[go: up one dir, main page]

WO1996038427A1 - Derives d'oxyimino aromatiques - Google Patents

Derives d'oxyimino aromatiques Download PDF

Info

Publication number
WO1996038427A1
WO1996038427A1 PCT/JP1996/001271 JP9601271W WO9638427A1 WO 1996038427 A1 WO1996038427 A1 WO 1996038427A1 JP 9601271 W JP9601271 W JP 9601271W WO 9638427 A1 WO9638427 A1 WO 9638427A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
different
carbon atoms
same
substituents
Prior art date
Application number
PCT/JP1996/001271
Other languages
English (en)
Japanese (ja)
Inventor
Hiroaki Yanagisawa
Takashi Fujita
Koichi Fujimoto
Kunio Wada
Minoru Oguchi
Takao Yoshioka
Toshihiko Fujiwara
Hiroyoshi Horikoshi
Original Assignee
Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Priority to AU57018/96A priority Critical patent/AU5701896A/en
Publication of WO1996038427A1 publication Critical patent/WO1996038427A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms

Definitions

  • the present invention relates to insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes mellitus (GDM), obesity, impaired glucose tolerance, i. Impaired glucose tolerance (IGT), diabetic complications (eg, Aromatic oximino derivatives having an effect of improving retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc., arteriosclerosis, polycystic ovary syndrome (PCOS), etc .; Preventive drugs for hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance, hypertension, osteoporosis, cachexia, fatty liver, diabetic complications, arteriosclerosis, etc., which contain a mino derivative as an active ingredient And / or a therapeutic agent, and a preventive and / or therapeutic agent for a disease other than the above-mentioned diseases, which is caused by insulin resistance such as gestational diabetes mellitus, polycystic ovary syndrome and the like.
  • GDM gestational diabetes mellitus
  • sulfonylurea compounds such as insulin and tolbutamide and glibizide have been used as therapeutic agents for diabetes and hyperglycemia.
  • thiazolidinedione derivatives for example, insulin-independent diabetes agents
  • JP-A-55-226636 JP-B-62-42903
  • Japanese Patent Application Laid-Open No. 60-511189 Japanese Patent Publication No. 2-31079
  • Japanese Patent Application Laid-Open No. 61-85372 Japanese Patent Application Laid-Open No.
  • non-IGT NGT
  • Engl. J. Med., 331 (18), 1226-1227 (1994) It is suggested that a drug that improves insulin resistance is useful as a preventive drug for the onset of diabetes in normal individuals as described above.
  • the present inventors are highly safe, prevent hyperlipidemia, hyperglycemia, obesity> glucose intolerance, hypertension, osteoporosis, cachexia, fatty liver, diabetic complications, arteriosclerosis, etc.
  • Aromatic oximino derivatives for the purpose of developing drugs and therapeutic drugs, and preventive and therapeutic drugs for diseases caused by insulin resistance such as gestational diabetes mellitus and polycystic ovary syndrome other than the above diseases
  • the present inventors have made intensive studies and completed the present invention.
  • the present invention has an effect of improving insulin resistance, hyperlipidemia, hyperglycemia, gestational diabetes, obesity, glucose intolerance, diabetic complications, arteriosclerosis, polycystic ovary syndrome, and the like.
  • the aromatic oximino derivative of the present invention has the general formula (I).
  • R ′ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, an octogen atom, Group, amino group, monoalkylamino group having 1 to 4 carbon atoms or dialkyl having the same or different and having 1 to 4 carbon atoms
  • A represents a lumino group
  • R a represents an alkylene group having 1 to 6 carbon atoms
  • A represents a methylene group, an oxygen atom, a sulfur atom or a group N (—R 3 ) 1 (where R 3 is hydrogen Atom, an alkyl group having 1 to 6 carbon atoms or an acyl group having 1 to 8 carbon atoms.)
  • B is the same or different and represents 1 to 3 substituents
  • An arylene group having 6 to 10 carbon atoms which may have, 1 to 3 same or different and 1 to 3 nitrogen atoms which may have the following
  • Y is an oxygen atom, a sulfur atom or a group N (—R 6 )-(wherein R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 8 carbon atoms ) Is shown.
  • the substituent (a) is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, and a 2 to 5 carbon atoms.
  • R ′ represents an alkyl group having 1 to 6 carbon atoms
  • examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 2 —Pentyl, 3-bentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylbromo, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 2-hexyl, 3-to Xyl, 2-methylpentyl, 3-methylpentyl, 4-methylbentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylmethyl There may be mentioned groups such as rubutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, and 1,2,2-trimethylpropy
  • R 1 represents an alkoxy group having 1 to 4 carbon atoms
  • examples of the alkoxy group include groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, and t-butoxy. I can give it. Preferably it is methoxy.
  • R 1 represents an alkylthio group having 1 to 4 carbon atoms
  • examples of the alkylthio group include groups such as methylthio, ethylthio, butylpithio, isopropylthio, butylthio, isobutylthio, s-butylthio, and t-butylthio.
  • methylthio ethylthio, butylpithio
  • isopropylthio butylthio
  • isobutylthio isobutylthio
  • s-butylthio s-butylthio
  • t-butylthio t-butylthio
  • R 1 represents a halogen atom
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • they are a fluorine atom, a chlorine atom and a bromine atom.
  • R 1 represents a monoalkylamino group having 1 to 4 carbon atoms
  • examples of the monoalkylamino group include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t— And groups such as butylamino.
  • Preferred are methylamino and ethylamino.
  • R 1 is the same or different and represents a dialkylamino group having 1 to 4 carbon atoms
  • examples of the dialkylamino group include N, N-dimethylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, —Methyl-N—isopropylamino, N—Methyl-N-butylamino, N, N—Getylamino, N—Ethylu N—V.Pyramino, N—Ethyl N—Butylamino, N, N—Pyramino, N, N-propyl Examples include groups such as N-butylamino and N, N-dibutylamino.
  • R 2 represents an alkylene group having 1 to 6 carbon atoms.
  • the alkylene group include methylene, ethylidene, ethylene, 1-methylethylene, 2-methylethylene, 1-ethylethylene, 2-ethylethylene, 1.1-ethylethylene, 1,2-methylethylethylene, 2, 3-methylethylethylene, 3,3-methylethylene, trimethylene, 1-methyltrimethylene, 3-methyltrimethylene, 1-ethyltrimethylene, 3-ethylethylmethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, Examples include groups such as 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • It is preferably an alkylene group having 2 to 5 carbon atoms, most preferably ethylene, 1-methylethylene, 2-methylethylene, trimethylene, 1-methyltrimethylene, 3-methyltrimethylene, 1-ethyltrimethylene. , 3-ethyltrimethylene and 2-methyltrimethylene.
  • A is Kiichi N (- R 3) - indicates a (wherein, R 3 is a hydrogen atom, a Ashiru group having 8 or having 1 to alkyl group or a carbon that having a six 1 -C.)
  • R 3 is an alkyl group having 1 to 6 carbon atoms
  • examples of the alkyl group include the same groups as the alkyl groups described for R 1 .
  • Preferably it is methyl.
  • R 3 is an acyl group having 1 to 8 carbon atoms
  • the acyl group is, for example, formyl, acetyl, brobinyl, butyryl, isoptyryl, nozylyl, isovaleryl , Vivaloyl, Hexanoyl, Heptanoyl, Octanoyl and the like.
  • the group N (—R 3 ) is, for example, imino, methylimino, ethylimino, propylimino, isopropylimino, butylimino, isobutylimino, s-butylimino, t-butylimino.
  • A is preferably methylene, oxygen atom, a sulfur atom or a group one N (- CH 3) Ri Ah one, and most preferably methylene or oxygen atom.
  • the unsubstituted arylene group includes, for example, phenyl Groups such as diene, 1,2-naphthylene, and 2,3-naphthylene can be provided. Preferably it is phenylene.
  • B may be the same or different and may have 1 to 3 substituents (a) 1 to 3 containing a nitrogen atom, an oxygen atom and a no or sulfur atom divalent 5 to 6 member
  • substituents a
  • examples of the unsubstituted heterocyclic group include divalent heterocyclic groups such as furan, thiophene, thiazole, oxazole, pyridine, pyrimidine, pyrazine, pyrigidine, and triazine. be able to.
  • B is the same or different and may have 1 to 3 substituents (a) 1 to 4 divalent condensed heterocyclic ring group containing nitrogen atom, oxygen atom and / or sulfur atom
  • the unsubstituted heterocyclic group includes, for example, quinoline, isoquinoline, benzofuran, benzothiophene, indole, benzothiazole, benzimidazole, benzoxazole, benzodioxane, 1.3-benzodioxane Kiso And heterocyclic divalent groups such as benzene, benzoxazine, benzothiazine, dihydrobenzoxazine, dihydrobenzothiazine, quinazoline, phthalazine, quinoxaline, benzopyran and benzothiovirane.
  • the substituent (a) represents an alkyl group having 1 to 6 carbon atoms
  • examples of the alkyl group include the same groups as the alkyl groups described for R ′. It is preferably an alkyl group having 1 to 4 carbon atoms, and most preferably methyl or ethyl.
  • the substituent (a) represents an alkoxy group having 1 to 4 carbon atoms
  • the alkoxy group may be the same as the alkoxy group described for R 1 .
  • Preferable is methoxy, ethoxy, or isopropoxydioxide, and most preferably methoxy.
  • the substituent (a) represents an alkylthio group having 1 to 4 carbon atoms
  • the alkylthio group is the same as that described for R ′.
  • the alkylthio groups can be mentioned. Preferably it is methylthio and ethylthio, most preferably methylthio.
  • the substituted moiety (a) represents an aliphatic acyloxy group having 2 to 5 carbon atoms
  • examples of the aliphatic acyloxy group include acetyloxy, propanoyloxy, butyryloxy, isoptyryloxy, norreloxy, isovaleryloxy
  • Examples include groups such as bivaloyloxy. Preferred are acetyloxy, propanoyloxy and vivaloyloxy.
  • the substituent (a) represents a halogen atom
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • they are a fluorine atom, a chlorine atom and a bromine atom.
  • the substituent (a) represents a monoalkylamino group having 1 to 4 carbon atoms
  • the monoalkylamino group may be the same as the monoalkylamino group described for R ′.
  • Preferred are methylamino and ethylamino.
  • dialkylamino group examples include the same groups as the dialkylamino groups described for R ′. Preferred are N, N-dimethylamino and N, N-getylamino.
  • substituents (a) are the same or different and each are an aryl group having 6 to 10 carbon atoms which may have three substituents (b); Examples thereof include groups such as phenyl, 1-naphthyl, and 2-naphthyl.
  • an aryl group having the same or different one or two substituents (b) is preferred.
  • substituent (a) is the same or different and represents an aralkyl group having 7 to 11 carbon atoms which may have 1 to 3 substituents (b), unsubstituted aralkyl
  • benzyl group include groups such as benzyl, phenethyl, 3-phenylbrovir, 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • substituent (a) is the same or different and represents an aryloxy group having 6 to 10 carbon atoms which may have 1 to 3 substituents (b), an unsubstituted aryloxy group and Examples thereof include groups such as phenyloxy, 11-naphthyloxy and 2-naphthyloxy.
  • the substituent (a) is the same or different and represents an arylthio group having 6 to 10 carbon atoms which may have 1 to 3 substituents (b), the unsubstituted aryl Examples of the luthio group include phenylthio, 11-naphthylthio, 2-naphthylthio and the like.
  • substituted moiety (a) is the same or different and represents an arylsulfonyl group having 6 to 10 carbon atoms which may have 1 to 3 substituted moiety (b), it is unsubstituted aryl.
  • the sulfonyl group include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.
  • an unsubstituted aromatic alkoxy group examples include groups such as benzoyloxy, 11-naphthoyloxy, and 2-naphthoyloxy. Preferably, it is benzoyloxy.
  • substituent (a) is the same or different and represents an arylsulfoxy group having 6 to 10 carbon atoms which may have 1 to 3 substituents (b), unsubstituted arylsulfo
  • substituents (b) unsubstituted arylsulfo
  • the xy group include phenylsulfoxy, 1-naphthylsulfoxy, 2-naphthylsulfoxy and the like.
  • it is phenylsulfoxy.
  • the substituent (a) is the same or different and represents an arylsulfonylamino group having 6 to 10 carbon atoms which may have 1 to 3 substituents (b), the unsubstituted amino group
  • the reelsulfonylamino group include groups such as phenylsulfonylamino, 1-naphthylsulfonylamino, and 2-naphthylsulfonylamino. Preferred is phenylsulfonylamino.
  • Substituent (a) is Kiichi N (- R 4) - R 5 (wherein, to R 4 is C 6 carbon atoms which may have a to 1 the same or different three substituents (b) 1 0 is an arylsulfonyl group, and R s is an alkyl group having 1 to 4 carbon atoms.)
  • R 4 represents an unsubstituted arylsulfonyl group, for example, phenylsulfonyl And groups such as 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • the alkyl group for R 5 may be mentioned methyl, Echiru, propyl, iso-propyl, heptyl, Isopuchiru, s- heptyl, groups such as t one-butyl. Therefore, Kiichi N (- R 4) - in R 5, R 4 represents an unsubstituted Ari Rusuruhoniru group, if R 5 represents an alkyl group, such as N- Fuwenirusuru Honiru N- Mechiruamino, N- Fuenirusuruho Nil-N-ethylamino, N-phenylsulfonyl-N-propylamino, N-phenylsulfonyl-N-isopropylamino, N-phenylsulfonyl-N-butylamino, N- (1-naphthylsulfonyl) -N-methylamino , N— (1-Naph
  • substituents (a) may be the same or different and have 1 to 3 substituents (b)
  • examples of the unsubstituted heterocyclic group include monovalent heterocyclic groups such as furan, thiophene, thiazole, oxazole, pyridine, pyrimidine, virazine, pyridazine and triazine. Can be.
  • frans-2-yl Preference is given to frans-2-yl, frans-3-yl, thiophen-2-yl, thisaifen-3-yl, pyridin-12-yl, pyridin-1-3-yl And pyrimidine 4-yl, pyrimidine 15-yl, virazine 12-yl, and more preferably furan 1-yl.
  • the unsubstituted fused heterocyclic group includes, for example, quinoline, isoquinoline, benzofuran, benzothiophene, indole, benzothiazole, benzoimidazole, benzoyloxazole, benzoxazine, benzothiazine, dihydrobenzoxazine, Examples thereof include monovalent groups of a complex ring such as dihydrobenzothiazine, quinazoline, phthalazine, quinoxaline, benzopyran, benzothiopyran, and benzotriazine.
  • substituent (b) represents an alkyl group having 1 to 6 carbon atoms
  • examples of the alkyl group include the same groups as the alkyl groups described for R 1 .
  • it is methyl, ethyl or propyl, most preferably methyl.
  • the alkoxy group may be the same as the alkoxy group described for R 1 . Preferred are methoxy, ethoxy and propoxy, most preferably methoxy.
  • the substituent (b) represents an alkylthio group having 1 to 4 carbon atoms
  • examples of the alkylthio group include the same groups as the alkylthio groups described for R 1 . Preferably it is methylthio, ethylthio, propylthio, and most preferably methylthio.
  • substituent (b) is showing a Ariru group having 1 0 C 6 -C, is the said ⁇ Li Lumpur group phenyl, 1 - naphthyl, may force 5 be mentioned groups such as 2-naphthyl. Preferably it is phenyl.
  • the substituent (b) represents a halogen atom
  • examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • it is a chlorine atom or a bromine atom.
  • X is
  • Y represents a group N (—R 6 ) 1 (wherein R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 8 carbon atoms).
  • R 6 is an alkyl group having 1 to 6 carbon atoms
  • examples of the alkyl group include the same alkyl groups as those described for R ′. It is preferably an alkyl group having 1 to 3 carbon atoms, and most preferably methyl.
  • R 6 is an acyl group having 1 to 8 carbon atoms
  • the acyl group is the same as the aliphatic acyl group described for R 3 or benzoyl, o—toluoyl, m—toluoyl, p—toluoyl And other aromatic acyl groups.
  • acyl groups acetyl and propionyl are preferred.
  • Kiichi N (- R 6) - as the same groups or Benzoi Louis Mi Roh and I amino groups mentioned in A, o - DOO Ruoi Louis Mi Bruno, m -. DOO Luo Yi Louis Mi Bruno p - Tono Leo And groups such as illumino.
  • Y is preferably an oxygen atom. So here
  • Examples of the aralkyl group having 7 to 11 carbon atoms in which the substituents (a) are the same or different and have 1 to 3 substituents (b) include, for example, o-cyclobenzyl, m- Benzyl, p-chlorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-methylbenzyl, m-methylbenzyl, p-Methylbenzyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-methylthiobenzyl, m-methylthiobenzyl, p-methylthiobenzyl, o-nitrobenzyl, m-nitro Benzyl, p-diphenyl benzyl, 2-biphen
  • Examples of the arylthio group having 1 to 3 substituents (b) having the same or different substituents (a) and having 1 to 3 substituents and having 6 to 10 carbon atoms include, for example, m-chlorophenylthio, p-chloro M-fluorophenylthio, p-bromophenylthio, m -methylphenylthio, p-methylphenylthio, m -methoxyphenylthio, p-methoxyphenylthio, m -methylthiophenylthio , P-methylthiophenylthio, 3,4-dichlorophenylthio, 2,4-dichlorophenylthio, 3,5-dimethyloxyphenylthio, 3,4,5-trichlorothiophenyl;
  • Examples of the arylsulfonyl group having 1 to 3 substituents (b) having the same or different substituents (a) and having 1 to 3 substituents and having 6 to 10 carbon atoms include, for example, o-chlorophenylsulfonyl , M-chlorophenylsulfonyl, p-chlorophenylsulfonyl, p-fluorophenylsulfonyl, o-fluorophenylsulfonyl, m-bromophenylsulfonyl, p-bromophenylsulfonyl, o-toluenesulfonyl M-toluenesulfonyl, p-toluenesulfonyl, o-metoxy Phenylsulfonyl, m-methoxyphenylsulfonyl, P-methoxyphenylsulf
  • Examples of the aromatic acyloxy group having 7 to 11 carbon atoms in which the substituents (a) are the same or different and have 1 to 3 substituents (b) include, for example, o-benzoyloxy. , M-black benzoyloxy, p-black benzoyloxy, p-fluorobenzoyloxy, m-bromobenzoyloxy, p-bromobenzoyloxy, p-nitrobenzoyloxy, o-toluoyloxy, m-torulo Yloxy, p-toluoyloxy, o-methoxybenzoyloxy, o-methoxybenzoyloxy, m-methoxybenzoyloxy, p-methoxybenzoyloxy, m-methylthiobenzoyloxy, p-methylthio Benzoyloxy, 2,4-diclo-benzobenzoyl, 3,4-diclo-benzobenzo
  • Examples of the arylsulfoxy group having 1 to 3 substituents (b) having the same or different substituents (a) and having 1 to 3 substituents (b) include, for example, Enylsulfoxy, m-chlorophenylsulfoxy, p-chlorophenylsulfoxy, p-fluorophenylsulfoxy, o-bromophenylsulfoxy, m-bromophenylsulfoxy, p-bromophenylsulfoxy Xy, p-ditrophenylsulfoxy, o-toluenesulfoxy, m-toluenesulfoxy, p-toluenesulfoxy, o-methoxyphenylsulfoxy, m-methoxyphenylsulfoxy, p-methoxyphenylsulfoxy , M-methylthiophenylsulfoxy, P
  • R 5 represents an alkyl group having 1 to 4 carbon atoms, for example, N-methyl-N— (2-cyclobenzenebenzenesulfonyl) amino, N-methyl-N— (3-cyclobenzenebenzenesulfonyl) amino , N-Methyl-N- (4-chlorobenzenesulfonyl) amino, N-methyl-N- (3-fluorobenzenesulfonyl) amino, N-methyl-N- (2-bromobenzenesulfonyl) amino, N-methyl-N-( 3-Bromobenzenesulfonyl) amino, N-methyl-N- (4-bromobenzenesulfonyl) amino, N-methyl-N— (p-toluen
  • Substitutions (a) are the same or different and have 1 to 3 substitutions (b).
  • Examples of the 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and hydrogen or sulfur atoms include 5-bromofuran-2-yl, 4-chlorothiophene-2-yl Yl, 2-methylthiazol-4-yl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-
  • substituents (a) are the same or different and have 1 to 3 substituents (b).
  • B may be the same or different and have 1 to 3 substituents (a), and the substituents (a) may be the same or different and have 1 to 3 substituents (b)
  • substituents (a) may be the same or different and have 1 to 3 substituents (b)
  • a phenylene group having the same or different and having 1 to 3 substituents (a) having alkyl having 1 to 6 carbon atoms includes, for example, 3-methyl-1,2-phenylene, 4 -Methyl-1,2-phenylene, 3-ethyl-1,2-phenylene, 4-ethyl-1,2-phenylene, 3-propyl-1,2-phenylene, 4-propyl-1,2- Phenylene, 3-Isopropyl-1,2-phenylene, 4-Isopropyl-1,1,2-phenylene, 3-t-butyl-1,2-phenylene, 4-t-butyl-1,2- Phenylene, 3,4-dimethyl-1,2-phenylene, 3,5-dimethyl-1,2-phenylene, 4,5-dimethyl-1,2-phenylene, 4-isopropyl-13-methyl- 1,2-Phenylene, 4,5-diisopropyl-1,2-phenylene, 3,4,5-trimethyl-1,2-phenyl Les emissions;
  • the same or different 1 to 3 substituted phenylene groups having (a) alkoxy having 1 to 4 carbon atoms include, for example, 3-methoxy-11,2-phenylene and 4-phenylene. Methoxy-1,2-phenylene, 3-ethoxy1,
  • the same or different phenylene groups having 1 to 3 alkylthio having 1 to 4 carbon atoms as 1 to 3 substituents (a) include, for example, 3-methylthio-1,2-phenylene, 4 1,2-phenylene, 3-methylthio-1,2-phenylene, 4-ethylthio-1,2-phenylene, 3-isopropylthio-1,1,2-phenylene, 4-1 Isobro virthio-1,2-phenylene; 4)
  • the same or different phenylene groups having 1 to 3 substituents (a) and having an aliphatic alkoxy having 2 to 5 carbon atoms include, for example, 3-acetoxy 1, 2- Phenylene, 4-acetoxy 1,2-phenylene, 3-propanolyl 1,2-phenylene, 4-propanolyl 1,2-phenylene, 3- Bivaloyloxy 1,2-phenylene, 41-Bivaloyloxy-1,2-phenylene, 4,5-diacetoxy 1,2-phenylene;
  • Examples of the same or different phenylene groups having a halogen atom as 1 to 3 substituents (a) include, for example, 3-chloro-1,2-phenylene, 4-chloro-1,2 —Phenylene, 3-fluoro-1,2-phenylene, 4-fluoro-1,2-phenylene, 3-bromo-1,2-phenylene, 4-promo-1,2-phenylene, 3,4-dichloro-1,2-phenylene, 4,5-dichloro-1,2-phenylene, 3,5-dichloro-1,2-phenylene, 3,4,5-trichloro Rho 1,2-phenylene, 3,4-dibromo-1,2-phenylene, 4,5-dibromo-1,2-phenylene, 3,4,5-tribromo-1,2-phenylene Nylene, 4-chloro-5-fluoro-1,2phenylene, 4-bromo-5-chloro-1,2-phenylene;
  • Examples of the same or different phenylene group having 1 to 3 substituents (a) and having hydroxy include, for example, 3-hydroxy-11,2-phenylene, and 4-hydroxy. Droxy 1, 2-phenylene, 4, 5-dihydroxy 1, 2-phenylene
  • phenylene group having nitro group examples include 3-nitro1,2-phenylene, 4-nitro One, one, two-phenylene;
  • Examples of the same or different phenylene groups having 1 to 3 amino groups as the substituted moiety (a) include, for example, 3-amino-1,2-phenylene, 4-amino-11, 2-phenyrene;
  • phenylene group which may have a group include 3-phenyl-1,2-phenylene, 4-phenyl-1,2-phenylene, 3- (1-naphthyl) 1-1, 2-phenylene, 4-1 (1-naphthyl) 1-1, 2-phenylene, 3-1-1 (2-naphthyl) 1-1,2-phenylene, 4-1-1 (2-naphthyl) 1-1, 2- Phenylene, 4- (o-chlorophenyl) 1-1,2-phenylene, 4- (m-chlorophenyl) 1-1,2-phenylene, 4- (p-chlorophenyl) 1-1 , 2-phenylene, 4- (m-bromophenyl) 1-1,2-phenylene, 4- (p-bromophenyl) 1-1 , 2-phenylene, 4- (m-bromophenyl) 1-1,2-phenylene, 4- (p-bromophenyl) 1-1 , 2-phenylene, 4- (
  • the phenylene group which may have) include 3-benzyl-1,2-phenylene, 4-benzyl-1,2-phenylene, 3-phenyl-1,1,2-phenylene, 4-Phenyl-1,2-phenylene, 4- (o-cyclobenzyl) 1-1,2-phenylene, 4- (m-cyclobenzyl) 1-1,2-phenylene, 4- ( p-Bromobenzyl) 1-, 2-phenylene, 4- (m-bromobenzyl) 1,2-phenylene, 4- (p-bromobenzyl) 1,2-phenylene, 4 1- (m-methylbenzyl) 1-1,2-phenylene, 4- (p-methylbenzyl) 1-1,2-phenylene, 4- (p-methoxy) Benzyl) one 1, 2-phenylene, 4- (o-cyclobenz
  • arylsulfonyl having 6 to 10 carbon atoms wherein the arylsulfonyl is the same or different and has 1 to 3
  • the phenylene which may have the substituent (b) include 3-phenylsulfonyl-1,2-phenylene, 4-phenylsulfonyl-1,2-phenylene, and 4-1 Naphthylsulfonyl) 1-1,2-phenylene, 4- (2-naphthylsulfonyl) 1-1,2-phenylene, 4-1 (o-tonolenesulfonyl) 1-1,2-phenylene, 4-1 ( m-toluenesulfonyl) 1-1,2-phenylene, 4- (p-toluenesulfonyl) 1-1,2-phenylene, 3-
  • the same or different 1 to 3 substituents (a) have an aromatic acyloxy having 6 to 10 carbon atoms, and the aromatic acyloxy is the same or different and has 1 to 3
  • Examples of the phenylene group which may have a substituent (b) include 3-benzoyloxy 1,1,2-phenylene, 4-benzoyloxy-1,2-phenylene, and 4- (1-naphthyl). Triyloxy) 1,2-phenylene, 4- (2-naphthoyloxy) 1,2-phenylene, 4- (m-methylbenzoyloxy) 1,1,2-phenylene, 4- (P —Methylbenzoyl) 1
  • phenylene groups which may be the same or different and have 1 to 3 substituents (b) include 3-phenylsulfonylamino-1,2-phenylene and 4-phenylsulfonyl Amino-1,2-phenylene, 3- (p-toluenesulfonylamino) 1-1,2-phenylene, 41- (p-toluenesulfonylamino) 1-1,2-phenylene, 4 1- (o-chlorophenylsulfonylamino) 1,1,2-phenylene, 4- (p-chlorophenylsulfonylamino) 1-1,2-phenylene, 4- (p-bromophenyl) Sulfonylamino) 1-1,2-phenylene, 41- (
  • phenylene group include 3- (N-methyl-N-phenylsulfonylamino) 1-1,2-phenylene and 41- (N-methyl-N-phenylsulfonylamino) 1-, 2-phenylene, 4- (N-ethyl-N-phenylsulfonylamino) — 1,2-phenylene, 3 -— [N-methyl-1-N- (1-naphthylsulfonyl) amino] 1-, 2-phenylene, 4- [N-methyl-N- (1-naphthylsulfonyl) amino] — 1,2-phenylene, 41- [N-Provyl-N- (1-naphthylsulfonyl) Amino] 1-1,2-phenylene,
  • substituents (a) a 5- to 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and Z or sulfur atoms
  • substituents (b) examples include, for example, 3- (2-furyl) -11,2-phenylene, 4- (2-furyl) -1, 2-phenylene, 3- (2-Chenyl) 1-1
  • the phenylene group optionally having 1 to 3 substituents (b) includes, for example, 3- (2-quinolyl) 1-1,2-phenylene , 4- (2-quinolyl) 1-1,2-phenylene, 3- (3-quinolyl) 1-1,2-phenylene, 4- (3-quinolyl) 1-1,2-phenyl Len, 3— (7-quinolyl) -1,2, -phenylene, 4- (7-quinolyl) 1-1,2-phenylene, 3- (6-isoquinolyl) -1,2— Phenylene, 4-1- (6-isoquinolyl) 1 1,2-phenylene, 3- (7-isoquinolyl) 1-1,2-phenylene, 4-1-1-7-isoquinolyl) -1 1,2-phenylene, 3- (6-methylquinolin-1-yl)
  • ID B is the same or different and has 1 to 3 substituents (a), and the substituent (a) is the same or different and may have 1 to 3 substituents (b).
  • 1 represents a styrene group
  • naphthylene groups having 1 to 3 substituents (a) and alkyl having 1 to 6 carbon atoms include, for example, 6-methyl-1,
  • 2-naphthylene 4-methyl-2,3-naphthylene, 5-methyl-2,3-naphthylene, 6-methyl-2,3-naphthylene, 6-ethyl-1,2-naphthylene, 5-ethyl-2,3-naphthylene, 6 —Methyl-2,3-naphthylene, 6-propyl-1,2, naphthylene, 6-propyl-1,2,3-naphthylene, 6—isopropyl-1,2, naphthylene, 6—isopropyl-1,2,3— Naphthylene, 6-t-butyl-1,2-naphthylene, 6-t-butyl-2,3-naphthylene, 6,7-dimethyl-1,2-naphthylene, 6,7-dimethyl-2,3-naphthylene, 5,6,7 — Trimethyl-2,3-naphthy
  • naphthylene groups having 1 to 3 substituted (a) alkoxy having 1 to 4 carbon atoms include, for example, 6-methoxy-1,2-naphthylene, 4-meth Kissy 2, 3-naphthylene, 5-methoxy 2,
  • 3-naphthylene 6-methoxy-2,3-naphthylene, 6-ethoxy-1,2-naphthylene, 5-ethoxy-12,3-naphthylene, 6-ethoxy2,3-naphthylene, 6-a Sopropoxy 1,2-Naphthylene, 6-I Sopropoxy-1,2,3-naphthylene, 6— "t-butoxy-1,2-naphthylene, 6-t-butoxy 2,3-naphthylene, 6,7-dimethoxy 2, 3-naphthylene;
  • naphthylene groups having 1 to 3 substituents (a) and having alkylthio having 1 to 4 carbon atoms include, for example, 6-methylthio-1,2-naphthylene, 4 -Methylthio_2,3-naphthylene, 5-methylthio-1,2,3-naphthylene, 6-methylthio-1,2,3-naphthylene, 6-ethylthio1,2-naphthylene, 5-ethylthio-1,2,3-naphthylene, 6-Ethylthio 2,3-naphthylene, 6-Isopropylthio-1,2-naphthylene, 6-Soprovirthio-1,2,3-naphthylene;
  • naphthylene having 1 to 3 substituents (a) and having an aliphatic alkoxy having 2 to 5 carbon atoms for example, 6-acetoxy 1, 2-naphthylene, 5-acetoxy 2, 3-naphthylene, 6-acet Toxic 2,3-naphthylene, 6-propanoyloxy 1,2-naphthylene, 6-propanoyloxy-1,2,3-naphthylene, 6,7-dioxy 2,3 naphthylene;
  • Examples of the same or different naphthylene groups having 1 to 3 substituents (a) and having a halogen atom include 6-chloro-1,2-naphthylene, 4-chloro-1,2,3-naphthylene Chloro-2,3-naphthylene, 6-chloro mouth P—2,3-naphthylene, 6-fluoro-1,2-naphthylene, 6-fluoro-1,2,3-naphthylene, 6-bromo-1,2-naphthylene, 5 —Bromo-1,3-naphthylene, 6-bromo-2,3-naphthylene, 5,6-dichloro-2,3-naphthylene, 6,7-dichloro-2,3-naphthylene, 5,6,7-tributyl mouth 2,3-naphthylene;
  • Examples of the same or different naphthylene groups having 1 to 3 substituents (a) and having hydroxy include, for example, 4-hydroxy-1,2-naphthylene, 6-hydroxy-1,2— Naphthylene, 5-hydroxy 2,3-naphthylene, 6-hydroxy 2,3-naphthylene, 6,7-dihydroxy 1,2-naphthylene, 6,7-dihydroxy 2,2,3-naphthylene;
  • Naphthylene groups having the same or different and having 1 to 3 substituents (a) having a nitrogen atom include, for example, 5-nitro-1,2-naphthylene, 6-nitro1,2 —Naphthylene, 412-mouth 1,2,3-naphthylene, 5-2-troth 2,3-naphthylene, 6-two-trough 2,3-naphthylene;
  • naphthylene groups having 1 to 3 substituted amino groups such as 6-amino-1,2-naphthylene, 4-amino-1,2,3-naphthylene, —Amino 2,3-naphthylene, 6-amino 2,3-naphthylene;
  • Examples of the same or different naphthylene group having 1 to 3 carbon atoms as a substituted or unsubstituted monoalkylamino group having 1 to 4 carbon atoms include, for example, 4-methylamino 1,2- Naphthylene, 6-methylamino 1,2-naphthylene, 4-methylamino 2,3-naphthylene, 5-methylamino 1,2,3-naphthylene, 6-methylamino 2,3-naphthylene, 4- Etylamino 1 and 2-Naphthy Len, 5-propylamino-1,2,3-naphthylene, 6-isopropylamino-1,2-naphthylene;
  • the same or different naphthylene group having 1 to 3 substituents (a) and having the same or different dialkylamino having 1 to 4 carbon atoms is, for example, 5-(N, N-dimethylamino-1-1,2-naphthylene, 6- (N, N-dimethylamino) 1-1,2-naphthylene, 4- (N, N-dimethylamino) -2,3-naphthylene, 5- (N, N— Dimethylamino) 1,2,3-naphthylene, 6— (N, N-dimethylamino) 1,2,3-naphthylene, 5— (N-ethyl-N-methylamino) 1-1,2-naphthylene, 6— (N-ethylyl) N-methylamino) 1, 2,3-naphthylene, 5— (, N-Jetylamino) 1-1,2-naphthylene,
  • aryloxy having 6 to 10 carbon atoms wherein the aryloxy groups are the same or different and 1 to 3 substituted
  • the naphthylene group which may have (b) include 6-phenoxy-11,2-naphthylene, 6-phenoxy-12,3-naphthylene, and 6- (m-methylphenoxy) -12 , 3-naphthylene, 6- (p-methylphenoxy) 1-2,3-naphthylene, 6- (m-methoxyphenoxy) 1-2,3-naphthylene, 6- (p-methylphenoxy) 1-2,3 —Naphthylene, 6— (p-1-2-phenoxy) 1-2,3-naphthylene, 6— (m-chlorophenoxy) 1,2,3-naphthylene, 6— (p-chlorophenoxy) 1-2,3-naphthylene , 6- (m-brom
  • Examples of the naphthylene group which may have b) include 6-phenylthio-1,2-naphthylene, 6-phenylthio-1,2,3-naphthylene, and 4- (m-methylphenylthio) 1-2. , 3-Naphthylene, 6- (m-methylphenylthio) 1-2,3-naphthylene, 6- (P-methylphenylthio) 1-2,3-naphthylene, 6— (p-Methoxyphenylthio) 1-2, 3-naphthylene;
  • arylsulfonyl having 6 to 10 carbon atoms (a), wherein the arylsulfonyl is the same or different and has 1 to 3
  • the naphthylene group which may have a substituent (b) include 6-phenylsulfonyl-1,2-naphthylene, 5-phenylsulfonyl-2,3-naphthylene and 6-phenylsulfonyl-2,3 —Naphthylene, 6- (1-naphthylsulfonyl) 1-1,2-naphthylene, 5— (2-naphthylsulfonyl) -1,2,3-naphthylene, 6— (2-naphthylsulfonyl) 1-2,3-naphthylene, 5 — (O-toluenesulfonyl) 1-1,2-na
  • substituents (b) include, for example, 5-phenylsulfonylamino-1,2-naphthylene, 6-phenylsulfonylamino-1,2-naphthylene, and 5-phenyl.
  • Naphthylene group For example, 5- (N-methyl-N-phenylsulfonylamino) 1-1,2-naphthylene, 6- (N-methyl-N-phenylsulfonylamino) 1-1,2-naphthylene, 5 — (N-methyl-N-phenylsulfonylamino) 1,2,3-naphthylene, 6— (N-methyl-N-phenylsulfonylamino) 1,2,3-naphthylene, 5— [N-methyl-N — (1-Naphthylsulfonyl) amino] 1,1,2-naphthylene, 6— [N-methyl-N— (1-naphthylsulfonyl) amino, 1,2,
  • Good naphthylene groups include, for example, 6- (2-furyl) 1-1,2-naphthylene, 5- (2-furyl) -12,3-naphthylene, 6- (2-furyl) 1-2,3- Naphthylene, 6- (2-Chenyl) 1-1,2-naphthylene, 6- (2-Chenyl) -1,2,3-naphthylene, 6- (2-pyridyl) 1-1,2-Naphthylene, 6- (2-) Pyridyl) 1,2,3
  • the naphthylene group which may have 1 to 3 different substituents include 6- (2-quinolyl) 1-1,2-naphthylene and 6- (2-quinolyl) -1 2,3-naphthylene, 6- (3-quinolyl) 1-1,2-naphthylene, 6- (3-quinolyl) -1,2,3-naphthylene, 6- (7-quinolyl) 1-1,2-naphthylene , 6— (7-quinolyl) -1,2,3-naphthylene, 6— (6-isoquinolyl) -1,2, naphthylene, 6— (6-isoquinolyl) 1,2,3-naphthylene, 6— ( 7—I soquinolyl) 1,2—naphthylene
  • B is the same or different and represents a divalent 5- to 6-membered heterocyclic group containing 1 to 4 nitrogen, oxygen or / and sulfur atoms having 1 to 3 substituents (a) ,
  • the same or different divalent heterocyclic groups having 1 to 3 substituents (a) and alkyl having 1 to 4 carbon atoms include, for example, 5-methylpyridine-1,2,3-diyl, —Methylpyridine-1,2,3-diyl, 5-methylpyridin-1,3,4-diyl, 6-methylviridine-1,3,4-diyl, 5,6-dimethylpyridin-1,2,3-diyl;
  • Examples of the same or different divalent heterocyclic groups having 1 to 3 substituted (a) alkoxy having 1 to 4 carbon atoms include, for example, 5-methoxypyridine-1,2,3-diyl , 6-Methoxyviridine-1,2,3-diyl, 5-Methoxypyridine-1,3,4-diyl, 6-Methoxypyridine-13,4-diyl, 6-Ethoxypyridine-12,3-diyl, 6-Di Trixyviridine-1,3-diyl, 6-isopropoxypyridine-1,2,3-diyl, 6-isopropoxypyridine-1,3,4-diyl;
  • Examples of the divalent heterocyclic group having the same or different 1 to 3 substituents (a) and having a halogen atom as a (a) include, for example, 5-chloroviridine-12,3-diyl, 6-chloropyridin-12 , 3-diyl, 5-chloropyridin-1,3,4-diyl, 6-clopyridin-3,4-diyl, 5-promobilidine-1,2,3-diyl, 6-bromopyridin-2,3 —Diyl, 5-Dibromopyridine-1,3,4 Gil, 6-bromopyridin-1,3-diyl; 5,6-dichropyridine-1,2-diyl;
  • the same or different 1 to 3 substituents (a) have aryl having 6 to 10 carbon atoms, and the aryls are the same or different and have 1 to 3 substituents (b)
  • the divalent heterocyclic group which may have For example, 4-phenylfuran-1,2,3-diyl, 4-phenylthiophene-1,2,3-diyl, 5-phenylpyridine-12,3-diyl, 6-phenylpyridine-1,2,3-diyl, 6 1-phenylbiidine 1, 3,4-diyl, 6- (4-chlorophenyl) pyridin-1,3,4-diyl, 6- (4-methoxyphenyl) pyridin 1,3,4-diyl, 5 1 (2-naphthyl) pyridin-1,2-diyl;
  • the same or different 1 to 3 substituents (a) have an aralkyl having 7 to 11 carbon atoms, and the aralkyl has the same or different 1 to 3 substituents (b).
  • Examples of the divalent heterocyclic group which may be used include, for example, 5-benzylpyridin-1,2,3-diyl, 6-benzylpyridine-1,2,3-diyl, 5-benzylpyridin-1,3,4-diyl, 6-benzylpyridine-1,3-diyl; 6- (4-methylbenzyl) pyridine-1,2,3-diyl;
  • the same or different 1 to 3 substituents (a) have a heterocyclic group, and the heterocyclic group has the same or different 1 to 3 substituents (b).
  • the divalent complex group include, for example, 6- (2-pyridyl) viridine-1,2,3-diyl and ⁇ - (6-methylbiridin-1,3-yl) pyridin-12.3- Jirire, 6 1- (6-Methylviridine-1-3-yl) Pyridin-2,3-diyl, 6- (5-Methylpyridin-1-3-yl) Pyridin-1,2,3-diyl, 6— (6-Fue Nylviridine 1- 3-yl) Pyridine 1-, 3- 3-yl;
  • B is the same or different and represents a divalent fused heterocyclic group containing 1 to 4 nitrogen, oxygen and / or sulfur atoms having 1 to 3 substituents (a),
  • the same or different divalent heterocyclic groups having 1 to 3 substituted (a) alkyl having 1 to 4 carbon atoms include, for example, 6-methylquinoline-1,2,3-diyl, 7-Methylquinoline-1,2,3-diyl, 6-Methylquinoline-1,3,4-diyl, 7-Methylquinoline-1,3,4-diyl, 4,6-Dimethylol 2 H-1,4 Zonzoxazine-1,2,3-diyl, 4,6-dimethyl-2H-1,4,1-benzothiazine-1,2,3-diyl, 5,6,7-trimethylquinolinyl 2,3-diyl;
  • the same or different divalent heterocyclic groups having 1 to 3 substituents (a) and having alkoxy having 1 to 4 carbon atoms include, for example, 6-methoxyquinoline 1 2 , 3-diyl, 2-methoxyquinoline-6,7-diyl, 2-methoxyquinoline-1 7.8-diyl; '
  • the same or different 1 to 3 substituents (a) have a heterocyclic group, and the heterocyclic group has the same or different 1 to 3 substituents (b).
  • a divalent heterocyclic group for example,
  • B may be the same or different and have 1 to 3 substituents (a), and the substituents (a) may be the same or different and have 1 to 3 substituents (b).
  • Divalent 5- to 6-membered heterocyclic group containing three nitrogen, oxygen and Z or sulfur atoms or divalent containing 1 to 4 nitrogen, oxygen and Z or sulfur atoms When a condensed heterocyclic group is used, it is preferably 5-bromopyridine-12,3-diyl, 5-phenoxypyridine-12,3-diyl, 5-phenylpyridin-12,3-diyl, 6-methyl Pyridine-1,2,3-diyl, 6-chloropyridin-2,3-diyl, 6-phenylpyridine-1,2,3-diyl, 6-methoxypyridin-1,2,3-diyl, 6-a Sopropoxyviridine 1-, 3-diyl, 6-phenoxypyridine 1-, 3-diyl, 6-cloth Pyridin-1,3-diy
  • the arylene group and the divalent heterocyclic group exemplified as the groups in the general formula (I) have two bonds.
  • the group B described above includes any group.
  • B has a group showing basicity (for example, an amino group, a monoalkylamino group, etc.) as the substituent (a), the corresponding acid is obtained according to a conventional method.
  • the salt can be obtained by treating with Such salts include, for example, salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; nitrates, perchlorates, sulfates, phosphates Inorganic acid salts such as methanesulfonic acid, trifluoromethanesulfonic acid, and lower alkanesulfonic acid salts such as ethanesulfonic acid; benzenesulfonic acid, and salts of arylarylsulfonic acids such as p-toluenesulfonic acid; glutamic acid And organic salts of carboxylic acids such as fumaric acid, succinic acid, cunic acid, tartaric acid and maleic acid; and the like.
  • hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid
  • the compound having the general formula (I) can be converted into a salt according to a conventional method since the 5-membered ring represented by X contains an imido group portion.
  • Examples of such salts are salts of alkali metals such as lithium, sodium and potassium; salts of alkaline earth metals such as calcium and norm; magnesium salts; Inorganic salts such as aluminum salts; and amine salts such as ammonia, methylamine, dimethylamine, and dicyclohexylamin; and organic base salts such as basic amino acid salts such as lysine and arginine.
  • it is a pharmacologically acceptable salt.
  • the compound having the general formula has various isomers. 4 ⁇
  • X represents a 2,4-dioxothiazolidine-15-ylmethyl group or a 2,4-dioxoxazolidine-15-ylmethyl group
  • the position is an asymmetric carbon atom.
  • stereoisomers based on these asymmetric carbon atoms, and equivalent and unequal mixtures of these isomers are all represented by a single formula. Accordingly, the present invention includes all such isomers and mixtures of these isomers.
  • X is 2,4-dioxothiazolidine-15-ylmethyl (Xb), and 2,4-dioxoxazolidine-15-ylmethyl (Xc)
  • Xb 2,4-dioxothiazolidine-1-5-yridenylmethyl
  • Xc 2,4-dioxoxazolidine-15-ylmethyl
  • the present invention provides a compound which is converted into an aromatic oximino derivative represented by the general formula (I) by being metabolized in a living body, that is, a so-called prodrug of the aromatic oximino derivative represented by the general formula (I). Is also included.
  • preferred compounds include
  • R 1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a methoxy group, a methylthio group, a fluorine atom, a chlorine atom, a nitro group, an amino group, a methylamino group, an ethylamino group, a dimethylamino group or a getylamino group.
  • R 2 is an alkylene group having 2 to 5 carbon atoms
  • A is a methylene group, an oxygen atom, a sulfur atom, a group N (—R 3 ) 1 (wherein R 3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2 to 5 carbon atom
  • R 3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2 to 5 carbon atom
  • (4) B is the same or different and may have 1 or 2 phenylene groups which may have the following substituents (a); and 1 or 2 identical or different phenylene groups having 1 or 2 substituents (a) Naphthylene group which may have 1 or 2 same or different 4 divalent 5- or 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms, oxygen atoms and Z or sulfur atoms or 1 to 3 nitrogen atoms which may have (a) , Divalent fused heterocycle containing oxygen and sulfur or sulfur atoms
  • the substituent (a) is an alkyl group having 1 to 4 carbon atoms, a methoxy group, a methylthio group, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a nitro group, an amino group, a methylamino group
  • An ethylamino group, a dimethylamino group, a dimethylamino group, a phenylsulfonyl group, 1 to 3 identical or different phenyl groups which may have the following substituents (b), 1 to 3 identical or different
  • a benzyl group optionally having the following substituents (b), 1 to 3 phenyl groups optionally having the following substituents (b), 1 or 3 3 to 3 phenoxy groups optionally having the following substituents (b), identical or different, 1 to 3 phenylthio groups optionally having the following substituents (b), the same Or a monovalent 5- or 6-membered ring containing
  • (b) is a monovalent fused heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and Z or a sulfur atom which may have
  • the substituent (b) is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, and a 6 to 10 carbon atoms.
  • Y is an oxygen atom, a sulfur atom, a group —N (—R 6 ) — (wherein, R 6 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 2 to 5 carbon atoms) Represents a silyl group)), and
  • R 1 is a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, main Bok alkoxy group, a methylthio group, full Tsu atom, a chlorine atom, a nitro group. Amino group, Mechiruami amino group, ⁇ > 0
  • R 2 is an alkylene group having 2 to 5 carbon atoms
  • ⁇ is a methylene group, an oxygen atom, a sulfur atom, a group N (—R 3 ) 1 (where R 3 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a 2 to 5 carbon atoms A) represents a acyl group.
  • B is the same or different and may have 1 or 2 substituents (a) below, and the same or different and has 1 or 2 substituents (a) below.
  • a naphthylene group which may be the same or different and has 1 or 2 substituted or unsubstituted (a) one or two nitrogen atoms, oxygen atoms and divalent 5 Or 6-membered heterocyclic ring or divalent fused heterocyclic ring containing 1 to 3 nitrogen, oxygen and Z or sulfur atoms
  • substituent (a) is an alkyl group having 1 to 4 carbon atoms, a methoxy group, a methylthio group, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a nitro group, an amino group, and a methylamino group.
  • a benzyl group optionally having the following substituents (b), 1 to 3 same or different phenethyl groups optionally having the following substituents (b), 1 to 3 identical or different
  • (b) is a monovalent fused heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms and Z or a sulfur atom which may have
  • the substituent (b) is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, and a 6 to 10 carbon atoms.
  • X is a 2,4-dioxothiazolidine-1-5-ylmethyl group, a 2,4-dioxoxazolidin-1-5-ylmethyl group or a 3,5-dioxoxazodiazolidine-2-ylmethyl group;
  • ⁇ is an oxygen atom, a sulfur atom, a group ⁇ (-R 6 ) — (wherein R 6 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an acyl group having 2 to 5 carbon atoms)
  • R 6 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an acyl group having 2 to 5 carbon atoms
  • R 1 is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a chlorine atom
  • substituent (a) is an alkyl group having 1 to 4 carbon atoms, a methoxy group, an ethoxy group, a methylthio group, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, the same or different,
  • Two phenyl groups optionally having the following substituents (b), the same or different benzyl groups optionally having one or two following substituents (b), the same or A phenoxy group which may have 1 or 2 different substituents (b) different from each other, or a phenyl group which may have 1 or 2 different substituents (b) same or different;
  • a luthio group, a phenylsulfonyl group which may be the same or different and has 1 or 2 substituents (b) below, and 1 or 2 same or different lower substituents (b) b) one to three nitrogen sources optionally having A monovalent 5- or 6-membered heterocyclic group containing a hydrogen atom
  • the substituent (b) is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, and a 6 to 10 carbon atoms.
  • X is 2,4-dioxothiazolidine-1-ylmethyl group, 2,4-dioxoxazolidine-15-ylmethyl group or 3,5-dioxoxazodiazolidine A compound which is one 2-ylmethyl group,
  • Y is an oxygen atom, a sulfur atom, Kiichi NH-, Kiichi N (- C Hs) one or group one N (- C 0 CH 3) a first compound, and
  • R 1 is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom or a chlorine atom,
  • R 2 is an alkylene group having 2 to 5 carbon atoms
  • A is a methylene group, oxygen atom, sulfur atom, group NH— or
  • B is the same or different and may have 1 or 2 substituents (a) below, and the same or different and has 1 or 2 substituents (a) below.
  • substituent (a) is an alkyl group having 1 to 4 carbon atoms, a methoxy group, an ethoxy group, a methylthio group, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, the same or different
  • substituents (b) which may have 1 or 2 substituents (b) below, which may be the same or different and has 1 or 2 substituents (b) below.
  • a good benzyl group the same or different and one or two phenyl groups which may have the following substituents (b), the same or different and one or two different substituents (b)
  • a phenylthio group which may have 1 or 2 same or different phenylsulfonyl groups which may have 1 or 2 substituents (b) below
  • a monovalent 5- to 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, an oxygen atom and a Z or sulfur atom which may have the following two substituents (b), or the same Or a monovalent condensed heterocyclic group containing 1 to 3 nitrogen atoms, oxygen atoms, or phosphorus and sulfur atoms which may have 1 or 2 substituents (b) different from the above.
  • the substituent (b) is an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, and a 6 to 10 carbon atoms.
  • X is a 2,4-dioxothiazolidine-1-ylmethyl group, a 2,4-dioxoxazolidine-1-5-ylmethyl group or a 3,5-dioxoxazodiazolidine-12-ylmethyl group,
  • a compound wherein Y is an oxygen atom, a sulfur atom, a group N H-, a group N (-C Ha) one or a group N (-C 0 C H)
  • R 2 is an ethylene group, a 1-methylethylene group, a 2-methylethylene group, a 1-ethylethylene group, a 2-ethylethylene group, a trimethylene group, a 1-methyltrimethylene group, a 3-methyltrimethylene group, A compound that is a 1-ethyltrimethylene group or a 3-ethyltrimethylene group,
  • a compound wherein A is a methylene group, an oxygen atom, a sulfur atom or a group N (-CH) 1;
  • R 1 is a hydrogen atom
  • R 2 is ethylene group, 1-methylethylene group, 2-methylethylene group, 1-ethylethylene group, 2-ethylethylene group, trimethylene group, 1-methyltrimethylene group, 3-methyltrimethylene group, 1-ethyl A trimethylene group or a 3-ethyltrimethylene group,
  • A is a methylene group, an oxygen atom, a sulfur atom or a group N (-CH) 1 and B is the same or different and may have one or two substituents (a) shown below.
  • a quinolinyl 2,3-diyl group which may have the following two substituents (a) [wherein the substituent (a) is a methyl group, an ethyl group, an isopropyl group; t-butyl] Group, methoxy group, ethoxy group, methylthio group, 6 5 Atom, chlorine, bromine,
  • X is 2,4-dioxothiazolidin-1-5-ylmethyl group or 2,4-dioxoxazolidin-1-5-ylmethyl group;
  • R 2 is an ethylene group, a monomethylethylene group, a 2-methylethylene group, a trimethylene group, a 1-methyltrimethylene group or a 3-methyltrimethylene group;
  • (24) B is a phenylene group which may be the same or different and has 1 or 2 substituents (a) below, and has 1 or 2 same or different substituents (a) below
  • An optionally substituted naphthylene group which may be the same or different, and may have one or two substitutions (a) below, or a 2,3-pyridindiyl group or the same or different one or two
  • a 3,4-pyridinyl group which may have a substituent (a), wherein the substituent (a) is a methyl, ethyl, isopropyl, t-butyl, methoxy group , Ethoxy, methylthio, chlorine, bromine, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-3-pyridyl, p- Tril group, 3-chloro phenyl group '4 Mono phenyl group, 3,4-dichlorophenyl group , 3,5-d
  • R 1 is a hydrogen atom, ⁇ , ⁇ >
  • R 2 is an ethylene group, i-methylethylene group, 2-methylethylene group, trimethylene group, 1-methyltrimethylene group or 3-methyltrimethylene group;
  • A is a methylene group or an oxygen atom;
  • B is the same or different and may have 1 or 2 substituents (a) below, and the same or different and has 1 or 2 substituents (a) below.
  • a 2,3-pyridinediyl group which may have the same or different 1 or 2 substituents (a) below or 1 or 2 same or different substituents 1 or 2 3,4-Pyridinediyl group which may have a moiety (a) wherein the substituted moiety (a) is a methyl group, an ethyl group, an isopropyl group, a t-butyl group, a methoxy group, an ethoxy group, a methylthio group Group, chlorine atom, bromine atom, phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 6-methyl-13-pyridyl group, p-tolyl group, 3-chlorophenyl group, 4-- Black phenyl group, 3, 4-dichloro phen
  • X is a 2,4-dioxothiazolidine-1-ylmethyl group
  • the compound having the above general formula (I) of the present invention can be produced according to the following Method A to Method D.
  • R ', R 2, A , B, -X and Y indicate the same groups as those described above.
  • U is a hydroxyl group, a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom), or a group — 0 S 0 2 —R 7 (where R 7 is a carbon atom such as methyl or ethyl)
  • R 7 is a carbon atom such as methyl or ethyl
  • b represents a phenyl group substituted with a halogen atom (preferably a chlorine, bromine or iodine atom).
  • X ′ is Xa, Xb. Xc and Xd, a group in which one of the groups —NH— is protected by a trimethylphenyl group (hereinafter referred to as a trityl group) (that is, -[C (P h)]-).
  • a trityl group a trimethylphenyl group
  • Step A1 is a step for preparing a compound having the general formula (IV). It is achieved by reacting a compound having the general formula (II) with a compound having the general formula (III).
  • the reaction is usually suitably carried out in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • examples of the solvent include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; methylene chloride, chloroform, and 1,2-dichloroethane.
  • Such halogenated hydrocarbons such as getyl ether, dioxane, and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide; Nitriles such as cetonitrile and propionitol; esters such as ethyl formate and ethyl acetate; or a mixed solvent thereof is preferably used.
  • the reaction is carried out at a temperature of from 10 ° C to 100 ° C, preferably from 20 ° C to 80 ° C.
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 1 hour to 3 days, preferably 5 hours to 3 days.
  • U is a halogen atom or Groups In one 0 S 0 2 - R 7 ( . R 7 is as defined above) in the case is in an inert solvent, is achieved Ri by that in the presence of a base.
  • the base used is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate; sodium hydride, potassium hydride.
  • ⁇ sodium hydrogen carbonate, hydrogen hydrogen carbonate Alkali-like carbon-carbon hydride, such as um: 1.5-X- [3.
  • tertiary amines such as 7-en, ⁇ , ⁇ , ⁇ , ⁇ ⁇ , ⁇ , ⁇ ⁇ Carbonate, Alkali metal hydride or Alkali metal alkoxide.
  • the solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and hebutane; methyl ether, dioxane, and tetrahydrofuran.
  • Ethers such as dimethylformamide, dimethylacetamide and amides such as ⁇ -methylpyrrolidone; ketones such as aceton and 2-butanone; acetonitol And nitriles such as propionitol; sulfoxides such as dimethylsulfoxide; or a mixed solvent thereof. More preferred are ethers, amides, ketones, and sulfoxides.
  • reaction When this reaction is carried out in the presence of a phase transfer catalyst such as benzyl triethyl ammonium hydroxide or tetrabutyl ammonium hydroxide, sodium hydroxide or hydroxide is used as the base.
  • a phase transfer catalyst such as benzyl triethyl ammonium hydroxide or tetrabutyl ammonium hydroxide
  • sodium hydroxide or hydroxide is used as the base.
  • the reaction is carried out using an alkali metal hydroxide such as calcium in a two-phase solvent of water and a halogenated hydrocarbon such as methylene chloride and chloroform. It is carried out at 20 ° C, preferably at 1 ° C to 100 ° C. ,
  • the reaction time varies depending on the reagents used, the reaction temperature, the solvent and the like, and is usually 30 minutes to 48 hours, preferably 1 hour to 16 hours.
  • Step A2 is a step of producing a compound having the general formula (I), and is achieved by removing the trityl group, which is a protecting group of the general formula (IV).
  • the compound represented by the general formula (IV) is converted to a compound such as ant II, acetic acid, trifluoroacetic acid, trifluoromethansulfonic acid, hydrochloric acid and / or sulfuric acid in the presence or absence of a solvent. It is carried out by reacting with an acid.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • hydrogen peroxide such as benzene, toluene.
  • Xylene, hexane, and hebutane is used.
  • Jechil 21 14 4 ' Ethers such as furan; alcohols such as methanol, ethanol, and isopropanol; aminos such as dimethylformamide, dimethylacetamide, and hexamethylphosphate triamide.
  • Halogenated hydrocarbons such as methylene chloride, chloroform, i, 2-dichloroethane; ditriles such as acetate and propionitrile; ethyl formate, acetic acid Esters such as ethyl; water; or a mixed solvent thereof is preferably used.
  • the reaction temperature varies depending on the acid used, but is from 110 ° C to 120 ° C, preferably from 0 ° C to 100 ° C.
  • the reaction time varies depending on the acid used, the reaction temperature, the solvent and the like, but is usually from 10 minutes to 24 hours, preferably from 30 minutes to 16 hours.
  • This step can also be achieved by subjecting the compound represented by the above general formula (IV) to a catalytic hydrogenation reaction.
  • the catalyst used include palladium monocarbon, palladium black, platinum oxide, platinum black and the like, and palladium monocarbon is preferable.
  • the reaction is usually suitably performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; getyl ether, dioxane, and tetrahydro.
  • Ethers such as drofuran; alcohols such as methanol, ethanol, and isopronoxanol; amides such as dimethylformamide, dimethylacetamide, hexamethyl triamide; chloride Halogenated hydrocarbons such as methylene, chloroform, 1,2-dichloroethane; nitriles such as acetate and brothol; ethers such as ethyl formate and ethyl acetate Esters; strong rubonic acids such as formic acid and acetic acid; water; or a mixed solvent thereof is preferably used.
  • the reaction temperature is from 1 ° C to 140 ° C, preferably from 20 ° C to 100 ° C.
  • the reaction may be accelerated by adding a carboxylic acid such as ninnic acid, acetic acid, or trifluoroacetic acid; or an inorganic acid such as hydrochloric acid or sulfuric acid.
  • a carboxylic acid such as ninnic acid, acetic acid, or trifluoroacetic acid
  • an inorganic acid such as hydrochloric acid or sulfuric acid.
  • R ′, R 2 , A, B, X and Y represent the same groups as described above.
  • U is a hydroxyl group, a halogen atom, or Groups In one 0 S 0 2 (preferably Ru Oh chlorine atom, a bromine atom or an iodine atom.) - R 7 (wherein, R 7 is methyl, carbon atoms such as Echiru 1 An alkyl group having 1 to 6 carbon atoms, a halogen atom such as trifluoromethyl and a halogenated alkyl group having 1 to 6 carbon atoms, phenyl, or lower alkyl at the p-position (for example, methyl and ethyl), nitrite And b represents a phenyl group substituted with a halogen atom (preferably a chlorine, bromine or iodine atom).
  • X ′ is Xa, Xb, Xc and Xd, a group in which one group NH— of these groups is protected by a trimethylphenyl group (hereinafter referred to as a trityl group).
  • a trityl group a trimethylphenyl group
  • Step B1 is a step of producing a compound having the general formula (IV), wherein the compound having the fiS formula (V) is reacted with the compound having the fission formula (VI). It is done by this. 1 4 C
  • the reaction is usually suitably carried out in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane and heptane; methylene chloride, chloroform and 1,2-dichloromethane.
  • Halogenated hydrocarbons such as ethane; ethers such as getyl ether, dioxane, tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide Compounds; ditriols such as acetate nitrile and propionitol; esters such as ethyl acetate and ethyl acetate; or a mixed solvent thereof is preferably used.
  • the reaction is carried out at a temperature of from 10 ° C to 100 ° C, preferably from 20 ° C to 80 ° C.
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually 1 hour to 3 hours, preferably 5 hours to 3 days.
  • One U is a halogen atom or a group 0 S 0 2 - R 7 ( . R 7 is as defined above) in the case is in an inert solvent, Ri is achieved by the a this is reacted in the presence of a base .
  • the base used is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate; sodium hydride, lithium hydride, lithium hydride.
  • Metal hydrides such as: sodium methoxide, sodium ethoxide, alkali metal alkoxide, alkali metal alkoxides such as lithium methoxide; butyl lithium Alkyl lithiums, such as lithium and methyllithium; lithium amides, such as lithium getylamide, lithium diisopropyl amide, lithium bis (trimethylsilyl) amide; sodium hydrogen carbonate Alkali metal bicarbonate such as lithium; 1,5-diazabicyclo [4.3.0] non-5-5-ene, 1,8-diazabicyclo [5.4.0] 7-E down, N, is N- Jie Sopu ⁇ Piruechirua tertiary ⁇ Mi emissions Do you Yo of the actual emissions, preferably Al Li gold)! Charcoal K 14 Salt, alkaline metal hydride or alkaline metal al
  • the solvent used in the reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and hebutane; and methyl ether, dioxane, and tetrahydrofuran.
  • Amides such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; ketones such as aceton and 2-butane; acetonitril; Ditriles such as propionotriyl; sulfoxides such as dimethyl sulfoxide, or a mixed solvent thereof can be suitably used. More preferred are ethers, amides, ketones, and sulfoxides.
  • phase transfer catalyst such as benzyl triethyl ammonium hydroxide or tetrabutyl ammonium hydroxide
  • sodium hydroxide is used as a base.
  • the reaction is carried out using an alkali metal hydroxide such as potassium hydroxide in a two-phase solvent consisting of water and a halogenated hydrocarbon such as methylene chloride and chloroform. To 120 ° C., preferably from 100 ° C. to 100 ° C.
  • the reaction time varies depending on the reagents used, the reaction temperature, the solvent and the like, and is usually 30 minutes to 48 hours, preferably 1 hour to 16 hours.
  • Step B2 is a step of producing the compound represented by the general formula (I), and is achieved by removing the trityl group, which is the protecting group of the general formula (IV). That is, it is achieved by performing the reaction according to the step A1.
  • R 1 , R 2 , A, B, X and Y represent the same groups as described above.
  • X '' indicates X or X '.
  • Step C1 is a step of producing a compound having the general formula (IX), and is achieved by reacting a compound having the general formula (VII) with a compound having the general formula (VIII). You.
  • the reaction is usually suitably carried out in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and is, for example, a hydrocarbon such as benzene, toluene, xylene or hexane; an ether such as dimethyl ether, dioxane, or tetrahydrofuran.
  • Alcohols such as methanol, 'ethanol and iso- ⁇ -nonol; amides such as dimethylformamide, dimethylacetamide and hexamethyl folic acid triamide; methylene chloride; , 1,2-Halogenated hydrocarbons such as dichloroethylene; nitriles such as acetonitril and propionitol: esters such as ant IS ethyl and S ethyl vinegar ⁇ : Pyrimidine, .triethylamine, ⁇ '.N-diisopamine, such as viramine ⁇ ;:: and these f ⁇ 48; A mixed solvent is preferably used.
  • Reaction B H temperature is carried out between 0 ° C and 120 ° C, preferably between 20 and 100 ° C ⁇ 2, C
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, but is usually from 1 hour to 24 hours, and preferably from 1 hour to 16 hours.
  • Step C2 is a step of producing a compound having the general formula (I), wherein when the group X ′′ in the general formula (VI) is X ′, the protecting group of X ′ is removed. This is done for the purpose of Therefore, this step can also be achieved by reacting the compound represented by the general formula (VI) according to step A2.
  • R 1 , R 2 , A, B and Y represent the same groups as described above.
  • Method D Among the compounds having the general formula (I), the method X is for producing a X a or X b is a reduction compound, i.e. formula (I d,) or a compound represented by (I d 2) It is.
  • Step D1 is a process for producing a compound represented by the general formula (XII), wherein the compound represented by the general formula (X) and the fluorobenzaldehyde derivative represented by the general formula (XI) are present in the presence of a base. Achieved by reacting below.
  • Bases used are, for example, alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydride, lithium carbonate and lithium hydride.
  • it is an alkali metal carbonate, an alkali metal hydride or an alkali metal alkoxide.
  • the reaction is usually suitably carried out in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • hydrocarbons such as benzene, toluene, xylene, hexane and heptane; getyl ether, dioxane Ethers such as methane and tetrahydrofuran; amides such as dimethylformamide, dimethylacetamide and ⁇ -methylbi-lidone; ketones such as aceton and 2-butanone
  • nitriles such as acetonitrile and propionitol
  • sulfoxides such as dimethylsulfoxide; or a compound thereof can be used.
  • ethers Preferable are ethers, amides, ketones and sulfoxides. 1 ⁇ .0
  • a phase transfer catalyst such as benzyl triethyl ammonium hydroxide or tetrabutyl ammonium hydroxide
  • sodium hydroxide is used as a base.
  • the reaction is carried out in a two-phase solvent of water and a halogenated hydrocarbon, such as methylene chloride and chloroform, using an alkali metal hydroxide such as a hydrating hydroxide.
  • the reaction temperature is from 110 ° C to 120 ° C, preferably from 10 ° C to 100 ° C. done in c.
  • the reaction time varies depending on the reagent used, the reaction temperature, the solvent and the like, and is usually 3 minutes to 48 hours, preferably 1 hour to 16 hours.
  • Step D2 is a step of producing a compound having the general formula (Id,), and is performed by a condensation reaction between the compound having the general formula (XII) and 2,4-thiazolidinazine (XIII). Is achieved.
  • the reaction is performed in the presence or absence of a catalyst.
  • the catalyst used may be, for example, organic amines such as piberidine and pyridine; sodium acetate, lithium acetate, and the like.
  • Acetate salts of alkali metals such as organic amine salts such as biperidinium acetate and piperidinium benzoate.
  • the reaction is usually suitably carried out in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction.
  • examples of the solvent include hydrocarbons such as benzene, toluene, xylene, and hexane; and acetyl ether, dioxane, and tetrahydrofuran.
  • Alcohols such as methanol, ethanol, and isopropanol; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric acid triamide; methylene chloride-close-mouth form 1,2, -Halogenated hydrocarbons such as dichloroethane; ditritols such as acetate and propionitol; esters such as ethyl formate and ethyl acetate; or these It is possible to use a mixed solvent.
  • the reaction temperature is between 2 ° C and 15 ° C, preferably between 60 ° C and 120 ° C.
  • the reaction time varies depending on the reaction reagent, reaction temperature, solvent and the like, and is usually 1 hour to 3 days, preferably 2 hours to 16 hours.
  • Step D3 is a step of producing a compound having the general formula (Id 2 ), and selectively adding hydrogen to the compound having the general formula (Id 2 ) in the presence of a catalyst. This is achieved by:
  • Examples of the catalyst used include palladium monocarbon and palladium black, and palladium-carbon is preferred.
  • the reaction is usually suitably performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction, and examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and hebutane; and hydrocarbons such as getyl ether, dioxane, and tetrahydrofuran.
  • Ethers include hydrocarbons such as benzene, toluene, xylene, hexane, and hebutane; and hydrocarbons such as getyl ether, dioxane, and tetrahydrofuran.
  • Ethers alcohols such as methanol, etasol, and isopropanol
  • amides such as dimethylformamide, dimethylacetamide, and hexamyl phosphoric acid triamide
  • organic acids such as formic acid, acetic acid, and propionic acid
  • water Or a mixed solvent thereof
  • This reaction is generally carried out under normal pressure or under pressure of hydrogen, preferably at normal pressure to 30 atm.
  • the reaction temperature is from 0 ° C to 150 ° C, preferably from 0 ° C to 100 ° C.
  • the reaction time varies depending on the hydrogen pressure, the reaction temperature, the solvent and the like, but is usually 30 minutes to 3 days, preferably 30 minutes to 1 day.
  • the compound having the general formula (VII) used as a starting material in the above-mentioned "Method C” has a known force or a known method [for example, Inglold and Thorpe, J. Chem. Soc., 115, 149 (1919), Gilmore, J. Am. Chem. Soc., 73, 5879 (1951), V. Auwers, Chem.
  • the target compound obtained in each of the above steps can be purified, if necessary, by a conventional method, for example, by column chromatography, recrystallization, precipitation, or the like.
  • reaction mixture is extracted by adding an appropriate solvent, and the solvent is distilled off from the extract.
  • the obtained residue can be purified by subjecting it to column chromatography using a silica gel or the like to obtain the desired product as a pure product.
  • the ' ⁇ -nuclear magnetic resonance spectrum (270 MHz) measured with tetramethylsilane as the internal standard in the double-mouthed form was as follows.
  • the ' ⁇ -nuclear magnetic resonance spectrum (270 MHz) measured with tetramethylsilane as the internal standard in the double-mouthed form was as follows.
  • the ' ⁇ -nuclear magnetic resonance spectrum (270 MHz) measured with tetramethylsilane as the internal standard in the double-mouthed form was as follows.
  • the ' ⁇ -nuclear magnetic resonance spectrum (270 MHz) measured with tetramethylsilane as the internal standard in the double-mouthed form was as follows.
  • the ' ⁇ -nuclear magnetic resonance spectrum (270 MHz) measured with tetramethylsilane as the internal standard in the double-mouthed form is as follows.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne des dérivés d'oxyimino aromatiques représentés par la formule générale (I) ou des sels de ces dérivés utiles en tant qu'agent préventif et/ou remède, contre de maladies provoquées par la résistance insulinique, l'hyperglycémie, les complications du diabète, etc. Dans la formule (I), R1 représente l'hydrogène, etc., R2 représente alkylène C¿1-6?, A représente le méthylène, etc., B représente un arylène C6-10 ayant éventuellement le substituant (a), etc., X représente un des composés de formule (Xa), (Xb), (Xc) ou (Xd) et Y représente oxygène, etc., le substituant (a) représentant alkyle C1-6, etc.
PCT/JP1996/001271 1995-06-02 1996-05-15 Derives d'oxyimino aromatiques WO1996038427A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57018/96A AU5701896A (en) 1995-06-02 1996-05-15 Aromatic oxyimino derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP13700295 1995-06-02
JP7/137002 1995-06-02

Publications (1)

Publication Number Publication Date
WO1996038427A1 true WO1996038427A1 (fr) 1996-12-05

Family

ID=15188510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/001271 WO1996038427A1 (fr) 1995-06-02 1996-05-15 Derives d'oxyimino aromatiques

Country Status (2)

Country Link
AU (1) AU5701896A (fr)
WO (1) WO1996038427A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058510A1 (fr) * 1998-05-11 1999-11-18 Takeda Chemical Industries, Ltd. Derives d'acide oxyminoalcanoique ayant un effet hypoglycemique et hypolipidemique
US6103907A (en) * 1996-04-04 2000-08-15 Sankyo Company, Limited Phenylalkylcarboxylic acid compounds and compositions for treating hyperglycemia
US6756360B1 (en) 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
WO2004080947A1 (fr) * 2003-03-13 2004-09-23 Ono Pharmaceutical Co., Ltd. Composes derives d'imino ether et medicaments renfermant ces composes comme principe actif
WO2009072807A3 (fr) * 2007-12-03 2009-07-30 Amorepacific Corp Prévention ou traitement de troubles associés au métabolisme des graisses maladies grâce à une composition pharmaceutique contenant des dérivés de 2.cyclopentène-1-one oxime

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0708098A1 (fr) * 1994-10-07 1996-04-24 Sankyo Company Limited Dérivés d'oximes, leur préparation et leur utilisation thérapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0708098A1 (fr) * 1994-10-07 1996-04-24 Sankyo Company Limited Dérivés d'oximes, leur préparation et leur utilisation thérapeutique

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6103907A (en) * 1996-04-04 2000-08-15 Sankyo Company, Limited Phenylalkylcarboxylic acid compounds and compositions for treating hyperglycemia
WO1999058510A1 (fr) * 1998-05-11 1999-11-18 Takeda Chemical Industries, Ltd. Derives d'acide oxyminoalcanoique ayant un effet hypoglycemique et hypolipidemique
US6251926B1 (en) 1998-05-11 2001-06-26 Takeda Chemical Industries, Ltd. Oxyiminoalkanoic acid derivatives with hypoglycemic and hypolipidemic activity
US6495581B1 (en) 1998-05-11 2002-12-17 Takeda Chemical Industries, Ltd. Oxyiminoalkanoic acid derivatives
RU2213738C2 (ru) * 1998-05-11 2003-10-10 Такеда Кемикал Индастриз, Лтд. Производные оксииминоалкановой кислоты, фармацевтическая композиция и средство для регуляции ретиноидных рецепторов
EP1428531A1 (fr) * 1998-05-11 2004-06-16 Takeda Chemical Industries, Ltd. Dérivés d'acide oximinoalcanoique à activité hypoglycémique et hypolipidémique
US6924300B2 (en) 1998-05-11 2005-08-02 Takeda Chemical Industries, Ltd. Oxyiminoalkanoic acid derivatives
US6756360B1 (en) 1998-12-24 2004-06-29 Metabasis Therapeutics, Inc. Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes
WO2004080947A1 (fr) * 2003-03-13 2004-09-23 Ono Pharmaceutical Co., Ltd. Composes derives d'imino ether et medicaments renfermant ces composes comme principe actif
WO2009072807A3 (fr) * 2007-12-03 2009-07-30 Amorepacific Corp Prévention ou traitement de troubles associés au métabolisme des graisses maladies grâce à une composition pharmaceutique contenant des dérivés de 2.cyclopentène-1-one oxime
WO2009072808A3 (fr) * 2007-12-03 2009-08-20 Amorepacific Corp Composition cosmétique pour amincissement corporel contant des dérivés de 2-cyclopentène-1-one oxime

Also Published As

Publication number Publication date
AU5701896A (en) 1996-12-18

Similar Documents

Publication Publication Date Title
JP4234344B2 (ja) スルホンアミド含有複素環化合物
JP5335932B2 (ja) 制癌剤である二置換ピリジン誘導体
CN104822687B (zh) 抗纤维化吡啶酮类
AU2020204425A1 (en) Pyridone amides as modulators of sodium channels
TWI321130B (en) Novel pharmaceutical compounds
RU2582995C2 (ru) Производные гетероарилсульфонамидов, их получение и применение для лечения человека
CN113631541B (zh) 酰胺类化合物制备方法及其在医药领域的应用
CN110225911B (zh) 噁二唑酮瞬时受体电位通道抑制剂
KR20020016795A (ko) 신규 화합물, 이의 용도 및 이의 제조 방법
WO2013027168A1 (fr) Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs de bromodomaine
KR20090020543A (ko) 당뇨병의 치료를 위한 헤테로바이사이클릭 설폰아마이드 유도체
CN103159695B (zh) 可抑制hiv复制并对耐药hiv病毒株有效的噻唑类化合物及其制备方法和用途
SK164598A3 (en) 5-phenoxyalkyl-2,4-thiazolidinedione derivative, method for the preparaton thereof, intermediate products for its preparation and pharmaceutical composition containing same
US20240116903A1 (en) Tetrahydroquinoline derivative and medicinal use thereof
RU2287529C2 (ru) Новые гетероциклические производные и их медицинское использование
WO1996038427A1 (fr) Derives d'oxyimino aromatiques
JP2013047223A (ja) 医薬
KR20120027321A (ko) 신규 옥사졸리디논 유도체
WO2009103007A2 (fr) Composés modulateurs des récepteurs de l’hormone stéroïdienne et procédés
JPH0948770A (ja) 芳香族オキシイミノ誘導体
JPH08157461A (ja) スルホン誘導体
FR2642756A1 (fr) Derives cycloaminoalkoxyphenyle, leur procede de preparation ainsi que les compositions pharmaceutiques ou veterinaires en contenant
HK40039964B (zh) 三环化合物
HK40009776A (en) Oxadiazolones as transient receptor potential channel inhibitors
HK1187345B (en) Derivatives of heteroarylsulfonamides, their preparation and their application in human therapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN CZ HU KR MX NO NZ RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA