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WO2000066124A1 - Agents preventifs ou inhibiteurs destines a une hepatopathie - Google Patents

Agents preventifs ou inhibiteurs destines a une hepatopathie Download PDF

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Publication number
WO2000066124A1
WO2000066124A1 PCT/JP2000/002813 JP0002813W WO0066124A1 WO 2000066124 A1 WO2000066124 A1 WO 2000066124A1 JP 0002813 W JP0002813 W JP 0002813W WO 0066124 A1 WO0066124 A1 WO 0066124A1
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WIPO (PCT)
Prior art keywords
group
substituent
therapeutic agent
substituted
substituent group
Prior art date
Application number
PCT/JP2000/002813
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English (en)
Japanese (ja)
Inventor
Takaichi Shimozato
Hiromi Doi
Tomio Kimura
Original Assignee
Sankyo Company, Limited
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Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU43151/00A priority Critical patent/AU4315100A/en
Publication of WO2000066124A1 publication Critical patent/WO2000066124A1/fr

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Classifications

    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to a preventive or therapeutic agent for liver injury containing a pyrrole derivative as an active ingredient.
  • pyrrole derivatives which are the active ingredients of the agent for preventing or treating liver damage according to the present invention are known and disclosed in W097 / 5877 and W097 / 5878. However, it is not disclosed that these compounds are effective in preventing or treating liver damage. -
  • the present inventors have conducted extensive studies on the synthesis of pyrrole derivatives and their pharmacological actions over many years. As a result, compounds having two or three aromatic groups on the pyrrole ring are excellent for liver injury. The present inventors have found that they have a prophylactic and therapeutic effect, and have completed the present invention.
  • the present invention
  • R 1 and R 2 represents a heteroaryl group or a heteroaryl group substituted with a group selected from a substituent group, a substituent group 0 and a substituent group ⁇ ;
  • R 3 is a phenyl group; a substituent group ⁇ , a substituent group] 3, and a fuunyl group substituted with a group selected from the substituent group ⁇ ;
  • [Q is an arylene group, a heteroarylene group, an arylene group substituted with a group selected from substituent group / 3 and a group selected from substituent group ⁇ , a substituent group], and a group selected from group 3 and a substituent group ⁇ A substituted heteroarylene group, or a divalent group of a 3- to 8-membered saturated heterocyclic ring containing at least one nitrogen atom,
  • R 4 is a general formula 1 WR 5 , — OWR 5 , — S (O) m WR 5 , 1 N (WR 5 ) R 6 , -SO 2 N (WR 5 ) R 6 , —CON (WR 5 ) R 6 , one COWR 5 or
  • a group having one PO (OR 7 ) (OR 8 )
  • n 0, 1 or 2
  • W represents an alkylene group, a lower alkenylene group, a cycloalkylene group, a cycloalkeneylene group or a lower alkynylene group,
  • R ⁇ R 9 and R 1Q are the same or different and are each a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, and a C 2 to 15 carbon atom
  • R 7 and R 8 are the same or different and are each a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, or an alkynyl group having 2 to 15 carbon atoms Or an aralkyl group. ). ]; Or
  • Het represents a 3- to 8-membered saturated heterocyclic divalent group containing at least one nitrogen atom
  • R 11 is a hydrogen atom; a lower alkyl group; an aralkyl group; a lower alkylsulfonyl group; an arylsulfonyl group; a group selected from Substituent group ⁇ , Substituent group] 3 and Substituent group ⁇
  • D represents a single bond or one C (R 20 ) (R 21 ) (wherein R 2Q and R 21 are the same or different and each represent a hydrogen atom, a hydroxyl group, a halogen atom or a lower alkyl group).
  • R 12 represents a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group or a halogeno lower alkoxy group,
  • R 13 , R 14 , R 15 and R 16 are the same or different and each represent a hydrogen atom or a lower alkyl group
  • k represents an integer of 0 to 3 (k power; when 2 or 3, a plurality of groups R 12 may be the same or different groups);
  • n 0, 1 or 2.
  • Z 1 is an oxygen atom, a sulfur atom or> NR 22 (where R 22 is a hydrogen atom, 1 to 3 groups selected from at most 15 alkyl groups, alkenyl groups having 2 to 15 carbon atoms, alkynyl groups having 2 to 15 carbon atoms, substituent group 3 and substituent group ⁇ An alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms substituted with 1 to 3 groups selected from substituent group / 3 and substituent group ⁇ , Or an alkynyl group having 2 to 15 carbon atoms substituted with 1 to 3 groups selected from Substituent Group / 3 and Substituent Group ⁇ . )
  • R 23 is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, 1 to 15 alkynyl groups, a substituent
  • NHCONR c R d (wherein, R e and R d are the same or different, represent a hydrogen atom, 1 to 1 5 alkyl group or Araruki Le group carbon atoms).
  • a halogen atom, a cyano group, NR e R f (where R e and R f are the same or different and are each a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a halogeno lower alkyl group or Represents an aralkyl group or, together with the nitrogen atom to which they are attached, forms a heterocyclyl group containing at least one nitrogen atom.) OR e (wherein R e Is as defined above.) And SR e (wherein, R e is as defined above.) [Substituent group “y”
  • Aryl group, heteroaryl group, and heterocyclyl group (these groups may be substituted with 1 to 3 groups selected from substituent group i3 and substituent group ⁇ ). Of these, preferably,
  • Preventive or therapeutic agent for hepatic injury comprising a compound having the formula: or a pharmacologically acceptable salt or derivative thereof.
  • a preventive or therapeutic agent for hepatic disorder containing a compound having the above general formula (I-I), or a pharmaceutically acceptable salt or derivative thereof.
  • R 1 is a heteroaryl group or a heteroaryl group substituted with a group selected from substituent group ⁇ , substituent group and substituent group ⁇ ,
  • R 1 is a pyridyl group; a pyrimidinyl group; a pyridyl group substituted with a group selected from a substituent group ⁇ , a substituent group / 3 and a substituent group ⁇ ; or a substituent group; ] 3 and a prophylactic or therapeutic agent for liver injury, which is a pyrimidinyl group substituted with a group selected from the group of substitution groups ⁇ ,
  • R 1 is a pyridyl group or a pyridyl group substituted with a group selected from substituent group ⁇ , substituent group
  • R 1 is a 4-pyridyl group or a 4-pyridyl group substituted with a group selected from substituent group ⁇ , substituent group / 3 and substituent group ⁇ Agent
  • R 1 is an unsubstituted 4-pyridyl group preventive or therapeutic agent for liver injury, (9) Prevention or prevention of hepatic disorder, which is an aryl group substituted with 1 to 3 groups selected from R 2 aryl group or substituent group ⁇ , substituent group / 3 and substituent group Therapeutic agents,
  • R 2 force Fuyuniru group, or an unsubstituted group group substituent group; prevention or treatment of liver disorders which is Fuyuniru group substituted with 1 to 3 groups selected from 3 and substituent group ⁇ Agent,
  • R 2 force phenyl group, or 1 to 3 of the prevention of liver damage are replacement has been Fuyuniru group or a group of therapeutic agents selected from the following substituent group:
  • a halogen atom a C 4 alkyl group, a diphenyl 4- halogenoalkyl group,
  • Ci—C 4 alkoxy group Ci—C 4 halogenoalkoxy group
  • a prophylactic or therapeutic agent for liver injury which is an R 2 group; a phenyl group, or a phenyl group substituted with 1 to 3 groups selected from the following substituent groups:
  • Examples include a fluorine atom, a chlorine atom, a difluoromethoxy group, and a trifluoromethyl group.
  • a prophylactic or therapeutic agent for liver injury which is an aryl group substituted with 1 to 3 groups selected from R 1 aryl group or a substituent group ⁇ , and
  • R 2 force Heteroariru group, or an unsubstituted radical group mentioned preventive or therapeutic agent for hepatic disorders, which are Teroariru group to that is substituted with a substituent group i3 and substituent group "V or we selected the group In the above-mentioned agent for preventing or treating liver injury, more preferably,
  • a preventive or therapeutic agent for R 23 forces hydrogen atom or a C! Hepatopathy which is one C 4 alkyl group, as well as
  • R 23 is a hydrogen atom, a prophylactic or therapeutic agent for hepatic disorders is a methyl group or Echiru group.
  • a prophylactic or therapeutic agent for hepatic disorder which is a phenyl group substituted with a group selected from the group consisting of R 3 phenyl group or substituent group ⁇ , substituent group 0 and substituent group ⁇ .
  • an agent for preventing or treating liver damage which is a phenyl group substituted with a group selected from the group consisting of R 3 substituent group ⁇ , substituent group / 3 and substituent group ⁇ ;
  • R 3 is a fuunyl group substituted with a group selected from the following substituent groups:
  • R 3 is a fuunyl group substituted with a group selected from the following substituent groups:
  • R 3 Power 4 one (lower alkylthio) Fuyuniru, 4- (lower alkyl sulfide sulfonyl) phenyl, or 4- (lower alkylsulfonyl) preventive or therapeutic agent for hepatic disorders is phenyl
  • preventive or therapeutic agent for liver damage which is a group having the general formula (II)
  • preferred preventive or therapeutic agents for liver damage include:
  • a preventive or therapeutic agent for hepatic disorder which is Het, azetidul, pyrrolidinyl, imidazolidinyl, oxazolidinole, thiazolidinyl, piperidyl, piperazinyl, morpholinyl or thiomonorefolinyl;
  • R 11 force a hydrogen atom, a lower alkyl group, or imino prevention of liver damage is a protecting group of the groups or therapeutic agent
  • preventive or therapeutic agent for hepatic disorder wherein R 3 is a group having the general formula (III), preferred preventive or therapeutic agents for hepatic disorder include:
  • R 12 force; a halogen atom, CI- C 4 alkyl group, CI- C 4 halogenoalkyl group, CI- ⁇ alkoxy or C ⁇ - CA halogenoalkoxy prophylactic or therapeutic agent for hepatic disorders is a group,
  • R 12 forces a fluorine atom, a chlorine atom, a methyl group, a prophylactic or therapeutic agent for hepatic disorders, which are main butoxy group or Jifuruorome preparative alkoxy group,
  • liver injury ( 1) a prophylactic or therapeutic agent for liver injury wherein k is 0, (3 2) R 13 , R 14 , R 15 and R 16 forces; the same or different, a hydrogen atom or An agent for preventing or treating liver injury, which is an alkyl group,
  • R 13 , R ", R 15 and R 16 are the same or different and are a hydrogen atom or a methyl group.
  • A is a single bond, an oxygen atom, a carbonyl group, - S 0 2 -,
  • R 17 and R 18 are the same or different and are a hydrogen atom, a hydroxyl group, a halogen atom or a C, 1C 4 alkyl group,
  • R 17 and R 18 are the same or different and are a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group or an ethyl group,
  • R 19 force hydrogen atom or An agent for preventing or treating liver injury that is an alkyl group
  • R is a hydrogen atom, a methyl group or an ethyl group.
  • R 3 is a preventive or therapeutic agent for hepatic disorders is a group having the formula one Q-R 4
  • Q is an arylene group or a group selected from substituent group 13 and substituent group ⁇ A substituted or substituted arylene group for preventing or treating liver damage,
  • a prophylactic or therapeutic agent for liver injury which is a group having R 4 , general formula — S (O) m WR 5 , and
  • a preventive or therapeutic agent for liver injury wherein Q is a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom,
  • a preventive or therapeutic agent for hepatic disorder wherein Q is azetidinzil, pyrrolidinediyl, imidazolidinyl, oxazolidinediyl, thiazolidinediyl, piperidinediyl, piperazinezil, morpholinzil or thiomorpholinzil,
  • a preventive or therapeutic agent for hepatic disorder wherein Q is azetidinezil, pyrrolidinezil, piperidinezil or pyrazinzil,
  • the cyclic group represents a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom in the definition of Q,
  • R 4 a is in the definition of R 4, the general formula one WR 5, one S (O) m WR 5,
  • R 4 a force formula one WR 5, prophylactic or therapeutic agent for hepatopathy which is one S (O) m WR 5 or a group having one C OWR 5,
  • R 4 a force formula one WR 5 or prophylactic or therapeutic agent for hepatic disorders is a group having one COWR 5, and
  • R 4 a - general formula prophylactic or therapeutic agent for hepatic disorders is a group having one WR 5 also suitable.
  • preferred preventive or therapeutic agents for liver damage include: (56) A preventive or therapeutic agent for liver damage in which W is an alkylene group, a lower alkenylene group or a lower alkynylene group. ,
  • W is an agent for preventing or treating liver injury wherein the alkylene group is
  • R 5 is an azide group, a nitro group, a thiocyanato group or
  • a group PO (OR 7 ) (OR 8 ) wherein R 7 and R 8 have the same meaning as described above.
  • a prophylactic or therapeutic agent for hepatic disorder and
  • more preferred agents for preventing or treating liver damage include (64) R 22 , a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a group of substituents; 3 and substituent groups 1 to 15 carbon atoms substituted with 1 to 3 groups selected from ⁇ A prophylactic or therapeutic agent for liver injury, which is a alkyl group, and
  • Liver disorder comprising administering an effective amount of a compound specified as any one selected from the above (1) to (68), or a pharmacologically acceptable salt or derivative thereof.
  • Heteroaryl group in the definition of RR 2 , RR 9 , R 10 and [substituent group ⁇ ]; and “substituent group ⁇ , substituent group
  • Examples include groups such as oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxosaziazolyl, triazolyl, thiadiazolyl, vilanyl, pyridyl, pyridazininole, pyrimigel, and virazinyl.
  • a sulfur atom, an oxygen atom and / or a nitrogen atom such as furinole, chenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, vilanyl, pyridyl, pyridazinyl, pyrimidinyl, vilazinyl are substituted by 1 Or a 5- or 6-membered aromatic heterocyclic group containing 2 or more.
  • R 1 and R 2 preferably one of a 5- to 6-membered aromatic heterocyclic ring containing at least one nitrogen atom and which may further contain one sulfur atom, oxygen atom or nitrogen atom is preferred. And more preferably a monovalent group of a 6-membered aromatic heterocycle containing one or two nitrogen atoms, even more preferably pyridyl or pyrimigel.
  • it is 4-pyridyl or 4-pyrimidinyl, most preferably 4-pyridyl.
  • heteroaryl group may be condensed with another cyclic group, and examples of such a ring include indolyl, benzofuranyl, benzochel, isoquinolyl, quinolinol (preferably isoquinolyl). Ril, quinolyl).
  • the “substituent group ⁇ , substituent group” 3 and the substituent group “heteroaryl group substituted with a group selected from V” in the definitions of R 1 and R 2 are preferably a substituent group ⁇ , A heteroaryl group substituted with 1 to 3 groups selected from the group group / 3 and the substituent group ⁇ , more preferably the substituent group ⁇ , the substituent group
  • the aryl group in the aryl group substituted with a group selected from 3 and the substituent group "y” is preferably an aryl group having 6 to 10 carbon atoms, such as phenyl and naphthyl. It represents a monovalent group, more preferably phenyl.
  • aryl group is fused with a cycloalkyl group having 3 to 10 carbon atoms.
  • Such groups include, for example, 5-indanyl and the like.
  • aryl group substituted with a group selected from substituent group ⁇ , substituent group and substituent group ⁇ is preferably a substituent group ⁇ , a substituent group / Represents an aryl group substituted with 1 to 4 groups selected from 3 and the substituent group ⁇ , and more preferably selected from the substituent group, the substituent group / 3 and the substituent group ⁇ Is an aryl group substituted with one to three groups.
  • the “arylene group” of the “arylene group” and the “arylene group substituted with a group selected from the substituent group / 3 and the substituent group ⁇ ⁇ ⁇ ⁇ ” in the definition of Q include 6 to 14 carbon atoms. And represents a divalent group of an aromatic hydrocarbon, preferably a divalent group of an aromatic hydrocarbon having 6 to 10 carbon atoms such as phenylene and naphthylene, and more preferably , 1,4-phenylene, 1,3-phenylene or 1,4-naphthylene, most preferably 1,4-phenylene.
  • the “arylene group” may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include indane-1,4,7-diyl. it can.
  • the “arylene group substituted with a group selected from the substituent group / 3 and the substituent group ⁇ ” in the definition of Q is preferably 1 to 2 selected from the substituent group 0 and the substituent group ⁇ . And represents an arylene group substituted with one group, more preferably an arylene group substituted with one group selected from Substituent Group 3) and Substituent Group V.
  • heteroarylene group in the “heteroarylene group” and “heteroarylene group substituted with a group selected from the substituent group / 3 and the substituent group ⁇ /” refers to furanylene, chenylene, and pyrrole.
  • Rylene azepinylene, pyrazolylene, imidazolenylene, oxazolenylene, isoxoxolylene, thiazolenylene, isothiazolenylene, 1,2,3-oxoxadiazolylene, triazolinylene, thiadiazolylene, pyrazilenylene, pyrazirene, pyrazirene Sulfur atom like pyrimidinylene, pyrazinylene, oxygen A divalent group of a 5- to 7-membered aromatic heterocyclic ring containing 1 to 3 atoms and 1 or 3 nitrogen atoms.
  • it is a divalent group of a 5- to 6-membered aromatic heterocyclic ring containing one or two sulfur atoms, oxygen atoms and Z or nitrogen atoms, more preferably, chenylene, imidazolylene, It is pyridylene or pyragelen, even more preferably, cherenylene, and particularly preferably, 1,3-chenylene.
  • heteroarylene group may be condensed with another cyclic group, and examples of such a group include indole-4,7-diyl and benzothiophene_4,7-diyl. Can be.
  • heteroarylene group substituted with a group selected from the substituent group 3” and the substituent group ⁇ in the definition of Q is preferably selected from the substituent group 0 and the substituent group ⁇ 1
  • a divalent group of a 3- to 8-membered saturated heterocyclic ring containing at least one nitrogen atom includes one nitrogen atom, and further includes a sulfur atom
  • the group QR 4 is preferably represented by the following general formula (IV)
  • the cyclic group represents a “3- to 8-membered saturated heterocyclic divalent group containing at least one nitrogen atom” in the definition of Q).
  • Alkylene group in the definition of W means methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylinoleethylene, pentamethylene, 1,1 dimethylinoleto A straight-chain or branched-chain alkylene group having 1 to 10 carbon atoms, such as dimethylene, hexamethylene, heptamethylene, otatamethylene, nonamethylene, and decamethylene.
  • it is a linear or branched alkylene group having 1 to 4 carbon atoms, more preferably, 1 to 3 linear or branched alkylene groups, and still more preferably, Methylene, ethylene or trimethylene, particularly preferably methylene or ethylene.
  • the “lower alkenylene group” in the definition of W means a group having 2 to 2 carbon atoms such as vinylene, 1-methylvinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and the like. It represents six straight-chain or branched-chain alkenylene groups, preferably a straight-chain or branched-chain alkenylene group having 2 to 4 carbon atoms, more preferably vinylene, It is nylene or butenylene.
  • “Cycloalkylene group” in the definition of W means cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,2-cyclobutylene 3 carbon atoms such as hexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptanylene, 1,3-cycloheptanylene, 1,4-cycloheptanylene And preferably 7 to 7 cycloalkylene groups, more preferably a cycloalkylene group having 3 to 6 carbon atoms, and still more preferably cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentene Len or 1, 3-cyclohexylene.
  • cycloalkenedylene group in the definition of W means 1,2-cyclopropenylene, 1,3-cyclopropenylene, 1,2-cyclobutenylene, 1,3-cyclobutenylene, 1,4-cyclobutenylene, 1, 2-cyclopentenylene, 1,3-cyclopentenylene, 1,4-cyclopentenylene, 1,5-cyclopentenylene, 3,4-cyclopentenylene, 3,5-cyclopentenylene, 1,2— Cyclohexenylene, 1,3-cyclohexenylene, 1,4-cyclohexenylene, 1,5-cyclohexenylene, 1,6-cyclohexenylene, 3,4-cyclohexenylene, 3,5-cyclo Hexenylene, 3,6-cyclohexenylene, 4,5-cyclohexenylene, 1,2-cycloheptenylene, 1,3-cycloheptenylene, 1,4-cycloheptenylene, 2,3-cyclohexene Put
  • a cycloalkenylene group having 3 to 7 carbon atoms such as tenylene, 3,6-cycloheptenylene and 3,7-cycloheptenylene. It is preferably a cycloalkenylene group having 3 to 6 carbon atoms, and more preferably 1,2-cycloprobenylene, 1,2-cyclobutenylene, 1,3-cyclopentenylene or 1,3-cyclopentenylene. It is xenylene at the mouth.
  • lower alkynylene in the definition of W means a straight-chain or branched alkynylene having 2 to 6 carbons, preferably a straight-chain or branched alkynylene having 2 to 4 carbons. And more preferably ethynylene, propynylene, 1-butynylene or 2-pentinylene, and particularly preferably ethynylene or propynylene.
  • alkyl group having 1 to 15 carbon atoms examples include, for example, Methyl, ethyl, propyl, isopropyl, n-butyl, isobutynole, s-butynole, tert-butynole, n-pentynole, isopentynole, 2-methinolebutynole, neopentynole,
  • Lower alkyl groups (alkyl groups having 1 to 6 carbon atoms) such as 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl; more preferably, lower alkyl groups having 1 to 4 carbon atoms; It is an alkyl group, and more preferably, methyl, ethyl or propyl.
  • alkyl group having 1 to 15 carbon atoms Preferably, it is an alkyl group having 1 to 4 carbon atoms, more preferably, methyl, ethyl or propyl.
  • R 12 represents a lower alkyl group, it is particularly preferably a methyl group or an ethyl group, and most preferably a methyl group.
  • R 13 , R 14 , R 15 and / or R 16 represent a lower alkyl group, it is particularly preferably a methyl group.
  • a lower alkyl group is indicated, it is particularly preferably a methyl group or an ethyl group.
  • R ", RR f, RR b when showing the R e and Z or R d force lower alkyl group, preferably in particular, a methyl group or Echiru group.
  • Alkyl group in the definition of R e , R 7 , R 8 , R 9 , R 10 , R ", R 22 , R 23 , R a , R b , R c , R d , R e, and R f Represents a group in which an aryl group (eg, phenyl, naphthyl, etc.) is bonded to the above “alkyl group having 1 to 15 carbon atoms” (preferably, the above “lower alkyl group”).
  • aryl group eg, phenyl, naphthyl, etc.
  • Is for example, benzyl, indenylmethylinole, phenanthreninolemethinole, anthraceninolemethinole, ⁇ -naphthinolemethinole, ⁇ -naphthylmethyl, diph: t-ninolemethyl, triphenylenolemethinole, ⁇ -naphthinoleline 9-Anthri-noremetinole, piperonil, 1-funetinore, 2-funetinole, 1-naphthinolechinole, 2-naphthylechinore, 1-funetinolepropinole, 2-fueninole pro Pill, 3-pheninolepropyl, 1-naphthinolepropynole, 2-naphthylpropynole,
  • the aryl moiety of the “aralkyl group” may be substituted with one to three groups selected from the above “substituent group ⁇ ”, “substituent group i3” and “substituent group“ y ”.
  • substituted aralkyl groups are preferably 2-fluorobenzyl, 3-funoleno-benzinole, 4-funenole-benzinole, 2-chlorobenzinole, 3-chlorobenzinole, 4 —Black mouth veninole, 2-bromobenzinole, 3-bromobenzinole, 4-benzole, 3,5-diphnolenobenzole, 2,5-diphneololofenethinole, 2,6-difluorobenzyl , 2,4-diphneolelophenetine, 3,5-dibromobenzyl, 2,5-dibromophenetine, 2,6-dichlorobenzinole, 2,4-d
  • aralkyl group or an aralkyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group and more preferably an unsubstituted aralkyl group or a halogen atom or a lower alkyl group.
  • Heteroalkyl ⁇ reel alkyl group in the definition of RR 9 and R 1 G, the “heteroaryl group” is the "number 1 to 1 5 alkyl group having a carbon” (preferably, the “lower alkyl group )), And such groups preferably include groups such as furinolemethyl, chenylmethyl, pyridylmethyl, pyrimidinylmethyl, 3-methylpyridinylmethyl and 4-methylpyrimidinylmethyl.
  • R 6 , R 9 and R 1Q are the same as the group described later as “group forming“ derivative ”based on hydroxyl group or mercapto group”.
  • R 11 and “lower alkylsulfonyl group” in the definition of [substituent group ⁇ ], and “lower alkylsulfonylamino group” in the definition of [substituent group ⁇ ] refer to the aforementioned “lower alkylsulfonyl group”.
  • An alkyl group '' is a group in which a sulfonyl is bonded to, preferably, methinoles-noleshoninole, etinolesnoleshoninole, propinoresnoleshoninole, isopropinolesnoleshoninole, butinoresnolesnole Honinore, I Sobutinoresnorenohonore, s-Buchinoreshonorehonore, t—Buchinoreshonorenorinore, 2—Pentinoresnorenohonore, 3-pentylsulfonyl , 2-Methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropinolesnolephoninole, 1,2-dimethylpropylsulfonyl, 2 , 2 dimethinolepropinoresnorenolinole, he
  • a sulfonyl group refers to a group in which an aryl group (for example, phenyl, naphthyl, anthracenyl, etc.) is bonded to a sulfonyl, and examples of such a group include phenylsnolephonyl, 1-naphthylsulfonyl, and 2-naphthylsulfoyl. Such groups can be mentioned, and it is preferably phenylsulfonyl.
  • the term “mono-lower alkyl group” in the definition of R 11 refers to a group in which one hydrogen atom of the group is replaced with the above “lower alkyl group”, and is preferably methyl canolebamoyl, Ji carbamoyl, propyl force Rubamoiru shows isopropyl force Rubamoiru, butylcarbamoyl, iso-butylcarbamoyl, s- Buchirukaruno moil, mono one C 6 alkyl, such as t-butylcarbamoyl) force Rubamoiru. More preferably, mono (C, one C 4 alkyl) force Rubamoiru, particularly preferably a methylcarbamoyl, E Ji carbamoyl or propylcarbamoyl. Carbamoyl.
  • di (lower alkyl) force Rubamoiru group in the definition of R 11 represents two groups in which a hydrogen atom has been replaced by the "lower alkyl group” of the force Rubamoiru group, preferably, dimethylcarbamoyl, GETS It refers to di (C i -C 6 alkyl) -powered rubamoyl, such as tylcarbamoyl, dipropyl-powered rubamoyl. More preferably a di (C i- ⁇ 4 ⁇ alkyl) force Rubamoiru, particularly preferably dimethylcarbamoyl or Jechinore
  • R 11 refers to a group in which one hydrogen atom of a sulfamoyl group has been replaced with the above “lower alkyl group”.
  • One C 4 Anorekiru) ⁇ Mi Nosuruhoniru particularly preferably methyl ⁇ amino sulfonyl, a Echiruami Nosunorehoniru or Puropiruami Nosunorehoninore.
  • the “di (lower alkyl) aminosulfonyl group” in the definition of R 11 represents a group in which two hydrogen atoms of a sulfamoyl group have been replaced with the above “lower alkyl group”, preferably dimethylaminosulfonyl, Di (C i -C g alkyl) aminosulfonyl such as getylaminosulfonyl and dipropylaminosulfonyl. More preferably, it is di (C i -C 4 alkyl) aminosulfonyl, particularly preferably dimethylaminoaminosulfonyl or getylaminosulfoninole.
  • protecting group for imino group in the definition of R 11 includes, for example, formyl: acetyl, propionyl, butyrinole, isobutylyl, pentanoyl, vivaloyl, nolerinole, isovalerinole, otatanol, noelcarbinole, decylcarbonyl, 3-methinocarbonyl Ninore, 8-Methynolenoninolecanoleboninole, 3 —Ethyloctylcanoleboninole, 3,7-Dimethyloctylcarbonyl, Pendecylcarbonyl, Dodecylcarbinole, Tridecylcarbonyl, Tetradecylcarbonyl , Pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methinolepentadecylcarbon
  • C 5 alkylcarbonyl group “Lower alkoxycarbonyl group” such as methoxycarbonyl, ethoxycarbonyl, propoxyl-carbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl: benzyloxycarbonyl Nore, 4-methoxybenzyloxycanoleboninole, 3,4-dimethoxy One to two lower alkoxy or aryl groups with one or two lower radicals, such as n-in-l-oxycanoleboninole, 2-di-tropendino-reoxy-canole-bon-ile, 4-12-troben-ziloxycarbonyl May be substituted “aralkyloxycarbonyl group”; formyloxymethyl, acetooxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, bivaloyloxymethyl, valeryloxymethyl , Isonox
  • R 12 , R 17 , R 18 , R 20 , R 21 , R 23 and the term “halogen atom” in the definition of [substituted S group / 3] represent a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and are preferred. Represents a fluorine atom or a chlorine atom.
  • R 17 or R 18 represents a halogen atom, it is particularly preferably a fluorine atom.
  • halogeno lower alkyl group in the definition of R 12 , R e and R f is the above “lower lower alkyl group”.
  • Alkyl group represents a group substituted by the above “halogen atom”, and is preferably trifluoromethylinole, trichloromethinole, diphnoleolomethyi-, dichloromethinole, dibromomethyl, fluoromethyl, chloromethinole, bromomethyl, 2,2,2-trichloroethylene.
  • trifluoromethyl trichloromethinole, difluorometinole, fenoleolomethinole, chloromethinole, bromomethinole, 2-phnooleolochinole, and 3-phnolelotinole.
  • Mouth pill such as 4-fluorobutyl It is a nitrogenoalkyl group. Even more preferably, it is trifluoromethylinole, trichloromethinole, diphnoleolomethinole, phneolomethyl, most preferably trifluoromethyl.
  • the “lower alkoxy group” in the definition of R 12 represents a group in which an oxygen atom is bonded to the “lower alkyl group”, and is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or s-butoxy. , T-butoxy, pentyloxy,
  • a straight-chain or branched C ⁇ -Ce alkoxy group such as 1,2,2-trimethylpropoxy; More preferably a C i one C 4 alkoxy group, particularly preferably a main butoxy.
  • halogeno lower alkoxy group in the definition of R 12 represents a group in which an oxygen atom is bonded to the above “halogeno lower alkyl group”, and is preferably fluoromethoxy, difluoromethoxy, trifluorenomethoxy, or 2-phenylenoalkyl.
  • Ethoxy, 3-Hunorelov. mouth Straight or branched chains, such as oxy, 4-funoleolobutoxy, 2-chloroethoxy, 2-bromoethoxy;
  • ⁇ represents a halogenoalkoxy group. More preferably a ten 4 halogenoalkoxy group, and more preferably more, a Jifuruorome butoxy or preparative Rifuruorome butoxy, particularly preferably a Jifuruorome butoxy.
  • lower alkylsulfinyl group in the definition of [Substituent group ⁇ ] refers to a group in which sulfinyl is bonded to the above “lower alkyl group”, and is preferably methylsulfinyl, ethylsulfinyl, propinoles Norefininore, Isopropinoresnorefininole, Butinoresnorefininole, Isobutinoresnorefininole, S-Bucinoresnorefineinore, t—Buchinoresnorejuinore, Pentinores Norefininole, 2-pentinoresolefininole, 3-pentinoresolefininole, 2-methylbutylsulfinyl, 3-methylbutinolesulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropyl Sulfinyl, 2,2-dimethino
  • R e and R f together with the nitrogen atom to which they are attached form a “heterocyclyl group containing at least one nitrogen atom”, which contains one nitrogen atom, and A 5- to 7-membered non-aromatic heterocyclic group which may contain one oxygen atom, sulfur atom or nitrogen atom.
  • heterocyclyl group containing at least one nitrogen atom which contains one nitrogen atom
  • a 5- to 7-membered non-aromatic heterocyclic group which may contain one oxygen atom, sulfur atom or nitrogen atom.
  • Examples of such a group include morpholinyl, thiomorpholinol, pyrrolidinyl, pyrrolinyl, imidazolidinyl, Examples include imidazolinyl, pyrazolidinyl, birazolinyl, piperidyl, and piperazinyl.
  • it contains one nitrogen atom, and further contains one oxygen atom, sulfur atom or nitrogen atom.
  • heterocyclyl group containing at least one nitrogen atom may have an oxo group and a thio or oxo group, and such a group may be 2-oxomorpholinyl.
  • groups such as pyrrolidonyl.
  • groups OR e is preferably a hydroxyl group, a lower alkoxy group or a halogeno-lower alkoxy group, the "lower alkoxy group” and “halo genomic lower alkoxy group”, respectively, The same groups as the groups defined as R 12 are shown.
  • the group SR e in the definition of [Substituent group 3] preferably represents a lower alkylthio group or a halogeno lower alkylthio group.
  • lower alkylthio group refers to a group in which the above “lower alkyl group” is bonded to a sulfur atom, and is preferably a C 4 alkylthio group, more preferably methylthio, ethylthio, propylthio, isopropylthio, Butylthio, even more preferably methylthio, ethylthio, propylthio, most preferably methylthio;
  • halogeno lower alkylthio group refers to a group in which the above “halogeno lower alkyl group” is bonded to a sulfur atom, and is preferably a C 4 halogenoalkylthio group, more preferably difluoromethylthio, Trifluoromethylthio and 2,2,2-trifluoroethylthio.
  • heterocyclyl group in the definition of the substituent group means that 1 to 3 carbon atoms of a cycloalkyl or cycloalkenyl group having 5 to 7 carbon atoms are replaced with a sulfur atom, an oxygen atom and / or a nitrogen atom. Represents a non-aromatic heterocyclic group.
  • a sulfur atom, an oxygen atom and a nitrogen atom such as monorefolininole, thiomorpholinyl, pyrrolidinyl, pyrrolininole, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, and piperazinyl are 1 to 3 times.
  • 5 to 6-membered non-aromatic heterocyclic group more preferably morpholinyl, pyrrolidinyl, piberidi It is a 5- to 6-membered non-aromatic heterocyclic group containing one nitrogen atom, such as nore and piperazinyl, and which may further contain one oxygen atom or nitrogen atom.
  • heterocyclyl group may be condensed with another cyclic group, and examples of such a group include groups such as chromanyl, indolinyl, and isoindolinyl.
  • R 1 or R 2 represents ⁇ aryl group substituted with a group selected from substituent group i, substituent group i3 and substituent group ⁇ ''
  • the substituent is preferably a halogen atom
  • R 3 represents “a phenyl group substituted with a group selected from substituent group ⁇ , substituent group
  • the number of substituents of the group is preferably One to three.
  • the substituent is preferably a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a group NR e R f (where R e and R f are the same or different.
  • ⁇ Are the same or different and represent a hydrogen atom, a lower alkyl group or an aralkyl group) and a group —so 2 NR a R b (wherein, Ra and R b are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group), and more preferably, a lower alkylthio group.
  • “Pharmacologically acceptable salt” refers to a salt of the compound represented by the general formula (I) of the present invention, which can be converted into a salt, if necessary.
  • Such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; methanesulfonate, ethanesulfonate, benzenesulfone Acid salts, p—toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate, and acid addition salts of organic acids: as well as sodium, potassium, lithium Alkali metal salts such as salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, Glucosamine salt, phenyldaricin alkyl ester salt, ethylenediamine salt, N-methyldalcamine salt, guanidine salt, getylamine salt, Lietylamine
  • the compound (1) of the present invention is solvates (eg, For example, hydrates), and the present invention includes such solvates.
  • derivative refers to a compound represented by the general formula (I) of the present invention, which has a hydroxyl group, a mercapto group, an imino group, and a thio or phosphono group in a molecule thereof.
  • Derivatives can be obtained by protecting with a group that is removed by a chemical method such as electrolysis or photolysis, or by a group that is removed by a biological method such as hydrolysis in a living body. So its derivatives are shown.
  • Whether a compound is a ⁇ derivative '' protected by a ⁇ group removed by a chemical method such as hydrolysis, hydrogenolysis, electrolysis, or photolysis '' can be determined by subjecting the compound to normal hydrolysis, It can be determined by placing it under conditions used for reactions such as hydrogenolysis, electrolysis, and photolysis, and after a certain period of time, examining the reaction phase and detecting the original compound or a pharmacologically acceptable salt thereof.
  • Whether a compound is a “derivative” protected by a “group removed by a biological method such as hydrolysis in a living body” may be determined by, for example, determining whether the compound is a rat or mouse. It can be determined by intravenous injection to various experimental animals, then examining the body fluid of the animal, and detecting the base compound or its pharmacologically acceptable salt.
  • Examples of the group forming a “derivative” based on a hydroxyl group or a mercapto group include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pyrroinole, relinole, isolelinole, octanoinole, nonylcanolebonyl, and desinolene.
  • acyloxy 11 (acyloxy) “lower alkyl group” such as “lower alkyl group” ′; methoxycarbonyloxymethyl, ethoxycanoleboninoleoxymethyl, propyloxycarbonyloxymethyl, Isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, to the mouth Xyloxy carbonyloxy
  • acyloxy lower alkyl group
  • (Lower alkoxycarboxy) alkyl groups such as (ethoxycarbonyloxy) hexyl; (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4 —Methylphenyl) -1-2-oxo-1,3, -dioxolen-4-yl) methyl, [5- (4—methoxyphenyl) —2-oxo-1,3,3-dioxolen-4-inole] Methynole, [5 — (4-Funoleolophenyl) 1 2 —oxo 1, 3—dioxolene 4 —inole] Mechinore, [5-(4 1-open-mouth feninole) 1 2 —oxo 1 1, 3 —dioxolen 1 4- (yl) methyl, (2-oxo-1,3-dioxolen-4-yl)
  • the above “aliphatic acyl group” is preferable, and further more preferable.
  • it is a C IQ aliphatic acyl group, most preferably CC 4 aliphatic acyl group.
  • the above-mentioned “carbonyloxyalkyl group” is preferable.
  • the group forming a “derivative” based on a phosphono group is preferably the “halogeno lower alkyl”; 2-hydroxyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4 —Hydroxy “lower alkyl group” such as dihydroxybutyl and 4-hydroxybutyl; “lower aliphatic acyl” such as acetylmethyl; “lower alkyl group”; the “silyl group”; methoxyxetil, 1-ethoxyxetil; 1-Methyl-l-Methoxyxetil, 1- (Isopropoxy) ethyl, 2-Methoxyxyl, 2-Ethoxyl, 1,1-Dimethyl 1-Methoxyxyl, Ethoxymethyl, n-Propoxymethyl, Isopropoxymethyl, n -Lower alkoxy lower alkyl groups such as butoxymethyl and t-butoxymethyl, 2-methoxy Lower alkoxy
  • the compound having the general formula (I) may have an asymmetric center in the molecule, In such a case, optical isomers (R-form and S-form) are present, and the present invention also includes them.
  • Specific examples of the compound that is an active ingredient of the agent for preventing or treating liver damage according to the present invention preferably include compounds as shown in the following table.
  • CD CD-CD-CD Cm ⁇ ⁇ cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm cm
  • POM indicates bivaloyloxymethyl
  • Pr indicates propyl
  • ip r indicates isopropyl
  • Prop indicates propionyl
  • Pyr indicates pyridyl
  • Pyrm represents pyrimidinyl
  • preferred compounds include 1-1, 1-6, 1-17 to 1-19, 1-22, 1-37, 1-42, 1-153, 1- 58, 1–69, 1–74, 1–80, 1–81, 1–85, 1–90, 1–10 1, 1–106, 1 1 1 7 to 1–1 19, 1— 1 22, 1—1 3 7, 1—142, 1—1 53,
  • More preferred compounds include, but are not limited to, 1-1, 1-1-7, 1-22, 1-137, 1-53,
  • the most preferred compounds include
  • Even more preferred compounds are exemplified compound numbers 8 to 27, 8 to 28, 8 to 40, 8 to 41, 8 to 53, 8 to 54, 8 to 79, 8 to 80, 8 — 9 2, 8—93, 8—105, 8—106, 8—131, 8—132, 8—144, 8—145, 8—157, 8—1 5 8,8—1 7 0,8—1 7 1,8—1 8 3,8—1 8 4,8—1 9
  • Particularly preferred compounds are exemplified compound numbers 8-131, 8-13, 8-14, 8-15, 8-15, 8-15, 8-17.
  • 8—1 7 1, 8—2 1 0, 8—2 6 2, 8—54 8, 8—549, 8—5 61, 8—5 62, 8—5 74, 8—5 75, 8-5 887, 8-5 88 8, 13-7, 13-15, 13-20, 13-22 and 13-40 can be mentioned.
  • the most preferred compounds include
  • the compound represented by the general formula (I) may have an R 3 group or a substituent group ⁇ , a substituent group] 3 and a substituent group ⁇
  • Compounds wherein R 3 is a group having the general formula (III) can be prepared by the following AG methods:
  • R 3 is a compound represented by the following formula:
  • the compound that is a group having the general formula 1 Q—R 4 can be produced by the following H to N methods.
  • Method A A method for producing a compound (la) in which Z 1 is> NH, Z 2 is —CH R, and R 3 is a group having the general formula (III)]
  • the first step is a step of subjecting the keto alcohol compound (1) and the benzoyl acetate compound (2) to a condensation reaction in acetic acid in the presence of ammonium acetate to produce a pyrocarboxylic acid ester compound (3). It is carried out according to the method described in the literature (D. Davidson, J. Org. Chem., 3, 361 (1938)).
  • the second step is a step of hydrolyzing or hydrolyzing the pyrocarboxylic acid ester compound (3), followed by a decarboxylation reaction to produce the compound (la).
  • reaction of this step a hydrolysis reaction or a hydrogenolysis reaction using an ordinary acid or alkali commonly used in organic synthetic chemistry is applied, and in the subsequent decarboxylation reaction, decarboxylation by acid, alkali or heat is performed. The reaction is applied.
  • the oxidation reaction is carried out in an inert solvent (for example, aliphatic hydrocarbons such as hexane, heptane, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as form, carbon tetrachloride, and dichloroethane; phenolic alcohols such as methanol, ethanol, propanol, and butanol; and esters such as ethyl acetate, propyl acetate, butyl acetate, and ethyl propionate.
  • an inert solvent for example, aliphatic hydrocarbons such as hexane, heptane, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons such as form, carbon tetrachloride, and dichloroethane; phenolic alcohols such as methanol,
  • Carboxylic acids such as acetic acid and propionic acid; water: or a mixed solvent thereof, preferably a halogenated hydrocarbon (especially methylene chloride, chloroform, dichloroform)
  • Oxidants eg peracetic acid, perbenzoic acid, m- chloroperbenzoic acid such as perbenzoic acid
  • hydrogen peroxide eg peracetic acid, perbenzoic acid, m- chloroperbenzoic acid such as perbenzoic acid
  • hydrogen peroxide eg peracetic acid, perbenzoic acid, m- chloroperbenzoic acid such as perbenzoic acid
  • hydrogen peroxide sodium meta-perchlorate
  • metal peroxide It may be an alkali metal perhalogenate such as sodium periodate or metaperiodic acid rim, preferably peracids or hydrogen peroxide, particularly preferably m-chloroperoxygen.
  • Method B Method for producing compound (Ib) in which A is an oxygen atom or 1 N (R 19 ) of compound (Ia)]
  • a ′ represents an oxygen atom or —N (R 19 ).
  • T represents a leaving group
  • L represents a hydroxyl group
  • T represents one NHR 19 and L represents a leaving group.
  • the term "leaving group" in the definition of T and L generally means a group leaving as a nucleophilic residue, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; trichloromethyloxy; Trihalogenomethinoleoxy groups; lower alkenylsulfonyloxy groups such as methanesolephoninoleoxy and ethanesnolehonyloxy; halogeno groups such as trifluoromethanesulfonyloxy and pentafluoroethanesnolehoninoleoxy Lower alkyl group; benzenesulfonyloxy, p-toluenesulfoninoleoxy, p-nitrobenzene benzonolephoninoleoxy, and the like.
  • the third step is a step of subjecting the keto alcohol compound (1) and the benzoyl acetate compound (4) to a condensation reaction in acetic acid in the presence of ammonium acetate to produce a pyrocarboxylic acid ester compound (5), Implemented according to the first step.
  • the fourth step is a step of producing the compound (6) by hydrolyzing or hydrolyzing the pyrocarboxylic acid ester compound (5), followed by a decarboxylation reaction, and is carried out according to the second step.
  • the fifth step is a step of producing a compound (Ib) by closing the ring of the compound (6). a) When L of the compound (6) is a hydroxyl group, a ring-closing reaction can be performed according to the Mitsunobu reaction (DLHughes, Org. React., 42, 335 (1992)).
  • the reagent used in the Mitsunobu reaction is not particularly limited as long as it can be used in the Mitsunobu reaction, but is preferably a dithiol such as getyl azodicarboxylate or diisopropyl azodicarboxylate.
  • Lower alkyl azodicarboxylates or 1, 1 '-(azodicarbonyl) azo compounds such as azodicarbonyls such as dipiperidine and triarylphosphines such as triphenylphosphine or tri-lower alkylphosphines such as tri-n-butylphosphine.
  • a combination of di-lower alkyl azodicarboxylates and triaryl phosphines and most preferably a combination of getyl azodicarboxylate and trif. It is a combination of enylphosphine.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as carbon form, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl ethyl formate, ethyl ethyl acetate, propyl acetate, butyl acetate, and dimethyl ether; dimethyl ether, diisopropyl ether, tetrahi Ethers such as drofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; And amides such as N-methinolei 2-pyrrolidone and hexamethylphosphorotr
  • the reaction is carried out at a temperature of from 120 ° C. to 100 ° C., preferably from 0 ° C. to 50 ° C.
  • reaction time varies depending on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 30 minutes to 12 hours. .
  • L of compound (6) is a leaving group
  • a ring closure reaction is carried out in a solvent in the presence or absence of a base.
  • Solvents used include, for example, alcohols such as methanol, ethanol, propanol, and isopropanol; getyl ether, diisopropinoleate Ethers such as toluene, tetrahydrofuran and dioxane; non-protonic polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile; methyl acetate and ethyl acetate Esters; aromatic hydrocarbons such as benzene, toluene, and xylene; and aliphatic hydrocarbons such as pentane, hexane, and heptane.
  • alcohols such as methanol, ethanol, propanol, and isopropanol
  • getyl ether, diisopropinoleate Ethers such as toluene, tetrahydrofuran and dioxane
  • alkali metal alkoxides such as sodium methoxide, sodium methoxide, potassium monobutoxide
  • alkali metal hydrides such as sodium hydride and lithium hydride
  • water Alkali metal hydroxides such as sodium oxide and potassium hydroxide
  • alkali metal carbonates such as sodium carbonate and potassium carbonate
  • the compound (5) in which m is 0 is used as a starting material in this step, the compound is equivalent to the cyclic sulfide compound (la ′) by performing a ring-closing reaction according to the above a) or b).
  • a compound in which m is 1 and a compound in which m is 2 can be produced by oxidizing this sulfide group. This oxidation reaction is performed according to the method described in the second step.
  • the sixth step is a step of reducing the 4-position of the pyrrole ring of the compound (la) or compound (lb) of the present invention to produce a compound (Ic) wherein R 2S is a lower alkyl group.
  • This step is carried out according to the method described in the literature (BVG Regorovich et al., Can. J. Chem., 46, 3291 (1968)).
  • the corresponding cyclic sulfoxide compound [the compound in which m is 1 in the general formula (Ic)] It can be produced by oxidation according to the method described in the two steps.
  • the cyclic sulfoxide compound in which m is 1 in the above general formula (Ic) is produced, the corresponding The compound can be produced by oxidizing a cyclic sulfide compound [compound in which m is 0 in the general formula (Ic)] according to the method described in the second step.
  • Method D A method for producing a compound (Id) in which A is — C (R 17 ) (R 18 )-(wherein, R 17 is a hydroxyl group, and R 18 is a hydrogen atom.) ]
  • the seventh step is the step of preparing compound (7).
  • a step of producing a compound (Id) of the present invention by reducing a carbonyl group for example, a metal borohydride such as sodium borohydride or lithium borohydride; aluminum hydride Lithium, aluminum hydride compounds such as lithium triethoxide aluminum; tellurmonium hydride; dibutyl aluminum hydride, organoaluminum hydride reduction such as di (methoxetoxy) aluminum dinadium dihydride Hydride test of chemicals
  • a reduction reaction using a drug or a catalytic reduction with hydrogen can be employed, and the reaction is performed, for example, in J.dale, J.Chem.Soc, 910 (1961) and FGBordwell et al., J.Org.Chem. , 33, 3385 (1968).
  • a compound in which R 18 is a lower alkyl group can be produced by reacting compound (7) with a Grignard reagent.
  • Method E A method for producing a compound (Ie) in which A is one C (R 17 ) (R 18 ) — (wherein, R 17 is a halogen atom and R 18 is a hydrogen atom.) ]
  • the eighth step is a step of preparing the compound (Ie) of the present invention by substituting the hydroxyl group of the compound (8) with a halogen atom.
  • a fluorination reaction with getylaminosulfur trifluoride (DAST); Thionyl, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine Z Chlorination reaction with carbon tetrachloride; hydrobromic acid, thionyl bromide, phosphorus tribromide, trifuunylphosphine / tetrabromide A bromination reaction with carbon; or an iodination reaction with hydroiodic acid or phosphorus triiodide can be employed, and the reaction is, for example, WJ Middleton, J. Org. Chem., 40, 575 (1957) and It is performed according to the method detailed in CRNoller & R. Dinsmore, Org. Synth., II, 358 (1943).
  • Method F A method for producing a compound (If) in which A is 1 C (R 17 ) (R 18 ) 1 (wherein R 17 and R 18 represent a halogen atom)]
  • the ninth step is to prepare the compound (7).
  • This is a step of producing a compound (If) of the present invention by gem-dihalogenating a carbonyl group, for example, gem-difluorination reaction with sulfur tetrafluoride or DAST; phosphorus pentachloride, thionyl chloride dimethylform A gem-dip mouth reaction with an amide; a gem-dibromination reaction with boron tribromide; or a gem-jodation reaction with trimethylsilicon iodide can be employed.
  • WJ Middleton J. Org. Chem. , 40, 574 (1975) and MEJung et al., J. Org. Chem., 43, 3698 (1978).
  • Step 10 is a compound (7) ) And a hydroxyamine derivative (9) to produce a compound (Ig) of the present invention, which is carried out by a conventional method (for example, EWBousquet, Org. Synth., II, 313 ( 1947).
  • a compound in which m is 0 when used as a starting material, a compound in which m is 1 and a compound in which m is 2 are obtained by performing an oxidation reaction according to the method described in the second step. Is obtained.
  • Compounds that are starting materials for the above-mentioned Method A and Method B, that is, compound (1 :), compound (2) and compound (4) are known compounds per se or can be converted from known compounds to known methods. It is a compound obtained by treating according to.
  • compound (2) can be produced according to the following method.
  • the process is a process in which a compound (10) is reacted with bromine to introduce a bromine atom into a benzene ring to produce a brominated compound (11).
  • a compound (10) is reacted with bromine to introduce a bromine atom into a benzene ring to produce a brominated compound (11).
  • a compound (10) is reacted with bromine to introduce a bromine atom into a benzene ring to produce a brominated compound (11).
  • a compound (10) is reacted with bromine to introduce a bromine atom into a benzene ring to produce a brominated compound (11).
  • an organometallic compound (12) is produced by reacting the brominated compound (11) with butyllithium or magnesium, and this compound is immediately reacted with carbon dioxide (CO 2 ).
  • the 13th step is a step of oxidizing a sulfur atom of the carboxylic acid compound (13) to obtain> S (O) m to obtain a compound (14), if desired. It is carried out according to.
  • the 14th step is to react the carboxylic acid compound (14) with a magnesium salt of malonic acid monoester in the presence of 1,1′-carbonyldiimidazole (CDI) and an organic base to obtain a compound. This is the step of manufacturing (2).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as carbon form, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene; esters such as ethyl ethyl formate, ethyl acetate, propyl acetate, butyl acetate, and getyl carbonate; and ethyl ether and diisopropyl ether Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetate Toamide, N-Me Amides such
  • the organic base used is not particularly limited as long as it is used as a base in a usual reaction.
  • examples thereof include amines such as pendecene, and preferably, triethylamine is used.
  • the reaction is carried out at a temperature of from 120 ° C. to 100 ° C., preferably from 0 ° to 50 °. It is.
  • the reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 10 minutes to 3 days, preferably from 1 hour to 24 days. Time.
  • R 23a represents a group other than a hydrogen atom defined as R 23 .
  • the keto alcohol compound (1) and the benzoyl acetate compound (17) are subjected to a condensation reaction in acetic acid in the presence of ammonium nitrate to produce a pyrocarboxylic acid ester compound (18).
  • This step is performed according to the method described in the literature (D. Davidson, J. Org. Chem., 3, 361 (1938)).
  • the 16th step is another method for producing the compound (18), and the oxime compound (16) and the compound (17) are reacted by heating in sulfuric acid in the presence of zinc dust, This is a step of performing reductive condensation.
  • the first 7 step pyromellitic one Rukarubon acid ester compound (1 8) to hydrolysis or hydrogenolysis followed by decarboxylation, of R 22 and R 23 activity of compounds of the present invention (1 'single A); This is a process for producing a compound ( ⁇ ′-A a) that is a hydrogen atom.
  • This step is carried out according to the method disclosed in W097Z58587 (in particular, SC HEME VI to S CHEME X).
  • R 22 a represents a group other than a hydrogen atom as defined as R 22.
  • the 1-position of the pyrrole ring of the compound (I′—Ac) [the compound (I′-Aa) or the compound (1′—Ab) produced by the above-mentioned Method H] more be modified with 22 a, is a step for preparing a compound of the present invention (1 'single a d).
  • This step for example, the compound (1 'single A c) in the presence of a phase transfer catalyst, the general formula: R 22 a - X (wherein, R 2 2 a shows the same meaning as defined above, X is And a halogen atom.) And carried out according to the method detailed in "The Chemistry of Heterocyclic Compounds, Vol. 48, Part 1, pages 432-436, John Wiley &Sons".
  • RR 2, R 3, R 22 a and R 24 are as defined above.
  • the keto-alcohol compound (1) and the compound (1 9) are reacted I Midazo Forming a compound in which R 22 is a hydrogen atom in the general formula (I-I B) by forming a monocyclic ring, a method described in detail in WO 93/14081. It is carried out according to.
  • the second 1 step by Rukoto to modification at the 1-position of the imidazole ring of the compound (I -B a) a group R 22 a, compound - a (I B b) a step of producing. This step is performed according to the above “18th step”.
  • Method K a compound in which, in the general formula (I), Z 1 is an oxygen atom and Z 2 is an oxygen atom [ie, a method for producing a compound having the following general formula (I-C)]
  • L ′ represents the above “leaving group” (preferably a halogen atom, particularly preferably It is a bromine atom. ),
  • the second step is a step of producing compound (22) by condensing compound (20) and compound (21) in the presence of a solvent.
  • solvent used examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; Non-protonic polar solvents, such as N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide; nitriles, such as acetonitrile; esters, such as methylinoleate acetate and ethylenoleate acetate; Aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as pentane, hexane, and heptane; or a mixed solvent thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane
  • the reaction temperature is usually from ⁇ 20 ° C. to 150 ° C., preferably from room temperature to 10 ° C.
  • the reaction time varies mainly depending on the reaction temperature, the solvent used and the like, but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.
  • the compound (22) is subjected to a ring-closing reaction to form an oxazole ring, thereby producing a compound (IC).
  • This step is performed according to the method described in detail in WO95 / 13067.
  • a to K the method for producing a compound in which the central ring is pyrrole, imidazole or oxazole in the general formula (I) has been described. (For example, "The Chemistry of Heterocyclic Compounds, Vol. 34, Vol. 37, Vol. 39, Vol. 44 and Vol.
  • R 3 is a group having the general formula —Q—R 4
  • R 4 is a general formula: —S (O) m —W—R 5 (wherein R 5 , m and W have the same meanings as described above.)
  • the “cation” in the definition of (M ”) + includes monovalent metal ions such as potassium ion, sodium ion and silver ion; and quaternary ammonium ions such as ammonium ion and tetrabutylammonium ion. Can be mentioned.
  • compound (23) is reacted with compound (24) in the presence of a solvent, and leaving group L ′ of compound (23) is reacted with (R 5 ) -anion of compound (24).
  • solvent used examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; N, N— Non-protonic polar solvents such as dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; benzene, toluene, Aromatic hydrocarbons such as xylene; aliphatic hydrocarbons such as pentane, hexane and heptane; or a mixed solvent thereof.
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane
  • ethers such as getyl ether, diisoprop
  • the reaction is usually carried out at a temperature of from 120 to 150 ° C, preferably from room temperature to 100 ° C.
  • the reaction time depends mainly on the reaction temperature, the solvent used, etc., but is usually 10 minutes. Between 30 and 48 hours, preferably between 30 minutes and 24 hours.
  • the oxidation reaction is carried out in an inert solvent (for example, aliphatic solvents such as hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane) Halogenated hydrocarbons such as liquid, formaldehyde, carbon tetrachloride and dichloroethane; alcohols such as methanol, ethanol, propanol and butanol; esters such as ethyl acetate, propyl acetate, butyl acetate and ethyl propionate.
  • Carboxylic acids such as acetic acid and propionic acid; water; and a mixed solvent thereof.
  • halogenated hydrocarbons and carboxylic acids Particularly preferred are dichloromethane and chloroform. In the form, dichloroethane or acetic acid.
  • peracids such as peracetic acid, perbenzoic acid, m-peroxybenzoic acid; hydrogen peroxide; sodium metaperchlorate, sodium metaperiodate, and metaperiodic acid
  • Metal perhalates such as chromium, and are preferably peracids or hydrogen peroxide, and particularly preferably m- chloroperbenzoic acid.
  • sulfide The compound or the sulfoxide compound is allowed to stand at a temperature of 120 ° C. to 150 ° C. (preferably 0 ° C. to 100 ° C.) for 10 minutes to 10 hours (preferably 30 minutes). To 5 hours).
  • the above oxidation reaction When one oxygen atom is added by the above oxidation reaction, 0.6 to 1.4 equivalents (preferably, 0.8 to 1.2 equivalents) of the oxidizing agent is added to 1 equivalent of the substrate. Is used. Further, the above oxidation reaction is carried out by using a sulfide compound as a substrate and using 1.5 to 3 equivalents (preferably 1.8 to 2.5 equivalents) of an oxidizing agent with respect to 1 equivalent of the substrate. A sulfone compound can be produced.
  • Method M Another method for producing a compound having the general formula (I-A) among the compounds having the general formula (I)]
  • Cyclic groups E, R 1 , R 2 , X, Z 1 and Z 2 are as defined above,
  • R 4 a is a general formula — WR 5 , -S (O) m WR 5 , — S 0 2 N (WR 5 ) R 6 ,
  • a group having one CON (WR 5 ) R 6 , one COWR 5 or —PO (OR 7 ) (OR 8 ) RR 6 , R 7 , R 8 , W and m are as defined above.
  • the compound (29) is reacted with the compound (30) to form a ring E of the compound (29) (this ring corresponds to the cyclic group E). and qualified the nitrogen atom in the group R 4 a, a step general formula (I) R 3 in the you produce the compound is a group having the general formula (IV).
  • an alkylation reaction an acylation reaction, a sulfonylation reaction, or a phosphorylation reaction of a secondary amine, which is widely used in organic synthetic chemistry, can be employed, usually in a solvent, in the presence of a base or Performed in the absence.
  • solvent used examples include ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; non-protonic polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide; Nitriles such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane. be able to.
  • ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane
  • non-protonic polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide
  • Nitriles such as methyl acetate and ethyl acetate
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • Examples of the base used include alkali metal hydroxides such as sodium methoxide, sodium methoxide and potassium-t-butoxide; alkali metal hydroxides such as sodium hydroxide and lithium hydroxide.
  • Alkali metal carbonates such as sodium carbonate and potassium carbonate; amines such as triethylamine, triptylamine, pyridine, picolin, 1,8-diazabicyclo [5.4.0] —7-indene.
  • Compounds serving as starting materials for the above methods H and J to N namely, compounds (1), (16), (17), (19), (20), (21), (2) 3), (24), (25), (26), (28), (29) and (30) are compounds known per se or from known compounds.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration.
  • an immiscible organic solvent such as water and ethyl acetate is added. It is obtained by separating the organic layer containing, drying with anhydrous magnesium sulfate or the like, and distilling off the solvent.
  • the obtained target compound can be used in a conventional manner, for example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium gel-based florisil.
  • the compound having the general formula (I), or a pharmaceutically acceptable salt or derivative thereof has an excellent effect in preventing or treating hepatic disorder.
  • the dosage form include tablets, capsules, granules, and powders. Oral administration using a syrup or the like, or parenteral administration using an injection or a suppository can be mentioned. These preparations are manufactured by a known method using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • excipients examples include sugar derivatives such as lactose, sucrose, glucose, mannite, and sorbite; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, and carboxymethyl starch. Crystal cell mouth, low-substituted hydroxypropylsenorellose, hydroxypropynolemethylcellulose, canoleboxymethylsenorellose, carboxymethinolecellulose canolesum, internally crosslinked carboxymethylcellulose sodium Such cellulose derivatives; Organic excipients such as dextran; pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate; phosphoric acid phosphate such as lucidum; and calcium carbonate And inorganic excipients such as calcium carbonate and sulfate such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannite, and sorbite
  • the lubricant examples include metal stearates such as stearate, calcium stearate, and magnesium stearate; talc; colloid sily; waxes such as veegum and gay; boric acid: adipic acid; sodium sulfate Dalicol; fumaric acid; sodium benzoate; DL-mouth isin; sodium fatty acid salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic anhydride, like silicic acid hydrate Silicic acids; and the above-mentioned starch derivatives.
  • metal stearates such as stearate, calcium stearate, and magnesium stearate
  • talc colloid sily
  • waxes such as veegum and gay
  • boric acid adipic acid
  • sodium sulfate Dalicol fumaric acid
  • sodium benzoate sodium benzoate
  • DL-mouth isin sodium
  • binder examples include polyvinylpyrrolidone, macrogol and the same compounds as the above-mentioned excipients.
  • disintegrant examples include compounds similar to the above-mentioned excipients and chemically modified starch / cellulose such as croscarmedium sodium, carboxymethyl starch sodium, and cross-linked polybutylpyrrolidone.
  • the stabilizer examples include: paraoxybenzoic acid esters such as methylparaben and propylparaben; anolecols such as chlorobutanol, benzyl alcohol, and phenylethynoleanol; phenols such as benzalkonium chloride; phenol and cresol; Thimerosal; dehydroacetic acid; and sorbic acid.
  • paraoxybenzoic acid esters such as methylparaben and propylparaben
  • anolecols such as chlorobutanol, benzyl alcohol, and phenylethynoleanol
  • phenols such as benzalkonium chloride
  • phenol and cresol Thimerosal
  • dehydroacetic acid and sorbic acid.
  • the amount of the compound having the general formula (I), or a pharmacologically acceptable salt or derivative thereof varies depending on symptoms, age, administration method, and the like. 0.1 mg (preferably 0.5 mg) as the lower limit and 200 mg (preferably 500 mg) as the upper limit in one or several divided doses depending on the symptoms It is desirable to administer. In the case of intravenous administration, for adults, the lower limit is 0.01 mg (preferably 0.05 mg) and the upper limit is 20 Omg (preferably 5 Omg) once or several times a day. And it is desirable to administer according to the symptoms.
  • malonic acid monomethyl ester potassium salt 11.89 g (76.14 mmol), triethylamine 21.23 ml (152.3 mmol) and magnesium chloride 9.66 g (101 .5 mmo1), 100 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 hours.
  • the above solution was added dropwise to the reaction mixture at 0 to 5 C, and after completion of the addition, the mixture was stirred at room temperature overnight, acidified with 1 N hydrochloric acid, and extracted with ethyl acetate.

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Abstract

L'invention concerne des agents préventifs ou thérapeutiques, destinés à une hépatopathie et contenant des composés correspondant à la formule générale (I), ou des sels ou dérivés de ceux-ci, acceptables sur le plan pharmacologique. Dans cette formule, soit R1, soit R2 représente hétéroaryle éventuellement substitué, l'autre représentant aryle éventuellement substitué, R3 représente H ou alkyle, et R4 représente phényle éventuellement substitué, ou analogue.
PCT/JP2000/002813 1999-04-28 2000-04-28 Agents preventifs ou inhibiteurs destines a une hepatopathie WO2000066124A1 (fr)

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Cited By (7)

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WO2002057254A1 (fr) * 2001-01-18 2002-07-25 Sankyo Company, Limited Compositions destinees a la prevention et au traitement de l'hepatopathie
WO2002057255A1 (fr) * 2001-01-22 2002-07-25 Sankyo Company, Limited Derives du pyrrole substitues en 4 ou 5
EP1278520A1 (fr) * 1999-11-12 2003-01-29 Merck & Co., Inc. Derives de diaryle piperidyle pyrrole en tant qu'agents antiprotozoaires
WO2003022832A1 (fr) * 2001-09-05 2003-03-20 Smithkline Beecham P.L.C. Pyridylfurans et pyrroles inhibiteurs de la kinase raf
US7109202B2 (en) 2000-11-21 2006-09-19 Novartis Ag Aminothaizoles and their use as adenosine receptor antagonists
US7122666B2 (en) 1999-07-21 2006-10-17 Sankyo Company, Limited Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
WO2009035997A2 (fr) * 2007-09-14 2009-03-19 Cara Therapeutics, Inc. Hétérocycles benzo-fusionnés

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WO1995013067A1 (fr) * 1993-11-08 1995-05-18 Smithkline Beecham Corporation Oxazoles pour le traitement de maladies induites par la cytokine
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EP1278520A4 (fr) * 1999-11-12 2003-05-02 Merck & Co Inc Derives de diaryle piperidyle pyrrole en tant qu'agents antiprotozoaires
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WO2002057254A1 (fr) * 2001-01-18 2002-07-25 Sankyo Company, Limited Compositions destinees a la prevention et au traitement de l'hepatopathie
WO2002057255A1 (fr) * 2001-01-22 2002-07-25 Sankyo Company, Limited Derives du pyrrole substitues en 4 ou 5
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