Phenoxyalkyl carboxylic acid derivatives and their use in lowering triglyceride levels - Patents.com

Abstract

A method of reducing triglyceride synthesis and / or reducing triglyceride accumulation in the liver of a subject, comprising administering to the subject a compound of formula (I): Methods are described herein that include administering a metabolite thereof, or a pharma- ceutically acceptable salt thereof. JPEG2024522030000024.jpg2887

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 194,829, filed May 28, 2021, which is incorporated by reference in its entirety herein.

[0002] The present technology relates to decreasing triglyceride synthesis and / or lowering triglyceride levels in the liver of a patient by administering a phenoxyalkyl carboxylic acid, such as MN-001 or MN-002. Summary of the Invention

[0003] In one embodiment, there is provided a method of reducing triglyceride synthesis in the liver of a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0004] [ka] [In the formula, m is 2, 3, 4 or 5, n is 3, 4, 5, 6, 7 or 8, and X l and X 2 each independently represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, provided that X l and X 2 and (b) cannot both be oxygen atoms. Provided herein are methods comprising administering a metabolite thereof, or a pharma- ceutically acceptable salt thereof.

[0005] In another embodiment, there is provided a method of reducing triglyceride accumulation in the liver of a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0006] [ka] [In the formula, m is 2, 3, 4 or 5, n is 3, 4, 5, 6, 7 or 8, and X l and X 2 each independently represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, provided that X l and X 2 and (b) cannot both be oxygen atoms. or a metabolite thereof, or a pharma- ceutically acceptable salt thereof.

[0007] In some embodiments, the compound of formula (I) is a compound of formula (IA).

[0008] [ka]

[0009] In some embodiments, a metabolite of a compound of formula (I) is administered, which is a compound of formula (IB).

[0010] [ka]

[0011] In some embodiments, the subject has been diagnosed with hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, pre-diabetes, or diabetes. In some embodiments, the subject is considered healthy. In some embodiments, the compound of formula (I) is administered orally. In some embodiments, the compound of formula (I) is administered once a day, twice a day, or three times a day. In some embodiments, the compound of formula (I) is administered as a liquid or solid dosage form. In some embodiments, the compound of formula (I) is administered orally in a solid dosage form, and the compound of formula (I) is in an orthorhombic crystal form. In some embodiments, the compound of formula (I) is administered in an amount ranging from 50 mg / day to 2,000 mg / day, optionally in one, two, or three divided doses. In some embodiments, the compound of formula (I) is administered in dosages of 50 mg, 75 mg, 100 mg, 200 mg, 500 mg, 750 mg or 1,000 mg once daily, twice daily or three times daily. [Brief description of the drawings]

[0012] [Figure 1] Figure 1 shows the measurement of intracellular triglyceride levels in HepG2 cells after 48 hours of incubation with one or more selected from arachidonic acid, T0901317 and MN-001.Y-axis: Δ intracellular triglyceride (μg / mg / protein). [Diagram 2] FIG. 1 shows the measurement of CD36 mRNA expression levels from HepG2 cells after treatment with one or more selected from arachidonic acid, T0901317 and MN-001. Y-axis: relative mRNA expression compared to control (arbitrary units). [Diagram 3] Figure 1 shows the measurement of ABCG1 mRNA expression level from HepG2 cells after treatment with one or more selected from arachidonic acid, T0901317 and MN-001.Y-axis: relative mRNA expression (arbitrary units) compared to control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0014] As used herein, "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If the use of the term would not be clear to a person of ordinary skill in the art given the context in which it is used, "about" will mean up to ±10% of the particular term.

[0015] "Administering" a drug to a patient or "administration of" a drug to a patient (and grammatical equivalents of this phrase) includes both direct administration, including self-administration, and indirect administration, including the act of prescribing the drug. For example, as used herein, a physician who instructs a patient to self-administer a drug and / or provides a prescription for a drug to a patient is administering a drug to a patient.

[0016] The "C" placed in front of the base X " refers to the number of carbon atoms in the group being X.

[0017] "Alkyl" refers to a monovalent acyclic hydrocarbyl group having 1 to 12 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0018] "Aryl" refers to a monovalent aromatic hydrocarbyl group having up to 10 carbon atoms. Non-limiting examples of aryl include phenyl and naphthyl.

[0019] "Heteroaryl" refers to an aromatic group having 1-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the aromatic ring, where the nitrogen and / or sulfur atoms of the heteroaryl are optionally oxidized (e.g., N-oxide, -S(O)-, or -S(O)2-). Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. Non-limiting examples of heteroaryls include pyridyl, pyrrolyl, indolyl, thiophenyl, and furyl.

[0020] "Cycloalkyl" refers to a monovalent non-aromatic cyclic hydrocarbyl group having three to twelve carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0021] "Heterocyclyl" refers to a monovalent non-aromatic cyclic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring, where the nitrogen and / or sulfur atoms of the heteroaryl are optionally oxidized (e.g., N-oxide, -S(O)-, or -S(O)2-). Such heteroaryl groups can have a single ring (e.g., piperidinyl or tetrahydrofuranyl) or multiple condensed rings, which may or may not be aromatic and / or contain heteroatoms, provided that the point of attachment is through an atom of the non-aromatic heterocyclyl group. Non-limiting examples of heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, and the like.

[0022] "Amino" refers to -NH2.

[0023] "Alkylamino" is -NHR B R Bis a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclyl groups.

[0024] "Dialkylamino" is -N(R B )2, where R B is defined as above.

[0025] "Comprising" shall mean that the methods and compositions include the recited elements, but do not exclude others. "Consisting essentially of," when used to define methods and compositions, shall mean excluding other elements of any essential importance to the combination for the recited purpose. "Consisting of" shall mean excluding trace elements of other ingredients, and more than substantial method steps of administering the compositions of the invention or process steps for producing the compositions or achieving the intended result. Embodiments defined by each of these transition terms and phrases are within the scope of the present invention.

[0026] An "effective amount" of a compound as used herein is an amount that, when administered to a patient, has an intended therapeutic effect, e.g., an amount that reduces, improves, ameliorates, or eliminates one or more symptoms of a pathological condition in a patient. A full therapeutic effect does not necessarily occur by administration of a single dose (or dosage), but may occur only after administration of a series of doses. Thus, an effective amount may be administered in one or more administrations.

[0027] "Pharmaceutically acceptable" refers to non-toxic and suitable for administration to patients, including human patients.

[0028] "Pharmaceutically acceptable salt" refers to a salt that is non-toxic and suitable for administration to a patient.Non-limiting examples include alkali metal salts, alkaline earth metal salts, and various primary, secondary and tertiary ammonium salts.When the ester of the compound of formula (I) contains a cationic moiety, for example, when the ester contains an amino acid ester, the salt can contain various carboxylate, sulfonate and mineral acid salts.Some non-limiting examples of salts include sodium salt, potassium salt and calcium salt.

[0029] "Protecting group" refers to a well-known functional group that, when attached to a functional group, renders the resulting protected functional group inert to reactions and corresponding reaction conditions carried out on other parts of the compound, and can react under deprotection conditions to regenerate the original functionality. The protecting group is selected to be compatible with the remainder of the molecule. "Carboxylic acid protecting groups" protect the carboxylic acid functionality of phenoxyalkyl carboxylic acids during their synthesis. Non-limiting examples of carboxylic acid protecting groups include benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, benzhydryl, and trityl. Additional examples of carboxylic acid protecting groups can be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis., 2nd Edition, 1991, John Wiley & Sons, Inc., and McOmie Protective Groups in Organic Chemistry, 1975, Plenum Press, Inc. Methods for protecting and deprotecting carboxylic acids disclosed herein can be found in the art, specifically in Greene and Wuts, supra, and the references cited therein.

[0030] "Treating" a pathological condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. In various aspects and embodiments of the present disclosure, beneficial or desired clinical results include, but are not limited to, reduction, alleviation or amelioration of one or more symptoms or negative effects of or associated with elevated triglyceride levels in the liver, improvement in one or more clinical outcomes, reduction in the extent of disease, delay or slowing of disease progression, improvement, remission or stabilization of the disease conditions described herein, and other beneficial results.

[0031] Triglyceride accumulation and synthesis in the liver The liver is the central organ of fatty acid metabolism. Fatty acids are generated in the liver by hepatocyte uptake from plasma and de novo biosynthesis. In conditions of overnutrition and obesity, hepatic fatty acid metabolism is altered, and triglycerides (TG) usually accumulate in hepatocytes. Long-term accumulation of TG in the liver can lead to and is indicative of liver diseases such as fatty liver, NAFLD and NASH. However, TG accumulation in the liver does not necessarily correlate with elevated serum TG levels, and vice versa. For example, patients with early hypertriglyceridemia may exhibit elevated TG levels in serum, but do not exhibit TG accumulation in the liver until the disease has progressed further. Patients suffering from metabolic disorders such as insulin resistance, prediabetes or diabetes may also exhibit TG accumulation in the liver if the metabolic disorder is not properly treated. This hepatic TG accumulation may occur without elevated serum TG due to increased de novo TG synthesis. As TG accumulation in the liver is a risk factor for liver disease, there is a need for therapeutic options to prevent and / or treat TG accumulation and TG synthesis in the liver.

[0032] method In one embodiment, there is provided a method of reducing triglyceride synthesis in the liver of a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0033] [ka] [In the formula, m is an integer of 2 to 5, n is an integer of 3 to 8, and X l and X 2 each independently represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, provided that X l and X 2 and (b) cannot both be oxygen atoms. Provided herein are methods comprising, consisting essentially of, or consisting of administering a metabolite thereof, or a pharma- ceutically acceptable salt thereof.

[0034] In another aspect, provided herein is a method of reducing triglyceride accumulation in the liver of a subject comprising, consisting essentially of, or consisting of administering to the subject an effective amount of a compound of formula (I), a metabolite thereof, or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) is as defined above.

[0035] In some embodiments, the subject has been diagnosed with hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, prediabetes, or diabetes. In some embodiments, the subject is considered healthy.

[0036] As used herein, "metabolites thereof" refers to metabolites that exhibit substantially similar therapeutic activity as the compounds of formula (I). Non-limiting examples of such metabolites include -O-(CH2) n These include compounds in which the -COCH3 group of the compound of formula (I) attached to a phenyl containing CO2H moiety is metabolized to a 1-hydroxyethyl (-CH(OH)Me) group.

[0037] Such metabolites containing a 1-hydroxyethyl group contain an asymmetric center at position 1 of the 1-hydroxyethyl group. The corresponding enantiomers and mixtures thereof, including racemic mixtures, are included within the metabolites of the compounds of formula (I) utilized herein.

[0038] In some embodiments, the compound of formula (I) is a compound of formula (IA) (or MN-001).

[0039] [ka]

[0040] In some embodiments, the metabolite of the compound of formula (I) and (IA) is the compound of formula (IB) (or MN-002).

[0041] [ka]

[0042] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered once a day, twice a day, or three times a day. In some embodiments, the compound is administered as a liquid or solid dosage form. In some embodiments, the compound is administered orally in a solid dosage form and exists in an orthorhombic crystalline form that is substantially free of other polymorphs.

[0043] In some embodiments, the compound is administered in an amount ranging from 50 mg / day to 5,000 mg / day, optionally in 1, 2 or 3 divided doses. In some embodiments, the compound is administered in a dosage of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg or 2000 mg once, twice or three times daily. In some embodiments, the compound is administered at 50 mg once a day (qd), 50 mg twice a day (bid), 50 mg three times a day (tid), 100 mg once a day, 100 mg twice a day, 100 mg three times a day, 500 mg once a day, 500 mg twice a day, 500 mg three times a day, 750 mg once a day, 750 mg twice a day, 750 mg three times a day, or 500 mg three times a day for 5 days, followed by 750 mg twice a day for another 5 days. In some embodiments, the compound is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, or indefinitely.

[0044] In some embodiments, the compound of Formula (I), its metabolite, or a pharma- ceutically acceptable salt thereof, is the sole active agent used in the methods disclosed herein.

[0045] synthesis The synthesis and some biological activities of the compounds of formula (I) are described in U.S. Patent No. 4,985,585, which is incorporated herein by reference in its entirety. For example, the compounds of formula (IA) can be prepared by reacting the phenols of formula (II):

[0046] [ka] wherein R is a carboxylic acid protecting group. and a compound of formula (III):

[0047] [ka] to produce a compound of formula (IC):

[0048] [ka] The acid protecting group or R group is prepared by providing a carboxylic acid such as carboxylic acid ester, carboxylic acid ester, or carboxylic acid ester. Non-limiting examples of the acid protecting group or R group include C1-C6 alkyl, benzyl, benzhydryl and trityl, where the benzyl, benzhydryl or trityl group is optionally substituted with C1-C6 alkyl, halo, and / or C1-C6 alkoxy groups. It will be apparent to one skilled in the art that leaving groups other than the bromo group of formula (III) may be used. Non-limiting examples of such other leaving groups include chloro or tosylate.

[0049] Deprotection of the protected carboxylic acid of formula (IC) gives a compound of formula (IA). Based on this disclosure, it will be apparent that compounds of formula (IC) are useful in some embodiments according to the present invention. Non-limiting examples of deprotection methods include alkaline hydrolysis and hydrogenolysis under a catalyst such as H2 and Pd / C or Pt / C.

[0050] The reaction is carried out in an inert organic solvent, such as, but not limited to, acetone, methyl ethyl ketone, diethyl ketone, or dimethylformamide. The nucleophilic substitution reaction can be carried out below room temperature up to the reflux temperature of the solvent, in the presence of an inorganic base such as potassium carbonate or sodium carbonate, and optionally in the presence of potassium iodide. The reaction can be analyzed by thin layer chromatography or 1 The reaction is carried out for a time sufficient to give substantial product as determined by known methods such as H-NMR. Other compounds utilized herein are made by following the procedures described herein, appropriately substituting starting materials, and / or following methods known to those skilled in the art. See also U.S. Patent No. 5,290,812, which is incorporated herein by reference in its entirety.

[0051] The compound of formula (IA) is recrystallized under controlled conditions to obtain an essentially pure orthorhombic polymorph (e.g., 90% or more, preferably at least 95% of Form A) called Form A crystal. Polymorph Form A and the method for producing it are described in U.S. Patent Nos. 7,060,854 and 7,064,146, which are incorporated herein by reference in their entirety. Although all polymorphs of the compound of formula (I) are active, polymorph Form A is preferred. Under certain conditions, the solubility and bioavailability of this polymorph are superior to other polymorphs, and therefore Form A can provide improved solid formulations.

[0052] For example, Form A crystals can be obtained by dissolving the compound of formula (IA) in 5-10 parts by weight of ethanol at 25-40° C. to obtain a yellow-orange solution. The ethanol solution is charged with 1-10 parts of water and stirred at 20-25° C. for about 15-60 minutes, then at 5-10° C. for an additional 1-4 hours, preferably 2.0-3.0 hours, to produce an off-white suspension. To this suspension, 5-15 parts of water are added and the mixture is stirred at 5-10° C. for an additional 1-4 hours, preferably 1.5-2.0 hours. The solid white to off-white product is isolated by vacuum filtration, the filter cake is washed with water and dried in vacuum at 25-40° C. for 12-24 hours.

[0053] For compounds utilized herein that exist in enantiomeric form, such as some metabolites of the compound of formula (I) (e.g., the compound of formula IB), the two enantiomers can be optically resolved. Such resolution can be achieved, for example, but not limited to, by forming a diastereomeric salt of a base, such as (S)-(-)-1-(1-naphthyl)ethylamine, with the corresponding carboxylic acid compound, or by separating the enantiomers using chiral column chromatography. Intermediates of such compounds also exist in enantiomeric form and can be resolved in a similar manner.

[0054] Administration and Formulation The compounds utilized herein can be administered orally, or by intravenous, intramuscular, and subcutaneous injection, or transdermal methods. Effective dosage levels can range over a wide range, for example, from about 100 to 4000 mg per day. In some embodiments, the daily dosage range is 250 to 2,000 mg, administered 1, 2, or 3 times per day. In some embodiments, the dosage is 1000 mg twice per day. In some embodiments, suitable dosages include 1000 mg once per day, 1000 mg twice per day, and 750 mg three times per day.

[0055] The actual amount depends on the condition of the patient being treated.As those skilled in the art are aware, many factors that modify the action of active substances, such as age, weight, sex, diet and condition of the patient, administration time, administration rate and route, etc., are taken into consideration by the treating physician.The optimal dosage for a given condition can be confirmed by those skilled in the art using routine dosage determination tests.

[0056] The compounds utilized herein may be formulated into any pharma- ceutically acceptable form, including liquids, powders, creams, emulsions, pills, lozenges, suppositories, suspensions, solutions, and the like. Therapeutic compositions containing the compounds utilized herein are usually formulated with one or more pharma- ceutically acceptable ingredients according to known and well-established practices. Generally, tablets are formed utilizing a carrier such as modified starch, alone or in combination with 10% by weight carboxymethylcellulose (Avicel). The formulation is compressed at a pressure of 1,000 to 3,000 pounds in the tablet-forming process. Tablets are preferably compressed at a pressure of about 1.5 to 8.0 kp / cm. 2 , preferably 5.0 to 7.5 kp / cm 2 The average hardness of each of the tablets is shown. Disintegration times vary from about 30 seconds to about 15 or 20 minutes.

[0057] Formulations for oral use can be provided as hard gelatin capsules in which the therapeutically active compounds utilized herein are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with an oily medium, such as liquid paraffin or olive oil. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, and the like.

[0058] The compounds utilized herein can be formulated as aqueous suspensions in admixture with pharma- ceutically acceptable excipients, such as suspending agents, e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents, such as natural phosphatides, e.g., lecithin, or condensation products of alkaline oxides with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g., heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, e.g., polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monooleate. Such aqueous suspensions may also contain one or more preservatives, for example ethyl- or -n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as glycerol, sorbitol, sucrose, saccharin or sodium or calcium cyclamate.

[0059] Suitable formulations also include sustained release dosage forms such as those described in U.S. Pat. Nos. 4,788,055; 4,816,264; 4,828,836; 4,834,965; 4,834,985; 4,996,047; 5,071,646; and 5,133,974, the contents of which are incorporated herein by reference in their entireties.

[0060] Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, or solid preparations intended to be converted to liquid form preparations immediately before use.Emulsions can be prepared as liquids, for example as aqueous propylene glycol solutions, or may contain emulsifiers, for example lecithin, sorbitan monooleate or acacia.Aqueous liquids can be prepared by dissolving active ingredients in water and adding suitable colorants, flavorants, stabilizers and thickeners.Solid preparations can contain colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc. in addition to active ingredients.

[0061] The compounds utilized herein can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion), and can be presented in unit dose form with added preservatives in ampoules, prefilled syringes, small-volume drip or multiple dose containers.The compositions can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, e.g., solutions in aqueous polyethylene glycol.Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate), and can contain formulatory agents such as preservatives, wetting agents, emulsifying or suspending agents, stabilizing agents and / or dispersing agents.Alternatively, the active ingredient can be in the form of powder obtained by aseptic isolation of sterile solids or by lyophilization from a solution to be constituted before use with a suitable vehicle, e.g., sterile pyrogen-free water.

[0062] The compounds utilized herein can be formulated as ointments, creams or lotions for topical application to the epidermis, or as transdermal patches. Ointments and creams can be formulated, for example, with an aqueous or oily base, with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents or coloring agents. Preparations suitable for topical administration in the mouth include lozenges, which contain the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain the active agent in an inert base such as gelatin, glycerin, or sucrose and acacia; and mouthwashes, which contain the active agent in a suitable liquid carrier.

[0063] The compound utilized herein can be formulated for administration as suppository.In such preparation, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and active ingredient is dispersed homogeneously, for example by stirring.The homogeneous molten mixture is then poured into molds of convenient size, and allowed to cool and solidify.

[0064] The compounds utilized herein can be formulated for vaginal administration: pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0065] The compounds utilized herein can be formulated for nasal administration.The solution or suspension is directly applied to the nasal cavity by conventional means, for example, by using a dropper, pipette or spray.The formulation can be provided in the form of a single or multiple doses.The patient can administer a suitable amount of the solution or suspension by using a dropper or pipette.The spray can be administered by means of, for example, a metered atomizing spray pump.

[0066] The compounds utilized herein may be formulated for aerosol administration, including intranasal administration, particularly to the respiratory tract. The compounds generally have a small particle size, for example on the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant, such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredient may be provided in dry powder form, for example in the form of a powder mix of the compound in a suitable powder base, such as lactose, starch, starch derivatives, such as hydroxypropylmethylcellulose, and polyvinylpyrrolidine. The powder carrier forms a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, for example in gelatin or blister packs, from which the powder may be administered by an inhaler.

[0067] If desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. A common type of controlled release formulation that can be used in the present invention comprises an inert core such as a sugar sphere, a first layer coated with an inner drug-containing second layer, and an outer or third layer that controls drug release from the inner layer.

[0068] The core can be a water-soluble or swellable material and can be any material commonly used as a core or any other pharma- ceutically acceptable water-soluble or water-swellable material made into beads or pellets. The core can be a spherical material such as sucrose / starch (sugar spheres NF), sucrose crystals, or extruded and dried spheres typically made of excipients such as microcrystalline cellulose and lactose.

[0069] The substantially water-insoluble material in the first layer is generally a "GI insoluble" or "GI partially insoluble" film-forming polymer (dispersed or dissolved in a solvent). Examples include ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polymethacrylates such as ethyl acrylate / methyl methacrylate copolymer (EUDRAGIT® NE-30-D), ammonio methacrylate copolymer types A and B (EUDRAGIT® RL30D and RS30D), and silicone elastomers. A plasticizer is usually used together with the polymer. Exemplary plasticizers include dibutyl sebacate, propylene glycol, triethyl citrate, tributyl citrate, castor oil, acetylated monoglycerides, acetyl triethyl citrate, acetyl butyl citrate, diethyl phthalate, dibutyl phthalate, triacetin, fractionated coconut oil (medium chain triglycerides).

[0070] The second layer containing the active ingredient may consist of the active ingredient (drug) with or without a polymer as a binder. The binder, when used, is usually a hydrophilic binder, but may be water-soluble or water-insoluble. Exemplary polymers used in the second layer containing the active drug are hydrophilic polymers such as polyvinylpyrrolidone, polyalkylene glycols such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and its derivatives, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, acrylic acid polymers, polymethacrylates, or any other pharma- ceutically acceptable polymers. The ratio of drug to hydrophilic polymer in the second layer is usually in the range of 1:100 to 100:1 (w / w).

[0071] Polymers suitable for use in the third layer or membrane to control drug release can be selected from water-insoluble polymers or polymers with pH-dependent solubility, such as, for example, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, or mixtures thereof, optionally combined with a plasticizer, such as those described above.

[0072] Optionally, the controlled release layer includes, in addition to the above polymer, another material with different solubility characteristics to adjust the permeability of the controlled release layer and thereby adjust the release rate.Exemplary polymers that may be used as modifiers, such as together with ethyl cellulose, include HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polymers with pH-dependent solubility, such as cellulose acetate phthalate or ammonio methacrylate copolymers, and methacrylic acid copolymers, or mixtures thereof.If desired, additives such as sucrose, lactose, and pharmaceutical grade surfactants can also be included in the controlled release layer.

[0073] Unit dosage forms of preparations are also provided herein.In such dosage forms, the preparation is divided into unit doses containing an appropriate amount of active ingredient (for example, but not limited to, the compound of formula (I), its metabolites, or its pharma-ceutically acceptable salts).The unit dosage form can be a packaged preparation, the package containing a discrete amount of preparation, such as tablets, capsules, and powders, packaged in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these packaged forms.

[0074] Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th Edition, Easton, Pa. EXAMPLES

[0075] HepG2 cells (derived from a human hepatocellular carcinoma sample) were incubated with one or more of 10 μM arachidonic acid (ARA), 1 μM LXR agonist T0901317 ("T1317"), and 10 μM MN-001 for 48 hours. T1317 stimulates LXR-SREBP-1c ChREPB signaling, increases triglyceride (TG) synthesis in the liver, and aggravates hepatic steatosis. Intracellular triglyceride levels were measured after treatment (Figure 1).

[0076] Compared to vehicle, T1317 increased TG synthesis 3.8-fold, ARA increased TG synthesis 15.3-fold, and the combination of T1317 and ARA increased TG synthesis 24.3-fold.

[0077] Addition of MN-001 inhibited TG accumulation (TG synthesis) caused by ARA and / or T1317 in HepG2 cells. More specifically, addition of MN-001 suppressed the increase in TG synthesis caused by T1317 by 1.7-fold, and the increase in TG synthesis caused by ARA or the combination of T1317 and ARA by 3.7-fold. These results can be related to the reduction of TG and the suppression of fatty liver formation by suppressing VLDL secretion.

[0078] The effect of MN-001 on the mRNA expression of molecules related to TG metabolism: (1) fatty acid translocase / CD36, involved in the uptake of ARA into hepatocytes in the liver, and (2) ABCG1, which plays a role in controlling tissue lipid levels by mediating the transfer of cellular cholesterol to HDL, was also investigated by measuring RNA extracted from HepG2 cells using real-time PCR. For this purpose, RNA was extracted from HepG2 cells (after treatment for 48 h with one or more selected from 10 μM arachidonic acid (ARA), 1 μM T1317, and 10 μM MN-001) and converted to cDNA.

[0079] After conversion to cDNA, CD36 mRNA expression levels were measured by qPCR (Figure 2). Free fatty acids are taken up into cells via a receptor complex containing CD36, which is upregulated in insulin-resistant states. Saturated fatty acids (e.g., palmitic acid, stearic acid) and fructose induce the adipogenic pathway and promote fat accumulation by increasing CD36 expression and regulating ChREBP, which controls lipogenesis. In this experiment, ARA increased CD36 expression 1.8-fold compared to control, MN-001 decreased CD36 expression 0.6-fold compared to control, and the addition of MN-001 to ARA suppressed CD36 expression 0.6-fold compared to ARA alone. More specifically, treatment with MN-001 reduced CD36 expression by 39% and 43% in the absence and presence of ARA, respectively, suggesting that MN-001 inhibited the cellular uptake of ARA.

[0080] In addition, ABCG1 mRNA expression levels were also measured by qPCR (Figure 3). ABCG1 is known to be highly expressed in lipid-loaded macrophages and mediates cholesterol efflux to HDL. ABCG1 deficiency causes extensive intracellular cholesterol accumulation in macrophages and hepatocytes. In this experiment, MN-001 upregulated ABCG1 expression 17-fold compared to control, and ARA+MN-001 upregulated ABCG1 expression 9.7-fold compared to control. EXAMPLES

[0081] A phase 2, multicenter, double-blind, randomized, placebo-controlled study will be conducted to evaluate the efficacy, safety, and tolerability of MN-001. Patients with nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (DM), and hypertriglyceridemia will be informed and invited to participate in the study. The study will consist of a screening phase (up to 8 weeks), followed by a treatment phase (24 weeks), and a follow-up visit (approximately 1 week after the last dose).

[0082] The study population included male and female participants aged ≥21 and ≤75 years with a diagnosis of NAFLD (MRI-PDFF >8%), type 2 diabetes and hypertriglyceridemia as confirmed by MRI scan.

[0083] Co-primary objectives of the study: Change in liver fat content measured by MRI proton density fat fraction (MRI-PDFF) at 24 weeks Change from baseline in fasting serum triglyceride levels at week 24

[0084] Secondary purpose: To evaluate the safety and tolerability of MN-001 To evaluate the effect of MN-001 on lipid profile HDL-C, LDL-C and total cholesterol levels

[0085] Screening period (up to 8 weeks) A total of up to 8 weeks will be devoted to completing the screening assessments. During the screening phase, participants will be assessed for study eligibility. The following assessments will be performed: MRI-PDFF (Magnetic Resonance Imaging-Proton Density Fat Fraction), medical history with review of current and previous medications, height and weight, abbreviated physical examination including vital signs and a 12-ECG. Blood samples will be obtained for complete blood count (CBC), complete metabolic panel (CMP), fasting lipid panel, and coagulation panel (PT / INR). Urine tests will be performed and premenopausal female participants will have a serum human chorionic gonadotropin (β-hCG) pregnancy test.

[0086] Treatment period (24 weeks) MN-001 250 mg tablets orally twice daily or a matching dose of placebo will be administered twice daily for 24 weeks. Throughout the double-blind treatment (DBT) phase, safety parameters will be assessed and concomitant medications will be recorded.

[0087] At the end of the study All patients who complete the study will return for a follow-up visit approximately 1 week (± 3 days) after the end of treatment. Vital signs, weight, blood samples collected for clinical safety labs, as well as concomitant medications (CM) and adverse events (AEs) will be recorded.

[0088] Some embodiments Embodiment 1. A method of reducing triglyceride synthesis in the liver of a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0089] [ka] [In the formula, m is 2, 3, 4 or 5, n is 3, 4, 5, 6, 7 or 8, and X l and X 2 each independently represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, provided that X l and X 2 and (b) cannot both be oxygen atoms. Administering a metabolite thereof, or a pharma- ceutically acceptable salt thereof.

[0090] Embodiment 2. The method of embodiment 1, wherein the compound of formula (I) is a compound of formula (IA).

[0091] [ka]

[0092] Embodiment 3. The method of embodiment 1, wherein a metabolite of a compound of formula (I) is administered and is a compound of formula (IB).

[0093] [ka]

[0094] Embodiment 4. The method of any one of embodiments 1 to 3, wherein the subject has been diagnosed with hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, pre-diabetes, or diabetes.

[0095] Embodiment 5. The method of any one of embodiments 1 to 3, wherein the subject is believed to be healthy.

[0096] Embodiment 6 The method of any one of embodiments 1 to 5, wherein the compound of formula (I) is administered orally.

[0097] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the compound of formula (I) is administered once a day, twice a day, or three times a day.

[0098] Embodiment 8 The method of any one of embodiments 1 to 7, wherein the compound of formula (I) is administered as a liquid or solid dosage form.

[0099] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the compound of formula (I) is administered orally in solid dosage form, and the compound of formula (I) is present in orthorhombic crystalline form.

[0100] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the compound of formula (I) is administered in an amount ranging from 50 mg / day to 2,000 mg / day, optionally in 1, 2 or 3 divided doses.

[0101] Embodiment 11. The method of any one of embodiments 1 to 10, wherein the compound of formula (I) is administered once daily, twice daily or three times daily at a dosage of 50 mg, 75 mg, 100 mg, 200 mg, 500 mg, 750 mg or 1,000 mg.

[0102] Embodiment 12. A method of reducing triglyceride accumulation in the liver of a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0103] [ka] [In the formula, m is 2, 3, 4 or 5, n is 3, 4, 5, 6, 7 or 8, and X l and X 2 each independently represents a sulfur atom, an oxygen atom, a sulfinyl group, or a sulfonyl group, provided that X l and X 2 and (b) cannot both be oxygen atoms. or a metabolite thereof, or a pharma- ceutically acceptable salt thereof.

[0104] Embodiment 13. The method of embodiment 12, wherein the compound of formula (I) is a compound of formula (IA).

[0105] [ka]

[0106] Embodiment 14. The method of embodiment 12, wherein the metabolite of the compound of formula (I) is a compound of formula (IB).

[0107] [ka]

[0108] Embodiment 15. The method of any one of embodiments 12 to 14, wherein the subject has been diagnosed with hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), insulin resistance, prediabetes, or diabetes.

[0109] Embodiment 16 The method of any one of embodiments 12 to 14, wherein the subject is believed to be healthy.

[0110] Embodiment 17. The method of any one of claims 12 to 16, wherein the compound of formula (I) is administered orally.

[0111] Embodiment 18 The method of any one of embodiments 12 to 17, wherein the compound of formula (I) is administered once a day, twice a day, or three times a day.

[0112] Embodiment 19. The method of any one of embodiments 12 to 18, wherein the compound of formula (I) is administered as a liquid or solid dosage form.

[0113] Embodiment 20 The method of any one of embodiments 12 to 19, wherein the compound of formula (I) is administered orally in solid dosage form, and the compound of formula (I) is present in orthorhombic crystalline form.

[0114] Embodiment 21. The method of any one of embodiments 12 to 20, wherein the compound of formula (I) is administered in an amount ranging from 50 mg / day to 2,000 mg / day, optionally in 1, 2 or 3 divided doses.

[0115] Embodiment 22. The method of any one of embodiments 12 to 21, wherein the compound of formula (I) is administered once daily, twice daily, or three times daily at a dosage of 50 mg, 75 mg, 100 mg, 200 mg, 500 mg, 750 mg, or 1,000 mg.

[0116] While several embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein, in accordance with ordinary skill in the art, without departing from the technology in its broader aspects as defined in the following claims.

[0117] The embodiments illustratively described herein may be preferably implemented in the absence of any elements or limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc., are to be interpreted broadly and without limitation. Moreover, the terms and expressions employed herein are used as terms of description and not as terms of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, and it is recognized that various modifications are possible within the scope of the claimed technology. Moreover, the phrase "consisting essentially of" is understood to include the elements specifically described, as well as additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0118] The present disclosure is not limited by the specific embodiments described in this application. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from the spirit and scope thereof. In addition to those enumerated herein, functionally equivalent methods and compositions within the scope of the present disclosure will be apparent to those skilled in the art from the above description. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is limited only by the terms of the appended claims, and the full scope of equivalents to be given to such claims. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, or compositions, which may of course vary. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to be limiting.

[0119] Furthermore, where features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also described thereby in terms of any individual member or subgroup of members of the Markush group.

[0120] As will be understood by those skilled in the art, for all purposes, particularly in terms of written description, all ranges disclosed herein also encompass all possible subranges and combinations of subranges. Any range listed can be easily recognized as fully descriptive and allowing the same range to be broken down into at least equal parts, thirds, fourths, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, and an upper third, etc. As will also be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc., refers to a range that is inclusive of the number recited and can be broken down into the subranges discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

[0121] All publications, patent applications, issued patents, and other documents mentioned herein are incorporated by reference herein as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0122] Other embodiments are within the scope of the following claims.

Claims

1. A composition for reducing triglyceride synthesis in a target liver, 【Chemical 1】 [wherein, m is 2, 3, 4 or 5, n is 3, 4, 5, 6, 7 or 8, X ｌ and X ２ each independently represents a sulfur atom, an oxygen atom, a sulfinyl group or a sulfonyl group, provided that both X ｌ and X ２ are not oxygen atoms] comprising its metabolite, or a pharmaceutically acceptable salt thereof, wherein the subject is diagnosed with insulin resistance, prediabetes, or diabetes, the composition.

2. The composition according to claim 1, wherein the compound of formula (I) is a compound of formula (IA). [Chemical 2]

3. The composition according to claim 1, wherein the metabolite of the compound of formula (I) is administered and is a compound of formula (IB). 【Chemical Formula 3】

4. The composition according to any one of claims 1 to 3, wherein the compound of formula (I) is administered orally.

5. The composition according to any one of claims 1 to 4, wherein the compound of formula (I) is administered once a day, twice a day, or three times a day.

6. The composition according to any one of claims 1 to 5, wherein the compound of formula (I) is administered as a liquid or solid dosage form.

7. The composition according to any one of claims 1 to 6, wherein the compound of formula (I) is administered orally in a solid dosage form and the compound of formula (I) exists in an orthorhombic crystal form.

8. The composition according to any one of claims 1 to 7, wherein the compound of formula (I) is administered in an amount in the range of 50 mg / day to 2,000 mg / day, optionally divided into 1, 2, or 3 doses.

9. The composition according to any one of claims 1 to 8, wherein the compound of formula (I) is administered once a day, twice a day, or three times a day at a dosage of 50 mg, 75 mg, 100 mg, 200 mg, 500 mg, 750 mg, or 1,000 mg.

10. A composition for reducing triglyceride accumulation in a target liver, 【Chemical Formula 4】 [wherein, m is 2, 3, 4 or 5; n is 3, 4, 5, 6, 7 or 8; X ｌ and X ２ each independently represents a sulfur atom, an oxygen atom, a sulfinyl group or a sulfonyl group, provided that both X ｌ and X ２ are not oxygen atoms] comprising or its metabolite or a pharmaceutically acceptable salt thereof, wherein the subject is diagnosed with insulin resistance, prediabetes, or diabetes, the composition.

11. The composition according to claim 10, wherein the compound of formula (I) is a compound of formula (IA). 【Chemical Formula 5】

12. The composition according to claim 10, wherein the metabolite of the compound of formula (I) is a compound of formula (IB). 【Chemical Formula 6】

13. The composition according to any one of claims 10 to 12, wherein the compound of formula (I) is administered orally.

14. The composition according to any one of claims 10 to 13, wherein the compound of formula (I) is administered once a day, twice a day, or three times a day.

15. The composition according to any one of claims 10 to 14, wherein the compound of formula (I) is administered as a liquid or solid dosage form.

16. The composition according to any one of claims 10 to 15, wherein the compound of formula (I) is administered orally in a solid dosage form and the compound of formula (I) is present in an orthorhombic crystalline form.

17. The composition according to any one of claims 10 to 16, wherein the compound of formula (I) is administered in an amount in the range of 50 mg / day to 2,000 mg / day, optionally in 1, 2 or 3 divided doses.

18. The composition according to any one of claims 10 to 17, wherein the compound of formula (I) is administered once, twice or three times a day at a dosage of 50 mg, 75 mg, 100 mg, 200 mg, 500 mg, 750 mg or 1,000 mg.

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