WO2018143638A1 - 4'-phosphopantetheinyl transferase enzyme inhibitor derived from mycobacterium tuberculosis, and pharmaceutical composition for preventing or treating tuberculosis, containing same as active ingredient - Google Patents
4'-phosphopantetheinyl transferase enzyme inhibitor derived from mycobacterium tuberculosis, and pharmaceutical composition for preventing or treating tuberculosis, containing same as active ingredient Download PDFInfo
- Publication number
- WO2018143638A1 WO2018143638A1 PCT/KR2018/001262 KR2018001262W WO2018143638A1 WO 2018143638 A1 WO2018143638 A1 WO 2018143638A1 KR 2018001262 W KR2018001262 W KR 2018001262W WO 2018143638 A1 WO2018143638 A1 WO 2018143638A1
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- Prior art keywords
- tuberculosis
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- branched
- formula
- pharmaceutically acceptable
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Images
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Definitions
- the present invention relates to a 4'-phosphopantetheinyl transferase enzyme inhibitor derived from Mycobacterium tuberculosis and a pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient.
- Tuberculosis includes tuberculosis bacteria including Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium microti, and Mycobacterium africanum (M.africanum).
- Mycobacterium tuberculosis-complex) (MTB-C) is a chronic infectious disease.
- the most common anti-tuberculosis agents prescribed for the treatment of tuberculosis are isoniazid, rifampicin, pyrazineamide and etambutol. Treatment by them often takes several months and can be extended as needed.
- a combination of various antibiotics is prescribed, but even in this case, the treatment of latent tuberculosis is very difficult, and multi-drug resistant tuberculosis bacteria (MDR-TB, isoniazid) And tuberculosis bacteria that do not die in primary treatment drugs such as rifampicin. Accordingly, there is a need for a lead substance for a new target group to replace the existing drug.
- the present inventors designed an inhibitor based on the three-dimensional structure of the target protein and the mutual binding of two ligands bound thereto for the development of an anti-tuberculosis drug targeting 4'-phosphopantetheinyl transferase, and thus derived a compound with high inhibition potential By performing an in vitro assay to confirm the inhibitory effect was completed the present invention.
- Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound as an active ingredient.
- Another object of the present invention to provide a health functional food for the prevention or improvement of tuberculosis containing the compound as an active ingredient.
- the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R 1 is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
- each ring heteroaryl consists of hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,
- a 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N
- a 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N
- an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
- Q is S, O or CH 2 ,
- M is S, O, CH 2 or NH
- K is CH or N
- B 1 , B 2 and B 3 are independently hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile or halogen.
- the present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a health functional food for preventing or improving tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- Compounds according to the present invention can significantly inhibit the 4'-phosphopanthethenyl transferase enzyme to remove Mycobacterium tuberculosis through the body's immune response, thereby having an effect that can be used for the prevention or treatment of tuberculosis.
- 1 is a three-dimensional structure of the proteins of Mycobacterium tuberculosis PptT (4'-phosphopantetheinyl transferase) and Mycobacterium smegmatis PptT.
- Figure 2 is a graph of the results of activity inhibition experiments using 6-NOBP (6-nitro-1,2-benzopyrone) as a control.
- 3 to 5 shows the inhibition of activity by varying the% (v / v) of dimethyl sulfoxide (DMSO) to find the optimum reaction conditions using 6-NOBP (6-nitro-1,2-benzopyrone) as a control.
- 6-NOBP 6-nitro-1,2-benzopyrone
- Figure 6 shows the process of confirming the inhibition of BpsA (Blue-pigment synthetase) activity of the compound compounds.
- Example 7 is a result graph of the PptT activity inhibition evaluation experiment of Example 1.
- Example 8 is a result graph of the PptT activity inhibition evaluation experiment of Example 2.
- the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
- R 1 is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
- each ring heteroaryl consists of hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,
- a 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N
- a 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N
- an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
- Q is S, O or CH 2 ,
- M is S, O, CH 2 or NH
- K is CH or N
- B 1 , B 2 and B 3 are independently hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile or halogen.
- R 1 is unsubstituted or substituted 5-8 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
- the substituted 5-8 heterocyclic heteroaryl consists of hydrogen, straight or branched chain C 1-5 alkyl, straight or branched chain C 1-5 alkoxy, nitro, nitrile, halogen and N, O and S 5-8 angular ring heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-8 angular ring heteroaryl containing one or more hetero atoms selected from the group,
- a 1 and A 2 are independently hydrogen, linear or branched C 1-5 alkyl, linear or branched C 1-5 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked N
- an unsubstituted 5-8 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
- M is S, O, CH 2 or NH
- K is CH or N
- B 1, B 2 and B 3 are independently hydrogen, straight or alkoxy, nitro of branched alkyl, linear or branched C 1-5 of C 1-5, a nitrile or a halogen.
- R 1 is , , or ego
- Q is S or CH 2 .
- M is S or O
- K is N or CH
- B 1 is -Cl or -CH 3
- B 2 and B 3 is independently -H or -CH 3.
- the compound represented by Formula 1 is any one selected from the following compound group.
- the compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
- Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like.
- Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloride
- the acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and adding an organic or inorganic acid.
- the solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.
- Bases can also be used to make pharmaceutically acceptable metal salts.
- Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
- Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
- the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.
- the present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound is characterized in that to prevent or treat tuberculosis by inhibiting the 4'-phosphopantetheinyl transferase (4'-phosphopantetheinyl Transferase), specific types of tuberculosis, tuberculosis tuberculosis, adrenal tuberculosis
- 4'-phosphopantetheinyl transferase 4'-phosphopantetheinyl Transferase
- specific types of tuberculosis tuberculosis tuberculosis
- adrenal tuberculosis There are renal tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tubercul
- tuberculosis may be characterized in that the tuberculosis caused by multidrug-resistant tuberculosis bacteria.
- the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, in the case of clinical administration. It may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are commonly used.
- Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
- Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
- binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
- compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by.
- the compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
- the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Based on an adult patient of 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and once or several times a day at regular time intervals as determined by the doctor or pharmacist. It may be administered in divided doses.
- the present invention provides a health food for preventing or improving tuberculosis using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- tuberculosis is tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, cholestatic tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung , Breast tuberculosis or spinal tuberculosis.
- the present invention provides a method for preventing or treating tuberculosis, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject (ie, a patient) in need thereof.
- the administration may be administered by a variety of known methods, it can be carried out by oral administration as one example.
- the present invention provides a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as a medicament.
- the title compound was provided by the Korea Compound Bank.
- the title compound was provided by the Korea Compound Bank.
- the title compound was provided by the Korea Compound Bank.
- the title compound was provided by the Korea Compound Bank.
- the PptT gene (Rv2794c) was inserted into the pET21a plasmid and cloned into E. coli cell line BL21 (DE3). After incubating E. coli in Luria Broth medium at 37 ° C, IPTG was added at a time point of OD600 of about 0.7 to express PptT and incubated at 16 ° C for 20 hours.
- the cells were stored at minus 80 ° C, and then crushed by ultrasound and subjected to primary purification using IMAC (Immobilized metallo-affinity chromatography), followed by SEC (Size exclusion chromatography) method. Final purification.
- the buffer solution containing PptT was composed of 50 mM Tris-HCl (pH 8.0), 200 mM NaCl.
- Inhibitors were designed based on the three-dimensional structure of the 4'-phosphopantetheinyl Transferase protein and the mutual binding of two ligands bound to it.
- 6-NOBP 6-nitroso-1,2-benzopyrone
- DMSO dimethyl sulfoxide
- the PptT inhibition assay presented in the present invention accurately inhibits PptT with specificity or non-specifically binds to BpsA (Blue-pigment synthetase), which is a result, BpsA (Blue- After pre-reacting the pigment synthetase) and the CoA-PptT conjugate to activate the BpsA (Blue-pigment synthetase) protein, which is a substrate, the assay was performed as shown in FIG. Through this, it was confirmed that all of the leading materials presented in the present invention did not inhibit BpsA (Blue-pigment synthetase).
- the assay was performed using a 96 well plate, and each well was tested to include 100 ⁇ M -0.001 ⁇ M inhibitor at the final concentration.
- the experiment was carried out with 73 ⁇ l of various components in each well: 2 ⁇ M PptT, 50 mM Tris (pH 8.0), 20 ⁇ M CoA, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl 2 , 32% (v / v) dimethyl sulfoxide (DMSO).
- BpsA Blue-pigment synthetase protein solution
- composition 50 mM Tris-HCl, pH 8.0, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl 2 , 20% (v / v) Dimethyl sulfoxide
- the enzyme reaction was started at 25 °C.
- the absorbance values of each well were read at 790 nm using SpectraMax M5 (Molecular Devices), and the absorbances of compounds and buffers were measured separately to correct the values and normal PptT activity was not inhibited.
- SpectraMax M5 SpectraMax M5
- PptT inhibitors and respective IC 50 values discovered through the results are shown in Table 2 below, and the respective graphs are shown in FIGS. 7 to 10.
- Example IC 50 ( ⁇ M) One 0.635 2 0.7955 3 2.282 4 1.817
- the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose.
- the following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
- the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
- tablets are prepared by tableting according to a conventional method for preparing tablets.
- the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
- the amount of the above ingredient is prepared per ampoule (2 ml).
- each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle. Sterilize to prepare the liquid.
- the compounds according to the present invention can significantly inhibit 4'-phosphopanthethenyl transferase enzyme, thereby allowing the removal of Mycobacterium tuberculosis through an immune response in the body, thereby useful for the prevention or treatment of tuberculosis.
Abstract
The present invention relates to a 4'-phosphopantetheinyl transferase enzyme inhibitor derived from Mycobacterium tuberculosis, and a pharmaceutical composition for preventing or treating tuberculosis, containing the same as an active ingredient.
Description
본 발명은 결핵균 유래의 4'-포스포판테테이닐 트랜스퍼레이즈(4'-phosphopantetheinyl transferase) 효소 저해물질 및 이를 유효성분으로 함유하는 결핵의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a 4'-phosphopantetheinyl transferase enzyme inhibitor derived from Mycobacterium tuberculosis and a pharmaceutical composition for preventing or treating tuberculosis containing the same as an active ingredient.
결핵은 미코박테리움 튜베쿨로시스(M.tuberculosis), 미코박테리움 보비스(M.bovis), 미코박테리움 미크로티(M.microti), 미코박테리움 아프리카눔(M.africanum)을 비롯한 결핵균군(Mycobacterium tuberculosis-complex)(MTB-C)에 의해 유발되는 만성 감염성 질환이다. Tuberculosis includes tuberculosis bacteria including Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium microti, and Mycobacterium africanum (M.africanum). Mycobacterium tuberculosis-complex) (MTB-C) is a chronic infectious disease.
세계적으로 전체 인구의 1/3이 결핵균에 감염되어 있는 것으로 추정되며 매년 약 800백만 명의 새로운 환자가 발생한다. 대부분의 감염자들은 증상이 없고 그 중 1/10 정도가 발병하며, 발병 시 적절한 치료를 하지 않으면 그 중 절반 이상이 사망에 이르게 된다. 전형적인 증상은 피가 섞인 가래를 동반한 기침, 오한, 식은땀, 체중 감소로 몸의 어느 기관에나 감염될 수 있기 때문에 감염된 기관에 따라 다양한 증상을 초래한다.It is estimated that one third of the world's population is infected with Mycobacterium tuberculosis and approximately 800 million new cases occur each year. Most infected people are asymptomatic and about one-tenth of them develop, and more than half of them die if they are not treated properly. A typical symptom is a cough with chilled phlegm, chills, cold sweats, and weight loss that can affect any organ in the body, causing a variety of symptoms depending on the affected organ.
결핵치료제로 가장 흔히 처방되는 항-결핵 제재는 이소니아지드, 리팜피신, 피라진아마이드, 에탐부톨이다. 이들에 의한 치료는 종종 여러 달이 소요되고 필요에 따라 치료기간이 연장될 수 있다. 또한, 결핵 치료제에 대한 내성이 생기는 위험을 감소시키기 위해서 여러 가지 항생제의 조합으로 복합 처방되고 있으나 이러한 경우에도 잠복하고 있는 결핵의 치료는 매우 어려우며 결핵치료제에 대한 다중약제내성결핵균(MDR-TB, 이소니아지드와 리팜피신과 같은 1차 치료약물에 죽지 않는 결핵균)이 증가되고 있어 결핵치료에 어려움이 있다. 이에 따라, 기존의 약물을 대체할 새로운 타겟군에 대한 선도물질이 필요한 상황이다.The most common anti-tuberculosis agents prescribed for the treatment of tuberculosis are isoniazid, rifampicin, pyrazineamide and etambutol. Treatment by them often takes several months and can be extended as needed. In addition, in order to reduce the risk of developing resistance to tuberculosis drugs, a combination of various antibiotics is prescribed, but even in this case, the treatment of latent tuberculosis is very difficult, and multi-drug resistant tuberculosis bacteria (MDR-TB, isoniazid) And tuberculosis bacteria that do not die in primary treatment drugs such as rifampicin. Accordingly, there is a need for a lead substance for a new target group to replace the existing drug.
최근 새로운 타겟군으로 4'-phosphopantetheinyl Transferase에 대한 연구가 진행되고 있다. 결핵균이 체내에 들어오면 대식세포 등이 이를 처리하여 몸의 건강을 유지하려 하나, 결핵균의 표면에 존재하는 다양한 특이 지질체들이 체내의 면역 시스템을 회피하게 하는데 4'-phosphopantetheinyl Transferase 단백질은 이러한 특이 지질체 형성 효소들의 상위 중심 조절인자이며 이를 효과적으로 저해하면 체내 면역 반응을 통해 결핵균의 제거가 가능하다. 최근 연구에서도 6'-phosphopantetheinyl Transferase가 결핵균의 복제 및 생존에 필요하다는 것이 증명된바 있으며(PLOS Pathogen. 2012 Dec;8(12):e1003097) 프랑스, 미국, 뉴질랜드 등의 연구팀에서도 6'-phosphopantetheinyl Transferase를 타겟으로 하여 항결핵제 개발을 위해 주력하고 있으나 현재까지 보고된 선도 물질은 없다.Recently, 4'-phosphopantetheinyl transferase has been studied as a new target group. When tuberculosis enters the body, macrophages and the like try to maintain the body's health, but various specific lipids on the surface of the tuberculosis cause the body's immune system to evade the 4'-phosphopantetheinyl transferase protein. It is an upper central regulator of body-forming enzymes and effectively inhibiting it allows the removal of Mycobacterium tuberculosis through the body's immune response. Recent studies have demonstrated that 6'-phosphopantetheinyl Transferase is necessary for the replication and survival of Mycobacterium tuberculosis (PLOS Pathogen. 2012 Dec; 8 (12): e1003097). It is focused on the development of anti-tuberculosis drugs targeted at, but no leading substance has been reported.
이에, 본 발명자들은 4'-phosphopantetheinyl Transferase를 타겟으로 한 항결핵제 개발을 위해 타겟 단백질의 삼차원 구조와 이와 결합한 두 종류의 리간드와의 상호 결합을 바탕으로 저해제를 설계하고 이를 통해 저해 가능성이 높은 화합물을 도출하여 in vitro assay를 수행하여 저해효과를 확인하므로 본 발명을 완성하였다.Therefore, the present inventors designed an inhibitor based on the three-dimensional structure of the target protein and the mutual binding of two ligands bound thereto for the development of an anti-tuberculosis drug targeting 4'-phosphopantetheinyl transferase, and thus derived a compound with high inhibition potential By performing an in vitro assay to confirm the inhibitory effect was completed the present invention.
본 발명의 목적은 신규한 4'-포스포판테테이닐 트랜스퍼레이즈(4'-phosphopantetheinyl transferase)효소 저해 화합물 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.It is an object of the present invention to provide novel 4'-phosphopantetheinyl transferase enzyme inhibitor compounds or pharmaceutically acceptable salts thereof.
본 발명의 다른 목적은 상기 화합물을 유효성분으로 함유하는 결핵의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound as an active ingredient.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로 함유하는 결핵의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Another object of the present invention to provide a health functional food for the prevention or improvement of tuberculosis containing the compound as an active ingredient.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
R1은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5-10 각환의 헤테로아릴 또는 
이고,R 1 is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
상기 치환된 5-10 각환의 헤테로아릴은 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-10 각환의 헤테로아릴이고,The substituted 5-10 each ring heteroaryl consists of hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,
상기 A1 및 A2는 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐이거나 A1 및 A2가 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로사이클로알킬을 형성하고;A 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N To form an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
상기 Q는 S, O 또는 CH2이고,Q is S, O or CH 2 ,
상기 M은 S, O, CH2 또는 NH이고,M is S, O, CH 2 or NH,
상기 K는 CH 또는 N이고, K is CH or N,
상기 B1, B2 및 B3은 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴 또는 할로겐이다.B 1 , B 2 and B 3 are independently hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile or halogen.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 결핵의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 결핵의 예방 또는 개선용 건강기능식품을 제공한다.Furthermore, the present invention provides a health functional food for preventing or improving tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 화합물들은 4'-포스포판테테이닐 트랜스퍼레이즈 효소를 유의하게 저해하여 체내 면역반응을 통한 결핵균의 제거가 가능하고, 이를 통해 결핵의 예방 또는 치료에 사용될 수 있는 효과가 있다.Compounds according to the present invention can significantly inhibit the 4'-phosphopanthethenyl transferase enzyme to remove Mycobacterium tuberculosis through the body's immune response, thereby having an effect that can be used for the prevention or treatment of tuberculosis.
도 1은 Mycobacterium tuberculosis PptT(4'-phosphopantetheinyl transferase)와 Mycobacterium smegmatis PptT의 단백질의 삼차원 구조이다.1 is a three-dimensional structure of the proteins of Mycobacterium tuberculosis PptT (4'-phosphopantetheinyl transferase) and Mycobacterium smegmatis PptT.
도 2는 대조물질인 6-NOBP(6-nitro-1,2-benzopyrone)를 사용한 활성 억제 실험 결과 그래프이다.Figure 2 is a graph of the results of activity inhibition experiments using 6-NOBP (6-nitro-1,2-benzopyrone) as a control.
도 3 내지 5는 대조물질인 6-NOBP(6-nitro-1,2-benzopyrone)를 사용하여 반응 최적조건을 찾기 위해 DMSO(Dimethyl sulfoxide)의 %(v/v)를 달리하여 실험한 활성 억제 실험 결과 그래프이다.3 to 5 shows the inhibition of activity by varying the% (v / v) of dimethyl sulfoxide (DMSO) to find the optimum reaction conditions using 6-NOBP (6-nitro-1,2-benzopyrone) as a control. Experimental results graph.
도 6는 실시예 화합물들의 BpsA(Blue-pigment synthetase) 활성 저해 확인 실험과정을 보여주는 것이다.Figure 6 shows the process of confirming the inhibition of BpsA (Blue-pigment synthetase) activity of the compound compounds.
도 7는 실시예 1의 PptT 활성 저해 평가 실험의 결과 그래프이다.7 is a result graph of the PptT activity inhibition evaluation experiment of Example 1.
도 8은 실시예 2의 PptT 활성 저해 평가 실험의 결과 그래프이다.8 is a result graph of the PptT activity inhibition evaluation experiment of Example 2.
도 9은 실시예 3의 PptT 활성 저해 평가 실험의 결과 그래프이다.9 is a graph showing the results of the PptT activity inhibition evaluation experiment of Example 3.
도 10은 실시예 4의 PptT 활성 저해 평가 실험의 결과 그래프이다.10 is a result graph of the PptT activity inhibition evaluation experiment of Example 4.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
R1은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5-10 각환의 헤테로아릴 또는 
이고,R 1 is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
상기 치환된 5-10 각환의 헤테로아릴은 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-10 각환의 헤테로아릴이고,The substituted 5-10 each ring heteroaryl consists of hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,
상기 A1 및 A2는 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐이거나 A1 및 A2가 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로사이클로알킬을 형성하고;A 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N To form an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
상기 Q는 S, O 또는 CH2이고,Q is S, O or CH 2 ,
상기 M은 S, O, CH2 또는 NH이고,M is S, O, CH 2 or NH,
상기 K는 CH 또는 N이고, K is CH or N,
상기 B1, B2 및 B3은 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴 또는 할로겐이다.B 1 , B 2 and B 3 are independently hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile or halogen.
바람직하게는,Preferably,
R1은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5-8 각환의 헤테로아릴 또는 
이고,R 1 is unsubstituted or substituted 5-8 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or ego,
상기 치환된 5-8 각환의 헤테로아릴은 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴, 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-8 각환의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-8 각환의 헤테로아릴이고,The substituted 5-8 heterocyclic heteroaryl consists of hydrogen, straight or branched chain C 1-5 alkyl, straight or branched chain C 1-5 alkoxy, nitro, nitrile, halogen and N, O and S 5-8 angular ring heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-8 angular ring heteroaryl containing one or more hetero atoms selected from the group,
상기 A1 및 A2는 독립적으로 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴, 할로겐이거나 A1 및 A2가 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-8 각환의 헤테로사이클로알킬을 형성하고;A 1 and A 2 are independently hydrogen, linear or branched C 1-5 alkyl, linear or branched C 1-5 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked N To form an unsubstituted 5-8 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;
상기 Q는 S, O 또는 CH2이고,Wherein Q is S, O or CH 2,
상기 M은 S, O, CH2 또는 NH이고,M is S, O, CH 2 or NH,
상기 K는 CH 또는 N이고, K is CH or N,
상기 B1, B2 및 B3은 독립적으로 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴 또는 할로겐이다.Wherein B 1, B 2 and B 3 are independently hydrogen, straight or alkoxy, nitro of branched alkyl, linear or branched C 1-5 of C 1-5, a nitrile or a halogen.
더욱 바람직하게는,More preferably,
R1은 
, 
, 
또는 
이고,R 1 is , , or ego,
Q는 S 또는 CH2이고,Q is S or CH 2 ,
M은 S 또는 O이고,M is S or O,
K는 N 또는 CH이고,K is N or CH,
B1은 -Cl 또는 -CH3이고,B 1 is -Cl or -CH 3,
B2 및 B3는 독립적으로 -H 또는 -CH3이다.B 2 and B 3 is independently -H or -CH 3.
가장 바람직하게는,Most preferably,
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나이다.The compound represented by Formula 1 is any one selected from the following compound group.
(1) N-(1-(6-(4H-1,2,4-트리아졸-4-일)피리딘-2-일)비닐)-5-(벤조[d]티아졸-2-일)-2-메틸벤젠아민;(1) N- (1- (6- (4H-1,2,4-triazol-4-yl) pyridin-2-yl) vinyl) -5- (benzo [d] thiazol-2-yl) 2-methylbenzeneamine;
(2) N-(5-(벤조[d]옥사졸-2-일)-2-클로로페닐카바모티오일)-4-플루오로벤즈아미드;(2) N- (5- (benzo [d] oxazol-2-yl) -2-chlorophenylcarbamothioyl) -4-fluorobenzamide;
(3) 3-클로로-N-(3-(5,7-디메틸벤조[d]옥사졸-2-일)-2-메틸페닐카바모티오일)벤즈아미드; 및(3) 3-chloro-N- (3- (5,7-dimethylbenzo [d] oxazol-2-yl) -2-methylphenylcarbamothioyl) benzamide; And
(4) N-(4-클로로-3-(옥사졸로[4,5-b]피리딘-2-일)페닐카바모티오일)-2,3-디하이드로벤조[b][1,4]다이옥신-6-카복스아미드.(4) N- (4-chloro-3- (oxazolo [4,5-b] pyridin-2-yl) phenylcarbamothioyl) -2,3-dihydrobenzo [b] [1,4] dioxine -6-carboxamide.
본 발명의 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids and the like, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro Zensulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 디클로로메탄, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried, and then crystallized under an organic solvent.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 입체 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, stereoisomers, hydrates, and the like that can be prepared therefrom.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 결핵의 예방 또는 치료용 약학적 조성물을 제공한다. 여기서, 상기 화합물은 4'-포스포판테테이닐 트랜스퍼레이즈(4'-phosphopantetheinyl Transferase)를 억제하여 결핵을 예방 또는 치료하는 것을 특징으로 하며, 결핵의 구체적인 종류로는 안결핵, 피부 결핵, 부신 결핵, 신장결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 또는 척추 결핵등이 있다.The present invention also provides a pharmaceutical composition for the prevention or treatment of tuberculosis containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the compound is characterized in that to prevent or treat tuberculosis by inhibiting the 4'-phosphopantetheinyl transferase (4'-phosphopantetheinyl Transferase), specific types of tuberculosis, tuberculosis tuberculosis, adrenal tuberculosis There are renal tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung disease, breast tuberculosis or spinal tuberculosis.
나아가, 상기 결핵은 다제내성 결핵균에 의해 발병되는 결핵인 것을 특징으로 할 수 있다.In addition, the tuberculosis may be characterized in that the tuberculosis caused by multidrug-resistant tuberculosis bacteria.
또한, 본 발명에 따른 약학적 조성물에 있어서, 상기 화학식 1로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.In addition, in the pharmaceutical composition according to the present invention, the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, in the case of clinical administration. It may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. which are commonly used.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and the like, optionally with bores such as starch, agar, alginic acid or its sodium salt and the like. Release or boiling mixtures and / or absorbents, colorants, flavors, and sweeteners.
상기 화학식 1로 표시되는 화합물을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다.Pharmaceutical compositions comprising the compound represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.In this case, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation, and prepared as a solution or suspension, and it is an ampule or vial unit dosage form. It can be prepared by. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.
나아가, 본 발명의 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70Kg인 성인 환자를 기준으로 할 때, 일반적으로 0.1-1000 mg/일이며, 바람직하게는 1-500 mg/일이며, 또한 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.Furthermore, the dosage of the compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. Based on an adult patient of 70 kg, it is generally 0.1-1000 mg / day, preferably 1-500 mg / day, and once or several times a day at regular time intervals as determined by the doctor or pharmacist. It may be administered in divided doses.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 하는 결핵의 예방 또는 개선용 건강식품을 제공한다.In another aspect, the present invention provides a health food for preventing or improving tuberculosis using the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
여기서 상기 결핵은 안결핵, 피부 결핵, 부신 결핵, 신장결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 또는 척추 결핵인 것을 특징으로 할 수 있다.Here, the tuberculosis is tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, cholestatic tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung , Breast tuberculosis or spinal tuberculosis.
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을, 이를 필요로 하는 대상(즉, 환자)에게 투여하는 단계를 포함하는, 결핵의 예방 또는 치료방법을 제공한다.Furthermore, the present invention provides a method for preventing or treating tuberculosis, comprising administering a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof to a subject (ie, a patient) in need thereof.
이때, 상기 투여는 공지된 여러가지 방법으로 투여할 수 있으며, 하나의 예시로 경구 투여 방법으로 수행할 수 있다.In this case, the administration may be administered by a variety of known methods, it can be carried out by oral administration as one example.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염의 약제(medicament)로서의 용도(use)를 제공한다.In addition, the present invention provides a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as a medicament.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예 및 실험예에 의해 제한되는 것은 아니다.However, the following Examples and Experimental Examples are only illustrative of the present invention, the present invention is not limited by the following Examples and Experimental Examples.
< 실시예 1> N -(1-(6-(4H-1,2,4- 트리아졸 -4-일)피리딘-2-일)비닐)-5-( 벤조[d]티아졸-2-일)-2-메틸벤젠아민 < Example 1> N - (1- (6- (4H-1,2,4- triazol-4-yl) pyridin-2-yl) vinyl) -5- (ben crude [d] thiazol-2-yl) 2-methylbenzeneamine
표제 화합물은 한국화합물은행에서 제공받아 사용하였다.The title compound was provided by the Korea Compound Bank.
< 실시예 2> N-(5-( 벤조[d]옥사졸 -2-일)-2- 클로로페닐카바모티오일 )-4- 플루오로벤즈아미드 <Example 2> N- (5- (benzo [d] oxazol-2-yl) -2-chloro-phenylcarbamoyl motif oil), 4-fluoro Robben's amide
표제 화합물은 한국화합물은행에서 제공받아 사용하였다.The title compound was provided by the Korea Compound Bank.
< 실시예 3> 3- 클로로 -N-(3-(5,7- 디메틸벤조[d]옥사졸 -2-일)-2- 메틸페닐카바모티오일)벤즈아미드 <Example 3> 3-Chloro -N- (3- (5,7- dimethyl-benzo [d] oxazol-2-yl) -2-methylphenyl cover motif oil) benzamide
표제 화합물은 한국화합물은행에서 제공받아 사용하였다.The title compound was provided by the Korea Compound Bank.
< 실시예 4> N-(4- 클로로 -3-( 옥사졸로[4,5-b]피리딘 -2-일) 페닐카바모티오일 )-2,3-디하이드로벤조[b][1,4]다이옥신-6-카복스아미드 <Example 4> N- (4- chloro-3- (oxazolo [4,5-b] pyridin-2-yl) phenylcarbamoyl motif oil) - 2,3-dihydro-benzo [b] [1,4 Dioxin-6-carboxamide
표제 화합물은 한국화합물은행에서 제공받아 사용하였다.The title compound was provided by the Korea Compound Bank.
상기 실시예 1 내지 4의 화합물의 구체적인 구조를 하기 표 1에 나타내었다.Specific structures of the compounds of Examples 1 to 4 are shown in Table 1 below.
| 실시예Example | 화학구조Chemical structure |
| 1One |
 |
| 22 |
 |
| 33 |
 |
| 44 |
 |
< 실험예 1> 4'- 포스포판테테이닐 트랜스퍼레이즈 (4'- phosphopantetheinyl transferase: PptT) 저해제 선별 및 활성 저해 평가 <Experimental Example 1>4'-phosphonate Pantheon table carbonyl Transferase (4'- phosphopantetheinyl transferase: PptT) inhibitor selection and activity inhibition evaluation
1-1. 실험준비1-1. Experiment preparation
(1) 결핵균 유래 4'-포스포판테테이닐 트랜스퍼레이즈 (4'-phosphopantetheinyl transferase: PptT)의 대장균을 통한 대량 발현(1) Mass expression of E. coli of 4'-phosphopantetheinyl transferase (PptT) derived from Mycobacterium tuberculosis
PptT 유전자 (Rv2794c)를 pET21a 플라스미드에 삽입후 이를 대장균 세포주 BL21(DE3)에 클로닝하였다. Luria Broth 배지에 대장균을 37℃에서 배양한 후 OD600이 0.7 정도 되는 시점에 IPTG를 넣어 PptT를 발현하고 16℃에서 20시간 동안 배양하였다.The PptT gene (Rv2794c) was inserted into the pET21a plasmid and cloned into E. coli cell line BL21 (DE3). After incubating E. coli in Luria Broth medium at 37 ° C, IPTG was added at a time point of OD600 of about 0.7 to express PptT and incubated at 16 ° C for 20 hours.
(2) PptT 단백질의 정제 및 분리(2) Purification and Isolation of PptT Proteins
배양한 대장균을 원심분리 한 다음 영하 80℃에 균체를 보관한 뒤, 초음파로 파쇄하고 이를 IMAC(Immobilized metallo-affinity chromatography)방법을 이용하여 1차 정제 후, SEC(Size exclusion chromatography)방법을 이용하여 최종 정제하였다. PptT를 보관하는 완충용액은 50mM Tris-HCl (pH 8.0), 200mM NaCl로 조성되었다.After centrifugation of the cultured Escherichia coli, the cells were stored at minus 80 ° C, and then crushed by ultrasound and subjected to primary purification using IMAC (Immobilized metallo-affinity chromatography), followed by SEC (Size exclusion chromatography) method. Final purification. The buffer solution containing PptT was composed of 50 mM Tris-HCl (pH 8.0), 200 mM NaCl.
(3) 저해제 물질의 선별(3) Screening of Inhibitor Substances
4'-phosphopantetheinyl Transferase 단백질의 삼차원 구조와 이와 결합한 두 종류의 리간드와의 상호 결합을 바탕으로 저해제를 설계하고 이를 통해 저해 가능성이 높은 1500 여종의 화합물을 도출하여 in vitro assay를 수행하였다. Inhibitors were designed based on the three-dimensional structure of the 4'-phosphopantetheinyl Transferase protein and the mutual binding of two ligands bound to it.
1-2. 실험방법1-2. Experiment method
(1) BpsA(Blue-pigment synthetase) assay를 통한 저해제 검출 (1) Inhibitor detection through BpsA (Blue-pigment synthetase) assay
대량의 화합물 assay 전, 효소 활성도의 정확성을 위해 대조물질인 6-NOBP (6-nitroso-1,2-benzopyrone) 를 사용하여 반응 최적 조건을 찾아 거짓양성반응 화합물이 나오지 않도록 필터링 하였고 그 결과를 도 2 및 도 3-5에 나타내었다. 이를 통해 32%(v/v)의 DMSO(Dimethyl sulfoxide)가 첨가되어야 반응이 지속적이고 안정적으로 나옴을 확인하였다.Before the mass compound assay, 6-NOBP (6-nitroso-1,2-benzopyrone), a reference material, was used to determine the optimum conditions for the enzyme activity and to filter out the false positive compounds. 2 and FIGS. 3-5. Through this, 32% (v / v) of DMSO (dimethyl sulfoxide) was added to confirm that the reaction was continued and stable.
또한, 본 발명에서 제시한 PptT 저해 assay법이 특이성을 가지고 정확히 PptT를 저해하는지 아니면 기질인 BpsA(Blue-pigment synthetase)에 비특이적 결합을 하여 결과적으로 저해하는지를 확인하고자 선별된 화합물에 대해 BpsA(Blue-pigment synthetase)와 CoA-PptT 결합체를 미리 반응하여 기질인 BpsA(Blue-pigment synthetase) 단백질을 선 활성화를 시킨 뒤, 해당 저해 선도 물질을 처리하여 도 6에 나타난 바와 같이 assay를 수행하였다. 이를 통해 본 발명에서 제시한 선도물질의 경우 모두 BpsA(Blue-pigment synthetase)를 저해하지 않음을 확인하였다.In addition, to determine whether the PptT inhibition assay presented in the present invention accurately inhibits PptT with specificity or non-specifically binds to BpsA (Blue-pigment synthetase), which is a result, BpsA (Blue- After pre-reacting the pigment synthetase) and the CoA-PptT conjugate to activate the BpsA (Blue-pigment synthetase) protein, which is a substrate, the assay was performed as shown in FIG. Through this, it was confirmed that all of the leading materials presented in the present invention did not inhibit BpsA (Blue-pigment synthetase).
(2) PptT 저해활성(IC50) 측정(2) Determination of PptT Inhibitory Activity (IC 50 )
96 well plate를 사용하여 assay를 수행하였고, 각 well에는 최종농도로 100 μM -0.001μM의 저해제가 들어가도록 실험을 수행하였다. 실험은 각 well에 73μl의 다양한 성분들 즉, 2μM PptT, 50mM Tris(pH 8.0), 20μM CoA, 8mM L-glutamine, 5mM ATP, 10mM MgCl2, 32%(v/v) DMSO(Dimethyl sulfoxide)를 가하고, 기질인 25μl BpsA(Blue-pigment synthetase) 단백질 용액(조성:50mM Tris-HCl, pH 8.0, 8mM L-glutamine, 5mM ATP, 10mM MgCl2, 20%(v/v) DMSO(Dimethyl sulfoxide))를 넣어 25℃에서 효소 반응을 개시하였다. 효소 반응 후 30분 뒤에 SpectraMax M5(Molecular Devices) 장비를 이용하여 흡광도 790nm에서 각 well의 흡광 수치를 읽었으며 화합물 및 완충용액이 미치는 흡광도를 따로 측정하여 수치를 보정하였고, 저해 받지 않는 정상적인 PptT 활성을 기준으로 각 화합물의 PptT 활성에 대한 저해도를 측정하였다. 이를 GraphPad Prism 소프트웨어를 이용하여 IC50(inhibitory concentration at 50%)를 계산하였다.The assay was performed using a 96 well plate, and each well was tested to include 100 μM -0.001μM inhibitor at the final concentration. The experiment was carried out with 73 μl of various components in each well: 2 μM PptT, 50 mM Tris (pH 8.0), 20 μM CoA, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl 2 , 32% (v / v) dimethyl sulfoxide (DMSO). 25 μl BpsA (Blue-pigment synthetase) protein solution (composition: 50 mM Tris-HCl, pH 8.0, 8 mM L-glutamine, 5 mM ATP, 10 mM MgCl 2 , 20% (v / v) Dimethyl sulfoxide) The enzyme reaction was started at 25 ℃. Thirty minutes after the enzyme reaction, the absorbance values of each well were read at 790 nm using SpectraMax M5 (Molecular Devices), and the absorbances of compounds and buffers were measured separately to correct the values and normal PptT activity was not inhibited. As a reference, inhibition of PptT activity of each compound was measured. The IC 50 (inhibitory concentration at 50%) was calculated using GraphPad Prism software.
1-3. 실험결과1-3. Experiment result
이를 통해 발굴된 PptT 저해물질과 각 IC50 수치를 하기 표 2에 나타내었으며, 각각의 결과 그래프를 도 7-도 10에 나타내었다.PptT inhibitors and respective IC 50 values discovered through the results are shown in Table 2 below, and the respective graphs are shown in FIGS. 7 to 10.
| 실시예Example | IC50(μM)IC 50 (μM) |
| 1One | 0.6350.635 |
| 22 | 0.79550.7955 |
| 33 | 2.2822.282 |
| 44 | 1.8171.817 |
한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
<제제예 1> 약학적 제제의 제조 Preparation Example 1 Preparation of Pharmaceutical Formulation
1-1. 산제의 제조1-1. Manufacture of powder
화학식 1의 화합물 500 ㎎ 500 mg of compound of formula 1
유당 100 ㎎ Lactose 100 mg
탈크 10 ㎎ Talc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
1-2. 정제의 제조 1-2. Manufacture of tablets
화학식 1의 화합물 500 ㎎ 500 mg of compound of formula 1
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ Lactose 100 mg
스테아린산 마그네슘 2 ㎎ 2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다. After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
1-3. 캅셀제의 제조 1-3. Manufacture of capsule
화학식 1의 화합물 500 ㎎ 500 mg of compound of formula 1
옥수수전분 100 ㎎ Corn starch 100 mg
유당 100 ㎎ Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다. According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
1-4. 주사제의 제조 1-4. Preparation of Injectables
화학식 1의 화합물 500 ㎎500 mg of compound of formula 1
주사용 멸균 증류수 적량Appropriate sterile distilled water for injection
pH 조절제 적량pH adjuster
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다. According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
1-5. 액제의 제조 1-5. Preparation of liquid
화학식 1의 화합물 100 ㎎ 100 mg of compound of Formula 1
이성화당 10 g 10 g of isomerized sugar
만니톨 5 g 5 g of mannitol
정제수 적량 Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve, the lemon flavor is added appropriately, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by the addition of purified water, and then filled into a brown bottle. Sterilize to prepare the liquid.
본 발명에 따른 화합물들은 4'-포스포판테테이닐 트랜스퍼레이즈 효소를 유의하게 저해하여 체내 면역반응을 통한 결핵균의 제거가 가능하고, 이를 통해 결핵의 예방 또는 치료에 유용하다.The compounds according to the present invention can significantly inhibit 4'-phosphopanthethenyl transferase enzyme, thereby allowing the removal of Mycobacterium tuberculosis through an immune response in the body, thereby useful for the prevention or treatment of tuberculosis.
Claims (10)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염:A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:[화학식 1][Formula 1]
(상기 화학식 1에서,(In Formula 1,R1은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5-10 각환의 헤테로아릴 또는이고,R 1 is unsubstituted or substituted 5-10 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or
ego,상기 치환된 5-10 각환의 헤테로아릴은 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-10 각환의 헤테로아릴이고,The substituted 5-10 each ring heteroaryl consists of hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile, halogen and N, O and S 5-10 cyclic heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-10 cyclic heteroaryl containing one or more hetero atoms selected from the group,상기 A1 및 A2는 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴, 할로겐이거나 A1 및 A2가 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-10 각환의 헤테로사이클로알킬을 형성하고;A 1 and A 2 are independently hydrogen, linear or branched C 1-10 alkyl, linear or branched C 1-10 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked to N To form an unsubstituted 5-10 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;상기 Q는 S, O 또는 CH2이고,Q is S, O or CH 2 ,상기 M은 S, O, CH2 또는 NH이고,M is S, O, CH 2 or NH,상기 K는 CH 또는 N이고, K is CH or N,상기 B1, B2 및 B3은 독립적으로 수소, 직쇄 또는 분지쇄 C1-10의 알킬, 직쇄 또는 분지쇄 C1-10의 알콕시, 나이트로, 나이트릴 또는 할로겐이다).B 1 , B 2 and B 3 are independently hydrogen, straight or branched chain C 1-10 alkyl, straight or branched chain C 1-10 alkoxy, nitro, nitrile or halogen). - 제1항에 있어서,The method of claim 1,R1은 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환 또는 치환된 5-8 각환의 헤테로아릴 또는이고,R 1 is unsubstituted or substituted 5-8 each ring heteroaryl containing one or more hetero atoms selected from the group consisting of N, O and S or
ego,상기 치환된 5-8 각환의 헤테로아릴은 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴, 할로겐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-8 각환의 헤테로아릴로 이루어지는 군으로부터 선택되는 1종 이상의 치환기가 치환된 5-8 각환의 헤테로아릴이고,The substituted 5-8 heterocyclic heteroaryl consists of hydrogen, straight or branched chain C 1-5 alkyl, straight or branched chain C 1-5 alkoxy, nitro, nitrile, halogen and N, O and S 5-8 angular ring heteroaryl substituted with one or more substituents selected from the group consisting of unsubstituted 5-8 angular ring heteroaryl containing one or more hetero atoms selected from the group,상기 A1 및 A2는 독립적으로 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴, 할로겐이거나 A1 및 A2가 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 포함하는 비치환된 5-8 각환의 헤테로사이클로알킬을 형성하고;A 1 and A 2 are independently hydrogen, linear or branched C 1-5 alkyl, linear or branched C 1-5 alkoxy, nitro, nitrile, halogen or A 1 and A 2 are linked N To form an unsubstituted 5-8 cyclic heterocycloalkyl comprising at least one hetero atom selected from the group consisting of O and S;상기 Q는 S, O 또는 CH2이고,Q is S, O or CH 2 ,상기 M은 S, O, CH2 또는 NH이고,M is S, O, CH 2 or NH,상기 K는 CH 또는 N이고, K is CH or N,상기 B1, B2 및 B3은 독립적으로 수소, 직쇄 또는 분지쇄 C1-5의 알킬, 직쇄 또는 분지쇄 C1-5의 알콕시, 나이트로, 나이트릴 또는 할로겐인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.Wherein B 1, B 2 and B 3 are independently hydrogen, linear or branched alkoxy, nitro alkyl, linear or branched C 1-5 of C 1-5, the compound characterized in that the nitrile or halogen, or Pharmaceutically acceptable salts thereof. - 제1항에 있어서,The method of claim 1,R1은,
,
또는
이고,R 1 is
,,orego,Q는 S 또는 CH2이고,Q is S or CH 2 ,M은 S 또는 O이고,M is S or O,K는 N 또는 CH이고,K is N or CH,B1은 -Cl 또는 -CH3이고,B 1 is -Cl or -CH 3 ,B2 및 B3는 독립적으로 -H 또는 -CH3인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염.B 2 and B 3 is independently —H or —CH 3 , or a pharmaceutically acceptable salt thereof. - 제1항에 있어서,The method of claim 1,상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:Compound represented by Formula 1 is any one selected from the following compound group or a pharmaceutically acceptable salt thereof:(1) N-(1-(6-(4H-1,2,4-트리아졸-4-일)피리딘-2-일)비닐)-5-(벤조[d]티아졸-2-일)-2-메틸벤젠아민;(1) N- (1- (6- (4H-1,2,4-triazol-4-yl) pyridin-2-yl) vinyl) -5- (benzo [d] thiazol-2-yl) 2-methylbenzeneamine;(2) N-(5-(벤조[d]옥사졸-2-일)-2-클로로페닐카바모티오일)-4-플루오로벤즈아미드;(2) N- (5- (benzo [d] oxazol-2-yl) -2-chlorophenylcarbamothioyl) -4-fluorobenzamide;(3) 3-클로로-N-(3-(5,7-디메틸벤조[d]옥사졸-2-일)-2-메틸페닐카바모티오일)벤즈아미드; 및(3) 3-chloro-N- (3- (5,7-dimethylbenzo [d] oxazol-2-yl) -2-methylphenylcarbamothioyl) benzamide; And(4) N-(4-클로로-3-(옥사졸로[4,5-b]피리딘-2-일)페닐카바모티오일)-2,3-디하이드로벤조[b][1,4]다이옥신-6-카복스아미드.(4) N- (4-chloro-3- (oxazolo [4,5-b] pyridin-2-yl) phenylcarbamothioyl) -2,3-dihydrobenzo [b] [1,4] dioxine -6-carboxamide.
- 제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 결핵의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating tuberculosis, comprising the compound represented by Formula 1 of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- 제5항에 있어서,The method of claim 5,상기 화합물은 4'-포스포판테테이닐 트랜스퍼레이즈(4'-phosphopantetheinyl Transferase)를 억제하여 결핵을 예방 또는 치료하는 것을 특징으로 하는 약학적 조성물.The compound is a pharmaceutical composition, characterized in that to prevent or treat tuberculosis by inhibiting 4'-phosphopantetheinyl transferase (4'-phosphopantetheinyl transferase).
- 제5항에 있어서,The method of claim 5,상기 결핵은 안결핵, 피부 결핵, 부신 결핵, 신장결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 또는 척추 결핵인 것을 특징으로 하는 약학적 조성물.The tuberculosis may include eye tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung disease, A pharmaceutical composition, characterized in that it is breast tuberculosis or spinal tuberculosis.
- 제5항에 있어서,The method of claim 5,상기 결핵은 다제내성 결핵균에 의해 발병되는 결핵인 것을 특징으로 하는 약학적 조성물.The tuberculosis is a pharmaceutical composition, characterized in that the tuberculosis caused by multidrug-resistant tuberculosis bacteria.
- 제1항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 하는 결핵의 예방 또는 개선용 건강식품.A health food for the prevention or improvement of tuberculosis comprising the compound represented by the formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- 제9항에 있어서,The method of claim 9,상기 결핵은 안결핵, 피부 결핵, 부신 결핵, 신장결핵, 부고환 결핵, 림프선 결핵, 후두 결핵, 중이 결핵, 장결핵, 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선 결핵, 폐허증, 유방 결핵 또는 척추 결핵인 것을 특징으로 하는 건강식품.The tuberculosis may include eye tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, biliary tuberculosis, bone tuberculosis, throat tuberculosis, lymph node tuberculosis, lung disease, Health foods, characterized in that the tuberculosis or vertebral tuberculosis.
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| KR1020170014330A KR102051449B1 (en) | 2017-02-01 | 2017-02-01 | 4'-phosphopantetheinyl transferase enzyme inhibitors derived from Mycobacterium tuberculosis and pharmaceutical composition for use in preventing or treating tuberculosis containing the same as an active ingredient |
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Non-Patent Citations (4)
| Title |
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| DATABASE Chemical Abstract 11 June 2002 (2002-06-11), retrieved from STN Database accession no. 428447-05-6 * |
| DATABASE Chemical Abstract 19 January 2004 (2004-01-19), retrieved from STN Database accession no. 639055-48-4 * |
| DATABASE Chemical Abstract 22 July 2001 (2001-07-22), retrieved from STN Database accession no. 347332-12-1 * |
| PARK, S. W. ET AL.: "Target-based Identification of Whole- cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium Tuberculosis", CHEMISTRY & BIOLOGY, vol. 22, no. I, 2015, pages 76 - 86, XP055534978 * |
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