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WO1998009956A1 - Derives 2,3-dihydrobenzofuranne et medicament pour l'hepatopathie comprenant ceux-ci en tant que principe actif - Google Patents

Derives 2,3-dihydrobenzofuranne et medicament pour l'hepatopathie comprenant ceux-ci en tant que principe actif Download PDF

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Publication number
WO1998009956A1
WO1998009956A1 PCT/JP1997/003168 JP9703168W WO9809956A1 WO 1998009956 A1 WO1998009956 A1 WO 1998009956A1 JP 9703168 W JP9703168 W JP 9703168W WO 9809956 A1 WO9809956 A1 WO 9809956A1
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Prior art keywords
group
substituted
unsubstituted
lower alkyl
hydrogen atom
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Japanese (ja)
Inventor
Mikio Kurokawa
Takayuki Yoshida
Huminori Sato
Nobuo Matsuoka
Kunihisa Satomura
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Sumitomo Pharma Co Ltd
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Dainippon Pharmaceutical Co Ltd
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Priority to AU41368/97A priority Critical patent/AU4136897A/en
Publication of WO1998009956A1 publication Critical patent/WO1998009956A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • a therapeutic drug for liver disease containing it as an active ingredient
  • the present invention relates to 2,3-dihydrobenzene diazofuran (or benzothiophene) derivatives. See 3-Amino or Iminnow 2, 3-Jihi Droben
  • the present invention relates to a zofuran (or benzothiophene) derivative and a therapeutic agent for liver disease containing the same as an active ingredient.
  • Liver diseases include acute hepatitis, chronic hepatitis, fulminant hepatitis, cirrhosis, hepatic failure, liver cancer, fatty liver, etc.
  • the causes are also various, including hepatitis virus, alcohol, drugs, autoimmunity, and metabolic abnormalities. It is said that these cause the disease and eventually lead to liver cancer.
  • cirrhosis is the basis for most liver cancers, and treatment of acute hepatitis may prevent irritation and prevent chronic hepatitis from progressing to cirrhosis. Treatment is considered clinically important.
  • a representative drug clinically evaluated as a therapeutic agent for the above-mentioned liver diseases is an interferon preparation *.
  • Interferon preparations have been shown to be effective for chronic viral hepatitis, but the efficacy rate is relatively low.
  • interferon preparations have a high incidence of side effects such as fever and leukopenia, and long-term treatment with interstitial pneumonia (pulmonary fibrosis), autoimmune diseases (thyroiditis), psychiatric neuropathy, cardiomyopathy This is a problem because serious side effects such as these occur.
  • pulmonary fibrosis pulmonary fibrosis
  • autoimmune diseases thyroiditis
  • psychiatric neuropathy psychiatric neuropathy
  • cardiomyopathy This is a problem because serious side effects such as these occur.
  • Ma since the administration method is intravenous injection and is not effective orally, there are restrictions on the administration form.
  • Other drugs include corticosteroids, liver protectants, branched-chain amino acids, glucagon and insulin.
  • hepatoprotective agents include glycyrrhizin preparations (injection for intravenous injection), germanium preparations (propagermanium, etc.), herbal medicine Sho-saiko-to, gallstone dissolving agent ursodeoxycholic acid, tiopronin, maloylate, polyenphosphatidylcholine and so on.
  • glycyrrhizin preparations injection for intravenous injection
  • germanium preparations propagermanium, etc.
  • herbal medicine Sho-saiko-to, gallstone dissolving agent ursodeoxycholic acid, tiopronin, maloylate, polyenphosphatidylcholine and so on.
  • An object of the present invention is to provide an excellent therapeutic agent for liver disease which is highly safe and is effective orally.
  • the present invention relates to a novel 2,3-dihydrobenzozofuran (or benzothiophene) derivative represented by the following general formula (I) or a physiologically acceptable acid thereof, which is useful as a medicament, particularly as a therapeutic drug for liver disease.
  • the present invention relates to an addition salt and a use thereof as a therapeutic agent for liver disease containing the active ingredient as an active ingredient.
  • R i and R 2 are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an aceethoxy lower alkyl group, a lower alkoxy lower alkyl group;
  • a lower alkyl group, a lower alkylsulfonyl group, or a combination of R 1 and R 2 may form a methylene group;
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halo Gen atom, hydroxy group, acyloxy group, lower alkylsulfonyl group, lower alkoxy group, cyclo lower alkyloxy group, aralkyloxy group, nitro group, amino group, cyano group, carbamoyl group, sulfamoyl group, carboxyl group or lower alkoxycarbo means alkenyl group, R 5 a and R 5 b is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, Ararukiru group or R 5 a and R 5 b forms a connexion ring such together the same or different ⁇
  • R 6 is a hydrogen atom;
  • R 8 (where R 8 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or an acyl group), substituted or unsubstituted C 8 alkyl group (substituent is cyclo lower ⁇ alkyl group of the alkyl group, Ariru group, Heteroariru group, arsenate Dorokishi group, a lower alkoxy group, Ararukiruokishi group, Ariruokishi group, Ashiruokishi group, amino group, mono-lower alkyl Wakashi Ku Di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfon
  • R 7 represents a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group
  • X represents an oxygen atom or a sulfur atom.
  • R 10— and R 2 ⁇ are 4-1CH 3 and 7—0 CH 3 and R 3 and R 4 Except when one is a hydrogen atom and the other is 6-0 H)
  • the compound of the present invention is represented by the above general formula (I), and is specifically represented by the following general formula (II) or general formula (III).
  • R i and R 2 are the same or different from each other and are a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an acetyloxy lower alkyl group, a lower alkoxy lower alkyl group, Roxy lower alkyl group, acyl group, lower alkylsulfonyl group or R 1 and R 2 may be combined to form a methylene group,
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkyl sulfonyl group A xy group, a lower alkoxy group, a cyclo-lower alkyloxy group, an aralkyloxy group, a nitro group, an amino group, a cyano group, a carbamoyl group, a sulfamoyl group, a carboxyl group or a lower alkoxycarbonyl group;
  • R 5 a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a cyclo-lower Arukiru group, Ararukiru group or R 5 a and R 5 b is may form a connexion ring such together,
  • R 6 is a hydrogen atom, one OR 8 (where R 8 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or an acyl group), substituted or unsubstituted C i -C 8 alkyl group (substituents of the alkyl group are cyclo lower alkyl group, aryl group, heteroaryl group, hydroxy group, lower alkoxy group, aralkyloxy group, aryloxy group, acyloxy group, amino group, Mono-lower alkyl or di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkyl sulfonyl group , An arylsulfonyl group
  • X represents an oxygen atom or a sulfur atom.
  • R 6 is OH
  • R 1 0- and R 2 ⁇ — are 4-0 CH 3 and 7— OCH 3
  • one of R 3 and R 4 is a hydrogen atom and the other is 6-0 H
  • R 1 and R 2 are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an aceethoxy lower alkyl group, a lower alkoxy lower alkyl group; R 1 and R 2 may be combined with each other to form a methylene group, or a lower alkoxyl alkyl group, an acyl group, a lower alkyl sulfonyl group, or
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy Group, lower alkoxy group, cyclo-lower alkyloxy group, aralkyloxy group, nitro group, amino group, cyano group, carbamoyl group, sulfamoyl group, carboxyl group or quaternary alkoxycarbonyl group, R 5a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, Ararukiru group or R 5 a and R 5 b is may form a connexion ring such together,
  • R 6 is a hydrogen atom, —OR 8 (where R 8 is a hydrogen atom, a lower alkyl group, Mouth lower alkyl group, Ararukiru group, a Ariru group or Ashiru group), substitution or unsubstituted C.
  • the alkyl group is a cyclo-lower ⁇ alkyl group, Ariru group, Heteroari Ichiru group , Hydroxy group, lower alkoxy group, aralkyloxy group, aryloxy group, acyloxy group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, ⁇ One or more selected from a arylthio group, a lower alkylsulfinyl group, an arylsulfinyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an acyl group, a carboxyl group and a lower alkoxycarbonyl group) , Lower mouth alkyl group, aryl group, hete Ariru group, -CO- R 9
  • R 7 represents a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and X represents an oxygen atom or a sulfur atom.
  • R 6- and R 7 are both hydrogen atom
  • R 10- and R20- is 4 one ⁇ _CH 3 and 7 0 (: 11 3 a and the other while the hydrogen atoms of R 3 and R 4 6-3 except H), or a physiologically acceptable acid addition salt thereof.
  • preferred compounds are those in which X is an oxygen atom and R 1 and R 2 are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkyl group.
  • Sulfonyl group or R 1 and R 2- a methylene group connected together and R 3 and R 4 are the same or different from each other and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkyl group a Suruhoniruokishi or a lower alkoxy group, R 5 a and R
  • R 5 b is the same or different and is a hydrogen atom or a lower alkyl group
  • R 6 is a hydrogen atom, a lower alkyl group, —OR 8 (where R 8 is a lower alkyl group), —C0—R 9
  • R 9 is a substituted or unsubstituted ⁇ ⁇ (: an alkyl group (the substituent of the alkyl group is one or more selected from a hydroxy group, an acyloxy group or a lower alkoxy group); -CHR 10 (where R 10 is a hydrogen atom, a lower alkyl group or an aryl group) or one SOR 11 (where R 11 is a lower alkyl group or an aryl group) or a compound thereof or its physiology And acid addition salts which are chemically acceptable.
  • R 1 and R 2 are the same or different from each other and are a hydrogen atom, a C! C ⁇ alkyl group, an acyl
  • R 3 and R 4 are the same or different from each other and are a hydrogen atom, a hydroxy group, an acyloxy group or a C i Cg alkoxy group, and R 5a and R 5b are one or different hydrogen atoms or C—C 3 A compound wherein R 6 is a hydrogen atom or one OR 8 (where R 8 is a C i -C 3 alkyl group) or a physiologically acceptable acid addition salt thereof.
  • R 1 and R 2 are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkyl group.
  • a sulfonyl group or R] and R 2 — Represents a methylene group
  • R 3 and R 4 are the same or different and are each a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy or a lower alkoxy group
  • R 5 a and R 5 b are the same or different connexion hydrogen atom or a lower alkyl group
  • R 6 is water atom, a substituted or unsubstituted C.
  • alkyl group (said alkyl group arsenide Dorokishi group ,
  • R 10 is a hydrogen atom, a lower alkyl group or an aryl group
  • S ⁇ 2 R 11 1 where Ri 1 is a lower alkyl group) a group or Ariru a group
  • R 7 is hydrogen atom or a lower ⁇ Le kill group (provided that when R 6 and R 7 are both hydrogen atom, R 10- and R 2 0- is 4 _0 (11 3 and 7— 0 CH 3 and R 3 and R
  • More preferred compounds are those in which R 1 and R 2 in formula (III) are the same or different from each other and are a hydrogen atom, a CiC ⁇ alkyl group or an acyl group, and R 3 and R 4 are the same or different from each other.
  • R 5 a and R 5 b are taken the same or different hydrogen atom or a C] -C 3 alkyl group
  • R 6 is a hydrogen atom , Replace Or an unsubstituted C ⁇ -C3 alkyl group (the substituent of the alkyl group is one or more selected from a hydroxy group, an acyloxy group or a carboxyl group), and one CO—R 9 (where R 9 is a hydrogen atom or a substituted or unsubstituted C
  • a C 3 alkyl group (substituent of the alkyl group is a hydroxy group or an acyloxy group)) or one S ⁇ 2 R 11 (where R 11 is C) to a C 3 alkyl group or a phenyl group
  • R 7 is a hydrogen atom (provided that when R 6 and R 7 are both hydrogen atoms, R 10 — and R 20 — are 4-—CH 3 and 7—OCH 3 and one of R 3 and R 4 is a hydrogen atom and the other is 6—
  • Still another preferred compound of the present invention has the following general formula (III-A):
  • R 1 and R 2 are the same or different from each other and represent a hydrogen atom, a lower alkyl group, an acyl group,
  • R 3 represents a hydrogen atom, a lower alkyl group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group,
  • R 4 represents a hydrogen atom, a lower alkyl group, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group,
  • R 5 a and R 5 b are the same or different, represent a hydrogen atom or a lower alkyl group
  • R 6 is a hydrogen atom, a substituted or unsubstituted C-C 8 alkyl group (substituted with an alkyl group is a hydroxy group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, an acyloxy group, One or more selected from a carboxyl group or a lower alkoxycarbonyl group), —CO—R 9 (where R 9 is a hydrogen atom, a substituted or unsubstituted Ci Ciz alkyl group (substituted alkyl group) The group is one or more selected from a hydroxy group, an acyloxy group, a substituted or unsubstituted aryloxy group or a lower alkoxy group)), or one S 0 2 R 11 (where R 11 is Lower alkyl or substituted or unsubstituted aryl).
  • R 7 represents a hydrogen atom or a lower alkyl group
  • Specific preferred compounds of the general formulas (III) and (III-A) include 3-amino-4-hydroxy-15,6-dimethoxy-1,2,3-dihydrobenzofuran hydrochloride,
  • physiologically acceptable acid addition salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, and maleic acid.
  • the “lower alkyl group” and the “lower alkyl” portion mean a linear or branched alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group. And a pentyl group.
  • the “substituted or unsubstituted C i C g alkyl group” refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms including a hexyl group, a heptyl group, an octyl group and the like in addition to the lower alkyl group.
  • the substituent is a cyclo lower alkyl group, an aryl group, a heteroaryl group, a hydroxy group, a lower alkoxy group, an aralkyloxy group, an aryloxy group, an acyloxy group, an amino group, a mono-lower alkyl or di-lower alkylamino group, Acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkyl sulfoninole group, arylsulfonyl group, acyl Group, carboxyl group or lower alkoxycarbonyl group.
  • the "substituted or unsubstituted C i ⁇ C 1 2 alkyl group" the ( ⁇ Ji 8
  • the alkyl group a linear or branched alkyl group having 1 to 12 carbon atoms, including a nonyl group, a decyl group, a decyl group, a dodecyl group, etc., and a cyclo lower alkyl group as a substituent ,
  • a hydroxy group, an acyloxy group, an aryloxy group or a lower alkoxy group is preferred.
  • “Cyclo-lower alkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • the “aryl group” and the “aryl group” mean a phenyl group, a naphthyl group and the like, and the ring may have a substituent.
  • Preferred substituents on the ring include a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a hydroxy group, an amino group and a nitro group.
  • the “aralkyl group” and the “aralkyl” portion mean a straight-chain or branched alkyl group having 1 to 3 carbon atoms substituted by the above “aryl group”, for example, phenylmethyl group, 1-phenylethyl group, 2-phenylethyl group. And 3-phenylpropyl group, naphthylmethyl group, 2-naphthylethyl group and the like.
  • phenyl group or naphthyl group may have the same substituent as described above.
  • the “lower alkoxy” and “lower alkoxy” moieties mean a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropyloxy, butoxyl, Examples include an isoptyloxy group, a tert-butyloxy group, and a pentyloxy group.
  • “Acyl group” means a lower alkanoyl group, a benzoyl group, or a naphthoyl group.
  • “Lower alkanoyl group” means an alkanoyl group having 1 to 3 carbon atoms, and examples include a formyl group, an acetyl group and a propionyl group.
  • “Heteroaryl group” means a 5- or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • heterocyclic group is one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, and an amino group. May have a substituent.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the compounds of the present invention and their physiologically acceptable acid addition salts may exist as hydrates and Z or solvates. Therefore, such forms are naturally included in the compounds of the present invention.
  • the compounds of the present invention have two asymmetric carbon atoms on the dihydrobenzofuran or dihydrobenzothiophene ring, which can exist as different stereoisomers. Therefore, these stereoisomers are also included in the compounds of the present invention.
  • the compounds of the present invention include those having an asymmetric carbon atom in the side chain substituent thereof, and they may exist as stereoisomers. These stereoisomers are also included in the compounds of the present invention.
  • the present invention The compounds of the formula (1) include those having a double bond in the side chain substituent thereof, and there are geometrical isomers of cistran. These geometrical isomers are also included in the compound of the present invention.
  • R 6 is a hydrogen atom, a substituted or unsubstituted salkyl group, lower alkyl group, Ararukiru group, Ariru group, hetero Ariru group or compound is an 0
  • R 8 is a hydroxylamine derivative or an amine derivative corresponding to the compound represented by the following general formula (IV), by methods known It can be produced by reacting.
  • the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base.
  • Examples thereof include reactive derivatives of alcohol (eg, alkyl halide, alkyl tosylate, alkyl methanesulfonate).
  • Examples of the acylation method include a reaction with a corresponding reactive derivative of a carboxylic acid, for example, a substitution reaction with an acylating agent such as an active ester, an acid anhydride or an acid halide.
  • the method of sulfonylation includes reaction with the corresponding reactive derivative of sulfonic acid, for example, lower alkane sulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and the like. Substitution reaction with a sulfonylating agent can be mentioned.
  • the compound (lib) in which R 6 is —0 R 8 (R 8 is the above R 8 group other than a hydrogen atom) and R 1 is a hydrogen atom can also be produced by the method of Production Method 1.
  • the compound can be produced by treating the compound of the present invention represented by the general formula (Ila) with lysic acid in a suitable inert solvent.
  • the Lewis acid include anhydrous sodium chloride, anhydrous aluminum chloride, boron trichloride, boron tribromide and boron trifluoride.
  • the solvent include methylene chloride, benzene and nitrobenzene.
  • R, R 2 and R 8 are the same groups as described above except for a hydrogen atom;
  • R 6 is the same group as cited above other than a hydrogen atom, a hydroxyl group, R 2 ⁇
  • Examples of the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base.
  • an alkylating agent for example, a reactive derivative of an alcohol (an alkyl halide, an alkyl tosylate, an alkyl Methanesulfonate).
  • the acylation method includes reaction with a corresponding reactive derivative of rubonic acid, for example, active ester, acid anhydride, or acid halide.
  • a substitution reaction with an acylating agent such as an id.
  • the method of sulfonylation includes reaction with the corresponding reactive derivative of sulfonic acid, for example, lower alkane sulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride. Reaction with a sulfonylating agent such as a product.
  • R 7 is a hydrogen atom
  • R 6 is a hydrogen atom
  • — oR 8 substituted or unsubstituted C i ⁇ C 8 alkyl group
  • a lower cycloalkyl group
  • Ariru group or to Teroari - a le radical compound is represented by the following general formulas manufacturing by the manufacturing method 1 (II)
  • R 6 is a hydrogen atom, —OR8, a substituted or unsubstituted Ci Cg alkyl group, a cyclo-lower alkyl group, a CO—R 9 , an aryl group or a heteroaryl group, and R] to R 5a , R5b and X are the same as above)
  • the reduction method is appropriately selected from known reduction methods depending on the type of the substituent of the compound represented by the general formula ( ⁇ ) or the properties of other functional groups.
  • platinum oxide palladium-carbon, Atmospheric pressure using a catalyst such as nickel Is catalytic hydrogen reduction in a hydrogen atmosphere under pressure, reduction with metallic sodium in an alcohol solvent such as ethanol or propanol, sodium mouma gum / acetic acid, aluminum-amalgam Z water, borane-tetrahydrofuran complex, hydrogenation Sodium borohydride Z tetrachloride titanium, sodium borohydride Z nickel dichloride hexahydrate, sodium borohydride molybdenum oxide, sodium trifluoroacetoxyborohydride, lalancet reagent
  • R 6 is —OR 8
  • a certain compound can be produced by acylating or sulfonylating a compound represented by the following general formula (V) produced by the above-mentioned production method by a conventional method.
  • R 7 is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R i to R 5a, R 5b and X are the same as described above.
  • a method of acylation the corresponding carboxylic acid Reaction with a reactive derivative, for example, a substitution reaction with an acylating agent such as an alkyl ester, an active ester, an acid anhydride or an acid halide, or condensation with the corresponding carboxylic acid itself in the presence of a condensing agent Reaction.
  • condensing agent examples include ⁇ , ⁇ '-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid hydrochloride, ⁇ , ⁇ '-carbonyldiimidazole, ⁇ , ⁇ , 1-carbodilsuccinic acid imid, 1—ethoxycarboryl 2-ethoxy-1,2, -dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride, benzotriazole-1-yloxystris ( Dimethylamino) phosphodium hexafluorophosphate.
  • the method of sulfonylation includes reaction with a corresponding reactive derivative of sulfonic acid, for example, lower alkylsulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and the like. And a substitution reaction with a sulfonylating agent.
  • a corresponding reactive derivative of sulfonic acid for example, lower alkylsulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and the like.
  • R 7 is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R 6 is a substituted or unsubstituted C 1 -C 8 alkyl group.
  • Compound is may force 5 also be produced by a method represented by the following Method A or Method B.
  • R 7 is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R 1 to R 5a, R 5b, R 9 and ⁇ ⁇ ⁇ are the same as described above.
  • a force appropriately selected from known methods according to the type of the substituent of the compound represented by the general formula (III) or the properties of the other functional groups for example, oxidized platinum, noradium monocarbon, Catalytic hydrogen reduction in a hydrogen atmosphere at normal pressure or under pressure using a catalyst such as Raney Nickel, borane-tetrahydrofuran complex, sodium borohydride / titanium tetrachloride, sodium borohydride nickel nickel dichloride, sodium borohydride / molybdenum oxide, hydrogenated triflumizole Ruo b acetoxy boron sodium, Raranse' preparative reagent (Lalancette 's reagent; NaBH 2 S 3), hydrogenated Bisume Toki Chez butoxy aluminum two ⁇ beam sodium, such as lithium aluminum hydride Examples thereof include a method using a reducing agent.
  • R 7 is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R 1 to R 5a, R 5b and X are the same as described above.
  • Examples of the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base.
  • an alkylating agent for example, a reactive derivative of a corresponding alcohol (eg, an alkyl halide or an alkyl tosylate) is used. Rates, alkyl methanesulfonates, etc.).
  • the compound containing a functional group in 6 can be led to another compound of the present invention by chemical modification according to a conventional method.
  • Chemical modifications include, for example, alkylation, acylation, sulfonylation, hydrolysis, oxidation and reduction methods.
  • the compound of the present invention produced by the above production methods 1 to 7 is isolated and purified by a conventional method such as various chromatographic methods, recrystallization, and reprecipitation.
  • the compounds of the present invention can be obtained in the form of a free base or an acid addition salt depending on the selection of starting compounds, reaction and treatment conditions, and the like.
  • the acid addition salt can be prepared by a conventional method, for example, treatment with a base such as alkali carbonate or alkali hydroxide to give a free salt. Can be changed to base.
  • the free base can be converted to an acid addition salt by treating it with various acids according to a conventional method.
  • the compound of the present invention is obtained in the form of a complex with borane, it can be converted to an acid addition salt by treating with an acid.
  • the 2,3-dihydrobenzofuran-3-one derivative can be obtained from commercially available gas or starting materials that can be synthesized by known methods. Male supervision, Asakura Shoten Publishing First Edition, Tokyo, 1959, and THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS Vol. 29, pp 210-219, written by M. Ahmed, John Wiley and Sons IN Publishing, ew York 1954) It can be produced by a known method or a method analogous thereto.
  • the introduction of a hydroxyl group at the 7-position of certain 2,3-dihydrobenzofuran-13-one derivatives requires the use of ⁇ -butyl lithium notrimethoxyborane reagent. Can be done.
  • the introduction of a lower alkyl group at the 2-position of a certain 2,3-dihydrobenzofuran-13-one derivative can be carried out by alkylation with an alkylating agent in the presence of a strong base.
  • the 2,3-dihydrobenzothiophene-3-one derivative can also be prepared from commercially available catalysts or starting materials that can be synthesized by known methods, for example, as described in “THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, pp66-75, HD Hartough. Published by Interscience Publhers, INC., New York 1974 and Advances in HETEROCYCLIC CHEMISTRY Vol. 11, p.225, edited by AR Katritzky et al., Published by Academic Press, New York and London, 1970.
  • a method analogous thereto for example, a method of intramolecularly closing an S- (o-carboxylphenyl) thioglycolic acid derivative followed by decarboxylation, or an S-polysubstituted phenyl
  • a 2,3-dihydrobenzothiothiophene-3-one derivative can be produced by a method utilizing an intramolecular ring closure reaction of a dithioglycolic acid derivative.
  • each test compound was tested using a D-(+)-galactosamine-induced liver injury model in rats and a D-(+)-galactosamine-nolipopolysaccharide-induced liver injury model in mice. They were screened and their inhibitory effects were evaluated.
  • Test Example 1 Inhibitory effect on D-galactosamine-induced liver injury model:-s1c: Dissolved and diluted in a male male Wistar rat (about 200 g body weight, 7-9 weeks old) with physiological saline for injection.
  • D — (+) Galactosamine (250 mg Z kg) was administered subcutaneously once a day for 4 consecutive days to induce liver damage.
  • the test compound (dose: 3 Omg / kg) was suspended or dissolved in 0.5% methylcellulose solution or olive oil and orally administered 1 hour after each induction for 4 consecutive days.
  • 24 hours after the final administration of D-galactosamine heart blood was collected under pentobarbital anesthesia, and AST (G0T) and ALT (GPT) in plasma were measured.
  • the inhibition rate (%) was calculated by the following formula (where the inducer means D — (+) galactosamine). The results are shown in Tables 1 and 2. Induced agent treated group actual value-each test compound administration group actual measured value
  • Inhibition rate (%) ; X 100 Inducer treated group actual value-solvent control group actual value
  • Test compounds (compound Nos. 3, 85, 164, 172 and 305) were orally administered for 2 consecutive weeks using ICR female mice (7-week old) (Dose: 30 OmgZk gZl once daily) ). As a result, none of the test compounds died.
  • the compound of the present invention has an inhibitory effect on the D-(+)-galactosamine-induced hepatic injury model and the D-galactosamine / ribopolysaccharide-induced hepatic injury model. It showed extremely low toxicity and high safety. Therefore, the compound of the present invention is useful as a therapeutic drug for liver diseases and can be used as a therapeutic / prophylactic drug for various liver disorders in animals including humans. Specifically, for example, acute hepatitis, chronic hepatitis, drug-toxic liver injury, It can be used to treat or prevent viral hepatitis, alcoholic hepatitis, jaundice, and cirrhosis.
  • the dosage form is orally administered as tablets, capsules, granules, fine granules, powders, syrups, suspensions, etc. It is administered parenterally or rectally as drops, suppositories, gels, tablets, etc.
  • These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other suitable medium at the time of use. Tablets and granules may be coated by a known method.
  • the drug is prepared by dissolving the drug in water for injection, but if necessary, add a pH regulator, buffer, isotonic agent, stabilizer, solubilizer, etc.
  • the dosage depends on the administration method, the patient's symptoms, age, treatment type (prevention or treatment), etc., usually 0.1 mg to 200 mg per adult per day, preferably 2 mg to 8 mg. 0 mg is administered once or several times a day.
  • the carrier for pharmaceuticals includes an excipient, a binder, a disintegrant, and a lubricant.
  • Carriers that do not react with the compound of the present invention such as antioxidants, coating agents, surfactants, fluidity enhancers, flavoring agents, coloring agents, plasticizers, fragrances, etc. Is appropriately selected and used.
  • excipients such as glucose, sucrose, lactose, mannitol, xylitol, sorbitol, crystalline cellulose, sodium carboxymethyl cellulose, calcium hydrogen phosphate, starch, sodium carboxymethyl starch, dextrin ,.
  • cyclodextrin, ⁇ -cyclodextrin Examples include xistrin, carboxyvinyl polymer, light caustic anhydride, titanium oxide, magnesium aluminate metasilicate, polyethylene glycol, and medium-chain fatty acid triglycerides.
  • binder examples include crystalline cellulose, methylcellulose, Echiruseru loin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene-vinyl pyrrolidone, polyvinyl alcohol, gum arabic, alpha starch, pullulan, gelatin, agar, Taraganto, alginic acid sodium And propylene glycol alginate.
  • Disintegrators include, for example, crystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, starch, hydroxypropyl starch, partially modified starch Can be
  • lubricant examples include stearic acid, aluminum stearate, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated vegetable oil, sucrose fatty acid ester, dimethylpolysiloxane, polyethylene glycol, waxes, Hydrogenated vegetable oils;
  • antioxidants examples include propyl gallate, dibutyl hydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, and citric acid.
  • the coating agent examples include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethyl.
  • surfactants include polyoxyethylene hard castor oil, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbates, sodium lauryl sulfate, macrogols Sucrose fatty acid esters and soybean lecithin.
  • Examples of the fluidity promoter include light caustic anhydride, dried palm hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
  • Examples of the flavoring agent include citric acid, adipic acid, ascorbic acid, and menthol.
  • Examples of the colorant include a tar dye and titanium oxide.
  • Examples of the plasticizer include trimethyl citrate, triacetin, and ethanol.
  • compositions can contain the compound of the present invention in an amount of 0.01% or more, preferably 0.05 to 70%. These formulations may also contain other therapeutically active ingredients.
  • M e methyl group
  • E t ethyl group
  • i—P r isopropyl group
  • Pr cyclopropyl group
  • i-Bu isobutyl group
  • cPen cyclopentyl group
  • Phe phenyl group
  • Bz benzyl group
  • Ac acetyl group
  • the solution is heated under reflux for 20 minutes to decompose the amine-borane complex, and then added with a 10% aqueous sodium hydroxide solution under ice-cooling to make the solution more viscous.
  • the mixture is extracted with ethyl acetate, and the organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the solvent is distilled off under reduced pressure, and the obtained residue is dissolved in ethyl acetate, and 30% (v / v) ethanol hydrochloride is added under ice-cooling and stirring.
  • the precipitated crystals are collected by filtration and recrystallized from ethanol-ethyl ether to give 3.1 g of the title compound (Compound No. 81). Melting point 1 98 ° (:.
  • NHC0CH CH- (3, 4-
  • HC0CH CH- (3,4- 4 ⁇ UMe UMe UMe u U LI N
  • a mixture of 1 47 g and 6 g of 4-dimethylaminopyridine is stirred overnight at room temperature. Pour the reaction solution into ice water and extract with ethyl acetate. The organic layer is washed successively with a saturated aqueous solution of copper sulfate, water, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 66 g of 2,5-diacetoxy-3,4,6-trimethoxyacetophenone, which is used for the next reaction without further purification.
  • the organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • the solvent is distilled off under reduced pressure to obtain 9.6 g of 2,3-dihydroxy-14-methoxy ⁇ -bromoacetophenone. Use for the next reaction without further purification.

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Abstract

On décrit des dérivés 3-amino- ou imino-2,3-dihydrobenzofuranne (ou benzothiophène), représentés par la formule générale (I), un sel d'addition d'acide de ceux-ci, acceptable sur le plan pharmacologique, ainsi qu'un médicament pour l'hépatopathie comprenant ces dérivés en tant que principe actif. Dans cette formule, R1 et R2, qui peuvent être semblables ou différents, représentent chacun H, un groupe alkyle inférieur, ou un groupe acryle, ou bien R1 et R2 se combinent l'un avec l'autre pour former un groupe méthylène ou analogue, R3 et R4, qui peuvent être semblables ou différents, représentent chacun H, OH, un groupe acyloxy, ou un groupe alcoxy inférieur, R?5a et R5b¿, qui peuvent être semblables ou différents, représentent chacun H, un groupe alkyle inférieur ou analogue, ...A-R6 représente =N-R?6 ou -NR6R7, R6¿ représente H, -OR8, un groupe alkyle C¿1?-C8 substitué ou non, -CO-R?9¿, ou -SO¿2R?11, et X représente O ou S.
PCT/JP1997/003168 1996-09-09 1997-09-09 Derives 2,3-dihydrobenzofuranne et medicament pour l'hepatopathie comprenant ceux-ci en tant que principe actif Ceased WO1998009956A1 (fr)

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AU41368/97A AU4136897A (en) 1996-09-09 1997-09-09 2,3-dihydrobenzofuran derivative and hepatopathy remedy comprising the same as active ingredient

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JP8/261436 1996-09-09
JP26143696 1996-09-09

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999003824A1 (fr) * 1997-07-15 1999-01-28 Agro-Kanesho Co., Ltd. Agent de lutte contre les maladies ou de lutte anti-parasitaire contenant un derive bicyclique a substitution alcoxyamino en tant qu'ingredient actif
WO2000002874A3 (fr) * 1998-07-09 2000-02-24 Univ Strathclyde Inhibiteurs d'adhesion cellulaire dependants de l'integrine
WO2002000180A3 (fr) * 2000-06-29 2002-05-23 Henkel Kgaa Derives d'indigo
JP2009102437A (ja) * 1996-12-09 2009-05-14 Bayer Ag ２−ヒドロキシアセトフェノンオキシム誘導体
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors
WO2012093100A1 (fr) * 2011-01-05 2012-07-12 Syngenta Participations Ag Dérivés de pyrazol-4-ylcarboxamide en tant que microbiocides
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009102437A (ja) * 1996-12-09 2009-05-14 Bayer Ag ２−ヒドロキシアセトフェノンオキシム誘導体
WO1999003824A1 (fr) * 1997-07-15 1999-01-28 Agro-Kanesho Co., Ltd. Agent de lutte contre les maladies ou de lutte anti-parasitaire contenant un derive bicyclique a substitution alcoxyamino en tant qu'ingredient actif
US6291399B1 (en) 1997-07-15 2001-09-18 Agro-Kanesho Co., Ltd. Agent for controlling diseases and insect pests, containing alkoxyimino-substituted bicyclic derivative as active ingredient
WO2000002874A3 (fr) * 1998-07-09 2000-02-24 Univ Strathclyde Inhibiteurs d'adhesion cellulaire dependants de l'integrine
WO2002000180A3 (fr) * 2000-06-29 2002-05-23 Henkel Kgaa Derives d'indigo
US7576094B2 (en) 2004-12-13 2009-08-18 Eli Lilly And Company Spiro derivatives as lipoxygenase inhibitors
WO2012093100A1 (fr) * 2011-01-05 2012-07-12 Syngenta Participations Ag Dérivés de pyrazol-4-ylcarboxamide en tant que microbiocides
CN103313972A (zh) * 2011-01-05 2013-09-18 先正达参股股份有限公司 作为杀微生物剂的吡唑-4-基甲酰胺衍生物
US8653003B2 (en) 2011-01-05 2014-02-18 Syngenta Participations Ag Pyrazol-4-yl carboxamide derivatives as microbiocides
CN103313972B (zh) * 2011-01-05 2015-04-08 先正达参股股份有限公司 作为杀微生物剂的吡唑-4-基甲酰胺衍生物
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ
KR20200019979A (ko) 2017-06-23 2020-02-25 쿄와 기린 가부시키가이샤 α, β 불포화 아미드 화합물
US11447471B2 (en) 2017-06-23 2022-09-20 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound

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