Sulfo-N-succinimidyl oleate (SSO) derivatives and a pharmaceutical composition for preventing or treating nontuberculous mycobacteria infections comprising the same

Abstract

The present invention relates to a sulfo-N-succinimidyl oleate (SSO) derivative and a pharmaceutical composition containing the same for the prevention or treatment of non-tuberculous mycobacterial infections. According to one aspect of the present invention, the sulfo-N-succinimidyl oleate (SSO) derivative has a CD36 inhibitory effect and can inhibit the growth and proliferation of non-tuberculous mycobacteria, thereby having an effect that can be usefully employed for the prevention or treatment of non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung disease.

Description

Technology Field

[0001] The invention relates to a sulfo-N-succinimidyl oleate (SSO) derivative and a pharmaceutical composition containing the same for the prevention or treatment of non-tuberculous mycobacterial infections. Background Technology

[0002] Species of the genus Mycobacterium are classified into two groups based on the degree of pathogenicity and infectivity to the host: the tuberculosis group, which includes obligate pathogenic bacteria such as Mycobacterium tuberculosis and Mycobacterium leprae, and nontuberculous mycobacteria (NTM), which are opportunistic species excluding these.

[0003] Non-tuberculous mycobacteria are widely distributed in nature, and the morbidity of disease-causing bacteria varies depending on the species. Specifically, M. avium complex (MAC), M. abscessus (MAB), and M. kansasii have relatively high morbidity, while M. fortuitum has relatively low morbidity. Diseases caused by non-tuberculous mycobacteria are broadly classified into four characteristic clinical syndromes: lung disease, lymphadenitis, skin, soft tissue, and bone infections, and disseminated disease. Among these, lung disease is the most common form, accounting for more than 90% of all diseases.

[0004] Reports of lung diseases caused by non-tuberculous mycobacteria have been increasing since 2000, and currently, lung diseases caused by MAC are the most frequently reported in most developed countries. In Korea, lung diseases caused by MAC are reported to account for approximately 70-80% of all causative agents of non-tuberculous mycobacterial lung diseases, with MAB reported as the second most observed causative agent. Lung diseases caused by the aforementioned non-tuberculous mycobacteria manifest with symptoms such as cough, fever, hemoptysis, and sputum.

[0005] As non-tuberculous mycobacteria are ubiquitous in the surrounding natural environment, people are periodically exposed to the bacteria in their daily lives; however, respiratory infections and clinical diseases are reported to occur frequently in middle-aged or older women with a low body mass index. In particular, recent clinical reports indicate that these patients have a high rate of disease exacerbation and mortality, as well as a high rate of disease progression to refractory status despite long-term antibiotic treatment.

[0006] Unlike pulmonary tuberculosis, the therapeutic effect of lung diseases caused by the aforementioned non-tuberculous mycobacteria is not yet satisfactory despite the implementation of combination antibiotic therapy. Furthermore, since the disease primarily affects elderly patients aged middle-aged or older, there is a high incidence of side effects associated with the use of various antibiotics and treatment regimens.

[0007] Meanwhile, CD36 (HGNC:1663, EntrezGene:948, Ensembl:ENSG00000135218, OMIM: 173510, UniProtKB: P16671) is a receptor protein known for several different functions, as indicated by various other names. In particular, CD36 is known as a fatty acid translocase.

[0008] Meanwhile, sulfo-N-succinimidyl oleate (SSO) is known as a CD36 inhibitor.

[0009] Accordingly, the inventors confirmed that MAC, an intracellular pathogen, utilizes the lipid resources of host cells for survival and replication, and confirmed that the CD36 inhibitor SSO inhibits MAC growth within host cells by inhibiting fatty acid absorption. Furthermore, the inventors synthesized derivatives of SSO and completed the present invention by confirming that SSO derivatives inhibit MAC growth within host cells by inhibiting fatty acid absorption. Prior art literature

[0010] Korean Registered Patent No. 10-2132712 The problem to be solved

[0011] One aspect of the present invention is to provide a sulfo-N-succinimidyl oleate (SSO) derivative, or a stereoisomer, racemic mixture, solvate, or salt thereof.

[0012] Another aspect is to provide a compound of formula I, or its stereoisomers, racemic mixtures, solvates, or salts thereof.

[0013] Another aspect provides a pharmaceutical composition for the prevention or treatment of non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung disease, comprising the above compound, or a stereoisomer, racemic mixture, solvate, or salt thereof.

[0014] Another aspect is to provide a health functional food for the prevention or improvement of non-tuberculous mycobacterial infection or non-tuberculous mycobacterial lung disease, comprising the above compound, or a stereoisomer, racemic mixture, solvate, or salt thereof. means of solving the problem

[0015] One aspect of the present invention provides a sulfo-N-succinimidyl oleate (SSO) derivative, or a stereoisomer, racemic mixture, solvate, or salt thereof.

[0016] Another aspect provides a compound of the following formula I, or a stereoisomer, racemic mixture, solvate, or salt thereof:

[0017] [Chemical Formula I]

[0018]

[0019] In the above formula,

[0020] X is -CH2-, -O- or -S- and;

[0021] R1 -H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen;

[0022] R 2 -H, halogen, -OR 4 , -SR 4 , or -COOR 4 And,

[0023] The above R 4 -H, C respectively 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkynyl;

[0024] R 3 is substituted or unsubstituted C 8-22 alkyl or C 8-22 It is alkenil, and

[0025] Here, C 8-22 alkyl or C 8-22 In the case where an alkenyl is substituted, C 8-22 alkyl or C 8-22 Each hydrogen atom of an alkenyl is independently C 1-12 Alkyl, C 2-12 Alkenyl, and C 2-12 It is substituted with one or more selected from the group consisting of alkynyl groups.

[0026] The above sulfo-N-succinimidyl oleate derivative may be a compound of the above chemical formula I.

[0027] In one embodiment, the compound of Formula I, or its stereoisomer, racemic mixture, solvate, or salt thereof may be a CD36 (cluster of differentiation 36) inhibitor, specifically an inhibitor of the expression or activity of CD46.

[0028] The above CD36 expression or activity inhibitor may be a substance that reduces the expression of the CD36 gene or the activity of the CD36 protein.

[0029] In one embodiment, the CD36 expression or activity inhibitor may inhibit the growth, proliferation, or infection of non-tuberculous mycobacteria. The inhibition of growth, proliferation, or infection may occur through inhibition of fatty acid absorption by the cells.

[0030] In this specification, the term “stereoisomer” refers to an isomer resulting from a difference in the spatial arrangement of atoms or atomic groups within a molecule, and includes both optical isomers and geometric isomers. Optical isomers are formed when four atoms or atomic groups bonded to an asymmetric carbon atom form a pair of enantiomers depending on the bonding method, and if there are two asymmetric carbon atoms within the molecule, they become diastereomers; this includes all stereoisomers that can be formed depending on the number of asymmetric carbons. Additionally, geometric isomers are formed when unsaturated hydrocarbons are present, and this includes all geometric isomers that can be formed.

[0031] In this specification, the term “racemic” refers to the right-handedness of chiral molecules ( R ) Optical isomers and left-handedness( S It refers to a substance that does not exhibit optical activity because equal amounts of optical isomers are mixed.

[0032] In this specification, the term "solvate" refers to a molecular complex between a compound according to the present invention and solvent molecules, and may mean a compound of the present invention or a salt thereof comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. Examples of solvates include, but are not limited to, a compound according to the present invention combined with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or a mixture thereof.

[0033] Additionally, it may be convenient or desirable to prepare, purify, and / or handle a substantial solvate of a compound. The term "solvate" may be used herein in the ordinary sense to refer to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. Where the solvent is water, the solvate may be conveniently referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc.

[0034] In one embodiment, in the above formula I, X may be -CH2-, -O-, or -S-.

[0035] In one embodiment, in the above formula I, X may be -CH2- or -O-.

[0036] In one embodiment, in the above formula I, R 1 -H, or C 1-6 It can be an alkyl.

[0037] In one embodiment, in the above formula I, R 1 It can be -H.

[0038] In one embodiment, in the above formula I, R 2 is -OR 4 , or -COOR 4 and, the above R 4 Each independently -H or C 1-6 It can be an alkyl.

[0039] In one embodiment, in the above formula I, R 2 is -OR 4 , or -COOR 4 and, the above R 4 Each independently -H or C 1-6 It can be an alkyl.

[0040] In one embodiment, in the above formula I, R 2 -COOR 4 and, the above R 4 Each independently -H or C 1-6 It can be an alkyl.

[0041] In one embodiment, in the above formula I, R 2 -COOR 4 and, the above R 4 It can be -H.

[0042] In one embodiment, in the above formula I, R 3 Unsubstituted C 8-22 alkyl or C 8-22 It could be alkenil.

[0043] In one embodiment, in the above formula I, R 3 It can be an unsubstituted alkenyl.

[0044] In one embodiment, in the above formula I, X is -CH2-, -O- or -S-; and R 1 -H, or C 1-6 It is alkyl; R 2 is -OR 4 , or -COOR 4 and, the above R 4 Each independently -H or C 1-6 It is alkyl; R 3 Unsubstituted C 8-22 alkyl or C 8-22 It could be alkenil.

[0045] In one embodiment, in the above formula I, X is -CH2- or -O- and R 1 -H, or C 1-6 It is alkyl; R 2 is -OR 4 , or -COOR 4 and, the above R 4 Each independently -H or C 1-6 It is alkyl; R 3 Unsubstituted C 8-22 alkyl or C 8-22 It could be alkenil.

[0046] In one embodiment, in the above formula I, X is -CH2-, -O- or -S-; and R 1 is -H and; R2 -COOR 4 and, the above R 4 Each independently -H or C 1-6 It is alkyl; R 3 Unsubstituted C 8-22 alkyl or C 8-22 It could be alkenil.

[0047] In one embodiment, in the above formula I, X is -CH2-, -O- or -S-; and R 1 is -H and; R 2 -COOR 4 and, the above R 4 Each independently -H or C 1-6 It is alkyl; R 3 Unsubstituted C 8-22 It could be alkenil.

[0048] In one embodiment, in the above formula I, X is -CH2- or -O- and R 1 is -H and; R 2 -COOR 4 and, the above R 4 Each independently -H or C 1-6 It is alkyl; R 3 Unsubstituted C 8-22 It could be alkenil.

[0049] In one embodiment, R of the above formula I 3 It may be an aliphatic chain of a saturated fatty acid having 8 to 22 carbon atoms or an unsaturated fatty acid having 8 to 22 carbon atoms.

[0050] In one embodiment, the saturated fatty acid may be selected from the group consisting of caprylic acid, pelargonic acid, capric acid, neodecanoic acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, and behenic acid.

[0051] In one embodiment, the saturated fatty acid may be selected from the group consisting of myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, and arachidic acid.

[0052] In one embodiment, the saturated fatty acid may be selected from the group consisting of palmitic acid, margaric acid, stearic acid, isostearic acid, nonadecylic acid, and arachidic acid.

[0053] In one embodiment, the saturated fatty acid may be selected from the group consisting of margaric acid, stearic acid, isostearic acid, and nonadecylic acid.

[0054] In one embodiment, the saturated fatty acid may be selected from the group consisting of stearic acid and isostearic acid.

[0055] In one embodiment, the unsaturated fatty acid is lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, alpha-linolenic acid, gamma-linolenic acid, alpha-eleostearic acid, beta-eleostearic acid, columbinic acid, pinolenic acid, It can be selected from the group consisting of mead acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosatetraenoic acid and docosatetraenoic acid.

[0056] In one embodiment, the unsaturated fatty acid may be selected from the group consisting of palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, alpha-eleostearic acid, beta-eleostearic acid, columbinic acid, pinolenic acid, and stearidonic acid.

[0057] In one embodiment, the unsaturated fatty acid may be selected from the group consisting of oleic acid, elaidic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, alpha-eleostearic acid, beta-eleostearic acid, columbinic acid, and pinolenic acid.

[0058] In one embodiment, the unsaturated fatty acid may be selected from the group consisting of palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, and eicosenoic acid.

[0059] In one embodiment, the unsaturated fatty acid may be selected from the group consisting of oleic acid, elaidic acid, and vaccenic acid.

[0060] In one embodiment, the unsaturated fatty acid may be oleic acid.

[0061] In one embodiment, R of the above formula I 2 may have the arrangement shown in the following chemical formula II:

[0062] [Chemical Formula II]

[0063] .

[0064] In one embodiment, the compound of formula I may be a compound selected from the group consisting of the following:

[0065] (S) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid,

[0066] (R) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid,

[0067] (S) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid and

[0068] (R) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid.

[0069] In one embodiment, the compound of formula I may be a compound selected from the group consisting of the following:

[0070] (S) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid and

[0071] (S) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid.

[0072] Another aspect provides a pharmaceutical composition for the prevention or treatment of non-tuberculous mycobacterial infection or non-tuberculous mycobacterial lung disease, comprising the above compound, or a stereoisomer, racemic mixture, solvate, or salt thereof.

[0073] In one embodiment, the pharmaceutical composition may include the compound, or its stereoisomer, racemic mixture, solvate, or salt thereof as an active ingredient.

[0074] In this specification, the term "containing as an active ingredient" means containing an effective amount of a pharmaceutical composition sufficient to exhibit a preventive or therapeutic effect against non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung disease.

[0075] In a pharmaceutical composition according to one embodiment, the salt may be a pharmaceutically acceptable salt.

[0076] In this specification, the term “pharmaceuticalally acceptable” means a substance that can be effectively used for a desired purpose without causing excessive toxicity, irritation, or allergic reactions, etc., within the scope of pharmaceutical judgment.

[0077] In this specification, the term “pharmaceuticalally acceptable salt” means a salt according to one aspect of the present invention that is pharmaceutically acceptable and has the desirable pharmacological activity of a parent compound. A salt of a parent compound may be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base, e.g., sodium, calcium, magnesium, or potassium, or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Generally, where feasible, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile may be used. The pharmaceutically acceptable salt comprises both the addition salt of an acid or base and its stereochemical isomer forms, and may be, for example, an addition salt of an organic acid or an inorganic acid. The above salt includes any salt that maintains the activity of the parent compound in the subject of administration and does not cause undesirable effects, and is not particularly limited.

[0078] These salts include inorganic and organic salts, for example, acetic acid, nitric acid, aspartic acid, sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid, lactic acid, non-carboxylic acid, non-sulfuric acid, non-tartaric acid, oxalic acid, butyric acid, calcium idete, carbonic acid, chlorobenzoic acid, citric acid, idetic acid, toluenesulfonic acid, fumaric acid, gluteptic acid, esylic acid, pamoic acid, gluconic acid, methylnitric acid, malonic acid, hydrochloric acid, hydroiodoic acid, hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelic acid, mucinous acid, It may be napsylic acid, muconic acid, p-nitromethanesulfonic acid, hexamic acid, pantothenic acid, monohydrogen phosphate, dihydrogen phosphate, salicylic acid, sulfamic acid, sulfanilic acid, or methanesulfonic acid. In addition, the forms of the salt include salts of alkali and alkaline earth metals such as ammonium salts, lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts; salts having organic bases such as benzathine, N-methyl-D-glucarmine, and hydrabamin salts; and salts having amino acids such as arginine and lysine. In addition, the salt forms may be converted into a free form by treatment with a suitable base or acid.

[0079] In this specification, the term “prevention” refers to any act of suppressing or delaying the onset of a target disease, “treatment” refers to any act of improving or beneficially altering a target disease and associated metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” refers to any act of reducing parameters related to the target disease, such as the severity of symptoms, by administering a composition according to the present invention.

[0080] In a pharmaceutical composition according to one embodiment, the compound, or its stereoisomer, racemic mixture, solvate, or salt thereof, may inhibit the growth, proliferation, or infection of non-tuberculous mycobacteria. The inhibition of said growth, proliferation, or infection may occur through the inhibition of fatty acid absorption by the cells.

[0081] In one embodiment, the non-tuberculous mycobacteria are Mycobacterium avium (Mav), Mycobacterium abscessus subsp. abscessus (Mabc), Mycobacterium abscessus subsp. massiliense (Mmass), and Mycobacterium abscessus subsp. bolétyi.bolletii), Mycobacterium Intracellurare, Mycobacterium chimaera, Mycobacterium Scrofulaceum, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium Genevans, Mycobacterium simiae, Mycobacterium terrae, Mycobacterium It may be one or more selected from the group consisting of Mycobacterium nonchromogenicum, Mycobacterium celatum, Mycobacterium gordonae, Mycobacterium szulgai, Mycobacterium mucogenicum, Mycobacterium xenopi, and Mycobacterium aubagnens. The above nontuberculous mycobacteria may be multidrug-resistant (MDR) nontuberculous mycobacteria, examples of which include KMRC-010, KMRC-011, KMRC-012, and KMRC-013.

[0082] In one embodiment, the infection may include one or more selected from the group consisting of skin, soft tissue, and bone infections, lung diseases, lymphadenitis, and disseminated diseases.

[0083] In one embodiment, the pharmaceutical composition may further include an acid-fast antibacterial agent or an antituberculosis agent, or be administered in combination with an acid-fast antibacterial agent or an antituberculosis agent.

[0084] In one embodiment, the acid-fast therapeutic agent or antituberculosis agent is rifamficin, rifabutin, rifapentine, pyrazinamide, ciprofloxacin, capeomycin, fluoroquinolone, cycloserine, ethambutol, amoxicillin / clavulanate, ofloxacin, levofloxacin, isoniazid, streptomycin, kanamycin, prothionamide, moxifloxacin, amikacin, prothionamide, It may be one or more selected from the group consisting of ethionamide, cycloserine, thioacetazone, clofazimine, derivative of dianomidiphenylsulfone, clarithromycin, azithromycin, and linezolid.

[0085] In addition, co-administration with one or more additional therapeutic substances includes simultaneous or sequential administration in any order.

[0086] Specifically, in this specification, “combined administration” may be achieved by administering individual components of a therapeutic regimen simultaneously, sequentially, in reverse order, or individually. A combined therapeutic effect may be obtained by administering two or more drugs simultaneously, sequentially, or in reverse order, or by administering them alternately at regular or indeterminate intervals. A combined therapy may be defined as one that provides a synergistic effect while being therapeutically superior to the efficacy obtained by administering one or the rest of the components of the combined therapy at a normal dose, provided, for example, through the degree of response, response rate, time to disease progression, or survival time.

[0087] Combination therapy can provide a "synergistic effect," that is, the effect achieved when active substances are used together is greater than the sum of the effects achieved when each active substance is used individually. A synergistic effect can be achieved when active substances are (1) co-formulated and combined into unit dosage forms and administered or delivered simultaneously; (2) delivered as individual formulations in succession, alternating, or in parallel; or (3) by some other method of administration. When delivered via alternation therapy, a synergistic effect can be achieved, for example, by sequential administration or delivery of active substances by individual injections using separate syringes. A "synergistic combination" produces an effect superior to the sum of the effects of the individual active substances in the combination.

[0088] Combination therapy can provide "additive" effects, meaning that the effect achieved when active substances are used together is equivalent to the sum of the results obtained when the active substances are used individually.

[0089] In this specification, the terms “entity” and “patient” are used interchangeably. An entity may be an animal. In some embodiments, the entity is a mammal, such as a non-human animal (e.g., a cow, pig, horse, cat, dog, rat, mouse, monkey, or other primates). In some embodiments, the entity is a cynomolgus monkey. In some embodiments, the entity is a human.

[0090] In this specification, the term "therapeutic effective dose" refers to an amount of drug, e.g., an anti-CD36 antibody, effective in achieving a desired therapeutic or prophylactic outcome. In some cases, the desired outcome is the treatment of a disease or disorder in an individual. The level of the therapeutic effective dose may be determined based on factors including the type and severity of the patient's disease, the drug's activity, sensitivity to the drug, the time of administration, the route of administration and elimination rate, the duration of treatment, concurrently used drugs, and other factors well known in the medical field. The compositions of this specification may be administered as individual therapeutic agents or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. That is, the total effective dose of the compositions of this specification may be administered to a patient as a single dose, or administered via a fractionated treatment protocol involving long-term administration of multiple doses. It is important to administer an amount that achieves maximum effect with a minimum amount without side effects, taking all of the above factors into account, and this can be easily determined by a person skilled in the art.

[0091] In this specification, terms such as “treating,” “treatment,” “for treating,” “relief,” or “for alleviating” refer to therapeutic measures that cure, slow down, alleviate symptoms, and / or halt the progression of a diagnosed pathological condition or disorder. Accordingly, subjects requiring treatment include subjects who have already been diagnosed with or are suspected of having a disorder.

[0092] Meanwhile, the above composition of the present specification may further include a pharmaceutically acceptable carrier and may be formulated together with the carrier.

[0093] In this specification, the term “pharmaceuticalally acceptable carrier” refers to a carrier or diluent that does not irritate living organisms and does not impair the biological activity and properties of the administered compound. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include sterile and biocompatible saline solution, sterile water, Ringer’s solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures of one or more of these components; if necessary, other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added. Additionally, diluents, dispersants, surfactants, binders, and lubricants may be added to formulate the composition into injectable formulations such as aqueous solutions, suspensions, and emulsions, as well as pills, capsules, granules, or tablets.

[0094] A composition comprising the compound, or its stereoisomer, racemic mixture, solvate, or salt thereof according to one embodiment of the present specification; and a pharmaceutically acceptable carrier may be applied to any formulation containing the same as an active ingredient, may be prepared as an oral or parenteral formulation, and may be formulated in a unit dosage form for ease of administration and homogeneity of dosage. Pharmaceutical formulations of the present specification include forms suitable for oral, rectal, nasal, topical (including cheek and under tongue), subcutaneous, vaginal, or parenteral (including intramuscular, subcutaneous, and intravenous) administration, or forms suitable for administration by inhalation or insufflation. The composition of the present specification may be formulated as an oral dosage form containing the active ingredient, for example, as a tablet, troche, lozenge, water-soluble or oily suspension, prepared powder or granule, emulsion, hard or soft capsule, syrup, or elixir.

[0095] As a parenteral administration formulation containing the composition of this specification as an active ingredient, it may be formulated in injectable forms such as subcutaneous injection, intravenous injection, or intramuscular injection, or as a spray such as a suppository infusion or an aerosol that can be inhaled through the respiratory tract. To formulate it as an injectable formulation, the composition of this specification may be mixed in water with a stabilizer or a buffer to prepare a solution or suspension, and this may be formulated for unit administration in ampoules or vials.

[0096] The dosage of the pharmaceutical composition of this specification varies depending on the patient's body weight, age, gender, health status, diet, time of administration, method of administration, excretion rate, and severity of the disease. As for the daily dosage, when administered parenterally, it is preferably 0.01 μg to 100 mg per kg of body weight per day, more preferably 1 μg to 50 mg. However, since the dosage may be increased or decreased depending on the route of administration, severity of obesity, gender, body weight, age, etc., the above dosage does not limit the range of this specification in any way.

[0097] Another aspect provides a health functional food for the prevention or improvement of non-tuberculous mycobacterial infection or non-tuberculous mycobacterial lung disease, comprising the above compound, or a stereoisomer, racemic mixture, solvate, or salt thereof.

[0098] In a health functional food according to one embodiment, the salt may be a food science acceptable salt.

[0099] In this specification, the term “food-acceptable salt” refers to a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. For example, the food-acceptable salt may be obtained by reacting the compound with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or an organic carboxylic acid such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. In addition, the compound may be obtained by reacting it with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, and amino acid salts such as arginine and lysine, but is not limited thereto.

[0100] In this specification, health functional foods may be formulated in any one form selected from the group consisting of powders, tablets, capsules, pills, granules, and liquids according to conventional methods known in the art, but are not limited thereto. They may be manufactured in various forms using methods known in the art.

[0101] In addition, it can be prepared in the form of a composition by mixing with a known substance or active ingredient known to have preventive, improving, or therapeutic activity for non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung diseases.

[0102] In addition, the health functional food of the present invention may include conventional food additives, and unless otherwise specified, suitability as a "food additive" is determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety. Examples of items listed in the "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid; natural additives such as persimmon dye, licorice extract, crystalline cellulose, sorghum dye, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline noodle additives, preservative preparations, and tar dye preparations.

[0103] In addition to the above, the health functional food of the present invention may include various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, the composition of the present invention may include fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination. Effects of the invention

[0104] A sulfo-N-succinimidyl oleate (SSO) derivative according to one aspect of the present invention has a CD36 inhibitory effect and can inhibit the growth and proliferation of non-tuberculous mycobacteria, and thus can be usefully employed in the prevention or treatment of non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung diseases. Brief explanation of the drawing

[0105] Figure 1 is a graph showing the fatty acid absorption capacity according to the treatment of an SSO derivative according to one aspect of the present invention. Figure 2 is a graph confirming the growth inhibitory effect of non-tuberculous acid-fast bacilli following treatment with an SSO derivative according to one aspect of the present invention. Specific details for implementing the invention

[0106] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention and do not limit the scope of the invention. Since the embodiments are subject to various modifications, they are not limited to the embodiments disclosed below but can be implemented in various forms.

[0107] Terms or words used in the specification and claims of the present invention shall not be interpreted as being limited to their ordinary or dictionary meanings, and shall be interpreted in a meaning and concept consistent with the technical spirit of the present invention, based on the principle that the inventor may appropriately define the concept of the terms to best describe his invention.

[0108] Throughout the specification of the present invention, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0109] Throughout the specification of the present invention, "A and / or B" means A or B, or A and B.

[0111] Example 1. Preparation and identification of sulfo-N-succinimidyl oleate (SSO) derivatives

[0112] 1.1 Compound SSO-02: (S) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid( (S) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid)

[0113] <Compound SSO-02>

[0114]

[0116] <Preparation of Compound SSO-02>

[0117]

[0119] compound A(L-Pyroglutamic acid; (S) 58 mg (0.45 mmol) of -5-Oxo-2-pyrrolidinecarboxylic acid (CAS 98-79-3) was dissolved in 2 mL of THF solvent, then the temperature was lowered to 0 °C, and 0.04 mL (0.45 mmol) of pyridine, compound B (Oleoyl chloride; CAS 112-77-6) (0.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum distillation. The resulting mixture was separated and purified by silica gel column chromatography (EtOAc:MeOH = 15:1 volume ratio) to obtain the compound SSO-02 57 mg (0.14 mmol, yield 48%) was obtained.

[0120] 1 H NMR data were measured as follows:

[0121] 1 H NMR (600 MHz, Chloroform-d) δ5.35-5.32 (m, 2H), 4.74-4.69 (m, 1H), 2.95-2.86 (m, 2H), 2.79-2.69 (m, 1H), 2.61-2.52 (m, 1H), 2.38-2.29 (m, 1H), 2.20-2.13 (m, 1H), 2.04-1.97 (m, 4H), 1.65-1.57 (m, 2H), 1.41-1.16 (m, 20H), 0.87 (t, J = 6.9 Hz, 3H).

[0123] 1.2 Compound SSO-04: (S) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid( (S) -3-oleoyl-2-oxooxazolidine-4-carboxylic acid)

[0124] <Compound SSO-04>

[0125]

[0127] <Preparation of Compound SSO-04>

[0128]

[0130] compound C ( (S) 126 mg (0.96 mmol) of -2-oxooxazolidine-4-carboxylic acid (CAS 19525-95-2) was dissolved in 4 mL of THF solvent, then the temperature was lowered to 0 °C, and 0.31 mL (2.26 mmol) of Et3N, compound B (Oleoyl chloride; CAS 112-77-6) (0.56 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, followed by vacuum distillation. The resulting mixture was separated and purified by silica gel column chromatography (EtOAc:MeOH = 20:1 volume ratio) to obtain the compound SSO-04 178 mg (0.45 mmol, yield 80%) was obtained.

[0131] 1 H NMR data were measured as follows:

[0132] 1 H NMR (600 MHz, DMSO-d6) δ5.35-5.30 (m, 2H), 4.76 (dd, J = 9.4, 3.3 Hz, 1H), 4.55 (t, J = 9.2 Hz, 1H), 4.34 (dd, J = 9.0, 3.3 Hz, 1H), 2.87-2.72 (m, 2H), 2.01-1.95 (m, 4H), 1.58-1.48 (m, 2H), 1.32-1.20 (m, 20H), 0.88-0.81 (m, 3H).

[0134] Reference Example 1. Culture of bone marrow-derived macrophages

[0135] Macrophages were isolated from bone marrow cells of 7-week-old BALB / c mice and used. First, a macrophage culture medium was prepared by mixing 10% of L929 cell line culture medium into High Glucose DMEM (Biowest Inc., Nuaile, France) containing 10% FBS (Biowest Inc., Nuaile, France), 100 U / ml penicillin, and 100 μg / ml streptomycin (Biowest Inc., Nuaile, France). 10 ml of the above macrophage culture medium was placed in a 90×15 mm Petri dish (SPL life science, Pocheon, South Korea), and the isolated macrophages were cultured for 3 days. Subsequently, an additional 10 ml of the above macrophage culture medium was added, and the macrophages were differentiated and used in the experiment.

[0137] Reference Example 2. Preparation of 7H10 solid medium for culture of non-tuberculosis acid-fast bacilli

[0138] 450 ml of distilled water and Difco in a 1-liter Erlenmeyer flask TM 9.5 g of Middlebrook 7H10 Agar (BD Bioscience, USA) powder was added. Subsequently, the Erlenmeyer flask was sterilized using an autoclave at 121°C for 15 minutes. After cooling the sterilized 7H10 agar medium to approximately 60°C, 10% OADC was added, and 23 ml was dispensed into 90×15 mm Petri dishes (SPL Life Science). The medium was then dried for one day before use as a solid medium.

[0140] Experimental Example 1. Confirmation of CD36 inhibitory efficacy of SSO derivatives

[0141] To confirm the CD36 inhibitory efficacy of an SSO derivative according to one aspect of the present invention, fatty acid uptake capacity was measured using macrophages treated with the SSO derivative.

[0142] Specifically, macrophages differentiated by the method of Reference Example 1 were treated with Trypsin-EDTA (TE) to isolate the cells, and then 1.5 × 10⁶ cells were placed in a 48-well cell culture plate (SPL Life Science). 5 Cells were seeded at a concentration of cells / well and cultured for 24 hours. Subsequently, the culture medium was removed and replaced with a medium containing 200 μM Sulfo-N-succinimidyl oleate (SSO, 11211; Cayman Chemical), 200 μM SSO-02 (Example 1), and 200 μM SSO-04 (Example 1), and cultured for 3 hours. Afterward, the cells were washed with PBS and treated with 0.5 μg / mL of Green fluorescently labeled fatty acid (C16 bodipy; #D3821, Invitrogen™). One hour after treatment, the intracellular Green fluorescence value was measured by flow cytometry. The results are shown in Figure 1.

[0143] Figure 1 is a graph showing the fatty acid absorption capacity according to the treatment of an SSO derivative according to one aspect of the present invention.

[0144] As shown in Figure 1, the SSO-02 and SSO-04 treatment groups exhibited superior fatty acid absorption capacity compared to the SSO treatment group. The above results indicate that the SSO derivative according to one aspect of the present invention has CD36 inhibitory efficacy similar to or better than that of SSO.

[0146] Experimental Example 2. Confirmation of the growth inhibitory effect of SSO derivatives on non-tuberculous acid-fast bacilli

[0147] To confirm the growth inhibitory efficacy of an SSO derivative according to one aspect of the present invention, experiments were performed using macrophages infected with non-tuberculosis mycobacteria.

[0148] Specifically, macrophages differentiated by the method of Reference Example 1 were treated with Trypsin-EDTA (TE) to isolate the cells, and then 1.5 × 10⁶ cells were placed in a 48-well cell culture plate (SPL Life Science). 5 Cells were seeded at the concentration of cells / well and cultured for 24 hours. Subsequently, the culture medium was removed and replaced with a medium containing 200 μM Sulfo-N-succinimidyl oleate (SSO, 11211; Cayman Chemical), 200 μM SSO-02 (Example 1), and 200 μM SSO-04 (Example 1), and cultured for 3 hours. After 3 hours, the culture medium was removed. M. avium The culture medium was replaced with a 5% medium containing SMC#7 at Multiplicity of infection (MOI): 3 and incubated for 4 hours. Next, the culture medium containing the strain was removed, and a 5% medium containing 200 μM SSO, 200 μM SSO-02, and 200 μM SSO-04 was added and cultured for a total of 72 hours.

[0149] Subsequently, the culture medium was removed from the 48-well plate, and the cells were washed twice using DPBS (Biowest Inc.). 1% Triton X-100 was diluted to 0.05% and added to the washed macrophages at a dose of 200 μl per well to lyse the macrophage membranes for 10 minutes. The lysate released from the lysed macrophages was diluted to 1 / 100 and 1 / 1000 and dropped at a dose of 50 μl per well onto a 7H10 solid medium prepared by the method of Reference Example 2, after which the cells were cultured in a microbial incubator for approximately 10 days. After 10 days, the Colony Forming Unit (CFU) of the cultured bacteria was measured to confirm the inhibitory effect on the growth of non-tuberculosis mycobacteria.

[0150] Figure 2 is a graph confirming the growth inhibitory effect of non-tuberculous acid-fast bacilli following treatment with an SSO derivative according to one aspect of the present invention.

[0151] As shown in Fig. 2, M. avium Unlike the macrophage control group (untreated control group), in which CFU increased 72 hours after SMC#7 infection, it was confirmed that CFU decreased in the groups treated with SSO, SSO-02, and SSO-04. The SSO-02 treatment group showed bacterial growth inhibitory efficacy similar to that of SSO, while the SSO-04 treatment group showed higher bacterial growth inhibitory efficacy than the SSO treatment group. The above results indicate that the SSO derivative according to one aspect of the present invention possesses excellent growth inhibitory efficacy against non-tuberculosis mycobacteria.

[0153] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the experimental examples and embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 delete Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 A compound selected from the group consisting of the following, or its stereoisomer, racemic mixture, solvate, or salt thereof: (S) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid, (R) -1-oleoyl-5-oxopyrrolidine-2-carboxylic acid, (S) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid and (R) -3-oleoyl-2-oxo-oxazolidin-4-carboxylic acid. Claim 7 A pharmaceutical composition for the prevention or treatment of non-tuberculous mycobacterial infection or non-tuberculous mycobacterial lung disease, comprising a compound according to claim 6, or a stereoisomer, racemic mixture, solvate, or salt thereof. Claim 8 A pharmaceutical composition according to claim 7, wherein the compound, or its stereoisomer, racemic form, solvate, or salt thereof inhibits the growth of non-tuberculous acid-mycobacteria by inhibiting fatty acid absorption. Claim 9 In claim 7, the above non-tuberculous acid-fast bacilli are Mycobacterium avium (Mav), Mycobacterium abscessus subsp. abscessus (Mabc), Mycobacterium abscessus subsp. massiliense (Mmass), and Mycobacterium abscessus subsp. bolétyi.bolletii), Mycobacterium Intracellurare, Mycobacterium chimaera, Mycobacterium Scrofulaceum, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium Genevans, Mycobacterium simiae, Mycobacterium terrae, Mycobacterium A pharmaceutical composition comprising one or more selected from the group consisting of Mycobacterium nonchromogenicum, Mycobacterium celatum, Mycobacterium gordonae, Mycobacterium szulgai, Mycobacterium mucogenicum, Mycobacterium xenopi, and Mycobacterium aubagnens. Claim 10 A pharmaceutical composition according to claim 7, wherein the infection is one or more selected from the group consisting of skin, soft tissue, and bone infections, lung diseases, lymphadenitis, and disseminated diseases. Claim 11 In claim 7, the pharmaceutical composition further comprises an acid-fast antibacterial agent or an antituberculosis agent, or is administered in combination with an acid-fast antibacterial agent or an antituberculosis agent. Claim 12 In claim 11, the above acid-fast bacilli therapeutic agents or antituberculosis agents are rifamficin, rifabutin, rifapentine, pyrazinamide, ciprofloxacin, capeomycin, fluoroquinolone, cycloserine, ethambutol, amoxicillin / clavulanate, ofloxacin, levofloxacin, isoniazid, streptomycin, kanamycin, prothionamide, moxifloxacin, amikacin, prothionamide, A pharmaceutical composition comprising one or more selected from the group consisting of ethionamide, cycloserine, thioacetazone, clofazimine, derivative of dianomidiphenylsulfone, clarithromycin, azithromycin, and linezolid. Claim 13 A health functional food for the prevention or improvement of non-tuberculous mycobacterial infections or non-tuberculous mycobacterial lung diseases, comprising a compound according to paragraph 6, or a stereoisomer, racemic mixture, solvate, or salt thereof. Claim 14 In paragraph 13, the above-mentioned non-tuberculous acid-fast bacilli are Mycobacterium avium (Mav), Mycobacterium abscessus subsp. abscessus (Mabc), Mycobacterium abscessus subsp. massiliense (Mmass), and Mycobacterium abscessus subsp. bolétyi.bolletii), Mycobacterium Intracellurare, Mycobacterium chimaera, Mycobacterium Scrofulaceum, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium ulcerans, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium Genevans, Mycobacterium simiae, Mycobacterium terrae, Mycobacterium A health functional food comprising one or more selected from the group consisting of Mycobacterium nonchromogenicum, Mycobacterium celatum, Mycobacterium gordonae, Mycobacterium szulgai, Mycobacterium mucogenicum, Mycobacterium xenopi, and Mycobacterium aubagnens. Claim 15 A health functional food according to Clause 13, wherein the above-mentioned infection is one or more selected from the group consisting of skin, soft tissue, and bone infections, lung diseases, lymphadenitis, and disseminated diseases.

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