WO1999057103A1 - Derive d'imidazole condense et agent therapeutique permettant de traiter une maladie du foie - Google Patents

Derive d'imidazole condense et agent therapeutique permettant de traiter une maladie du foie Download PDF

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WO1999057103A1
WO1999057103A1 PCT/JP1999/002309 JP9902309W WO9957103A1 WO 1999057103 A1 WO1999057103 A1 WO 1999057103A1 JP 9902309 W JP9902309 W JP 9902309W WO 9957103 A1 WO9957103 A1 WO 9957103A1
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group
carbon atoms
pyridyl
compound
phenyl
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Japanese (ja)
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Masaaki Nagasawa
Hiroyasu Nishioka
Takanori Suzuki
Yoshihide Segawa
Naoki Tsuzuike
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Zeria Pharmaceutical Co Ltd
Nippon Chemiphar Co Ltd
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Zeria Pharmaceutical Co Ltd
Nippon Chemiphar Co Ltd
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Priority to AU35388/99A priority Critical patent/AU3538899A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • the present invention relates to a novel condensed imidazole derivative effective as a medicinal component of a therapeutic agent for liver disease.
  • liver disease includes interferon (IFN), ursodeoxycholic acid, glycyrrhizic acid, DL-methionine, and glycyrrhizin.
  • IFN interferon
  • ursodeoxycholic acid ursodeoxycholic acid
  • glycyrrhizic acid glycyrrhizic acid
  • DL-methionine glycyrrhizin
  • Other compounds, such as glycyrrhizin are generally ineffective for oral administration and are usually used as injectable injections. Therefore, there is a strong demand for a therapeutic agent for liver disease that has no serious side effects and that shows a remarkable effect even by oral administration.
  • Japanese Patent Publication No. 36-10978 describes a 1-phenylbenzimidazole-2-thioether derivative having an antibacterial activity.
  • Japanese Patent Application Laid-Open No. 51-143696 discloses 1,3-dihydroimidazo [4,5-b] pyridin-2-one which is useful as an analgesic, antipyretic and anti-inflammatory agent. Thion is described.
  • Japanese Patent Application Laid-Open No. H8-73439 discloses a 1-benzyl-1,3, -dihydro-2H-benzimidazol-2-one derivative exhibiting affinity for a vasopressin and / or oxytocin receptor. .
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a novel condensed imidazole derivative having a chemical structure represented by the following general formula (1) or (2) shows an excellent therapeutic effect on liver disease. It has been found. Accordingly, the present invention provides a condensed imidazole derivative having the chemical structure represented by the general formula (1) or (2) or a pharmaceutically acceptable salt thereof, and a treatment for a liver disease containing the same as an active ingredient. In medicine.
  • X and Z represent N or CH;
  • A represents an N or C one R 5;
  • Y is, O, S represents SO, SO, or NH;
  • k represents 0 or 1;
  • m represents 0, 1 or 2;
  • n represents 1 or 2;
  • R 1 represents a phenyl group, pyridyl Group, dihydropyridyl 1-4-one group, phenyl group having 1-3 substituents, pyridyl group having 1-3 substituents, or dihydropyridyl 1-4-one having 1-3 substituents
  • R 2 and R 4 are a phenyl group, a pyridyl group, a fuunyl group having 1 to 3 substituents, a benzyl group having 1 to 3 substituents, or 1 to 3 substituents It represents a pyridyl group having a proviso that if X is CH, R 2 is a pyridyl group from 1 to 3 location
  • R 3 and R 4 are alkyl groups having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, C 1 -C Up to 6 alkoxy, hydroxy, halogen, nitro, cyano, amino, formyl, formylamino, alkylamino with 1 to 6 carbon atoms, cycloalkylamino with 5 to 7 carbon atoms Group, dialkylamino group having 2 to 12 carbon atoms, aralkylamino group having 7 to 10 carbon atoms, alkanoyl group having 2 to 7 carbon atoms, alkanoylamino group having 2 to 7 carbon atoms, carbon atom An N-alkanoyl N-alkylamino group, an aminocarbonyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a dialkylaminosulfony
  • a condensed imidazole derivative having a chemical structure represented by the general formula (1) or (2) of the present invention and a pharmaceutically acceptable salt thereof, and a method for synthesizing the derivative and the salt; and the condensed imidazole derivative or The therapeutic agent for liver disease containing the pharmacologically acceptable salt as an active ingredient will be described in detail.
  • R 1 and R 2 preferably represent the following groups, respectively.
  • R 1 is a phenyl group, a pyridyl group, a dihydropyridinole-4-one group, a halogen atom, a nitro group, an amino group, an alkylamino group having 1 to 6 carbon atoms, a formyl group, a formylamino group, a carbon atom
  • R 2 is a phenyl group, a pyridyl group, or a halogen atom, the number of carbon atoms:! Alkyl group having up to 6 carbon atoms, halogenated alkyl group having 1 to 6 carbon atoms, alkanol group having 2 to 7 carbon atoms, cyano group, amino group, nitro group, alkoxy group having 1 to 6 carbon atoms, carbon atom
  • R 1 and R 2 respectively represent the following groups.
  • R 1 is a phenyl group, a pyridyl group, a dihydropyridyl 1-4-one group, an aminophenyl group, a dimethylaminophenyl group, a nitrophenyl group, a carboxyphenyl group, a methoxycarbonylphenyl group, or an ethoxycarbonylphenyl group.
  • R 2 represents a phenyl group, a pyridyl group, a trifluoromethylphenyl group, a nitrophenyl group, a cyclophenyl group, a bromophenyl group, a cyanophenyl group, an acetinolphenyl group or a fluorophenyl group.
  • R 3 and R 4 preferably represent the following groups, respectively.
  • R 3 is a pyridyl group, a dihydroxypyridyl 4-one group when Z is N, or a halogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, a nitro group, an amino group, and a carbon atom of 1 Alkylamino group, formyl group, formylamino group of up to 6, dialkylamino group of 2 to 12 carbon atoms, cycloalkylamino group of 5 to 7 carbon atoms, aralkylamino group of 7 to 10 carbon atoms, carbon atom Alkanoylamino group having 2 to 7 carbon atoms, N-alkanolyl N-alkylamino group having 3 to 10 carbon atoms, carboxyl group, alkoxycarbonyl group having 2 to 7 carbon atoms, carbon atom having 2 to 12 carbon atoms A phenyl group or a pyridyl group having a substituent selected from the group consisting of
  • R 4 is a phenyl group, a pyridyl group, or a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 2 to 7 carbon atoms, a cyano group, Amino group, alkylamino group having 1 to 6 carbon atoms, dialkylamino group having 2 to 12 carbon atoms, cycloalkylamino group having 5 to 7 carbon atoms, aralkylamino group having 7 to 10 carbon atoms C 2 -C 7 alkylamino group, nitro group, C 1 -C 6 alkoxy group, C 2 -C 7 alkoxycarbonyl group, carboxyl group, aminocarbonyl group, 1-ureide A phenyl group, a pyridyl group, or a benzyl group having a substituent selected from the group consisting of a group or a
  • R 3 and R 4 respectively represent the following groups.
  • R 3 when Z is N, a pyridyl group, a carboxyphenyl group, an aminophenyl group, an acetylaminophenyl group, a methylaminophenyl group, an N-acetyl-N-methylaminophenyl group, an N-acetyl group N-ethylaminophenyl, N-acetyl-N-n-propylaminophenyl, N-acetyl-N-isopropylpropylamino, N-isopropylcarbonyl N-methylaminophenyl, formyl Aminophenyl group, dimethylaminophenyl group, dichloropyridyl group, cyclopentylaminophenyl group, phenylethylaminophenyl group or hydroxyphenyl group, and when Z is CH, pyridyl group, aminophenyl group Represents a benzyl group or an amino
  • R 4 is phenyl, pyridyl, nitrophenyl, trifluoromethylphenyl, methoxyphenyl, cyanophenyl, acetylphenyl, ethoxycarbonylphenyl, aminocarbonylphenyl, carboxyphenyl Represents a phenyl group, a chlorophenyl group, an 11-ureidophenyl group, an aminophenyl group, an acetylmethylaminophenyl group, or a dimethylaminophenyl group.
  • Alkyl group having 1 to 6 carbon atoms For example, methyl, ethyl, propyl, isopropynole, butynole, isobutynole, sec butynole, tert-butynole, pentynole, hexynole
  • Halogenated alkyl groups having 1 to 6 carbon atoms For example, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifinoleolomethyl, trichloromethyl, fluorethyl, chloroethylenol, bromoethylenol, Edo etinore, diphnoreolochinore, dichloroechinore, jib mouth moet ⁇ trifinorechore ⁇ /, trichloroechinore, tetrahnoreolochinore, tetrachloroechinore, tetrachloroenochinore, pentahunore Chlorophorenomethinole, Chlorophnorelomethinole, Bromochnorelomethinole, Bromochloromethinole,
  • Alkoxy group having 1 to 6 carbon atoms For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy
  • Halogen atom For example, fluorine, chlorine, bromine, iodine
  • alkylamino group having 1 to 6 carbon atoms for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino
  • Cycloalkylamino group having 5 to 7 carbon atoms for example, cyclopentylamino, cyclohexylamino, cycloheptylamino
  • dialkylamino group having 2 to 12 carbon atoms for example, dimethylamino, getylamino, dipropylamino, diisopropylamino, dibutylamino, disobutinoamino, disec-butinoleamino, dipentylamino, dihexylamino, methylethyl Amino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, methyl sec-butylamino, methyltert-butylamino, methylpentylamino, methylhexylamino, ethylpropylamino, ethylisopropylamino, Ethylbutylamino, ethylisobutylamino, ethyl sec-butylamino, ethyltert-butylamino, ethylp
  • aralkylamino group having 7 to 10 carbon atoms for example, benzylamino, phenylethylamino, phenylpropylamino, phenylbutylamino
  • Alkanol group having 2 to 7 carbon atoms for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and vivaloyl
  • alkanoylamino group having 2 to 7 carbon atoms eg, acetylamino, propionylamino, butyrylamino, isobutyrylamino, octyleramino, iso Valerylamino, Vivaloylamino, Cyclopentylcarbonylamino, Cyclohexinolecanoleboninoleamino, tert-Butinolecanoleboninoleamino
  • N-alkanoyl-N-alkylamino group having 3 to 10 carbon atoms For example, N-acetinolate N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N_n-propylamino, N-acetinolate N-isopropylamino, N-isopropinolecanoleponyl N-methinoleamino
  • (2 0) alkoxycarbonyl alkenyl group having a carbon number of 2-7 Example, main butoxycarbonyl, ethoxycarbonyl Kano levo alkenyl, propoxy Kano levo Nino les, isopropoxide Shikano levo sulfonyl, blanking butoxycarbonyl, isobutoxycarbonyl, S ec - Butoxycarbonyl, tert-butoxycanolebonyl, pentynoleoxycarbonyl, hexyloxycarbonyl
  • a dialkylaminosulfonyl group having 2 to 12 carbon atoms e.g., dimethylaminosulfonyl, acetylaminosulfonyl, dipropynoleaminosulfonyl, diisopropylaminosulfonyl, dibutylaminosulfonyl, diisobutylaminosulfonyl, Di sec-butylaminosulfonyl, ditert-butylaminosulfonyl, dipentylaminosulfonyl, dihexylaminosulfonyl, methylethylaminosulfonyl, methylpropylaminosulfonyl, methylisopropylaminosulfonyl, methylbutylaminosulfonyl, methinole Isobutynoleaminosulfonyl, methyl sec-butylaminosulfonyl, methinole
  • R e represents H.
  • R 5 And R 6 preferably represent H or a group of atoms which together form a benzene ring with the carbon atom to which they are attached.
  • NS 1 1 4 Pyridyl 3-acetylfueni 5 NS 1 0 4 -Pyridyl 3 Nitrophenyl 6 NS 1 0 2 -Pyridyl 3 .Nitrophenyl 7 NS 1 0 3 -Pyridyl 3 ⁇ Nittophenyl 8 NS 1 0 Phenyl 3 'Nitrophenyl 2 9 NS 1 0 4 -Pyridyl 3 Cyanophenyl 0 NS 1 0 4—Pyridyl 3
  • the compound of the general formula (1) can be obtained from a known compound or a compound synthesized by a method according to a known method, for example, by any one of the following synthetic routes (I), ( ⁇ ), and (III) It can be manufactured by the method described above.
  • the method is carried out by a method of adding an alkali and a simple halogen such as chlorine, bromine or the like, or a halogen hydrate.
  • the solvent is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include halogen solvents such as chloroform, methylene chloride and 1,2-dichloroethane, benzene solvents such as toluene, ethers, dioxane, and tetrahydrofuran. Polar solvents such as ether solvents and dimethylformamide can be used.
  • the ability to convert the diarylamine derivative (3) into an acid halide, or the action of a condensing agent, is activated, and then the soda azide is reacted, or diphenyl is directly reacted.
  • the reaction is carried out by heating or heating.
  • a polar solvent such as a halogen-based solvent, an ether-based solvent, a benzene-based solvent, or dimethylformamide is used.
  • the imidazoline compound (4a, 4b) can be led to the condensed imidazole derivative of the general formula (1) by halogenating with a halogenating agent and then reacting the compound (5).
  • the reaction between the halide of the imidazoline compound and the compound (5) is carried out, for example, in a polar solvent such as a halogen-based solvent, an ether-based solvent, a benzene-based solvent, or dimethylamide in a solvent such as triethylamine or diisopropylethylamine.
  • the reaction can be carried out at room temperature or by heating in the presence of a base such as an organic amine, sodium hydride, sodium hydroxide, hydroxylic sodium, sodium hydrogencarbonate or carbonic acid.
  • Some of the condensed imidazole derivatives of the general formula (1), wherein X is N, can be obtained by the method described in Japanese Patent Application Laid-Open No. 51-43696.
  • the compound can be produced using an H-imidazoline compound by a method similar to the method described in the above synthetic route (I).
  • Q-oxygen atom or zeo atom that is, an imidazoline derivative (6) is reacted with an aminoarylamine derivative (6) by carbon disulfide or urea according to a method described in JP-A-51-143696. 7a, 7b, which are tautomers).
  • This reaction can be performed, for example, by adding carbon disulfide or urea to an ethanol solution of the aminoarylamine derivative (6) in the presence of a base such as sodium hydroxide, and heating the mixture to reflux.
  • the imidazoline derivative (7a, 7b) is halogenated with a halogenating agent, and the compound (8) is reacted with the compound (8) in the same manner as described in the above synthesis route (I). This can lead to a condensed imidazole derivative of the general formula (1).
  • condensed imidazole derivatives of the general formula (1) wherein X is N can be obtained by the method described in JP-A-51-143696. It can be produced using an H-imidazoline compound by a method similar to the method described in the above synthetic route ( ⁇ ).
  • R hydrogen atom, lower alkoxy group or halogen atom. That is, the condensed imidazole derivative represented by the general formula (1), wherein k is 0, reacts the aminoarylamine derivative (6) with the carbonyl compound (9) Alternatively, it can be manufactured. The reaction can be carried out, for example, by heating the aminoarylamine derivative (6) and the carbonyl compound (9) in a polar solvent such as dimethylformamide.
  • R is a hydrogen atom
  • a condensed imidazole derivative represented by the general formula (1 ′) can be obtained by further treatment with an oxidizing agent such as iodine.
  • the compound of the general formula (2) is produced from a known compound or a compound synthesized by a method according to a known method, for example, by any one of the following synthetic routes (I) and (II) be able to.
  • H a I halogen atom
  • a di-lamine derivative (10) was produced by a method according to the method described in Japanese Patent Application Laid-Open No. 7-504676, and this diarylamine derivative (10) was converted to an acid amide Hoffman.
  • a isocyanato group By subjecting the hydroxycarbonyl group of the diarylamine derivative (10) to a isocyanato group by a known reaction such as a rearrangement reaction, a Curtius rearrangement reaction of acylazide, and a LOSSEN rearrangement reaction, the imidazoline compound (11a , Lib, which are tautomers).
  • a diarylamine derivative (10) is converted into an acid halide or a hydroxycarbonyl group is activated by the action of a condensing agent.
  • the method is carried out by a method of adding an alkali and a simple substance such as chlorine, bromine or the like or a simple substance such as hydrochloride.
  • the solvent is not particularly limited as long as it does not participate in the reaction.
  • halogen solvents such as chloroform, methylene chloride, and 1,2-dichloroethane
  • benzene solvents such as toluene, ether, dioxane, and the like.
  • An ethereal solvent such as tetrahydrofuran and a polar solvent such as dimethylformamide can be used.
  • a diarylamine derivative (10) is converted into an acid halide, or a condensing agent is activated to activate a hydroxycarbonyl group.
  • the reaction is carried out by directly reacting difluorophosphoryl azide to obtain an acyl azide, followed by heating or heating.
  • solvent examples include polar solvents such as chloroform, methylene chloride, halogen solvents such as 1,2-dichloroethane, benzene solvents such as toluene, ether solvents such as ether, dioxane, and tetrahydrofuran, and dimethylformamide. Solvents can be used.
  • the imidazoline compound (11a, lib) can be converted to a condensed imidazole derivative of the general formula (2) by reacting with the halogen compound (12).
  • the reaction is carried out, for example, in a polar solvent such as a halogen-based solvent, an ether-based solvent, a benzene-based solvent, or dimethylamide, in an organic amine such as triethylamine, diisopropylethylamine, sodium hydride, sodium hydroxide, or the like.
  • the reaction can be performed at room temperature or by heating in the presence of a base such as potassium hydroxide, sodium hydrogen carbonate, or potassium carbonate.
  • Some of the condensed imidazole derivatives represented by the general formula (2) wherein X is N can be synthesized by using the 1 H-imidazoline compound obtained by the method described in JP-A-51-143696. It can be produced by a method similar to the method described in the route (I).
  • an imidazoline derivative (14a, 14b, which is a tautomer) is obtained by reacting an aminoarylamine derivative (13) with urea or the like by a method according to the method described in JP-A-51-143696. ) Is obtained.
  • This reaction can be carried out, for example, by adding urea to an ethanol solution of the aminoarylamine derivative (13) in the presence of a base such as sodium hydroxide and heating the mixture to reflux.
  • this imidazoline derivative (14a, 14b) By reacting with the halogen compound (15) in the above, a condensed imidazole derivative represented by the general formula (2) can be obtained.
  • This reaction can be performed in the same manner as in the synthesis route (I).
  • Some of the condensed imidazole derivatives represented by the general formula (2), wherein X is N, can be obtained from 1H-imidazoline obtained by the method described in JP-A-51-143696.
  • the compound can be produced by a method similar to the method described in the above synthetic route (II) using the compound.
  • the condensed imidazole derivative represented by the general formula (1) or (2) is further subjected to a known oxidation reaction, reduction reaction, alkylation reaction, acylation reaction, rearrangement reaction, or the like to obtain another condensed imidazole derivative ( It can lead to 1) or (2).
  • the condensed imidazole derivative represented by the general formula (1) or (2) and a pharmacologically acceptable salt thereof of the present invention can be converted into a salt according to a conventional method.
  • Such salts include, for example, acid addition salts with inorganic salts such as hydrochloride, carbonate, sulfate, phosphate, hydrobromide, hydroiodide, or acetate, oxalate, malonic acid
  • Acid addition salts with organic acids such as salts, succinates, maleates, fumarates, lactates, malates, citrates, tartrates, methanesulfonates, or sodium salts, potassium salts,
  • Inorganic salts such as calcium salts and magnesium salts; and organic salts such as pyridine salts, ammonium salts, triethylamine salts, and ethanolamine salts.
  • the present invention includes various solvates such as hydrates of the condensed imidazole derivative represented by the general formula (1) or (2) of the present invention and pharmaceutically acceptable salts thereof, and polymorphs thereof.
  • the substances in the form include those in the form of a racemate, each diastereomer, a mixture of diastereomers, and all optical isomers.
  • the condensed imidazole derivative represented by the general formula (1) or (2) and a pharmacologically acceptable salt thereof of the present invention are particularly useful as a therapeutic agent for liver disease, and are commonly used for oral administration to humans.
  • Imidazole derivative represented by the general formula (1) or (2) which is a pharmaceutically active ingredient of the therapeutic agent for liver disease of the present invention, which can be used as a drug or parenteral agent (injection), and a pharmacologically acceptable salt thereof
  • injection parenteral agent
  • a pharmacologically acceptable salt thereof for the formulation of The usual methods in the technical field of formulation can be used, and as the dosage form, general dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories, etc. are used it can.
  • excipients include lactose, D-mannitol, crystalline cellulose, glucose and the like.
  • disintegrants include starch, carboxymethylcellulose calcium (CMC-Ca), and the like.
  • binder include hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and the like.
  • lubricant include magnesium stearate, talc and the like.
  • the dose to human is the amount of the condensed imidazole derivative represented by the general formula (1) or (2), which is the active ingredient of the therapeutic agent for liver disease of the present invention, and the pharmacologically acceptable salt thereof.
  • an amount in the range of about 0.5 mg to 100 mg per day is selected for oral administration, and an amount in the range of about 5 mg to 100 mg per day for oral administration is usually used. To be elected.
  • the condensed imidazole derivative represented by the general formula (1) or (2) and a pharmacologically acceptable salt thereof according to the present invention may be used, if necessary, in the treatment of known liver diseases such as interfuron and dalityrrhizin.
  • a therapeutic agent for liver disease can also be used in combination with the active ingredient of the drug.
  • the condensed imidazole derivative represented by the general formula (1) or (2) of the present invention has an excellent transaminase activity inhibitory effect in a mouse liver injury model induced by concanaparin A, which is a useful liver disease model. In addition, it also shows a significant inhibitory effect in the lipopolysaccharide-galactosamine-induced liver injury model. Therefore, the condensed imidazole derivatives and pharmacologically acceptable salts thereof of the present invention are useful as therapeutic agents for liver diseases such as hepatitis C, alcoholic hepatitis, and cirrhosis.
  • test compound was suspended or dissolved in a 0.5% aqueous methylcellulose solution, and 30 mg / kg of this suspension or solution was orally administered 1 hour before administration of concanavalin A.
  • a 0.5% methylcellulose aqueous solution was used as a control.
  • mice Seven-week-old male BALBZc mice (Charles River Japan Co., Ltd.) were used as groups of 6 mice, and an aqueous solution of D-galactosamine was administered intraperitoneally at a rate of 70 Omg / g, followed by lipopolysaccharide injection. A saline solution was administered at a dose of 3 / ig / kg via the tail vein.After 8 hours, orbital blood was collected under ether anesthesia, and GPT (serum) obtained by centrifuging the collected blood was used. Transaminase) activity was measured.
  • test compound was suspended or dissolved in a 0.5% aqueous methylcellulose solution, and this suspension or solution was orally administered at 30 mg / kg 1 hour before administration of D-galactosamine and lipopolysaccharide. .
  • a 0.5% aqueous methylcellulose solution was used as a control.
  • the test results are shown in Table 3 below.
  • the suppression rate is a value calculated by the following equation.
  • 3- (3-dithiophenyl) 1 3-dihydroimidazo [4,5-b] pyridin-2-one (40.0 g), phosphorus pentachloride (36.0 g), and oxychloride (200 mL), and the mixture was stirred under reflux with heating for 2 days. After allowing the reaction solution to cool, it was added to ice water, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (NHS iO 2 (NH—DM1020, manufactured by Fuji Silicon Ltd.), ethyl acetate). The product was triturated in ethyl ether to give 12.1 g of the title compound. Yield 28%
  • 3-Hydroxypyridine (208 mg) was added to a suspension of 60% sodium hydride (88 mg) in dimethylformamide (8 mL), and the temperature was raised from room temperature to 50. The mixture was stirred for 15 minutes while increasing the temperature to C. Next, add 3- (3-nitrophenyl) -12-chloro-3H-imidazo [4,5-b] pyridine (400 mg) obtained in 3) above, and raise the temperature from 50 ° C to 80 ° C. Stir for 15 minutes while increasing the temperature. After allowing the reaction solution to cool, ice water was added, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to obtain the title compound (118 mg). 24% yield
  • Example 4 4-pyridyl) methyl-3- (3-nitrophenyl) -1,3-dihydroimidazo [4,5-b] pyridin-2-one (Compound No. 42) Same method as in Example 1.
  • 3- (3-nitrophenyl) 1-1,3-dihydroimidazo [4,5-b] pyridin-2-one (400 mg) obtained in Step 4 in dimethylformamide solution was treated with 4-picolyl chloride 'hydrochloride (300 mg). And potassium carbonate (430 mg) were added, and the mixture was stirred at an internal temperature of 80 ° C for 3 hours.
  • the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, and then recrystallized from ethyl acetate to obtain the title compound (300 mg). 55% yield
  • N- (3-Nitrophenyl) -1,2-phenylenediamine (575 mg) and 4-pyridinecarbaldehyde (32 lmg) were heated at 110 ° C. (outer bath temperature) for 10 minutes.
  • Dimethylformamide (10 mL) and iodine (400 mg) were added thereto, and the mixture was heated at 110 ° C (outer bath temperature) for 3 hours.
  • the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform. This solution was washed with an aqueous solution of sodium thiosulfate, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from ethanol to obtain the title compound (20 Omg). Yield 25%
  • Example 8 1- (4-Aminofueniru) methyl - 3 - (3-nitrophenyl) - 1, 3- dihydric Doroimidazo [4, 5-b] pyridine one 2-one (Compound No. 4 4)
  • Example 20 1- (4-dimethylamino ⁇ Minofu enyl) methyl-3 - (3-black port phenyl) one 1, 3-dihydrazide Doroimidazo [4, 5-b] pyridine one 2-one (Formula compound No. 56 )
  • Example 25 4-Pyridyl) methyl-3- (4-nitrophenyl) 1-13-dihydroimidazo [4,5-b] pyridin-2-one (Compound No. 61) The title compound was obtained in a similar manner.
  • Example 26 1- (4-pyridyl) methyl-1- (3-pyridyl) -13 dihydroimidazo [4,5-b] pyridin-2-one (Compound No. 62) The method described in Example 4 The title compound was obtained in a similar manner to.
  • Example 28 1- (4-pyridyl) methyl-1- (3-acetylphenyl)-, 3-dihydromidazo [4,5-b] pyridin-2-one (Compound No. 64 The method described in Example 4 The title compound was obtained in a similar manner to.
  • Example 34 2- (4-Dimethylaminophenyl) methylthio-3- (3-ditrophenyl) -1H-imidazo [4,5-b] pyridine (Compound No. 2) The method described in Example 3 In a similar manner, the title compound was obtained.

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Abstract

L'invention concerne un dérivé d'imidazole condensé représenté par la formule (1) ou (2). Dans lesdites formules, X et Z sont N ou CH, A est N ou C-R5, Y est O, S, SO, SO¿2? ou NH, k vaut 0 ou 1, m vaut 0, 1 ou 2 et n vaut 1 ou 2; R?1¿ est un groupe phényle, un groupe pyridyle, un groupe dihydropyridyle-4-one ou autre du même genre; R2 et R4 sont un groupe phényle, un groupe pyridyle, un groupe phényle substitué ou autre du même genre; et R5 et R6 sont ensemble H ou un groupe d'atomes formant une chaîne aromatique avec les atomes de carbone auxquels ils sont rattachés. Il peut également s'agir d'un sel pharmaceutiquement acceptable du dérivé en question, ce dérivé ou ce sel constituant un agent thérapeutique efficace pour traiter une maladie du foie, sans effet néfaste important.
PCT/JP1999/002309 1998-04-30 1999-04-30 Derive d'imidazole condense et agent therapeutique permettant de traiter une maladie du foie Ceased WO1999057103A1 (fr)

Priority Applications (1)

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AU35388/99A AU3538899A (en) 1998-04-30 1999-04-30 Condensed imidazole derivative and therapeutic agent for liver disease

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JP10/136045 1998-04-30
JP13604598 1998-04-30

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WO2001002400A1 (fr) * 1999-07-02 2001-01-11 Eisai Co., Ltd. Composes imidazole fusionnes et medicaments contre le diabete sucre
WO2001078716A1 (fr) * 2000-04-19 2001-10-25 Fujisawa Pharmaceutical Co., Ltd. Dispersion solide a meilleur pouvoir absorbant
US7268145B2 (en) 1998-07-15 2007-09-11 Teijin Pharma Limited Thiobenzimidazole derivatives
WO2008129994A1 (fr) * 2007-04-18 2008-10-30 Kissei Pharmaceutical Co., Ltd. Dérivé à cycle fusionné azoté, composition pharmaceutique le comprenant, et son utilisation pour des usages médicaux
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
WO2010016490A1 (fr) * 2008-08-05 2010-02-11 第一三共株式会社 Dérivé d'imidazopyridin-2-one
US8501770B2 (en) 2009-12-30 2013-08-06 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8609688B2 (en) 2011-06-24 2013-12-17 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8815854B2 (en) 2011-06-24 2014-08-26 Arqule, Inc. Substituted imidazopyridinyl compounds
JP2021521142A (ja) * 2018-04-09 2021-08-26 ラクオリア創薬株式会社 Ｃｒｈｒ２拮抗薬としての縮合環状尿素誘導体
US11241013B2 (en) 2017-10-18 2022-02-08 Redag Crop Protection Ltd Benzimidazole compounds as agricultural chemicals
US11641858B2 (en) * 2016-04-13 2023-05-09 Redag Crop Protection Ltd. Agricultural chemicals
WO2024201308A1 (fr) * 2023-03-31 2024-10-03 주식회사 엘지화학 Nouveau composé dérivé de benzimidazolone utilisé comme inhibiteur de l'autotaxine

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WO1996038421A1 (fr) * 1995-06-02 1996-12-05 Berlex Laboratories, Inc. Derives de l'uree n, n-di(arylmethyle) cycliques utilises comme anti-coagulants

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268145B2 (en) 1998-07-15 2007-09-11 Teijin Pharma Limited Thiobenzimidazole derivatives
US6841549B1 (en) 1999-07-02 2005-01-11 Eisai Co., Ltd. Condensed imidazole compounds and a therapeutic agent for diabetes mellitus
JP4324338B2 (ja) * 1999-07-02 2009-09-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 縮合イミダゾール化合物及び糖尿病治療薬
WO2001002400A1 (fr) * 1999-07-02 2001-01-11 Eisai Co., Ltd. Composes imidazole fusionnes et medicaments contre le diabete sucre
WO2001078716A1 (fr) * 2000-04-19 2001-10-25 Fujisawa Pharmaceutical Co., Ltd. Dispersion solide a meilleur pouvoir absorbant
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
AU2008241853B2 (en) * 2007-04-18 2012-11-01 Kissei Pharmaceutical Co., Ltd. Nitrogenated fused ring derivative, pharmaceutical composition comprising the same, and use of the same for medical purposes
WO2008129994A1 (fr) * 2007-04-18 2008-10-30 Kissei Pharmaceutical Co., Ltd. Dérivé à cycle fusionné azoté, composition pharmaceutique le comprenant, et son utilisation pour des usages médicaux
TWI402073B (zh) * 2007-04-18 2013-07-21 Kissei Pharmaceutical A nitrogen-containing condensed ring derivative, a pharmaceutical composition containing the same, and a pharmaceutical use thereof
JPWO2008129994A1 (ja) * 2007-04-18 2010-07-22 キッセイ薬品工業株式会社 含窒素縮合環誘導体、それを含有する医薬組成物及びその医薬用途
US8217069B2 (en) 2007-04-18 2012-07-10 Kissei Pharmaceutical Co., Ltd. Nitrogenated fused ring derivative, pharmaceutical composition comprising the same, and use of the same for medical purposes
US8436012B2 (en) 2008-08-05 2013-05-07 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
CN102171210A (zh) * 2008-08-05 2011-08-31 第一三共株式会社 咪唑并吡啶-2-酮衍生物
WO2010016490A1 (fr) * 2008-08-05 2010-02-11 第一三共株式会社 Dérivé d'imidazopyridin-2-one
JP5630867B2 (ja) * 2008-08-05 2014-11-26 第一三共株式会社 イミダゾピリジン−２−オン誘導体
CN102171210B (zh) * 2008-08-05 2014-04-23 第一三共株式会社 咪唑并吡啶-2-酮衍生物
US8785438B2 (en) 2008-08-05 2014-07-22 Daiichi Sankyo Company, Limited Imidazopyridin-2-one derivatives
US8501770B2 (en) 2009-12-30 2013-08-06 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8815854B2 (en) 2011-06-24 2014-08-26 Arqule, Inc. Substituted imidazopyridinyl compounds
US8609688B2 (en) 2011-06-24 2013-12-17 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US8962619B2 (en) 2011-06-24 2015-02-24 Arqule, Inc. Substituted imidazopyridinyl-aminopyridine compounds
US11641858B2 (en) * 2016-04-13 2023-05-09 Redag Crop Protection Ltd. Agricultural chemicals
US11241013B2 (en) 2017-10-18 2022-02-08 Redag Crop Protection Ltd Benzimidazole compounds as agricultural chemicals
JP2021521142A (ja) * 2018-04-09 2021-08-26 ラクオリア創薬株式会社 Ｃｒｈｒ２拮抗薬としての縮合環状尿素誘導体
US11802120B2 (en) 2018-04-09 2023-10-31 Raqualia Pharma Inc. Fused cyclic urea derivatives as CRHR2 antagonist
WO2024201308A1 (fr) * 2023-03-31 2024-10-03 주식회사 엘지화학 Nouveau composé dérivé de benzimidazolone utilisé comme inhibiteur de l'autotaxine
EP4663630A4 (fr) * 2023-03-31 2026-04-22 Lg Chemical Ltd Nouveau composé dérivé de benzimidazolone utilisé comme inhibiteur de l'autotaxine

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