Pharmaceutical composition for preventing or treating gaucher disease

Abstract

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

Description

Technical Field

[0001] This disclosure relates to a pharmaceutical composition for the prevention or treatment of Gaucher disease. Background Technology

[0002] Gaucher disease (GD) is a genetic disorder caused by mutations in the glucocerebrosidase (GBA) gene, leading to the abnormal accumulation of glucosylceramide (GL1) in various organs, including the central nervous system (CNS). For Gaucher disease types 2 and 3, the neuropathic forms of the disease, currently approved drugs are ineffective in controlling central nervous system symptoms due to poor brain distribution.

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

[0004] Currently, the treatment for Gaucher disease is enzyme replacement therapy, such as Cerezyme, a recombinant form of GBA, administered intravenously. However, these protein drugs have several drawbacks: they have a short half-life in the blood, produce antibodies against the protein (which reduces the drug's effectiveness), are difficult to deliver the protein to lysosomes, and cannot be used to treat neuropathic Gaucher disease.

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

[0006] Technical issues

[0007] One object of this disclosure is to provide a therapy and a pharmaceutical composition for use therein, said therapy allowing the safe and effective administration of a dimethyl-2,3-dihydro-1H-indene derivative or a pharmaceutically acceptable salt thereof to patients with Gaucher disease.

[0008] However, the purposes of this disclosure are not limited to those described above, and other purposes not mentioned will become clear to those skilled in the art from the following description.

[0009] Technical solution

[0010] In the following description, various embodiments described herein will be described with reference to the accompanying drawings. Numerous specific details, such as specific configurations, compositions, and processes, are set forth in the description to provide a thorough understanding of the present disclosure. However, some 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 to avoid unnecessarily obscuring the present disclosure. References to “one embodiment” or “a particular embodiment” throughout the specification mean that a specific feature, configuration, composition, or characteristic described in connection with that embodiment is included in at least one embodiment of the present disclosure. Therefore, the phrases “in one embodiment” or “in a particular embodiment” appearing throughout the specification do not necessarily refer to the same embodiment of the present disclosure. Furthermore, specific features, configurations, compositions, or characteristics may be combined in one or more embodiments in any suitable manner.

[0011] In this disclosure, the terms “treatment” or “relief” may include, but are not limited to, any behavior that relieves or beneficially alters a disease by using the compositions of this disclosure.

[0012] In this disclosure, the term "prevention" may include, but is not limited to, any action that uses the compositions of this disclosure to block, suppress, or delay the symptoms of a disease.

[0013] Unless otherwise stated in the specification, all scientific and technical terms used in the specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0014] This disclosure relates to a method of administration of a pharmaceutical composition for the prevention or treatment of Gaucher disease (GD), said pharmaceutical composition comprising, as an active ingredient, a quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate of Formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof: [Formula 1]

[0015] The quinine cyclo-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, all of which are included within the scope of this disclosure.

[0016] The pharmaceutical composition may contain, but is not limited to, (S)-quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of Formula 2 as an active ingredient: [Equation 2]

[0017] The pharmaceutical composition may contain, but is not limited to, (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of Formula 3 as an active ingredient: [Formula 3]

[0018] The pharmaceutical composition may also contain a pharmaceutically acceptable salt of the compound as an active ingredient. The term "pharmaceutically acceptable salt" refers to a salt that is generally considered suitable for medical use by those skilled in the art, for example, because it is harmless to subjects who may be treated with the salt, or because any side effects it produces are tolerable in their respective treatments. Typically, pharmaceutically acceptable salts are those deemed acceptable by regulatory agencies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labour and Welfare. However, this disclosure also includes, in principle, salts of compounds according to this disclosure that are not pharmaceutically acceptable in themselves, for example, as intermediates in the production of compounds according to this disclosure or derivatives thereof with physiological functions, or as intermediates in the production of pharmaceutically acceptable salts of compounds according to this disclosure or derivatives thereof with physiological functions. The salts include water-insoluble salts, particularly water-soluble salts.

[0019] In each case, those skilled in the art can readily determine whether a compound or its physiologically functional derivative according to this disclosure can form a salt, i.e., whether the compound or its physiologically functional derivative according to this disclosure has potentially charged groups, such as amino, carboxylic acid groups, etc.

[0020] Exemplary salts are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and pharmaceutically conventional salts with bases that are water-insoluble or, particularly, water-soluble acid addition salts. Salts with bases may also be applicable depending on the substituents of the compounds disclosed herein. Acid addition salts can be formed, for example, by mixing a solution of the compounds disclosed herein 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. Similarly, 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, carboxyl, sulfate, phosphate, nitrate, alkyl sulfonate, and aryl sulfonate ions). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetates, alginates, arginine salts, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium edetate, camphorates, camphor sulfonates, dextrorotatory camphor sulfonates, carbonates, chlorides, citrates, diglucuronates, dihydrochlorides, dodecyl sulfates, edetates, ethanedisulfonates, ethanesulfonates, formates, fumarates, galacturonates, galacturonates, glucuronates, glutamates, glycerophosphates, hemisulfates, heptarates, hexanoates, hexylresorcinol salts, hydrobromide, hydrochloride, hydroiodide, 2- Hydroxyethanesulfonate, hydroxynaphthyl carboxylate, iodide, isobutyrate, hydroxyethyl sulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / bisphosphate, phthalate, picrate, neopentanoate, polygalacturonic acid ester, propionate, salicylate, stearate, sulfate, octanoate, succinate, tannate, tartrate, toluenesulfonate, undecenoate, valerate, etc.

[0021] Non-pharmaceutical acceptable salts (e.g., those that can be obtained as process products during industrial-scale production of the compounds disclosed herein) are also included in this disclosure and, if necessary, can be converted into pharmaceutically acceptable salts by methods known to those skilled in the art.

[0022] The pharmaceutical composition may contain camphor sulfonate of the compound as an active ingredient, but is not limited thereto.

[0023] The pharmaceutical composition may contain (1S)-(+)-10-camphor sulfonate of the compound as an active ingredient, but is not limited thereto.

[0024] The pharmaceutical composition may contain, but is not limited to, (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as an active ingredient: [Formula 4]

[0025] In this disclosure, the term "subject" refers to an individual who 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 can be, for example, a human or a non-human primate. As another example, the individual can be a laboratory mammal (e.g., a mouse, rat, rabbit, hamster, etc.). As another example, the individual can be a farm animal (e.g., a horse, sheep, cattle, pig, camel, etc.) or a domesticated animal (e.g., a dog, cat, etc.). Preferably, the individual can be a human.

[0026] In this disclosure, the term "Gaucher disease (GD)" refers to an autosomal recessive lysosomal storage disorder (LSD) characterized by a deficiency of glucocerebrosidase (GBA). Glucocerebrosidase functions in the lysosomes of cells to break down lipid glucocerebrosides. 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). This accumulation of glucosylceramide in the lysosomes of macrophages leads to abnormalities in the liver, spleen, and bone marrow, and causes blood disorders (anemia, thrombocytopenia, leukopenia), hepatosplenomegaly, bone destruction, and damage to the central nervous system. Gaucher disease is classified into the most common non-neuropathy type (Gaucher disease type 1) and neuropathic types, namely acute neuropathic Gaucher disease (Gaucher disease type 2) and chronic neuropathic Gaucher disease (Gaucher disease type 3). In neuropathic Gaucher disease, the toxic effects of glucosylceramide can lead to neuronal necrosis and loss in the nervous system. The prevention, improvement, or treatment of Gaucher disease targeted by this invention includes, but is not limited to, type 1, type 2, or type 3 Gaucher disease.

[0027] 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.

[0028] In this disclosure, the term "about" is intended to refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. For example, the degree of error may be indicated by the number of significant figures provided by the measurement, as understood in the art, and includes, but is not limited to, a variation of ±1 of the most accurate significant figure reported by the measurement. Typical exemplary degrees of error are within 20 percent (%) of a specified value or range of values, preferably within 10%, more preferably within 5%. Alternatively, particularly in biological systems, the terms "about" and "approximately" may refer to values ​​within the order of magnitude of a specified value, preferably within 5 times the specified value, more preferably within 2 times. Unless otherwise stated, the numerical quantities given in this specification are approximate, meaning that the terms "about" or "approximately" can be inferred when not explicitly stated. They include, but are not limited to, all numerical values ​​within the same or similar ranges. In this disclosure, when "about" is stated before a numerical range, the expression "about a to b" is understood to mean "about a to about b".

[0029] The dosages of the pharmaceutical compositions described below in this specification may refer to dosages for all mammals, including humans. As an example, a dosage in “mg / kg” may indicate the required dosage for a non-human mammal in the subject's context, but is not limited thereto. For instance, a dosage in “mg” may refer to a dosage for mammals, including humans, and particularly to the optimal dosage for humans, but is not limited thereto.

[0030] Furthermore, in this disclosure, the dosage of the active ingredient described below refers to the amount of a compound of formula 1, 2, or 3, excluding salts. Therefore, even if the aforementioned compounds are administered in the form of pharmaceutically acceptable salts, the dosage specified herein is calculated based on the active ingredient after the salts have dissociated in vivo. Alternatively, the dosage of the active ingredient may refer to the amount of a pharmaceutically acceptable salt of these compounds.

[0031] In this disclosure, the active ingredient can be from 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 ... The subjects were administered doses of approximately 40 mg / kg to 60 mg / kg, approximately 45 mg / kg to 60 mg / kg, approximately 50 mg / kg to 60 mg / kg, approximately 55 mg / kg to 60 mg / kg, approximately 5 mg / kg to 30 mg / kg, approximately 10 mg / kg to 30 mg / kg, approximately 15 mg / kg to 30 mg / kg, approximately 20 mg / kg to 30 mg / kg, or approximately 25 mg / kg to 30 mg / kg, but not limited thereto.

[0032] The active ingredient may be administered to the subject at doses 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, but is not limited thereto.

[0033] 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 from 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. mg, approximately 5 mg to 90 mg, approximately 6 mg to 90 mg, approximately 7 mg to 90 mg, approximately 7.5 mg to 90 mg, approximately 8 mg to 90 mg, approximately 9 mg to 90 mg, approximately 10 mg to 90 mg, approximately 15 mg to 90 mg, approximately 20 mg to 90 mg, approximately 25 mg to 90 mg, approximately 30 mg to 90 mg, approximately 40 mg to 90 mg, approximately 50 mg to 90 mg, approximately 60 mg to 90 mg, approximately 70 mg to 90 mg, approximately 80 mg to 90 mg, approximately 1 mg to 70 mg, approximately 2 mg to 70 mg, approximately 2.5 mg to 70 mg, approximately 3 mg to 70 mg, approximately 5 mg to 70 mg, approximately 6 mg to 70 mg, approximately 7 mg to 70 mg, approximately 7.5 mg to 70 mg, approximately 8 mg to 70 mg, approximately 9 mg to 70 mg, approximately 10 mg to 70 mg, approximately 15 mg to 70 mg mg, approximately 20 mg to 70 mg, approximately 25 mg to 70 mg, approximately 30 mg to 70 mg, approximately 40 mg to 70 mg, approximately 50 mg to 70 mg, approximately 60 mg to 70 mg, approximately 1 mg to 50 mg, approximately 2 mg to 50 mg, approximately 2.5 mg to 50 mg, approximately 3 mg to 50 mg, approximately 5 mg to 50 mg, approximately 6 mg to 50 mg, approximately 7 mg to 50 mg, approximately 7.Doses of 5 mg to 50 mg, approximately 8 mg to 50 mg, approximately 9 mg to 50 mg, approximately 10 mg to 50 mg, approximately 15 mg to 50 mg, approximately 20 mg to 50 mg, approximately 25 mg to 50 mg, approximately 30 mg to 50 mg, approximately 40 mg to 50 mg, approximately 1 mg to 30 mg, approximately 2 mg to 30 mg, approximately 2.5 mg to 30 mg, approximately 3 mg to 30 mg, approximately 5 mg to 30 mg, approximately 6 mg to 30 mg, approximately 7 mg to 30 mg, approximately 7.5 mg to 30 mg, approximately 8 mg to 30 mg, approximately 9 mg to 30 mg, approximately 10 mg to 30 mg, approximately 15 mg to 30 mg, approximately 20 mg to 30 mg, or approximately 25 mg to 30 mg were administered to the said subjects, but are not limited thereto.

[0034] In addition, the active ingredient may be administered to the subject in doses 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, but is not limited thereto.

[0035] The above dosage can be a single dose, but is not limited to this.

[0036] As an example, a single dose of the active ingredient may be from 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, but is not limited thereto.

[0037] As an example, a 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, but is not limited thereto.

[0038] In this invention, the aforementioned dosage may represent an effective amount of the active ingredient—quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate compound, its optical isomer, or a pharmaceutically acceptable salt thereof. Furthermore, the compound in the pharmaceutical composition may be contained in an amount corresponding to the stated dosage to ensure that the quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate compound is administered in vivo at the specified dosage.

[0039] The pharmaceutical composition may be administered to the subject at a frequency of once every 1 to 12 weeks. Specifically, the pharmaceutical composition may be administered to the subject at a frequency selected from the group consisting of once weekly (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W), once every 4 weeks (Q4W), once every 8 weeks (Q8W), and once every 12 weeks (Q12W).

[0040] As a specific example, the pharmaceutical composition may be administered on a once-weekly (QW) schedule.

[0041] As a specific example, the pharmaceutical composition may be administered at a rate of once every 2 weeks (Q2W).

[0042] As a specific example, the pharmaceutical composition may be administered at a rate of once every 3 weeks (Q3W).

[0043] As a specific example, the pharmaceutical composition may be administered at a rate of once every 4 weeks (Q4W).

[0044] As a specific example, the active ingredient may be administered at a dose of about 2.5 mg to 90 mg, 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, 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, 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, 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, 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, once every 3 or 4 weeks.

[0045] As a specific example, the active ingredient may be administered to the subject at a dose of about 1 mg to 90 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 90 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 67.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 45 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 22.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 20 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg to 15 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 2.5 mg to 10 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 2.5 mg to 5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 22.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 20 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 15 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 10 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 22.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 20 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 15 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 22.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 20 mg on a once-weekly (QW) basis.

[0046] As a specific example, the active ingredient may be administered to the 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 once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 2.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 3 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 7.5 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of about 10 mg on a once-weekly (QW) basis. As a specific example, the active ingredient may be administered to the subject at a dose of approximately 12.5 mg once weekly (QW). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg once weekly (QW). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 17.5 mg once weekly (QW). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg once weekly (QW). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 22.5 mg once weekly (QW).

[0047] As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 90 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 67.5 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 45 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 40 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 35 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 30 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 25 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 20 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 15 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 5 mg to 10 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 45 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 40 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 35 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 30 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 25 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 20 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 15 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 45 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 40 mg once every 2 weeks (Q2W).As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 35 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 30 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 45 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 40 mg once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 35 mg once every two weeks (Q2W).

[0048] As a specific example, the active ingredient may be administered to the 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, once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of about 5 mg, once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of about 7.5 mg, once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of about 10 mg, once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of about 12.5 mg, once every two weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 17.5 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 22.5 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 25 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 35 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 40 mg once every 2 weeks (Q2W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 45 mg once every 2 weeks (Q2W).

[0049] As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 90 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 67.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 60 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 50 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 40 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 30 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 20 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg to 15 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 67.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 60 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 50 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 40 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 30 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg to 20 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 67.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 60 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 50 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 40 mg every 3 weeks (Q3W).As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 30 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 67.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 60 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 50 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 40 mg every 3 weeks (Q3W).

[0050] As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg, approximately 15 mg, approximately 17.5 mg, approximately 20 mg, approximately 22.5 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 37.5 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 52.5 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, or approximately 67.5 mg, once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 7.5 mg, once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg, once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 17.5 mg, once every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 22.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 25 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 35 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 37.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 40 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 45 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 50 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 52.5 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 55 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 60 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 65 mg every 3 weeks (Q3W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 67.5 mg every 3 weeks (Q3W).

[0051] As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 90 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 80 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 70 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 60 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 50 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 40 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 30 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg to 20 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 90 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 80 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 70 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 60 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 50 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 40 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg to 30 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 90 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 80 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 70 mg every 4 weeks (Q4W).As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 60 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 50 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg to 40 mg every 4 weeks (Q4W).

[0052] As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, or approximately 90 mg, once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 10 mg, once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 15 mg, once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 20 mg, once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 25 mg, once every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 30 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 35 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 40 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 45 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 50 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 55 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 60 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 65 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 70 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 75 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 80 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 85 mg every 4 weeks (Q4W). As a specific example, the active ingredient may be administered to the subject at a dose of approximately 90 mg every 4 weeks (Q4W).

[0053] The administration period of the drug composition can be more than 1 week, more than 2 weeks, more than 3 weeks, more than 4 weeks, more than 5 weeks, more than 6 weeks, more than 8 weeks, more than 12 weeks, more than 20 weeks, more than 24 weeks, more than 28 weeks, more than 36 weeks, more than 48 weeks, etc., but there is no limit to the administration period of the drug composition as long as the subject's Gaucher disease symptoms are relieved.

[0054] The pharmaceutical composition may be administered orally or parenterally, but oral administration is preferred. Parenterally administration may include intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intraenteral, local, sublingual, or rectal administration.

[0055] The compound contained in the pharmaceutical composition as an active ingredient can be used to regulate plasma GL1 levels in a subject. As a specific example, the compound can be used to reduce plasma GL1 levels from abnormally high levels or even from normal levels. As a specific example, plasma GL1 levels can be reduced by at least about 10% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 20% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 30% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 40% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 50% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 60% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 70% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by at least about 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by about 50% to 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by approximately 60% to 80% compared to pre-treatment levels. As a specific example, plasma GL1 levels can be reduced by approximately 70% to 80% compared to pre-treatment levels.

[0056] As a specific example, plasma GL1 levels can be reduced by at least about 50% compared to pre-treatment plasma GL1 levels, and this reduction can be maintained 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.

[0057] As a specific example, plasma GL1 levels can be reduced by at least approximately 60% compared to pre-treatment levels, and this reduction can be maintained for at least approximately 3 days, at least approximately 5 days, at least approximately 7 days, at least approximately 10 days, at least approximately 14 days, at least approximately 21 days, at least approximately 25 days, at least approximately 28 days, at least approximately 31 days, at least approximately 33 days, or at least approximately 36 days compared to pre-treatment levels.

[0058] As a specific example, plasma GL1 levels can be reduced by at least about 70% compared to pre-treatment plasma GL1 levels, and this reduction can be maintained 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.

[0059] As a specific example, plasma GL1 levels can be reduced by at least approximately 80% compared to pre-treatment plasma GL1 levels, and this reduction can be maintained for at least approximately 3 days, at least approximately 5 days, at least approximately 7 days, at least approximately 10 days, at least approximately 14 days, at least approximately 21 days, at least approximately 25 days, at least approximately 28 days, at least approximately 31 days, at least approximately 33 days, or at least approximately 36 days compared to pre-treatment levels.

[0060] As a specific example, plasma GL1 levels can be reduced by approximately 70% to 80% compared to pre-treatment levels, and this reduction can be maintained for at least approximately 3 days, at least approximately 5 days, at least approximately 7 days, at least approximately 10 days, at least approximately 14 days, at least approximately 21 days, at least approximately 25 days, at least approximately 28 days, at least approximately 31 days, at least approximately 33 days, or at least approximately 36 days compared to pre-treatment levels.

[0061] The compound contained in the pharmaceutical composition as an active ingredient can cross the blood-brain barrier (BBB) ​​of a subject and modulate GL1 levels in the brain. As a specific example, the compound can 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 can be reduced by at least about 5% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 10% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 20% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 30% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 40% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 50% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 60% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least about 70% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by at least approximately 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by approximately 30% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by approximately 40% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by approximately 50% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by approximately 60% to 80% compared to pre-treatment levels. As a specific example, GL1 levels in the brain can be reduced by approximately 70% to 80% compared to pre-treatment levels.

[0062] As a specific example, the brain GL1 level can be reduced by at least about 30% compared to the pre-treatment brain GL1 level, and this reduction can be maintained 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 the pre-treatment level.

[0063] As a specific example, the brain GL1 level can be reduced by at least about 40% compared to the pre-treatment brain GL1 level, and this reduction can be maintained 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 the pre-treatment level.

[0064] As a specific example, the brain GL1 level can be reduced by at least about 50% compared to the pre-treatment brain GL1 level, and this reduction can be maintained 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 the pre-treatment level.

[0065] As a specific example, compared with the pre-treatment brain GL1 level, the GL1 level in the brain can be reduced by about 50% to 80%, and this reduction can be maintained 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.

[0066] In this disclosure, the "pharmaceutical composition" may be in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition may be administered to animals, particularly humans.

[0067] For use, the pharmaceutical compositions of this disclosure can be formulated according to conventional methods into oral preparations, topical preparations, suppositories, and sterile injectable solutions, such as powders, granules, capsules, tablets, and suspensions, but are not limited thereto. The pharmaceutical compositions of this disclosure may contain a pharmaceutically acceptable carrier. As pharmaceutically acceptable carriers, for oral administration, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavoring agents, etc., can be used; for injectable administration, buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc., can be used; for topical administration, matrices, excipients, lubricants, preservatives, etc. The pharmaceutical compositions of this disclosure can be prepared into various dosage forms by mixing with pharmaceutically acceptable carriers as described above. For example, for oral administration, the pharmaceutical compositions can be prepared into tablets, lozenges, capsules, elixirs, suspensions, syrups, orally disintegrating films, etc. For injectable administration, the pharmaceutical compositions can be prepared into single-dose ampoules or multi-dose forms. Furthermore, the pharmaceutical composition can be formulated into solutions, suspensions, tablets, capsules, sustained-release formulations, etc.

[0068] Examples of suitable carriers, excipients, and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Furthermore, the pharmaceutical compositions disclosed herein may further contain fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc.

[0069] The pharmaceutical compositions disclosed herein can be prepared in single-dose ampoules or multi-dose forms. Furthermore, the pharmaceutical compositions can be formulated into solutions, suspensions, tablets, pills, capsules, sustained-release formulations, etc.

[0070] Beneficial effects

[0071] This disclosure provides appropriate dosages and regimens for (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate, optical isomers thereof, or pharmaceutically acceptable salts thereof, particularly preferably (S)-quininecyclo-3-yl ((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate, which can effectively and without side effects treat Gaucher disease. Attached Figure Description

[0072] Figure 1 The results of in vitro GCS enzyme assays and GM1 cell assays of (1S)-(+)-10-camphor sulfonate (compound A), of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate prepared according to an embodiment of the present disclosure, are shown in Experimental Example 1, along with vengruelstat as a control.

[0073] Figures 2a to 2d The results of a single-dose pharmacokinetic analysis of (1S)-(+)-10-camphor sulfonate (compound A), of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (prepared according to an embodiment of this disclosure), are shown in Experimental Example 2.

[0074] Figure 3aThe graph shows the measurements of drug concentrations and relative GL1 levels in the brain or plasma of mice after administration of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (prepared according to an embodiment of this disclosure) over time. Figure 3b The graph shows the results of measurements of drug concentrations and relative GL1 levels in the brain or plasma over time after veglustat was administered to mice as a control.

[0075] Figures 4a to 4f The graph shows the results of measurements of changes in GL1 levels in brain tissue or plasma in mice after administration of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (prepared according to an embodiment of this disclosure) or veglustat as a control for a period of time.

[0076] Figure 5 The diagram shows the experimental design for behavioral testing, PD marker assessment, and survival analysis performed in Experimental Example 5 after (1S)-(+)-10-camphor sulfonate (compound A), of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (prepared according to an embodiment of this disclosure), was administered to a CBE-induced mouse model.

[0077] Figure 6a and Figure 6b The graph shows the measurement results of the change in survival rate after applying (1S)-(+)-10-camphor sulfonate (compound A), of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (prepared according to an embodiment of this disclosure), to a CBE-induced mouse model in Experimental Example 5.

[0078] Figure 7a and Figure 7bThe results of behavioral tests consisting of the suspension wire test and the rotarod test are shown in Experimental Example 5, after administration of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (prepared according to an embodiment of this disclosure) or vegrostat as a control to a CBE-induced mouse model. Data are expressed as mean ± standard error (SEM). Differences between groups were determined by one-way ANOVA and Tukey post-hoc test. p<0.05; p<0.01; p < 0.001; Or ####, p<0.0001, used for inter-group comparisons). The value in parentheses above each column represents the relative ratio compared to G2 (negative control group).

[0079] Figures 8a to 8f The graph shows the changes in total GL1 and total lyso-GL1 levels in plasma, brain, and liver tissues after administration of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (prepared according to an embodiment of this disclosure) or vegrostat as a control to a CBE-induced mouse model.

[0080] Figures 9a to 9d The figures show the changes in the expression levels of galectin-3, GFAP, NeuN, and CD8 in brain tissue of a CBE-induced mouse model after administration of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (as a control) or vegludec as a control. Data are expressed as mean ± SEM. Differences between groups were determined by one-way ANOVA and Tukey post-hoc test. p<0.05; p<0.01; p < 0.001; Or ####, p<0.0001, for intergroup comparisons). The value in parentheses above each column represents the relative ratio compared to G2 (negative control group). The expression level of each marker was assessed in the cortical region.

[0081] Figure 10 The graph shown in Experimental Example 6 illustrates the change in plasma drug concentration over time after administering 3 mg, 10 mg, or 30 mg of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) prepared according to an embodiment of the present invention to healthy adult male subjects.

[0082] Figure 11 This is a graph showing, in Experimental Example 6, the percentage change over time in plasma GL1 levels relative to baseline after administering 3 mg, 10 mg, or 30 mg of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) prepared according to an embodiment of the present invention to healthy adult male subjects.

[0083] Figure 12 This is a table summarizing the minimum and maximum doses of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphor sulfonate (compound A) under each dosing regimen, as described in Experimental Example 7 according to one embodiment of the present invention. Detailed Implementation

[0084] According to one embodiment of the present invention, the present invention relates to a pharmaceutical composition for the prevention or treatment of Gaucher disease (GD), comprising, as an active ingredient, a quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, its optical isomer, or a pharmaceutically acceptable salt thereof, of Formula 1, wherein the active ingredient is administered to a subject at a dose of 2.5 mg to 90 mg. [Formula 1]

[0085] The pharmaceutical composition may contain (S)-quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as an active ingredient, represented by Formula 2 below: [Equation 2]

[0086] The pharmaceutical composition may contain (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as an active ingredient, represented by Formula 3 below: [Formula 3]

[0087] The pharmaceutical composition may contain camphor sulfonate of the quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl) carbamate as an active ingredient.

[0088] The pharmaceutical composition may contain (1S)-(+)-10-camphor sulfonate of the quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl) carbamate as an active ingredient.

[0089] The pharmaceutical composition may contain (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as the active ingredient: [Formula 4]

[0090] The active ingredient may be administered to the subject once weekly (QW) at a dose of 2.5 mg to 22.5 mg.

[0091] The active ingredient can be administered to the subject once every 2 weeks (Q2W) at a dose of 5 mg to 45 mg.

[0092] The active ingredient can be administered to subjects once every 3 weeks (Q3W) at a dose of 7.5 mg to 67.5 mg.

[0093] The active ingredient can be administered to the subject once every 4 weeks (Q4W) at a dose of 10 mg to 90 mg.

[0094] The active ingredient may be administered to the subject once weekly (QW) 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.

[0095] The active ingredient may be administered to the subject once every 2 weeks (Q2W) at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg.

[0096] The active ingredient may be administered to the subject once every 3 weeks (Q3W) 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.

[0097] The active ingredient may be administered to the subject once every 4 weeks (Q4W) at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg.

[0098] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by at least 50%.

[0099] The pharmaceutical composition can prevent or treat Gaucher disease in human subjects with elevated plasma glucosylceramide (GL1) levels.

[0100] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by at least 70%.

[0101] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by 70% to 80%.

[0102] The pharmaceutical composition can be administered orally.

[0103] According to another embodiment of the present invention, the present invention relates to a method for treating Gaucher disease (GD), the method comprising administering to a subject in need a pharmaceutical composition comprising, as an active ingredient, a quinine cyclo-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, wherein the active ingredient may be administered at a dose of 2.5 mg to 90 mg.

[0104] The pharmaceutical composition may contain (S)-quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate as an active ingredient, as represented by Formula 2 above.

[0105] The pharmaceutical composition may contain (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate as an active ingredient, as represented by Formula 3 above.

[0106] The pharmaceutical composition may contain camphor sulfonate of the quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl) carbamate as an active ingredient.

[0107] The pharmaceutical composition may contain (1S)-(+)-10-camphor sulfonate of the quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl) carbamate as an active ingredient.

[0108] The pharmaceutical composition may contain (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate as an active ingredient, as represented by Formula 4 above.

[0109] The active ingredient may be administered to the subject once weekly (QW) at a dose of 2.5 mg to 22.5 mg.

[0110] The active ingredient can be administered to the subject once every 2 weeks (Q2W) at a dose of 5 mg to 45 mg.

[0111] The active ingredient can be administered to subjects once every 3 weeks (Q3W) at a dose of 7.5 mg to 67.5 mg.

[0112] The active ingredient can be administered to the subject once every 4 weeks (Q4W) at a dose of 10 mg to 90 mg.

[0113] The active ingredient may be administered to the subject once weekly (QW) 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.

[0114] The active ingredient may be administered to the subject once every 2 weeks (Q2W) at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg or 45 mg.

[0115] The active ingredient may be administered to the subject once every 3 weeks (Q3W) 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.

[0116] The active ingredient may be administered to the subject once every 4 weeks (Q4W) at a dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg.

[0117] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by at least 50%.

[0118] The pharmaceutical composition can prevent or treat Gaucher disease in human subjects with elevated plasma glucosylceramide (GL1) levels.

[0119] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by at least 70%.

[0120] The pharmaceutical composition can reduce plasma glucosylceramide (GL1) levels in human subjects by 70% to 80%.

[0121] The pharmaceutical composition can be administered orally.

[0122] The mode of the present invention

[0123] The present disclosure will be described in more detail below by way of examples. These examples are intended only 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 is not limited to these examples.

[0124] Example

[0125] [Example 1] (S)-quininylcyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3- Preparation of (1S)-(+)-10-camphor sulfonate of dihydro-1H-inden-1-yl)carbamate (hereinafter referred to as "compound A")

[0126] (S)-quininecyclo-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. The reaction mixture was heated to approximately 50 °C and stirred at this temperature for approximately 1 hour, then cooled to approximately 25 °C and stirred at this temperature for approximately 1 hour. The reaction mixture was filtered under reduced pressure, and the resulting wet cake was washed with ethyl acetate (3 ml). The resulting solid was dried under vacuum to give 1.2 g of the title compound, (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-yl)methanesulfonate (yield: 81%).

[0127] 1 H-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).

[0128] [Experimental Example 1] In vitro activity evaluation of compound A

[0129] The in vitro GCS enzyme and GM1 inhibitory activities of (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate prepared in Example 1 were evaluated, and the results are shown in Figure 1 As a control, vegrostat was used.

[0130] like Figure 1 As shown, (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quinine cyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate exhibits GCS enzyme and GM1 inhibitory activity at very low concentrations.

[0131] In the following experiments, the dosage of compound A was based on the amount of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate after dissociation of the camphor sulfonate in vivo.

[0132] [Experimental Example 2] Single-dose pharmacokinetics of compound A

[0133] The (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1S)-(+)-10-camphor sulfonate (compound A) prepared in Example 1 was administered orally (PO) or intravenously (IV) to mice, rats, and beagle dogs as experimental subjects, followed by single-dose pharmacokinetic analysis. The analytical results are shown in... Figures 2a to 2d .

[0134] [Experimental Example 3] Single-dose PK / PD of Compound A

[0135] The (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate (1S)-(+)-10-camphor sulfonate (compound A) prepared in Example 1 was administered to mice at a dose of 10 mg / kg, and the changes in drug concentration and relative GL1 level in the brain or plasma over time were analyzed. The analytical results are shown in... Figure 3a As a control group, vildrolactone was administered at a dose of 60 mg / kg, and the results were also shown... Figure 3b .

[0136] [Experimental Example 4] Measurement of changes in GL1 levels in the brain and plasma over time after administration of compound A

[0137] Mice were administered (1S)-(+)-10-camphor sulfonate (compound A), the (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate prepared in Example 1, at doses of 5 mg / kg every 3 days (Q3D), 10 mg / kg every 3 days (Q3D), 30 mg / kg every 3 days (Q3D), or 90 mg / kg every 3 days (Q3D). Changes in GL1 levels in brain tissue or plasma were then measured after a period of time. The results are shown in… Figures 4a to 4f As a control group, vildrolactone was administered once daily (QD) at doses of 30 mg / kg or 60 mg / kg. Figures 4a to 4f In this study, dosage is expressed as free base (salt correction factor of 1.48x has been applied). The values ​​above the column represent the relative GL1% compared to the normal control.

[0138] like Figures 4a to 4f As shown, when (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) was administered at a dose of 10 mg / kg every 3 days (Q3D), the drug concentrations in the brain and plasma increased by 50% to 100% after 24 to 72 hours. Furthermore, it can be seen that even when the dose of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) was increased to 90 mg / kg every 3 days (Q3D), there were no significant changes in clinical signs or weight. (The last sentence appears to be incomplete and possibly refers to a different topic.) max and C trough At the time point, the drug (compound A) at a dose of 10 mg / kg Q3D showed a stronger trend toward inhibiting brain GL1 than vildrolista, while the trend toward inhibiting plasma GL1 was weaker than that of vildrolista.

[0139] [Experimental Example 5] Dose- and regimen-dependent therapeutic effects of compound A in a CBE-induced mouse model

[0140] 1. Experimental Design

[0141] according to Figure 5The experimental design shown involves administering (1S)-(+)-10-camphor sulfonate (compound A), of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate to a CBE-induced mouse model for 4 weeks, followed by behavioral testing, PD marker assessment, and survival analysis. More specifically, (1S)-(+)-10-camphor sulfonate (compound A), the (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate, was administered orally once daily (QD) to a CBE-induced mouse model at doses of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, or 20 mg / kg, with vegrostat administered once daily (QD) as a control at doses of 20 mg / kg or 60 mg / kg.

[0142] 2. Survival rate change analysis

[0143] After administering (1S)-(+)-10-camphor sulfonate (compound A), the (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, to a CBE-induced mouse model at the above dosage and regimen, changes in survival were analyzed, and the results are shown in… Figure 6a and Figure 6b .

[0144] like Figure 6a and Figure 6b As shown, it can be confirmed that when (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) is administered once daily (QD) at a dose of 5 mg / kg or higher, the survival rate of mice is significantly increased compared with the control group.

[0145] 3. Behavioral Testing

[0146] After administering (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate to a CBE-induced mouse model at the above dosage and regimen, behavioral tests consisting of the suspension wire test and the rotarod test were performed, and the results are shown in... Figure 7a and Figure 7b .

[0147] like Figure 7aand Figure 7b As shown, it can be confirmed that when (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) is administered once daily (QD) at a dose of 2.5 mg / kg or higher, the time mice spend on the suspension wire or rotarod increases.

[0148] 4. Measurement of GL1 level changes

[0149] After administering (1S)-(+)-10-camphor sulfonate (compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate to a CBE-induced mouse model at the above-described doses and regimens, the levels of total GL1 and total lyso-GL1 in plasma, brain, and liver tissues were measured. The results are shown in... Figures 8a to 8f .

[0150] like Figures 8a to 8f As shown, it can be confirmed that when (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) is administered once daily (QD) at a dose of 2.5 mg / kg or higher, the levels of total GL1 and total lyso-GL1 in plasma, brain, and liver tissue are significantly reduced.

[0151] 5. Measurement of changes in biomarkers

[0152] After administering (1S)-(+)-10-camphor sulfonate (compound A), the (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate, to a CBE-induced mouse model at the above dosage and regimen, changes in the expression levels of galactolectin-3, GFAP, NeuN, and CD8 in brain tissue were measured. The results are shown in... Figures 9a to 9d .

[0153] like Figures 9a to 9dAs shown, it can be confirmed that when (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (1S)-(+)-10-camphorsulfonate (compound A) is administered once daily (QD) at a dose of 2.5 mg / kg or higher, the expression of the microglial cell marker galactolectin-3, the astrocyte marker GFAP, and the cytotoxic T cell marker CD8 decreases, while the expression of the neuronal nucleoprotein NeuN increases.

[0154] As can be seen, the (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate (compound A) of this disclosure dose-dependently reduced GL1 levels in normal mouse plasma by more than 90% and in brain tissue by up to 70%. Furthermore, as shown by the results of suspension wire and rotarod tests performed 4 weeks after oral administration of the drug (compound A) to a GD mouse model induced by conduitol beta-epoxide (CBE), the drug alleviated behavioral abnormalities and inhibited glial proliferation in brain tissue (measured by microglia and astrocyte infiltration). Furthermore, it can be seen that at doses above 10 mg / kg, the drug reduces GL1 accumulation in plasma by more than 90% and in the brain by more than 80%, and mice treated with the highest dose of compound A have a lifespan that is approximately 200% longer than untreated mice (mean survival time: 110 days vs. 36 days). In addition, compound A demonstrates excellent bioavailability in rodent and non-rodent pharmacokinetic studies.

[0155] Experiments conducted on rodents, such as mice, have shown that when (1S)-(+)-10-camphor sulfonate (compound A), the (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of this disclosure, is administered at a dose of about 5 mg / kg or more, it exhibits preventive, alleviating, or therapeutic effects against Gaucher disease. As a result of converting the 5 mg / kg or more dose in mice (rodents) to a human dose, the inventors of this disclosure have found that the appropriate dose level for humans of compound A is 3 mg or more, particularly 3 mg to 480 mg.

[0156] [Experimental Example 6] Single-dose administration, stepwise dose escalation, and first-time human trials of compound A in healthy adult male subjects Phase 1 clinical trial results

[0157] A clinical trial was conducted in South Korea to evaluate an oral formulation of (1S)-(+)-10-camphor sulfonate (Compound A) of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate 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 a single dose of Compound A. The stepwise dose-escalation design involved advancing to the next dose group only after the safety and tolerability of the previous dose group were confirmed. To date, 10 subjects have been assigned to each dose group (8 in the Compound A group and 2 in the placebo group), for a total of 3 cohorts. 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 drug concentration and GL1 level were measured using HPLC-MS / MS.

[0158] No obvious abnormal signs or side effects were observed in the clinical results.

[0159] The changes in plasma drug concentrations over time following oral administration of 3 mg, 10 mg, or 30 mg of compound A, as confirmed to date, were analyzed, and the results are shown in... Figure 10 .

[0160] Following a single oral administration of 3 mg, 10 mg, or 30 mg of compound A, the maximum plasma concentration (C) was observed between a minimum of 12 hours and a maximum of 36 hours post-administration. max Increasing the dose from 3 mg to 30 mg resulted in an average C... max and AUC inf The values ​​all increased approximately threefold. The half-life (t) of compound A... 1 / 2 The observation period is approximately 24 days (AUC). inf The area under the concentration-time curve extrapolated from the last quantifiable concentration to infinity; T max Reaching C max (Time).

[0161] In addition, changes in plasma GL1 levels over time after oral administration of 3 mg, 10 mg, or 30 mg of compound A were analyzed, and the results are shown in... Figure 11 .

[0162] Following a single oral administration of 3 mg, 10 mg, or 30 mg of compound A, the maximum decrease in plasma GL1 levels was observed between approximately 168 and 504 hours post-administration. At this time, the mean maximum decrease 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. The decrease in plasma GL1 levels was observed after administration, and although a slight increase in GL1 levels was noted on day 36, the decrease in GL1 levels persisted.

[0163] Based on the PK and PD results observed after administration of 3 mg, 10 mg or 30 mg of compound A, dosing regimens such as once weekly (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W) or once every 4 weeks (Q4W) may be considered.

[0164] [Experimental Example 7] Multiple Dosage and Protocol Design

[0165] Based on comprehensive experimental results, the target range for a reduction in plasma GL1 levels (%) was set at 70% to 80%. The dose required to achieve this target range is... Figure 12 The minimum and maximum doses for each dosing regimen are given as follows: once a week (QW), once every 2 weeks (Q2W), once every 3 weeks (Q3W), and once every 4 weeks (Q4W).

[0166] Although this disclosure has been described in detail with reference to specific features, it will be apparent to those skilled in the art that this description is merely a preferred embodiment and does not limit the scope of this disclosure. Therefore, the essential scope of this disclosure will be defined by the appended claims and their equivalents.

[0167] Industrial applicability

[0168] This invention provides a treatment regimen for treating Gaucher disease (GD) using quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, its optical isomer, or a pharmaceutically acceptable salt thereof, with optimized dosage and administration.

Claims

1. A pharmaceutical composition for the prevention or treatment of Gaucher disease (GD) comprising, as an active ingredient, a quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, its optical isomer, or a pharmaceutically acceptable salt thereof, of Formula 1, 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 according to claim 1, wherein the pharmaceutical composition comprises (S)-quininecyclo-3-yl(5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate of formula 2 as an active ingredient: [Equation 2] 。 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as an active ingredient, represented by formula 3: [Formula 3] 。 4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains camphor sulfonate of quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate as an active ingredient.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains (1S)-(+)-10-camphor sulfonate of quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-indene-1-yl)carbamate as an active ingredient.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises (1S)-(+)-10-camphor sulfonate of (S)-quininecyclo-3-yl((R)-5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)carbamate as an active ingredient: [Formula 4] 。 7. The pharmaceutical composition of claim 1, wherein the active ingredient is administered to the subject once weekly (QW) at a dose of 2.5 mg to 22.5 mg.

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 once weekly (QW) 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.

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 in human subjects by at least 50%. Or it can be used to prevent or treat Gaucher disease in human subjects with elevated plasma glucosylceramide (GL1) levels.

16. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces plasma glucosylceramide (GL1) levels in human subjects by at least 70%.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition reduces plasma glucosylceramide (GL1) levels in human subjects by 70% to 80%.

18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an orally administered pharmaceutical composition.

19. A method for treating Gaucher disease (GD), the method comprising administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising, as an active ingredient, a quinine cyclo-3-yl (5-(3-chloro-4-isopropoxyphenyl)-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl) carbamate, its optical isomer, or a pharmaceutically acceptable salt thereof, as represented by Formula 1. The active ingredient is administered in doses ranging from 2.5 mg to 90 mg. [Formula 1] 。

Images