WO2018169360A1 - Dérivé de quinoléine-5,8-dione comme inhibiteur de la tgase (2), et composition pharmaceutique le comprenant - Google Patents

Dérivé de quinoléine-5,8-dione comme inhibiteur de la tgase (2), et composition pharmaceutique le comprenant Download PDF

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WO2018169360A1
WO2018169360A1 PCT/KR2018/003117 KR2018003117W WO2018169360A1 WO 2018169360 A1 WO2018169360 A1 WO 2018169360A1 KR 2018003117 W KR2018003117 W KR 2018003117W WO 2018169360 A1 WO2018169360 A1 WO 2018169360A1
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alkyl
formula
alkenyl
cycloalkyl
hydrogen
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Korean (ko)
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송민수
임춘영
박가영
고은비
강지희
우서연
김숭현
황희종
이은혜
김효지
김수열
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재단법인 대구경북첨단의료산업진흥재단
국립암센터
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Publication of WO2018169360A1 publication Critical patent/WO2018169360A1/fr

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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D215/20—Oxygen atoms

Definitions

  • the present invention relates to a quinoline-5,8-dione derivative compound having a transglutaminase 2 (TGase 2) inhibitory activity, an isomer thereof, a pharmaceutically acceptable salt thereof, and a composition containing the same.
  • TGase 2 transglutaminase 2
  • Transglutaminase is a group of enzymes that form a covalent bond between a free amine group and the gamma-carboxamide group of glutamine inside a protein.It was first discovered in 1959, and its specific biochemical role was blood clotting in 1968. The protein was found in fibrin stabilizing factor (factor III).
  • TGase 2 type 2 glutaminase
  • TGase 2 expression is normally regulated. Not being found to play an important role in the pathological mechanism of many diseases.
  • TGase 2 Abnormally excessive expression of TGase 2 has been reported to play a major role in the development of diseases such as inflammatory diseases and autoimmune diseases. In addition, excessive expression of TGase 2 is known to induce neurodegenerative diseases, and recent studies have shown that tissue transglutaminase may have abnormally high levels in people with neurological diseases such as Huntington's and Parkinson's. .
  • TGase 2 plays a major role in experimental kidney and liver fibrosis, and the degree of fibrosis is reduced when the inhibitor is used to inhibit its activity.
  • An amine compound is known as a substance which suppresses TGase 2 activity, and typical examples thereof include cystamine and putrescine.
  • chemical inhibitors such as monodansylcababerine, w-dibenzylaminoalkylamine, 3-halo-4,5-dihydroisooxazole and 2-[(2-oxopropyl) thio] imidazolium derivatives have been developed. However, all are known to cause nonspecific in vivo inhibition of other enzymes.
  • TGase 2 inhibitory activity of glucosamine derivatives, chlorogenic acid, epigallocatechin gallate, curcumin, sparparm and ethacrynic acid has been known recently, it is still unclear whether significant activity will be shown in the treatment of TGase 2 related diseases in animals. It is unknown.
  • TGase 2 transglutaminase 2
  • TGase 2 which comprises a novel quinoline-5,8-dione derivative compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2.
  • the application provides a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, halogen, —C 1-6 alkyl, or —OC 1-6 alkyl
  • R 2 is hydrogen, halogen or —NH 2 , wherein one or more hydrogens of —NH 2 may be optionally substituted with R 4 ,
  • R is a C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, C 3- 10 cycloalkenyl or C 3- 10 heterocycloalkyl alkyl, wherein C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, C 3- 10 cycloalkenyl and C 3- 10 heteroaryl alkilneun cycloalkyl is unsubstituted or has at least one hydrogen of C 1- 6 alkyl, C 2- 6 alkenyl, -OH, -OC 1- 6 can be substituted with alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d, C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, or C 3- 10 heterocycloalkyl alkyl, wherein C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl and C 3- 10 heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C 1- 6 alkyl, -OH or halogen,
  • the C 3- 12 heteroaryl, and C 3- 12 heteroaryl, amino, C 3- 10 heterocycloalkyl contain 1 to 3 heteroatoms selected from O, N or S.
  • the present application is directed to a compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof; And it provides a composition comprising a pharmaceutically acceptable carrier.
  • the present application provides a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2, which is mediated by TGase 2 comprising a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient. to provide.
  • novel quinoline-5,8-dione derivative compounds, stereoisomers or pharmaceutically acceptable salts thereof according to the present invention have little side effects and exhibit an effect of inhibiting TGase 2 effectively.
  • novel quinoline-5,8-dione derivative compounds, stereoisomers or pharmaceutically acceptable salts thereof according to the present invention are for the treatment or prevention of disorders or diseases which are mediated by TGase 2 or in response to inhibitors of TGase 2 It can be usefully used.
  • FIG. 1 is a graph showing the tumor volume of the control (CT) confirmed in Experimental Example 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.
  • Figure 2 is a graph showing the tumor weight of the control (CT) confirmed in Experimental Example 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.
  • Figure 3 is a photograph showing the tumor of the control group confirmed in Experiment 3, the compound of Formula I 5 mg / kg administration group, the compound of Formula I 10 mg / kg administration group and the compound of Formula I 20 mg / kg administration group.
  • Figure 4 is a graph showing the weight of the control group and the compound of Formula I 100 mg / kg administration group confirmed in Experimental Example 3.
  • Figure 5 is a graph showing the plasma concentration of the control group and the compound of Formula I 10 mg / kg administration group confirmed in Experimental Example 4.
  • step of or “step of” does not mean “step for”.
  • the term "combination (s) thereof" included in the expression of a makushi form refers to one or more mixtures or combinations selected from the group consisting of components described in the expression of makushi form, It means to include one or more selected from the group consisting of the above components.
  • halo may be, but is not limited to, F, Cl, Br, or I.
  • alkyl or “alkyl group” may be a linear or branched, saturated or unsaturated, alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl , Hexyl, heptyl, octyl, nonyl, decyl, or isomers thereof, but is not limited thereto.
  • aryl or “aryl group”, alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring, eg, phenyl, substituted phenyl, as well as conjugated groups, Examples include, but are not limited to, naphthyl, phenanthrenyl, indenyl, tetrahydronaphthyl, indanyl, and the like.
  • the “aryl” or “aryl group” contains one or more rings having 5 or more atoms, and there may be 5 or fewer rings containing 22 or less atoms, and adjacent carbon atoms or Double bonds may be present alternately (resonance) between suitable heteroatoms.
  • the "aryl” or “aryl group” may be phenyl, phenyl substituted as described above, phenyl, naphthyl, or naphthyl substituted as described above, but is not limited thereto.
  • heteroaryl or “heteroaryl group”, alone or as part of another group, means a monocyclic or bicyclic aromatic ring containing at least one atom other than a carbon atom, for example, furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzodioxyyl, andazolyl, isoindolinyl, indenyl, quinolinyl and benzothiophenyl And the like, but are not limited thereto.
  • heteroaryl or “heteroaryl group” contains one or more rings having five or more atoms, and may have up to five rings containing up to 22 atoms, and adjacent carbon atoms or suitable heteroatoms. There may be alternating (resonant) double bonds in between.
  • heteroaryl or “heteroaryl group” may be substituted as described in the "aryl” or “aryl group”.
  • alkoxy or “alkoxy group” may include, but is not limited to, an alkoxy group having an oxygen atom bonded to an "alkyl group” as defined above.
  • amine or “amine group”, alone or as part of another group, refers to —NH 2, wherein the “amine group” may refer to one or two substituents, which may be the same or different, Such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, Optionally substituted with carbonyl or carboxyl.
  • substituents such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloal
  • the application provides a compound represented by Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen, halogen, -C 1- 6 alkyl, -OC 1- 6 alkyl,
  • R 2 is hydrogen, halogen or —NH 2 , wherein one or more hydrogens of —NH 2 may be optionally substituted with R 4 ,
  • R is a C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, C 3- 10 cycloalkenyl or C 3- 10 heterocycloalkyl alkyl, wherein C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, C 3- 10 cycloalkenyl and C 3- 10 heteroaryl cycloalkyl is unsubstituted or has one or more hydrogen may be substituted with C 1- 6 alkyl, C 2- 6 alkenyl, -OH, -OC 1- 6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d, C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, or C 3- 10 heterocycloalkyl alkyl, wherein C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl and C 3- 10 heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C 1- 6 alkyl, -OH or halogen,
  • the C 3- 12 heteroaryl, and C 3- 12 heteroaryl, amino, C 3- 10 heterocycloalkyl contain 1 to 3 heteroatoms selected from O, N or S.
  • R 1 is specifically hydrogen
  • -C 1- 3 may be an alkyl or -OC 1-3 alkyl, preferably hydrogen, -CH 3 or -O-CH 3, more preferably Preferably hydrogen or —O—CH 3 .
  • R 2 may specifically be hydrogen, Br or —NH 2 .
  • R 3 is specifically furanyl, thiophenyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzodioxyyl, indazolyl, Isoindolinyl, quinolinyl, pyridazinylamino, pyridinylamino, phenyl, indenyl, naphthalenyl, phenylamino, piperidinyl or cyclopropyl, more specifically furan-3-yl, thi Offen-2-yl, pyrazol-4-yl, pyrazin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, benzo [d] thiazole -5-yl, benzothiophen-2-yl, dihydro
  • R a may be specifically C 1- 3 alkyl, phenyl or morpholino imidazol.
  • R b may be specifically imidazol hydrogen, -NH 2, -NH (CH 3 ), C 1- 3 alkyl or C 2- 3 alkenyl.
  • R e may be specifically C 1- 3 alkyl, -OH, -OC 1- 3 alkyl, -COOH, -COOCH 3 or morpholino imidazol.
  • R 1 is —OC 1-3 alkyl
  • R 2 is hydrogen
  • R 1 is —O—CH 3 ,
  • R 2 is hydrogen
  • R 3 is pyrimidinyl, the pyrimidinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
  • R 5 is -OR a
  • R a is phenyl, the phenyl may be unsubstituted or one or more hydrogens may be substituted with —O—CF 3 .
  • R 1 is hydrogen, -C 3 alkyl, -OC 1- 1- 3 alkyl,
  • R 2 is Br
  • R 3 is furanyl, thiophenyl, pyrazolyl, pyrimidinyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl and the furanyl, thiophenyl, pyrazolyl, pyrimidy Neyl, benzothiazolyl, indazolyl, quinolinyl, phenyl, naphthalenyl or cyclopropyl may be unsubstituted or one or more hydrogens may be replaced with R 5 or ⁇ O.
  • R 1 is hydrogen, halogen, -C 1- 3 alkyl, -OC 1- 3 alkyl,
  • R 2 is —NH 2 , wherein one or more hydrogens of —NH 2 may be optionally substituted with R 4 ,
  • R 1 is hydrogen
  • R 2 is -NH 2
  • R 3 is phenyl, the phenyl may be unsubstituted or substituted with R 5 ,
  • R 5 is -OR a or a C 1- 6 alkyl, wherein the C 1- 6 alkyl in which one or more hydrogen may be substituted with R e,
  • R a is phenyl or piperidinyl, said phenyl or piperidinyl, and is unsubstituted or is at least one hydrogen may be substituted with C 1- 3 alkyl,
  • R e is morpholine.
  • R 1 is —O—CH 3 ,
  • R 2 is -NH 2
  • R 3 is pyrimidinyl or pyridinyl, wherein pyrimidinyl or pyridinyl may be unsubstituted or substituted with R 5 ,
  • R 5 is halogen or C 1- 3 alkyl, wherein C 1- 3 alkyl is optionally substituted with R e,
  • R e is halogen
  • R 1 is hydrogen, C 1-3 alkyl or —OC 1-3 alkyl
  • R 2 is hydrogen, Br or —NH 2 ,
  • R 3 is quinolinyl, naphthalenyl, indenyl, benzodioxyyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperidinyl or Cyclopropyl, the quinolinyl, naphthalenyl, indenyl, benzodioxyyl, benzothiazolyl, benzothiophenyl, isoindolinyl, indazolyl, phenylamino, pyrazinyl, pyridazinylamino, piperididi Neyl and cyclopropyl may be unsubstituted or one or more hydrogens may be substituted with R 5 or ⁇ O.
  • R is a C 1- 6 alkyl, C 1- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, C 3- 10 cycloalkenyl or C 3- 10 heterocycloalkyl alkyl, wherein R a is unsubstituted or has one or more hydrogen may be substituted with C 1- 6 alkyl, C 1- 6 alkenyl, -OH, -OC 1- 6 alkyl, -O-CF 3 or halogen,
  • R b is hydrogen, -NR c R d, C 1- 6 alkyl, C 1- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl, or C 3- 10 heterocycloalkyl alkyl, wherein C 1- 6 alkyl, C 2- 6 alkenyl, C 6- 12 aryl, C 3-12 heteroaryl, C 3- 10 cycloalkyl and C 3- 10 heteroaryl cycloalkyl or one or more unsubstituted and hydrogen may be substituted with C 1- 6 alkyl, -OH or halogen,
  • the C 3- 12 heteroaryl and C 3- 10 heteroaryl cycloalkyl may contain a hetero atom of 1 to 3 selected from O, N or S.
  • R 1 is hydrogen or —O—CH 3 ,
  • R 2 is hydrogen or —NH 2 ,
  • R 3 is phenyl, pyrimidinyl or pyridinyl, wherein the phenyl, pyrimidinyl and pyridinyl may be unsubstituted or one or more hydrogens may be substituted with R 5 ,
  • R 5 is halogen, C 1- 3 alkyl, -OR a, wherein the C 1- 3 alkyl is unsubstituted or substituted one or more hydrogen may be substituted with R e,
  • R a is phenyl or piperidinyl, said phenyl or piperidinyl, and is unsubstituted or is at least one hydrogen may be substituted with C 1- 3 alkyl or O-CF 3,
  • R e is halogen or morpholinyl.
  • the compound represented by Formula I is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in Table 1 below It may be a salt thereof, but is not limited thereto.
  • the compound represented by formula (I) is a quinoline-5,8-dione derivative compound, a stereoisomer or a pharmaceutical thereof, selected from the group consisting of compounds of the formula shown in the following [Table 2] It may be a salt thereof.
  • salts refer to salts commonly used in the medical arts, for example inorganic ionic salts, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodine, prepared from calcium, potassium, sodium and magnesium, and the like.
  • Inorganic acid prepared with acid, perchloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid , Organic acid salts prepared with glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid And amino acid salts made with sulfonate, glycine, arginine, lysine and the like prepared with naphthalenesulfonic acid, and the like, trimethylamine, triethylamine, ammonia, pyridine, Although
  • the compounds of formula (I) may contain one or more asymmetric carbons and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. Such isomers can be separated by conventional techniques, for example, compounds of formula (I) by cleavage such as column chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds of formula I can be stereospecifically synthesized using optically pure starting materials and / or reagents in known arrangements.
  • the present application is directed to a compound of Formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof; And one or more pharmaceutically acceptable carriers.
  • the carrier can be used, for example, sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, phosphoric anhydride Calcium hydrogen, or a mixture thereof may be used, but is not limited thereto.
  • the composition may include, but is not limited to, for example, an additive such as a binder, a disintegrant, a lubricant, a pH adjuster, an antioxidant, and the like.
  • an additive such as a binder, a disintegrant, a lubricant, a pH adjuster, an antioxidant, and the like.
  • the binder is, for example, starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone) , Hypromellose, hydroxypropyl cellulose, natural gums, synthetic gums, copovidone, gelatin, or mixtures thereof may be used, but is not limited thereto.
  • the disintegrating agent may include, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof may be used, but are not limited thereto.
  • starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch
  • Clay such as bentonite, montmorillonite, or veegum
  • Celluloses such as microcrystalline cellulose, hydroxypropy
  • the lubricant is, for example, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostea Latex, glyceryl palmitostearate, colloidal silicon dioxide or mixtures thereof, and the like, but are not limited thereto.
  • the pH adjusting agent may include, for example, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water, Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, calcium tribasic phosphate, and the like may be used, but are not limited thereto.
  • acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), precipitated calcium carbonate, ammonia water
  • Basic agents such as meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, calcium tribasic phosphate, and the like may be used, but are not limited thereto.
  • the antioxidant may be, for example, dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite and the like.
  • the dissolution aid may be polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium, poloxamer, and the like, but is not limited thereto.
  • compositions herein can be used for the prophylaxis or treatment of disorders or diseases mediated by TGase 2 or in response to inhibition of TGase 2 have.
  • the use of the compounds of formula (I) herein is not limited thereto.
  • the present application provides a pharmaceutical composition for the prophylaxis or treatment of a disorder or disease mediated by or in response to inhibition of TGase 2 comprising TGase 2 as an active ingredient comprising a compound of Formula I, a stereoisomer or a pharmaceutically acceptable salt thereof. to provide.
  • said disorder or condition mediated by or reactive to inhibition of TGase 2 is in a group consisting of inflammatory disease, nervous system disease, cancer, renal parenchymal disease, fibrosis or a combination thereof. It may be selected, but is not limited thereto.
  • the inflammatory diseases include, for example, degenerative arthritis, diabetes mellitus, autoimmune myositis, arteriosclerosis, Crohn's disease, inflammatory gastric ulcer, stroke, liver cirrhosis, meningitis, rhinitis, conjunctivitis, asthma, inflammatory skin disease, inflammatory bowel disease, rheumatoid inflammatory disease Or glomerulonephritis, but is not limited thereto.
  • the nervous system disease may be, for example, Alzheimer's disease, dementia, Parkinson's disease, or Huntington's disease, but is not limited thereto.
  • the cancer may include, for example, colon cancer, small intestine cancer, rectal cancer, colon cancer, anal cancer, esophageal cancer, gastric cancer, pancreatic cancer, gallbladder cancer, uterine cancer, cervical cancer, breast cancer, ovarian cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, and blood cancer. , Skin cancer, brain tumor, kidney cancer or bladder cancer, but is not limited thereto.
  • the fibrosis may be, for example, but not limited to pulmonary fibrosis or liver fibrosis.
  • the disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 is cancer, more preferably kidney cancer, brain cancer or gastric cancer.
  • a method of inhibiting TGase 2 activity in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).
  • Such subjects include, but are not limited to, mammals such as, for example, humans, monkeys, cattle, horses, dogs, cats, rabbits, rats, mice, and the like.
  • a compound of formula (I) herein for the manufacture of a medicament for the treatment of a disorder or disease mediated by TGase 2 or in response to inhibition of TGase 2 in a subject.
  • the application provides a process for the preparation of a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof.
  • the compounds of the formula (I), stereoisomers or pharmaceutically acceptable salts thereof described above are not limited to those prepared by the methods of preparation herein.
  • the method for preparing the quinoline-5,8-dione derivative compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is the same as in Scheme 1, which is obvious to those skilled in the art. This includes a manufacturing method that is modified to one level.
  • a compound of Formula 1-1 is reacted with nitric acid to synthesize a compound of Formula 1-2, and then a compound of Formula 1-3 is synthesized by a Pd / CH 2 reduction reaction. .
  • the compound of formula 1-3 is reacted with (E) -3-ethoxyacryloyl chloride to synthesize the compound of formula 1-4, and the compound of formula 1-4 is added dropwise to the sulfuric acid solution to react with formula 1-5
  • a compound of A compound of Formula 1-5 is synthesized by dissolving a compound of Formula 1-5 in a pyridine and dimethylformamide (DMF) solution and dropwise addition of phosphorus oxychloride (POCl 3 ).
  • the compound of Formula 1-8 may be synthesized by dropwise addition of an aqueous solution of cerium ammonium nitrate (CAN).
  • the compound of Formula 1-9 may be synthesized by reacting bromine with the compound of Formula 1-8.
  • the method for preparing the quinoline-5,8-dione derivative compound represented by Formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof is shown in Scheme 2, which is obvious to those skilled in the art. This includes a manufacturing method that is modified to one level.
  • a compound of Formula 10-1 is reacted with nitric acid to synthesize a compound of Formula 10-2, and then a compound of Formula 10-3 is synthesized by a Pd / CH 2 reduction reaction.
  • the compound of Formula 10-3 is reacted with acetyl chloride to synthesize the compound of Formula 10-4, and the compound of Formula 10-4 is reacted with H 2 O to synthesize the compound of Formula 10-5.
  • the compound of Formula 10-12 may be synthesized by desalting the compound of Formula 10-11.
  • step 1 1 , 2,4- Trimethoxy -5-nitrobenzene 1-2 Preparation of the compound
  • step 3 3 - Ethoxy -N- (2,4,5- Trimethoxyphenyl Acrylamide 1-4 Preparation of the compound
  • step 4 5 , 6,8- Trimethoxyquinoline -2 (1H) -one 1-5 Preparation of the compound
  • step 5 2 - Chloro -5,6,8- Trimethoxyquinoline Formula 1-6 Preparation of the compound
  • step 1 5 - Bromo -2- Methylisoindolin -1-one (Formula 5-2 Preparation of the compound
  • step 2 2 - methyl -5- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Isoindolin -1-one (Formula 5-3 Preparation of the compound
  • the 5-bromo-2-methyl synthesized in Step 1 sweep turned-1-one (Formula 5 -2, 2.1 g, 9.20 mmol ), potassium acetate (2.26 g, 23 mmol, 2.5 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (0.225 g, 0.28 mmol, 0.03 eq) and B 2 Pin 2 (2.34 g, 9.20 mmol, 1 eq) was dissolved in 1,4-dioxane (20 ml). The temperature was raised to 100 ° C. and the reaction mixture was stirred for 5 hours. After completion of the reaction, the mixture was extracted with dichloromethane.
  • step 1 3 '- Bromo -3,4- Dimethoxy -1,1'-biphenyl 9-2 Preparation of the compound
  • step 2 2 -(3 ', 4'- Dimethoxybiphenyl -3-yl) -4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan Formula 9-3 Preparation of the compound
  • step 1 4 -(4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) piperidine 10-2 Preparation of the compound
  • step 2 1 - Cyclopropyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenyl) piperidine 10-3 Preparation of the compound
  • Step 1 4- (4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) phenyl) piperidine (Formula 10 -2, 953 mg , 3.28 mmol) in tetrahydrofuran (THF) (20 ml) and methanol (20 ml), followed by (1-ethoxycyclopropoxy) trimethylsilane (3.3 ml, 16.42 mmol, 5 eq) and acetic acid (0.376 ml, 26.2 mmol, 3 eq) was added dropwise at room temperature.
  • THF tetrahydrofuran
  • methanol methanol
  • step 1 5 - Bromo -2- (4- ( Trifluoromethoxy ) Phenoxy Pyrimidine 11-3 Preparation of the compound
  • step 1 5 - Bromo -2- Phenoxypyrimidine Formula 12-2 Preparation of the compound
  • step 1 5 - Chloro -7- Nitroquinoline -8-ol (formula) 17-2 Preparation of the compound
  • step 2 7 - Aminoquinoline -8-ol (formula) 17-3
  • step 2 7 - Aminoquinoline -8-ol (formula) 17-3
  • step 2 7-aminoquinolin-8-ol (Formula 17-3 , 11 g, 68.7 mmol, 1 eq) was dissolved in THF (300 ml) and then N, N-diisopropylethylamine (48 ml, 275 mmol, 4 eq) was added dropwise and the reaction mixture was cooled to 0 ° C. Thereafter, acetylchloride (12 ml, 172 mmol, 2.5 eq) dissolved in THF (43 ml) was slowly added dropwise at the same temperature.
  • N- (8-hydroxyquinolin-7-yl) acetamide (Formula 17-5 , 14 g, 68 mmol) synthesized in step 4 was dissolved in DMF (200 ml), followed by potassium carbonate (14 g, 102 mmol, 1.5 eq) and benzylbromide (12 ml, 102 mmol, 1.5 eq) were added dropwise and stirred at 50 ° C. for 8 hours. After completion of the reaction, the mixture was dissolved in dichloromethane, filtered through celite, and the solvent was dried under reduced pressure. Thereafter, MPLC (hexanes / ethyl acetate) to separate and purify the target compound (Formula 17-6) was obtained.
  • step 6 7 - Acetamido -8-( Benzyloxy Quinoline 1- Oxide Formula 17-7 Preparation of the compound
  • step 1 4 -(4- Bromophenoxy ) Tetrahydro -2H-pyran (formula) 18-2 Preparation of the compound
  • step 2 4 , 4,5,5- Tetramethyl -2- (4- ( Tetrahydro -2H-pyran-4- Iloxy ) Phenyl) -1,3,2-dioxaborolane (formula) 18-3
  • 4 4,5,5- Tetramethyl -2- (4- ( Tetrahydro -2H-pyran-4- Iloxy ) Phenyl) -1,3,2-dioxaborolane (formula) 18-3
  • Step 1 synthesized 1- (4- (4- Bromophenoxy Piperidin-1-yl) -2,2-dimethylpropan-1-one 19-1 Preparation of the compound
  • step 2 4 -(4- Bromophenoxy Piperidine 19-2 Preparation of the compound
  • step 3 4 -(4- Bromophenoxy )-One- Isopropylpiperidine Formula 19-3 Preparation of the compound
  • step 4 1 Isopropyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2-yl) phenoxy) piperidine 19-4 Preparation of the compound
  • step 1 4 -(4- Bromophenoxy Pyridine 20-1 Preparation of the compound
  • step 2 4 -(4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Pyridine 20-2 Preparation of the compound
  • step 1 4- (4-bromophenoxy) pyridine synthesized in step 1 (Formula 20-1 , 109 mg, 0.44 mmol), potassium acetate (128 mg, 1.31 mmol, 3 eq), Pd (dppf) Cl 2 -CH 2 Cl 2 (11 mg, 0.013 mmol, 0.03 eq) and B 2 Pin 2 (133 mg, 0.52 mmol, 1.2 eq) was dissolved in DMSO (3 ml). The temperature was raised to 120 ° C and the reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite and extracted with ethyl acetate.
  • step 1 4 -(4- Bromophenoxy )-One- Methylpiperidine Formula 21-1 Preparation of the compound
  • step 2 1 - methyl -4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Piperidine 21-2 Preparation of the compound
  • step 1 4 -(4- Bromophenoxy )-One- Ethyl piperidine Formula 22-1 Preparation of the compound
  • step 2 1 -Ethyl-4- (4- (4,4,5,5- Tetramethyl -1,3,2- Dioxaborolan -2 days) Phenoxy Piperidine 22-2 Preparation of the compound
  • Step 1 methyl 1- (3- (5,6,8- Trimethoxyquinoline -2 days) phenyl) Ethanon Manufacture
  • step 2 2 -(3- Acetylphenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 3- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone (1 eq) synthesized in step 1 was dissolved in a small amount of acetonitrile (ACN), and then 0.6 M of cerium ammonium nitrate (CAN) (3 eq) aqueous solution was slowly added dropwise to 0 ° C. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • ACN acetonitrile
  • CAN cerium ammonium nitrate
  • step 1 5 , 6,8- Trimethoxy -2- (2- Methylpyrimidine Preparation of -5-yl) quinoline
  • step 2 6 - Methoxy -2- (2- Methylpyrimidine -5-yl) quinoline-5,8- Dion's Produce
  • step 1 1 -(3- (5,6,8- Trimethoxyquinoline -2-yl) phenyl) Prof Preparation of 2-en-1-one
  • reaction mixture was then separated and purified by MPLC (hexane / ethylacetate; 70:30) to give 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) prop-2-ene 1-one was obtained.
  • step 2 2 -(3- Acryloylphenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 5 , 6,8- Trimethoxy -2- Phenylquinoline Produce
  • step 2 6 - Methoxy -2- Phenylquinoline -5,8- Dion's Produce
  • step 3 7 - Bromo -6- Methoxy -2- Phenylquinoline -5,8- Dion's Produce
  • step 1 5 , 6,8- Trimethoxy Preparation of 2- (pyrimidin-5-yl) quinoline
  • step 2 6 - Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's Produce
  • step 3 7 - Bromo -6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's Produce
  • 6-methoxy-2- (pyrimidin-5-yl) quinolin-5,8-dione synthesized in step 2 (1 eq) was dissolved in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • Examples 69 and 70 were obtained using the same methods as described in Example 68, using R listed in Table 6 below in place 1 of pyrimidine-5-ylboronic acid.
  • Step 1 methyl 3- (7- Bromo -6- Methoxy -5,8- Dioxo -5,8- Dehydro Preparation of Quinolin-2-yl) benzoate
  • step 2 3 -(7- Bromo -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline -2-yl) Preparation of Benzamide
  • Methyl 3- (7-bromo-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoate synthesized in step 1 was dissolved in 7M ammonia in methanol solution. After dissolution, sodium cyanide (0.1 eq) was added dropwise at room temperature. The reaction mixture was stirred for 3 days at room temperature. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by PTLC (dichloromethane / methanol; 98: 2) to afford the title compound.
  • PTLC dichloromethane / methanol; 98: 2
  • step 1 5 , 7- Dibromoquinoline Preparation of Compounds of -8-ol
  • step 2 7 - Bromoquinoline -5,8- Dion's Produce
  • step 1 5,7-dibromoquinolin-8-ol synthesized in step 1 was slowly added dropwise to a sulfuric acid (20 eq) solution in which nitric acid (6 eq) was dissolved at 0 ° C. After stirring for 30 minutes at the same temperature, the reaction was terminated with ice water. Thereafter, the mixture was extracted with dichloromethane, the organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford 7-bromoquinoline-5,8-dione.
  • step 3 7 - Bromo -6- Ethoxyquinoline -5,8- Dion's Produce
  • step 1 2 - Phenylquinoline Preparation of 8-ol
  • step 2 5 , 7- Dibromo -2- Phenylquinoline Preparation of 8-ol
  • step 3 7 - Bromo -2- Phenylquinoline -5,8- Dion's Produce
  • step 1 5 , 6,8- Trimethoxy -2- (3- ( Trifluoromethoxy Preparation of Phenyl) quinoline
  • step 2 6 - Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • step 3 7 - Bromo -6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • 6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione synthesized in step 2 After (1 eq) was dissolved in chloroform, bromine (1.1 eq) was added dropwise at 0 ° C. and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione.
  • step 4 7 - Ah-do -6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • step 5 7 -Amino-6- Methoxy -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • Example 109 7 -Amino-2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 7 - Ah-do -2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 2 7 -Amino-2- (4- Chloro -3- Fluorophenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 5 , 6,8- Trimethoxy -2- (2- Methoxypyrimidine Preparation of -5-yl) quinoline
  • step 2 6 - Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's Produce
  • step 3 7 - Bromo -6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's Produce
  • 6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione (1 eq) synthesized in step 2 was dissolved in chloroform and then bromine (1.1 eq) at 0 ° C. ) was added dropwise and the reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (2-methoxypyrimidin-5-yl) quinolin-5,8-dione.
  • step 4 7 - Ah-do -6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's Produce
  • step 5 7 -Amino-6- Methoxy -2- (2- Methoxypyrimidine -5-yl) quinoline-5,8- Dion's Produce
  • step 1 7 - Ah-do -6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's Produce
  • step 2 7 -Amino-6- Methoxy -2- (pyrimidin-5-yl) quinoline-5,8- Dion's Produce
  • Step 1 (E)- methyl 3- (3- (7- Ah-do -6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) acrylate
  • Step 2 methyl 3- (3- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) phenyl) propanoate
  • step 1 2 -(3- Acetylphenyl ) -7- Ah-do -6- Methoxyquinoline -5,8- Dion's Produce
  • step 2 7 -Amino-2- (3- (1-hydroxyethyl) phenyl) -6- Methoxyquinoline -5,8- Dion's Produce
  • Methyl 2- (3-acetylphenyl) -7-azido-6-methoxyquinoline-5,8-dione (1 eq) synthesized in step 1 was dissolved in EtOAc / MeOH (1/1), and then Pd / C (1 eq) was added dropwise and stirred under hydrogen stream for 12 hours. After completion of the reaction, the mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • step 1 7 - Ah-do -6- Methoxy -2- (3- Nitrophenyl Quinoline-5,8- Dion's Produce
  • Example 44 using the same method as described in step 4 of Example 75, but replacing 7-bromo-6-methoxy-2- (3- (trifluoromethoxy) phenyl) quinoline-5,8-dione 7-azido-6-methoxy-2- (3- using 7-bromo-6-methoxy-2- (3-nitrophenyl) quinoline-5,8-dione (1 eq) synthesized in Nitrophenyl) quinoline-5,8-dione was obtained.
  • step 2 7 -Amino-2- (3- Aminophenyl ) -6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 2 -(3- Acetylphenyl ) -7-amino-6- Methoxyquinoline -5,8- Dion's Produce
  • step 2 2 -(3- Acryloylphenyl ) -7-amino-6- Methoxyquinoline -5,8- Dion's Produce
  • step 1 of example 40 Using the same method as described in step 1 of example 40, except that 1- (3- (5,6,8-trimethoxyquinolin-2-yl) phenyl) ethanone was synthesized in step 1 of this example.
  • the title compound was obtained using 2- (3-acetylphenyl) -7-amino-6-methoxyquinoline-5,8-dione.
  • step 1 7 - Ah-do -2- Phenylquinoline -5,8- Dion's Produce
  • step 2 7 -Amino-2- Phenylquinoline -5,8- Dion's Produce
  • step 1 7 - Bromo -2- (2- Chloropyridine -4-yl) quinoline-5,8- Dion's Produce
  • step 2 7 - Bromo -2- (2- Chloropyridine -4-yl) -6- Methylquinoline -5,8- Dion's Produce
  • step 3 7 -Amino-2- (2- Chloropyridine -4-yl) -6- Methylquinoline -5,8- Dion's Produce
  • step 1 7 - Bromo -2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • step 2 7 -Amino-2- (3- ( Trifluoromethoxy ) Phenyl) quinoline-5,8- Dion's Produce
  • Example 140 using the same method as described in Example 1, using R listed in Table 11 below instead of 3-acetylphenylboronic acid, and using 1,4-dioxane instead of dimethylether (DME) To the compound of Example 144 was obtained.
  • step 1 5 , 6,8- Trimethoxy -2-( Pyrazine Preparation of 2-yl) quinoline
  • step 2 6 - Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion Manufacture
  • Embodiments use the same method as that described for example 171, In Step 1, a 2- (tributyl's taenil) pyrazine instead of 2-methoxy-6- (tributyltin's taenil) pyrazine (Formula 16-2), the title The compound was obtained.
  • step 1 5 , 6,8- Trimethoxy Preparation of -2- (4- (trifluoromethyl) piperidin-1-yl) quinoline
  • reaction mixture was filtered through celite and the solvent was removed under reduced pressure. Extracted with ethyl acetate, washed with water, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 5,6,8-trimethoxy-2- (4- (trifluoromethyl) piperidin-1-yl) quinoline.
  • step 2 6 - Methoxy -2- (4- ( Trifluoromethyl ) Piperidin-1-yl) quinoline-5,8- Dion's Produce
  • Example 175 2 -(4,4- Difluoropiperidine -1-yl) -6- Methoxyquinoline -5,8- Dion's Produce
  • Example 176 2 , 7- Dibromo -6- Isopropylquinoline -5,8- Dion's Produce
  • Example 204 7 -Amino-6- Methoxy -2- (2- Nitrophenyl Quinoline-5,8- Dion's Produce
  • Example 205 7 -Amino-6- Methoxy -2- (6- Methoxypyrazine -2-yl) quinoline-5,8- Dion's Produce
  • Example 238 2 -Amino-4- (7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline 2-yl) benzoic acid
  • Methyl 2-amino-4- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) benzoic acid (1 eq) synthesized in Example 210 was added MeOH / After dissolving in H 2 O (1: 1), an aqueous solution of potassium hydroxide (35 eq) was added dropwise and reacted at 50 ° C. for 2.5 hours. After completion of the reaction, the mixture was neutralized with 1M aqueous hydrochloric acid, extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to afford the title compound as an orange solid.
  • step 1 7 - Bromo -6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's Produce
  • 6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione (1 eq) synthesized in Example 171 was dissolved in chloroform, and bromine (1.1 eq) was added dropwise at 0 ° C. The reaction mixture was stirred at rt for 12 h. After completion of the reaction, the mixture was extracted with dichloromethane. The organic layer was washed sequentially with H 2 O and brine, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give 7-bromo-6-methoxy-2- (pyrazin-2-yl) quinolin-5,8-dione.
  • step 2 7 - Ah-do -6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's Produce
  • step 3 7 -Amino-6- Methoxy -2-( Pyrazine -2-yl) quinoline-5,8- Dion's Produce
  • Example 240 6 -(7-amino-6- Methoxy -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 2-yl) -2-methoxynicotinic acid
  • Methyl 6- (7-amino-6-methoxy-5,8-dioxo-5,8-dihydroquinolin-2-yl) -2-methoxynicotinic acid (1 eq) synthesized in Example 214 was prepared using MeOH. / H 2 O (5/1), NaOH (5 eq) was added dropwise and stirred at 70 °C for 3 hours, and then cooled to room temperature. After completion of the reaction, the mixture was neutralized with 1M aqueous hydrochloric acid. The organic layer was extracted with ethyl acetate, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC (dichloromethane / methanol; 90:10) to afford the title compound.
  • Step 1 N- (2- (4- Chloro -3- Fluorophenyl ) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide
  • step 2 7 -Amino-2- (4- Chloro -3- Fluorophenyl Quinoline-5,8- Dion's Produce
  • N- (2- (4-chloro-3-fluorophenyl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was added to methanol. After dissolving, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • Step 1 N- (2- (5- Methoxypyrazine 2-yl) -5,8- Dioxo -5,8- Dihydroquinoline Preparation of 7-yl) acetamide
  • N- (2- (5-methoxypyrazin-2-yl) -5,8-dioxo-5,8-dihydroquinolin-7-yl) acetamide synthesized in step 1 was dissolved in methanol and then 4M.
  • Aqueous solution of potassium hydroxide (1.1 eq) was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • Example 265 Using the same method as described in Example 265, the title compound was obtained using 4- (trifluoromethyl) phenylboronic acid instead of 2-fluorophenylboronic acid.
  • N- (5,8-dioxo-2- (4- (trifluoromethyl) phenyl) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in Example 266 was methanol After dissolving in, 4M potassium hydroxide (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane and then anhydrous MgSO 4 Dried, and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • Step 1 N- (5,8- Dioxo -2-( Phenylamino ) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide
  • reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide.
  • Step 2 Preparation of 7-amino-2- (phenylamino) quinoline-5,8-dione
  • N- (5,8-dioxo-2- (phenylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) synthesized in step 1 was dissolved in methanol and then 4M potassium hydroxide A seed (1.1 eq) aqueous solution was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • Step 1 N- (5,8- Dioxo -2- (pyridine-2- Monoamino ) -5,8- Dihydroquinoline Preparation of 7-yl) acetamide
  • Step 2 Preparation of 7-amino-2- (pyridin-2-ylamino) quinoline-5,8-dione
  • step 1 N- (5,8-dioxo-2- (pyridin-2-ylamino) -5,8-dihydroquinolin-7-yl) acetamide (1 eq) was dissolved in methanol and then 4M Aqueous solution of potassium hydroxide (1.1 eq) was added dropwise and stirred at 70 ° C for 30 minutes. After completion of the reaction, the mixture was extracted with dichloromethane, dried over anhydrous MgSO 4 , and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by MPLC to give the title compound.
  • SRB sulforhodamine B
  • Renal cancer cell lines ACHN cells (containing 100 ⁇ l, containing 5,000 to 40,000 cells / well, adjusted according to the doubling time of each cell line) were incubated in 96-well microtiter plates. After 24 hours, 100 ⁇ l of the compound of Formula I herein were added to each well and the cultures were incubated at 37 ° C. for 48 hours. The cells were fixed with trichloroacetic acid (50 ⁇ l per well). Plates were incubated at 4 ° C. for at least 1 hour and up to 3 hours. The liquid was removed from the plate, washed five times with water and dried at room temperature for 12 to 24 hours.
  • Immobilized cells were stained with 100 ⁇ l SRB for 5 minutes at room temperature and plates were washed three times with 1% glacial acetic acid. And dried at room temperature for about 12 to 24 hours. SRB stained cells were lysed in 10 mM Trizma base and absorbance was measured at 515 nm.
  • GI 50 Greenth Inhibition of 50%
  • Tz is the average cell number (cells / ml) at the start of the culture
  • Ti is the average cell number (cells / ml) 48 hours after drug treatment
  • C is the average cell number (cells / ml) after 48 hours of the control group.
  • Transglutaminase measured the binding of [1,4, -14 C] putresin to succinated casein and observed that NDGA competes with putrescine to inhibit its response to the compounds of Formula I TGase 2 inhibitory activity was measured.
  • succinylated casein (Calbiochem, Cat. No. 573464) was dissolved in 2% concentration in 0.1 M tris-acetic acid buffer (pH 8.0) containing 10 mM CaCl 2 , 0.15 M NaCl, 1.0 mM EDTA. 5 mM DTT (1,4-dithiothritol) was also added immediately before use of the solution.
  • the reaction was terminated by the addition of 2 ml of cold 5% trichloroacetic acid (TCA). Assay vials were held at 4 ° C. for at least 1 hour to fix. The assay mixture was filtered through glass-fiber filter paper discs (Whatman GF / A) and washed with cold 5% TCA. The filter was placed in a counting vial and a scintillation cocktail solution was added. Counting vials were vortexed for 5 seconds and placed in the shaker for 30 minutes before counting.
  • TCA cold 5% trichloroacetic acid
  • Renal cancer cells were transplanted to cause kidney cancer in the mouse, and the compound synthesized in Example 120 was added to a solution consisting of 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water, and 5% soybean oil to give 5 mg. / kg, 10 mg / kg or 20 mg / kg was administered once a day for 6 days a week for 7 weeks, the negative control was 7.5% poloxamer, 30% polyethylene glycol, 57.5% distilled water and 5% soybean oil Solution was administered. The results are shown in [Fig. 1] to [Fig. 4] and [Table 26].
  • mice administered the compound of Formula I are much smaller in size and weight of the tumor than in the control group.
  • body weight of the mouse does not change significantly by the administration of the compound of formula (I), it can be seen that the compound of formula I is less toxic.
  • mice were orally administered with the compound synthesized in Example 120 at a 10 mg / kg dose, and blood was collected for 4 hours through the tail vein, and the concentration in blood was analyzed by LC-MS / MS. Quantitative results in blood are shown in [FIG. 5], and pharmacokinetic parameters are shown in [Table 27].
  • the compound of formula I synthesized in Example 120 had a rapid decrease in plasma concentration. As shown in Table 27, T max was 8.1 minutes and the average half-life was 79.9 minutes. It can be expected to disappear quickly .

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé dérivé de quinoléine-5,8-dione représenté par la formule chimique (I), son stéréoisomère, ou son sel pharmaceutiquement acceptable. Le composé représenté par la formule chimique (I), de la présente invention, présente un effet d'inhibition de la TGase (2), et une composition pharmaceutique le contenant peut être utile pour prévenir ou traiter les troubles ou les maladies qui sont médiés-es par la TGase (2) ou qui réagissent à l'inhibition de la TGase (2).
PCT/KR2018/003117 2017-03-16 2018-03-16 Dérivé de quinoléine-5,8-dione comme inhibiteur de la tgase (2), et composition pharmaceutique le comprenant WO2018169360A1 (fr)

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KR1020170032952A KR102002446B1 (ko) 2017-03-16 2017-03-16 TGase 2 억제제로서의 퀴놀린-5,8-디온 유도체 및 이를 포함하는 약제학적 조성물
KR10-2017-0032952 2017-03-16

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WO2020111263A1 (fr) * 2018-11-30 2020-06-04 Otsuka Pharmaceutical Co., Ltd. Composés hétérocycliques pour le traitement de l'épilepsie

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KR102258267B1 (ko) * 2018-03-16 2021-05-28 재단법인 대구경북첨단의료산업진흥재단 TGase 2 억제제로서의 퀴놀린-5,8-디온 유도체 및 이를 포함하는 약제학적 조성물
CN110240590A (zh) * 2019-07-16 2019-09-17 广州新民培林医药科技有限公司 一类嘧啶喹啉衍生物及其制备方法和应用

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