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WO2022240213A1 - Nouveau dérivé de benzothiazole, son procédé de préparation et son utilisation pour la prévention ou le traitement d'une maladie hépatique - Google Patents

Nouveau dérivé de benzothiazole, son procédé de préparation et son utilisation pour la prévention ou le traitement d'une maladie hépatique Download PDF

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Publication number
WO2022240213A1
WO2022240213A1 PCT/KR2022/006815 KR2022006815W WO2022240213A1 WO 2022240213 A1 WO2022240213 A1 WO 2022240213A1 KR 2022006815 W KR2022006815 W KR 2022006815W WO 2022240213 A1 WO2022240213 A1 WO 2022240213A1
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WO
WIPO (PCT)
Prior art keywords
thiazole
benzo
carboxylic acid
trifluoromethyl
chloro
Prior art date
Application number
PCT/KR2022/006815
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English (en)
Korean (ko)
Inventor
박지연
이승철
조혜임
최성일
박솜이
정진우
박찬우
최지원
김동규
Original Assignee
에이치케이이노엔 주식회사
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Publication of WO2022240213A1 publication Critical patent/WO2022240213A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel benzothiazole derivative, a method for preparing the same, and a use thereof for preventing or treating liver disease.
  • Non-alcoholic fatty liver disease refers to a case where the cause of fatty liver is not caused by viruses, drugs, heredity, or alcohol, and is closely related to metabolic syndrome such as insulin resistance, obesity, hypertension, and dyslipidemia. It is a chronic liver disease that is known to be closely related, and includes a series of processes ranging from simple steatosis in the liver to non-alcoholic steatohepatitis (NASH) and cirrhosis. Globally, the prevalence of non-alcoholic fatty liver disease is reported in various ways depending on the population group.
  • non-alcoholic steatohepatitis is expected to become the largest market among liver diseases in the future, and for this reason, many pharmaceutical companies are conducting research on NASH therapeutics targeting various targets in order to develop therapeutics.
  • NASH non-alcoholic steatohepatitis
  • pharmaceutical companies have yet to succeed in clinical trials because the disease onset mechanism is still unclear and there is no non-invasive diagnostic method for diagnosing the disease.
  • the US FDA recommends that even one item of the NAFLD activity score (NAFLD activity score) or fibrosis score (fibrosis score) in diagnosing NASH have a negative effect on the other items.
  • NAFLD activity score NAFLD activity score
  • fibrosis score fibrosis score
  • One object of the present invention is to provide novel benzothiazole derivatives.
  • Another object of the present invention is to provide a method for preparing the benzothiazole derivative.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating liver disease comprising the benzothiazole derivative as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating liver disease, comprising administering the pharmaceutical composition to a subject in need thereof.
  • Another object of the present invention is to provide a food composition for preventing or improving liver disease comprising the benzothiazole derivative as an active ingredient.
  • Another object of the present invention is to provide a feed composition for preventing or improving liver disease comprising the benzothiazole derivative as an active ingredient.
  • benzothiazole derivatives of the present invention can inhibit 17 ⁇ -HSD13 activity and further inhibit lipogenesis, they can be usefully used for preventing or treating liver diseases including non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.
  • a first aspect of the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof:
  • X is a simple bond, -NHCO-C 0-5 alkylene-, -N(C 1-4 alkyl)CO-C 0-5 alkylene-, -NHCO-C 0-5 alkylene-NHCO-, or - NHCO-C 0-5 alkylene-O-,
  • R 1 is carboxyl, or C 1-4 alkoxycarbonyl
  • R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen, or hydroxy
  • R 3 is C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
  • the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are unsubstituted or cyano, halogen, nitro, oxo, hydroxy, carboxyl, amino, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 alkoxy-C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkoxy, C 3-10 cyclo alkenyl, C 6-10 aryloxy, C 3-10 cycloalkyl-C 1-4 alkylcarbonyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylcarbonyl,
  • the C 6-10 aryl, C 3-10 cycloalkyl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl included in the substituents on the C 6-10 aryl, C 3-10 cycloalkyl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may each independently contain one or more additional substituents or not.
  • X is a simple bond, -NHCO-, -N(CH 3 )CO-, -N(CH 3 )CO-(CH 2 )-, -N(CH 3 )CO-(CH 2 ) 2 -, -NHCO-CH 2 -CH(CH 3 )-, -NHCO-(CH 2 ) 2 -NHCO-, or -NHCO-(CH 2 )-O-, but is not limited thereto.
  • R 1 may be carboxyl or ethoxycarbonyl, but is not limited thereto.
  • R 2 may be hydrogen, methyl, methoxy, fluoro, chloro, or hydroxy, but is not limited thereto.
  • R 3 is phenyl, pyridinyl, furanyl, thiophenyl, indolyl, benzotriazolyl, benzothiazolyl, benzoimidazolyl, pyrrolopyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl , pyrazolyl, pyrrolyl, spiroheptanyl, cyclobutyl, cyclohexyl, dihydropyridinyl, quinolinyl, imidazolyl, piperazinyl, or piperidinyl, but is not limited thereto, and of these ring structures
  • Substituents are unsubstituted or cyano, fluoro, chloro, bromo, iodo, nitro, oxo, hydroxy, carboxyl, amino, methyl, tert-butyl, ethenyl, propenyl, is
  • R 3 may be piperazinyl or piperidinyl, and the piperazinyl or piperidinyl may be unsubstituted or cyano, fluoro, chloro, bromo, io Do, nitro, oxo, hydroxy, carboxyl, amino, methyl, tert-butyl, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, methoxy, ethoxy, propoxy, isopropoxy, isobu Toxy, trifluoromethyl, difluoromethoxy, 1,1,1-trifluoroethoxy, methoxycarbonyl, methylcarbonyl, methylthio, methylamino, methoxyethoxy, cyclopropyl, cyclopropylmethyl Toxy, cyclopentenyl, phenoxy, cyclopentylethylcarbonyl,
  • the compounds of the present invention may exist in the form of pharmaceutically acceptable salts.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt of the present invention is a concentration that has a relatively non-toxic and harmless effective effect on patients, and any of the compounds represented by Formula 1 do not reduce the beneficial effects of the compound represented by Formula 1 by side effects caused by the salt. means any organic or inorganic addition salt of
  • Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • organic acids and inorganic acids can be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as the inorganic acid
  • methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid can be used as the organic acid.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • citric acid lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups which may be present in the compounds of Formula 1 above.
  • pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of a hydroxy group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate.
  • dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, etc. preparation of salts known in the art It can be produced through the method.
  • the salt of the benzothiazole derivative compound of the present invention is a pharmaceutically acceptable salt, and any salt of a benzothiazole derivative compound exhibiting pharmacological activity equivalent to that of the benzothiazole derivative compound may be used without limitation.
  • the compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as possible hydrates and all possible stereoisomers that can be prepared therefrom without limitation.
  • Solvates and stereoisomers of the compound represented by Formula 1 may be prepared from the compound represented by Formula 1 using methods known in the art.
  • the compound represented by Chemical Formula 1 according to the present invention may be prepared in a crystalline form or an amorphous form, and when prepared in a crystalline form, it may be optionally hydrated or solvated.
  • compounds containing various amounts of water may be included as well as stoichiometric hydrates of the compound represented by Formula 1.
  • Solvates of the compound represented by Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
  • a second aspect of the present invention provides a method for preparing the compound of the first aspect, or a pharmaceutically acceptable salt thereof, comprising a first step of reacting a compound represented by Formula 2 and Formula 3 below:
  • R' is -NHR" or halogen
  • R" is H or C 1-4 alkyl
  • X' is H, -C 0-5 alkylene-COOH, -CONH-C 0-5 alkylene-COOH, or -OC 0-5 alkylene-COOH;
  • R 1 is carboxyl, or C 1-4 alkoxycarbonyl
  • R 2 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halogen, or hydroxy
  • R 3 is C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
  • the C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are unsubstituted or cyano, halogen, nitro, oxo, hydroxy, carboxyl, amino, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxycarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 alkoxy-C 1-4 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkoxy, C 3-10 cyclo alkenyl, C 6-10 aryloxy, C 3-10 cycloalkyl-C 1-4 alkylcarbonyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylcarbonyl,
  • the first step is i) EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] pyridinium 3-oxide hexafluorophosphate, or Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), and PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) At least one catalyst selected from the group consisting of; 1-hydroxybenzotriazole (HOBt), or 4-dimethylaminopyridine (DMAP); And at least one Hunig's base selected from the group consisting of N, N-diisopropylethylamine (DIPEA), DI
  • the reactant in which R' is -NHR" can be reacted by the method of i), and when X' is hydrogen, the reactant in which R' is halogen and ii) It may be reacted by a method, but is not limited thereto.
  • the first step may be achieved by stirring at room temperature when using method i) or method ii), but is not limited thereto.
  • the reaction of the first step may be performed for 3 to 48 hours, but is not limited thereto.
  • the reaction of the first step is a polar organic solvent such as N,N-dimethylformamide (DMF), dichloromethane (DCM), or acetonitrile (ACN). It may be performed in a solution state in which a polar aprotic solvent is dissolved alone or in a mixture of two or more solvents, but is not limited thereto.
  • R 1 is C 1-4 alkoxycarbonyl
  • the product of the first step is reacted with a base, and then an acid is added to precipitate the second step. It may further include, but is not limited thereto.
  • a third aspect of the present invention provides a pharmaceutical composition for preventing or treating liver disease, comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • prevention means any activity that inhibits or delays the occurrence, spread, and recurrence of liver disease by administration of the composition of the present invention
  • treatment refers to the treatment of the disease by administration of the composition of the present invention. It means any action that improves or beneficially changes the condition.
  • the pharmaceutical composition of the present invention can exert pharmacological activity by inhibiting 17 ⁇ -HSD13 (17 ⁇ -Hydroxysteroid dehydrogenase type 13 or 17 ⁇ -HSD type 13).
  • 17 ⁇ -HSD13 is an enzyme encoded by the HSD17B13 gene, which is significantly overexpressed in the liver of patients with liver disease, such as non-alcoholic fatty liver disease, and is known to promote lipogenesis.
  • the liver disease includes non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, alcoholic hepatitis, alcoholic cirrhosis, Liver cirrhosis, liver cancer, liver failure and acute liver failure, cholangiocarcinoma, cholangiocarcinoma, primary biliary cholangitis, primary sclerosing cholangitis, jaundice, portal hypertension, cholelithiasis, acute or chronic cholecystitis, gallbladder polyps, gallbladder wall thickening, intrahepatic cholangitis , hilar cholangiocarcinoma, distal cholangiocarcinoma, and biliary obstruction.
  • NASH non-alcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • alcoholic hepatitis alcoholic hepatitis
  • the pharmaceutical composition according to the present invention contains 0.1 to 75% by weight, more preferably 1 to 75% by weight of the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition as an active ingredient. It may contain 50% by weight.
  • composition of the present invention may further include a pharmaceutically acceptable carrier, diluent or excipient, and may be prepared according to a conventional method according to each purpose of use, such as powder, granule, tablet, capsule, suspension, emulsion, syrup, It can be formulated and used in various forms such as oral formulations such as aerosols and injections of sterile injection solutions, and can be administered through various routes including oral administration or intravenous, intraperitoneal, subcutaneous, rectal, topical administration, and the like.
  • compositions examples include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil; and the like.
  • the composition of the present invention may further include fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the composition, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. Formulated by mixing.
  • lubricants such as magnesium stearate and talc may be used in addition to simple excipients.
  • Oral liquid preparations may include suspensions, solutions for internal use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents.
  • excipients such as wetting agents, sweeteners, aromatics, preservatives, etc.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions.
  • the suppositories are Witepsol, Macrogol, and Tween 61. Cacao fat, laurin fat, glycerogeratin and the like can be used. Meanwhile, conventional additives such as solubilizers, tonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives may be included in the injection.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount of the present invention means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level is the patient's health condition.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
  • the dosage may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., so the dosage is not limited to the scope of the present invention in any way.
  • the effective amount of the compound in the composition of the present invention may vary depending on the age, sex, and weight of the patient, and is generally 1 to 100 mg per kg body weight, preferably 5 to 60 mg daily or every other day, or 1 It can be administered in 1 to 3 divided doses per day. However, since it may increase or decrease according to the route of administration, severity of disease, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
  • a fourth aspect of the present invention provides a method for preventing or treating liver disease, comprising administering the pharmaceutical composition of the third aspect to a subject in need thereof.
  • subject of the present invention refers to monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, including humans who have developed or may develop the liver disease. It means all animals, including, and the disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject.
  • the pharmaceutical composition of the present invention may be administered in parallel with existing therapeutic agents.
  • the term "improvement" of the present invention refers to all activities that improve or beneficially change the symptoms of a subject suspected of or having the disease by using the food composition of the present invention.
  • administration means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue.
  • Intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, or intrarectal administration may be administered, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be administered by any device capable of transporting an active substance to a target cell.
  • Preferred administration modes and preparations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like.
  • Injections are formulated with aqueous solvents such as physiological saline and IV, non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.).
  • aqueous solvents such as physiological saline and IV
  • non-aqueous solvents such as vegetable oil, higher fatty acid esters (e.g., ethyl oleate, etc.)
  • alcohols e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.
  • Stabilizers e.g., ascorbic acid, sodium hydrogensulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • a pharmaceutical carrier such as a preservative (eg, phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
  • terapéuticaally effective amount used in combination with an active ingredient in the present invention refers to a benzothiazole derivative compound effective for preventing or treating a target disease, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable compound thereof. amount of possible salt.
  • the pharmaceutical composition of the present invention contains benzothiazole as an active ingredient.
  • known drugs used for the prevention or treatment of known diseases other than derivative compounds or pharmaceutically acceptable salts thereof may be further included.
  • a fifth aspect of the present invention provides a food composition for preventing or improving liver disease, comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the food composition according to the present invention includes forms such as pills, powders, granules, precipitates, tablets, capsules or liquids, and as foods to which the composition of the present invention can be added, for example, various foods, such as , beverages, gum, tea, vitamin complexes, and health supplements.
  • the compound of Formula 1 As an essential ingredient that can be included in the food composition of the present invention, there are no restrictions on other ingredients except for the compound of Formula 1 or a food-acceptable salt thereof, and, like conventional foods, various herbal extracts, food supplement additives, or natural carbohydrates, etc. may be included as an additional component.
  • the food auxiliary additives include food auxiliary additives common in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, stabilizers, and the like.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavors eg, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavors sacharin, aspartame, etc.
  • the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like may be contained.
  • it may contain fruit flesh for the manufacture of natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination.
  • the food composition includes health functional food and health supplement food.
  • the health functional food is the same term as food for special health use (FoSHU), and is a food manufactured and/or processed using raw materials or ingredients having useful functionality for the human body. As, in addition to nutritional supply, it means food with high medical and medical effects processed so that the bioregulatory function appears efficiently.
  • “function (sex)” means to obtain useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions.
  • food containing useful ingredients for the human body and recognized for its function and safety by the Ministry of Food and Drug Safety is called health functional food. It is classified as (supplementary) food.
  • the food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation.
  • the formulation of the food may also be prepared without limitation as long as the formulation is recognized as a food.
  • the food composition of the present invention can be prepared in various types of dosage forms, and unlike general medicines, it has the advantage of not having side effects that may occur when taking medicines for a long time by using food as a raw material, and has excellent portability.
  • a sixth aspect of the present invention provides a feed composition for preventing or improving liver disease, comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • feed-safe salt is as defined for food-grade acceptable salt.
  • feed refers to any natural or artificial diet, meal, etc., or component of said meal, intended for or suitable for consumption by animals.
  • the type of feed is not particularly limited, and feeds commonly used in the art may be used.
  • Non-limiting examples of the feed include vegetable feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, meal or grain by-products; Animal feed such as proteins, inorganic materials, oils, mineral oils, oils, single cell proteins, zooplankton, or food may be mentioned. These may be used alone or in combination of two or more.
  • the feed of the present invention may be powder feed, solid feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, raw feed, etc., but is not limited thereto.
  • the feed composition of the present invention may include a binder, an emulsifier, and a preservative added to prevent quality deterioration, and the feed composition may include a feed additive.
  • a feed additive There may be amino acids, vitamins, enzymes, flavors, non-protein nitrogen compounds, silicates, buffers, extractants, oligosaccharides, etc. added to the feed to increase efficacy.
  • it may further include a feed mixture and the like, but is not limited thereto.
  • Step 1-1 Preparation of ethyl 2-(6-(trifluoromethyl)ticotinamido)benzo[d]thiazole-6-carboxylate
  • 6-(trifluoromethyl)nicotinic acid (6-(trifluoromethyl)nicotinic acid. 258 mg, 1.35 mmol) dissolved in N,N-dimethylformamide (DMF, 2 mL), EDCI hydrochloride ( 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 345 mg, 1.80 mmol), HOBt (1-hydroxybenzotriazole, 243 mg, 1.80 mmol) solution, N,N-diisopropylethylamine (N,N-diisopropylethylamine , 0.78 mL, 4.50 mmol) and ethyl 2-aminobenzo[d]thiazole-6-carboxylate (200 mg, 0.90 mmol) were added at room temperature. The mixture was stirred at room temperature for one day. The reaction was terminated by adding distilled water, and the precipitated solid was filtered. The filtered solid
  • Step 1-2 Preparation of 2-(6-(trifluoromethyl)nicotinamido)benzo[d]thiazole-6-carboxylic acid
  • Examples 2 to 213 were synthesized by reacting in a manner similar to that of Example 1, but using appropriate reactants in consideration of the structure of the title compound.

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  • Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Polymers & Plastics (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

La présente invention concerne un nouveau dérivé de benzothiazole, son procédé de préparation et son utilisation pour la prévention ou le traitement de maladies hépatiques.
PCT/KR2022/006815 2021-05-12 2022-05-12 Nouveau dérivé de benzothiazole, son procédé de préparation et son utilisation pour la prévention ou le traitement d'une maladie hépatique WO2022240213A1 (fr)

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KR1020210061458A KR102682408B1 (ko) 2021-05-12 2021-05-12 신규한 벤조티아졸 유도체, 이의 제조방법 및 이의 간질환 예방 또는 치료 용도

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12145945B2 (en) 2023-03-10 2024-11-19 Breakpoint Therapeutics Gmbh Compounds, compositions, and therapeutic uses thereof

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WO2007086800A1 (fr) * 2006-01-27 2007-08-02 Astrazeneca Ab Nouveaux benzothiazoles substitués par un hétéroaryle
KR20080104042A (ko) * 2006-03-28 2008-11-28 하이 포인트 파마슈티칼스, 엘엘씨 히스타민 ｈ３ 수용체 활성을 갖는 벤조티아졸
WO2010124112A1 (fr) * 2009-04-22 2010-10-28 Janssen Pharmaceutica Nv Diamides d'azétidinyle inhibiteurs de la monoacylglycérol lipase
WO2020033782A1 (fr) * 2018-08-09 2020-02-13 Kineta, Inc. Activateurs de la voie du gène inductible par l'acide rétinoïque "rig-1" et leurs procédés d'utilisation
KR20200083528A (ko) * 2017-11-01 2020-07-08 브리스톨-마이어스 스큅 컴퍼니 파르네소이드 x 수용체 조정제로서의 스피로시클릭 화합물

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Publication number Priority date Publication date Assignee Title
WO2007086800A1 (fr) * 2006-01-27 2007-08-02 Astrazeneca Ab Nouveaux benzothiazoles substitués par un hétéroaryle
KR20080104042A (ko) * 2006-03-28 2008-11-28 하이 포인트 파마슈티칼스, 엘엘씨 히스타민 ｈ３ 수용체 활성을 갖는 벤조티아졸
WO2010124112A1 (fr) * 2009-04-22 2010-10-28 Janssen Pharmaceutica Nv Diamides d'azétidinyle inhibiteurs de la monoacylglycérol lipase
KR20200083528A (ko) * 2017-11-01 2020-07-08 브리스톨-마이어스 스큅 컴퍼니 파르네소이드 x 수용체 조정제로서의 스피로시클릭 화합물
WO2020033782A1 (fr) * 2018-08-09 2020-02-13 Kineta, Inc. Activateurs de la voie du gène inductible par l'acide rétinoïque "rig-1" et leurs procédés d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12145945B2 (en) 2023-03-10 2024-11-19 Breakpoint Therapeutics Gmbh Compounds, compositions, and therapeutic uses thereof
US12162895B2 (en) 2023-03-10 2024-12-10 Breakpoint Therapeutics Gmbh DNA polymerase theta inhibitor for treatment of cancer

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