulant, a lubricant, a wetting agent, a fragrance, an emulsifier, a preservative, or the like.

[0075] The pharmaceutical composition of the present disclosure may be prepared in the form of unit dosage ampoules or in multiple-dosage forms. In addition, the pharmaceutical composition may be formulated into solutions, suspensions, tablets, pills, capsules, sustained-release preparations, or the like.

[0076] The present disclosure provides an appropriate dose and regimen of a quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, particularly preferably a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, which may treat Gaucher disease with high efficiency and without side effects.

[0077] FIG. 1 shows the results ofin vitroGCS enzyme assay and GM1 cellular assay of a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) performed in Experimental Example 1 and venglustat as a control.

[0078] FIGS. 2a to 2d show the results of single-dose pharmacokinetic analysis performed after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) to mice, rats, or beagle dogs in Experimental Example 2.

[0079] FIG. 3a graphically shows the results of measuring the changes in drug concentration and relative GL1 level in the brain or plasma as a function of time after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) to mice in Experimental Example 3. FIG. 3b illustrates a graph showing the results of measuring the changes in drug concentration and relative GL1 level in the brain or plasma as a function of time after administering venglustat as a control to mice.

[0080] FIGS. 4a to 4f graphically show the results of measuring the change in GL1 level in brain tissue or plasma after a certain period of time after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) or venglustat as a control to mice in Experimental Example 4.

[0081] FIG. 5 shows an experimental design diagram for a behavioral test, PD marker evaluation and survival rate analysis, performed after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) to CBE-induced mouse models in Experimental Example 5.

[0082] FIGS. 6a and 6b graphically show the results of measuring the change in survival rate after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) to CBE-induced mouse models in Experimental Example 5.

[0083] FIGS. 7a and 7b show the results of performing a behavioral test consisting of a wire suspension test and a rotarod test after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) or venglustat as a control to CBE-induced mouse models in Experimental Example 5. The data are presented as mean ± SEM. Differences between groups were determined using one-way ANOVA followed by Tukey's post hoc test (*, p<0.05; **, p<0.01; ***, p<0.001; **** or ####, p<0.0001, for comparisons between groups). The values in parentheses above each bar represent the relative ratio compared to G2 (negative control group).

[0084] FIGS. 8a to 8f graphically show the results of measuring the changes in total GL1 level and total lyso-GL1 level in plasma, brain and liver tissues after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) or venglustat as a control to CBE-induced mouse models in Experimental Example 5.

[0085] FIGS. 9a to 9d graphically show the results of measuring the changes in the galectin-3, GFAP, NeuN and CD8 expression levels in the brain tissue after administering a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) (produced according to one Example of the present disclosure) or venglustat as a control to CBE-induced mouse models in Experimental Example 5. The data are presented as mean ± SEM. Differences between groups were determined using one-way ANOVA and Tukey's post-hoc test (*, p<0.05; **, p<0.01; ***, p<0.001; **** or ####, p<0.0001, for comparisons between groups). The values in parentheses above each bar represent the relative ratio compared to G2 (negative control group). The expression levels of each marker were evaluated, specifically in the cortical (cortex) region.

[0086] FIG. 10 is a graph illustrating the changes in plasma drug concentration over time after administering 3 mg, 10 mg, or 30 mg of (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A), prepared according to one embodiment of the present invention, to healthy adult male subjects in Experimental Example 6.

[0087] FIG. 11 is a graph illustrating the percent change in GL1 levels in plasma relative to baseline over time after administering 3 mg, 10 mg, or 30 mg of the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A), prepared according to one embodiment of the present invention, to healthy adult male subjects in Experimental Example 6.

[0088] FIG. 12 is a table summarizing the minimum and maximum doses of the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A), according to one embodiment of the present invention, for each dosing schedule in Experimental Example 7.

[0089] According to one embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating Gaucher disease (GD), containing, as an active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the active ingredient is administered to a subject at a dose of 2.5 mg to 90 mg:

[0090] [Formula 1]

[0091]

[0092] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 2 below:

[0093] [Formula 2]

[0094]

[0095] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 3 below:

[0096] [Formula 3]

[0097]

[0098] The pharmaceutical composition may contain, as the active ingredient, a camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0099] The pharmaceutical composition may contain, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0100] The pharmaceutical composition may contain, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 4 below:

[0101] [Formula 4]

[0102]

[0103] The active ingredient may be administered to the subject at a dose of 2.5 mg to 22.5 mg once a week (QW).

[0104] The active ingredient may be administered to the subject at a dose of 5 mg to 45 mg once every 2 weeks (Q2W).

[0105] The active ingredient may be administered to the subject at a dose of 7.5 mg to 67.5 mg once every 3 weeks (Q3W).

[0106] The active ingredient may be administered to the subject at a dose of 10 mg to 90 mg once every 4 weeks (Q4W).

[0107] The active ingredient may be administered to the subject at a dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg or 22.5 mg once a week (QW).

[0108] The active ingredient may be administered to the subject at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg once every 2 weeks (Q2W).

[0109] The active ingredient may be administered to the subject at a dose of 7.5 mg, 15 mg, 22.5 mg, 30 mg, 37.5 mg, 45 mg, 52.5 mg, 60 mg or 67.5 mg once every 3 weeks (Q3W).

[0110] The active ingredient may be administered to the subject at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg once every 4 weeks (Q4W).

[0111] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by at least 50% in a human subject.

[0112] The pharmaceutical composition may prevent or treat Gaucher disease in a human subject with elevated plasma glucosylceramide (GL1) levels.

[0113] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by at least 70% in a human subject.

[0114] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by 70% to 80% in a human subject.

[0115] The pharmaceutical composition may be administered orally.

[0116] According to another embodiment of the present invention, the present invention relates a method for treating Gaucher disease (GD), comprising administering a pharmaceutical composition containing, as an active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 1 above, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the active ingredient may be administered at a dose of 2.5 mg to 90 mg.

[0117] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 2 above.

[0118] The pharmaceutical composition may contain, as the active ingredient, (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 3 above.

[0119] The pharmaceutical composition may contain, as the active ingredient, a camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0120] The pharmaceutical composition may contain, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.

[0121] The pharmaceutical composition may contain, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 4 above.

[0122] The active ingredient may be administered to the subject at a dose of 2.5 mg to 22.5 mg once a week (QW).

[0123] The active ingredient may be administered to the subject at a dose of 5 mg to 45 mg once every 2 weeks (Q2W).

[0124] The active ingredient may be administered to the subject at a dose of 7.5 mg to 67.5 mg once every 3 weeks (Q3W).

[0125] The active ingredient may be administered to the subject at a dose of 10 mg to 90 mg once every 4 weeks (Q4W).

[0126] The active ingredient may be administered to the subject at a dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg or 22.5 mg once a week (QW).

[0127] The active ingredient may be administered to the subject at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg once every 2 weeks (Q2W).

[0128] The active ingredient may be administered to the subject at a dose of 7.5 mg, 15 mg, 22.5 mg, 30 mg, 37.5 mg, 45 mg, 52.5 mg, 60 mg or 67.5 mg once every 3 weeks (Q3W).

[0129] The active ingredient may be administered to the subject at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg once every 4 weeks (Q4W).

[0130] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by at least 50% in a human subject.

[0131] The pharmaceutical composition may prevent or treat Gaucher disease in a human subject with elevated plasma glucosylceramide (GL1) levels.

[0132] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by at least 70% in a human subject.

[0133] The pharmaceutical composition may reduce plasma glucosylceramide (GL1) levels by 70% to 80% in a human subject.

[0134] The pharmaceutical composition may be administered orally.

[0135] Hereinafter, the present disclosure will be described in more detail by way of examples. These examples are only intended to explain the present disclosure in more detail, and it will be apparent to those skilled in the art that the scope of the present disclosure according to the subject matter of the present disclosure is not limited by these examples.

[0136]

[0137] Examples

[0138]

[0139] [Example 1] Production of (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (hereinafter referred to as "Compound A")

[0140] (S)-Quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1 g, 2.07 mmol) was dissolved in ethyl acetate (20 ml), and then (1S)-(+)-10-camphorsulfonic acid (0.48 g, 2.07 mmol) dissolved in purified water (0.2 ml) was added thereto. The reaction mixture was heated to about 50 ℃ and stirred for about 1 hour at that temperature, and then cooled to about 25 ℃ and stirred for about 1 hour at that temperature. After the reaction mixture was filtered under reduced pressure, the resulting wet cake was washed with ethyl acetate (3 ml). The resulting solid was vacuum-dried to obtain 1.2 g of the title compound, (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (yield: 81%).

[0141] 1H-NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 7.68-7.67 (d, 1H), 7.64-7.62 (d, 1H), 7.57-7.54 (m, 1H), 7.46-7.44 (m, 2H), 7.27-7.22 (m, 2H), 4.93-4.90 (m, 1H), 4.82-4.66 (m, 2H), 3.73-3.68 (m, 1H), 3.28-3.19 (m, 5H), 2.89-2.85 (d, 1H), 2.80-2.64 (m, 3H), 2.39-2.36 (d, 1H), 2.28-2.20 (m, 2H), 2.08-2.03 (m, 1H), 1.95-1.73 (m, 6H), 1.33-1.31 (d, 6H), 1.30-1.26 (m, 2H), 1.16 (s, 3H), 1.05 (s, 3H), 0.90 (s, 3H), 0.74 (s, 3H).

[0142]

[0143] [Experimental Example 1] In Vitro Activity Evaluation of Compound A

[0144] Thein vitroGCS enzyme and GM1 inhibitory activities of the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) produced in Example 1 were evaluated, and the results are shown in FIG. 1. As a control, venglustat was used.

[0145] As shown in FIG. 1, it could be seen that the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) had GCS enzyme and GM1 inhibitory activities at very low concentrations.

[0146] In the following experiments, the dosage of Compound A is based on the amount of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate after dissociation of the camphorsulfonic acid salt in vivo.

[0147]

[0148] [Experimental Example 2] Single-Dose Pharmacokinetics of Compound A

[0149] The (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) produced in Example 1 was administered orally (PO) or intravenously (IV) to mice, rats, and beagle dogs as experimental subjects at a dose of 1 mg / kg, and then single-dose pharmacokinetic analysis was performed. The results of the analysis are shown in FIGS. 2a to 2d.

[0150]

[0151] [Experimental Example 3] Single-Dose PK / PD of Compound A

[0152] The (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl (R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) produced in Example 1 was administered to mice at a dose of 10 mg / kg, and then the changes in drug concentration and relative GL1 level in the brain or plasma as a function of time were analyzed. The results of the analysis are shown in FIG. 3a. As a control group, venglustat was administered at a dose of 60 mg / kg, and the results are also presented in FIG. 3b.

[0153]

[0154] [Experimental Example 4] Measurement of Time-Dependent Changes in GL1 Levels in Brain and Plasma after Administration of Compound A

[0155] The (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) produced in Example 1 was administered to mice at a dose of 5 mg / kg once every 3 days (Q3D), a dose of 10 mg / kg once every 3 days (Q3D), a dose of 30 mg / kg once every 3 days (Q3D), or a dose of 90 mg / kg once every 3 days (Q3D), and then after a certain period of time, the change in GL1 level in the brain tissue or plasma was measured. The results of the measurement are shown in FIGS. 4a to 4f. As a control group, venglustat was administered at a dose of 30 mg / kg or 60 mg / kg once daily (QD). In FIGS. 4a to 4f, the doses are presented as free base (salt correction factor 1.48x was applied). The value above the bar indicates relative GL1% vs. the normal control.

[0156] As shown in FIGS. 4a to 4f, it could be seen that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered at a dose of 10 mg / kg once every 3 days (Q3D), the concentration of the drug in the brain and plasma increased by 50 to 100% after 24 to 72 hours. In addition, it could be seen that, even when the dose of the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (Compound A) was increased to a dose of 90 mg / kg once every 3 days (Q3D), there were no particular changes in clinical signs or body weight. At near Tmaxand Ctroughtime points, the drug (Compound A) 10 mg / kg Q3D dose showed the trend of more potent brain GL1 suppression with lesser potent plasma GL1 suppression than venglustat.

[0157]

[0158] [Experimental Example 5] Dose- and Regimen-Dependent Therapeutic Effects of Compound A in CBE-Induced Mouse Model

[0159] 1. Experimental Design

[0160] According to the experimental design diagram shown in FIG. 5, the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered to CBE-induced mouse models for 4 weeks, and then a behavioral test, PD marker evaluation, and survival rate analysis were performed. More specifically, the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered orally to CBE-induced mouse models at a dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg once daily (QD), and venglustat was administered as a control at a dose of 20 mg / kg or 60 mg / kg once daily (QD).

[0161] 2. Analysis of Changes in Survival Rate

[0162] After the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered to the CBE-induced mouse models at the above-described dose and regimen, the change in survival rate was analyzed, and the results are shown in FIGS. 6a and 6b.

[0163] As shown in FIGS. 6a and 6b, it could be confirmed that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered at a dose of 5 mg / kg or more once daily (QD), the survival rate of the mice significantly increased compared to when the control was administered.

[0164] 3. Behavioral Test

[0165] After the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered to the CBE-induced mouse models at the above-described dose and regimen, a behavioral test consisting of a wire suspension test and a rotarod test was performed, and the results are shown in FIGS. 7a and 7b.

[0166] As shown in FIGS. 7a and 7b, it could be confirmed that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered at a dose of 2.5 mg / kg or more once daily (QD), the time the mice remained on the wire or rotarod increased.

[0167] 4. Measurement of Changes in GL1 Levels

[0168] After the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered to the CBE-induced mouse models at the above-described dose and regimen, the levels of total GL1 and total lyso-GL1 in the plasma, brain, and liver tissues were measured, and the results are shown in FIGS. 8a to 8f.

[0169] As shown in FIGS. 8a to 8f, it could be confirmed that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered at a dose of 2.5 mg / kg or more once daily (QD), both the total GL1 level and the total lyso-GL1 level in the plasma, brain and liver tissues were significantly reduced.

[0170] 5. Measurement of Changes in Marker Expression

[0171] After the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered to the CBE-induced mouse models at the above-described dose and regimen, the changes in the expression levels of galectin-3, GFAP, NeuN, and CD8 in the brain tissue were measured, and the results are shown in FIGS. 9a to 9d.

[0172] As shown in FIGS. 9a to 9d, it could be confirmed that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) was administered at a dose of 2.5 mg / kg or more once daily (QD), the expression of the activated microglia marker galectin-3, the astrocyte marker GFAP, and the cytotoxic T-cell marker CD8 was reduced, and the expression of NeuN protein, a neuronal nuclear protein, was increased.

[0173] It could be seen that the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) according to the present disclosure dose-dependently reduced the GL1 levels in the plasma of normal mice by 90% or more and in the brain tissue by up to 70%. In addition, as a result of performing the wire suspension test and the rotarod test after orally administering the drug (Compound A) to the mouse models of GD induced by conduritol beta-epoxide (CBE) for 4 weeks, it could be seen that the drug alleviated behavioral abnormalities and suppressed gliosis (measured by microglia and astroglia infiltration) in the brain tissue. In addition, it could be seen that the drug reduced GL1 accumulation in the plasma by 90% or more and in the brain by 80% or more at doses of 10 mg / kg or more, and that the lifespan of the mice treated with the highest dose of Compound A increased by about 200% compared to untreated mice (mean survival time: 110 days vs. 36 days). In addition, Compound A demonstrated excellent bioavailability in rodent and non-rodent pharmacokinetic studies.

[0174] In experiments conducted on rodents such as mice, it could be seen that, when the (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) according to the present disclosure was administered at a dose of about 5 mg / kg or more, it exhibited the effect of preventing, alleviating or treating Gaucher disease. As a result of converting the dose of 5 mg / kg or more for mice (rodents) to the dose for humans, the inventors of the present disclosure could see that the appropriate dose level of Compound A for humans is 3 mg or more, particularly 3 mg to 480 mg.

[0175]

[0176] [Experimental Example 6] Results of Single-Dose Administration, Stepwise Dose Increase, and First-in-Human Phase 1 Clinical Trial of Compound A in Healthy Adult Male Subjects

[0177] A clinical trial was conducted in South Korea to evaluate the oral formulation of (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (Compound A) prepared according to Example 1. The trial was conducted in healthy adult male volunteers using a randomized, double-blind, placebo-controlled, single-dose, dose-escalation design to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single-dose administration of Compound A. The stepwise dose-escalation design involved progressing to the next dose group only after confirming safety and tolerability in the previous dose group. Thus far, 10 subjects per dose group (8 in the Compound A group and 2 in the placebo group) have been assigned, with a total of 3 cohorts enrolled. Subjects received a single oral dose of 3 mg, 10 mg, or 30 mg of Compound A or placebo. Blood samples were collected after administration, and plasma concentrations of the drug and GL1 levels were measured using HPLC-MS / MS.

[0178] No significant abnormal signs or side effects were observed in the clinical results.

[0179] The changes in plasma drug concentration as a function of time after oral administration of 3 mg, 10 mg or 30 mg of Compound A ensured to date were analyzed, and the results are shown in FIG. 10.

[0180] Following a single oral administration of 3 mg, 10 mg, or 30 mg of Compound A, the maximum plasma concentration (Cmax) was observed between a minimum of 12 hours and a maximum of 36 hours post-dose. A dose escalation from 3 mg to 30 mg resulted in an approximately 3-fold increase in both the average Cmaxand AUCinfvalues. The half-life (t1 / 2) of Compound A was observed to be approximately 24 days (AUCinf: area under the concentration-time curve, extrapolated to infinity from the last quantifiable concentration; Tmax: time to reach Cmax).

[0181] Additionally, the changes in plasma GL1 levels over time were analyzed following oral administration of 3 mg, 10 mg, or 30 mg of Compound A, and the results are shown in FIG. 11.

[0182] Following a single oral administration of 3 mg, 10 mg, or 30 mg of Compound A, the maximum reduction in plasma GL1 levels was observed between approximately 168 to 504 hours post-dose. At this time, the maximum average reduction in plasma GL1 levels was approximately 15.6% for the 3 mg dose, approximately 39.1% for the 10 mg dose, and approximately 64.6% for the 30 mg dose. A reduction in plasma GL1 levels was observed post-administration, and while a slight increase in GL1 levels was noted by day 36, the reduction in GL1 levels remained sustained.

[0183] Based on the observed PK and PD results following the administration of 3 mg, 10 mg, or 30 mg of Compound A, dosing regimens of once every week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W), or once every 4 weeks (Q4W) may be considered.

[0184]

[0185] [Experimental Example 7] Multiple-Dose and Regimen Design

[0186] Based on the combined experimental results, the target range for the reduction (%) of plasma GL1 levels was set at 70% to 80%. The doses required to achieve this target range are presented in FIG. 12 as the minimum and maximum doses for each dosing regimen: once every week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W), and once every 4 weeks (Q4W).

[0187] Although the present disclosure has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this description is only of a preferred embodiment thereof, and does not limit the scope of the present disclosure. Thus, the substantial scope of the present disclosure will be defined by the appended claims and equivalents thereto.

[0188] The present invention provides a treatment regimen for Gaucher disease (GD) with optimized doses and dosing regimens with quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Claims

1.A pharmaceutical composition for preventing or treating Gaucher disease (GD), containing, as an active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the active ingredient is administered to a subject at a dose of 2.5 mg to 90 mg:[Formula 1]2.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains, as the active ingredient, (S)-quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 2 below:[Formula 2]3.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains, as the active ingredient, (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 3 below:[Formula 3]4.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains, as the active ingredient, a camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.5.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of the quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate.6.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains, as the active ingredient, a (1S)-(+)-10-camphorsulfonic acid salt of (S)-quinuclidin-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 4 below:[Formula 4]7.The pharmaceutical composition of claim 1, wherein the active ingredient is administered to the subject at a dose of 2.5 mg to 22.5 mg once a week (QW).8.The pharmaceutical composition of claim 1, wherein the active ingredient is administered to the subject at a dose of 5 mg to 45 mg once every 2 weeks (Q2W).9.The pharmaceutical composition of claim 1, wherein the active ingredient is administered to the subject at a dose of 7.5 mg to 67.5 mg once every 3 weeks (Q3W).10.The pharmaceutical composition of claim 1, wherein the active ingredient is administered to the subject at a dose of 10 mg to 90 mg once every 4 weeks (Q4W).11.The pharmaceutical composition of claim 7, wherein the active ingredient is administered to the subject at a dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg or 22.5 mg once a week (QW).12.The pharmaceutical composition of claim 8, wherein the active ingredient is administered to the subject at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg once every 2 weeks (Q2W).13.The pharmaceutical composition of claim 9, wherein the active ingredient is administered to the subject at a dose of 7.5 mg, 15 mg, 22.5 mg, 30 mg, 37.5 mg, 45 mg, 52.5 mg, 60 mg or 67.5 mg once every 3 weeks (Q3W).14.The pharmaceutical composition of claim 10, wherein the active ingredient is administered to the subject at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg once every 4 weeks (Q4W).15.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces plasma glucosylceramide (GL1) levels by at least 50% in a human subject,or to prevent or treat Gaucher disease in a human subject with elevated plasma glucosylceramide (GL1) levels.16.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces plasma glucosylceramide (GL1) levels by at least 70% in a human subject.17.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces plasma glucosylceramide (GL1) levels by 70% to 80% in a human subject.18.The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered orally.19.A method for treating Gaucher disease (GD), comprising administering a pharmaceutical composition containing, as an active ingredient, quinuclidin-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof,wherein the active ingredient is administered at a dose of 2.5 mg to 90 mg:[Formula 1]

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