WO1996023789A1 - Derives d'hexahydropyrazinoquinoline - Google Patents

Derives d'hexahydropyrazinoquinoline Download PDF

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Publication number
WO1996023789A1
WO1996023789A1 PCT/JP1996/000194 JP9600194W WO9623789A1 WO 1996023789 A1 WO1996023789 A1 WO 1996023789A1 JP 9600194 W JP9600194 W JP 9600194W WO 9623789 A1 WO9623789 A1 WO 9623789A1
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Prior art keywords
group
phenyl
quinoline
alkyl
general formula
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PCT/JP1996/000194
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English (en)
Japanese (ja)
Inventor
Koichi Kojima
Yuichi Aizawa
Naozumi Samata
Junichi Sakai
Kazuo Koyama
Toshiyuki Tonohiro
Masahiko Sugimoto
Takao Hara
Marie Hisamoto
Hiroshi Homma
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Sankyo Company, Limited
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Priority to AU45477/96A priority Critical patent/AU4547796A/en
Publication of WO1996023789A1 publication Critical patent/WO1996023789A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to hexahydrovirazinoquinoline derivatives and hexahydrobirazinoquino derivatives having excellent serotonin 1A receptor (hereinafter abbreviated as 5- HT1A receptor) action, sedative action against mental stress and hallucination-suppressing action.
  • 5- HT1A receptor serotonin 1A receptor
  • the present invention relates to a 5- H1LA receptor agonist containing a phosphorus derivative as an active ingredient.
  • Hexahydrobirazinoquinoline derivative has potent 5-HT A receptor agonizing action, sedative action against mental stress, and phantasmagoric effect, has few side effects such as drowsiness, anxiety, B disease, high blood pressure, schizophrenia
  • the present invention has been found to have a therapeutic or preventive action (particularly a therapeutic action) for sleep disorders, migraine, sexual dysfunction, sickness, dizziness, symptoms related to senile dementia (particularly delirium) and the like. completed.
  • the present invention provides a hexahydrovirazinoquinoline derivative having an excellent 5-HT 1A receptor agonistic action, a sedative action against mental stress, and a hallucinogenic action, a method for producing the same, and a 5-HT 1A receptor comprising the same as an active ingredient.
  • the hexanehydrobirazinoquinoline derivative of the present invention has the general formula (I):
  • R 1 represents a group having the formula: CO—R 3 ,
  • R 2 represents a hydrogen atom
  • R ′ and R 2 represent a group having the general formula (III) or (IV) formed together with the nitrogen atom to which they are bonded,
  • R 3 is a d-C alkyl group, a C 3 -C 10 cycloalkyl group, and may have 1 to 3 substituents selected from the same or different from the following substituent group A.
  • C 6 -C 14 aryl group, 1 to 3 of which may have a substituent C 7 is selected same or different from the following substituent group a - C * e Ararukiru group, mono C 3 - C! .
  • R 4 and R 5 are the same or different and each represent a hydrogen atom or a C, -C alkyl group
  • R 6 represents a C 6 —C aryl group which may have 1 to 3 substituents, which are the same or different and are selected from the following substituent groups:
  • the B-substituent group A includes a halogen atom, a C, -C6 alkyl group, a halogeno (: ⁇ -C6 alkyl group, a -C ⁇ alkoxy group, a C, -C * alkoxy C, a -C * alkyl group, d -C * alkylthio group, 1 to 3 ⁇ C s -C aryl group optionally having a B substituent (the B substituent is halogen, C, -C.
  • Alkyl or -C alkoxy a hydroxyl group, a thiol group, an amino group, a protected amino groups, carboxy sheet group, carboxy C l - C alkyl group, formyl group, C 2 - C 5 Arukanoiru groups, C 2 - C 5 alkoxycarbonyl group, a force Rubamoiru group, Represents a cyano group or a nitro group,
  • X represents a methylene or acid purple atom
  • m represents a fraction of 2 to 6.
  • the active ingredient of 5-HT l A receptor agonist of the present invention is a Kisahi Dorobirajinokino phosphorus derivatives to having the above general formula (I) or one general formula (II).
  • the “halogen atom” in the definition of the substituent group A may be, for example, a fluorine atom, a salt atom, a bromine atom or an iodine atom, preferably a fluorine atom. It is a purple atom or a chlorine atom, more preferably a fluorine atom.
  • “(:, -C 7 alkyl group)” in the definition of R 3 is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, a t-alkyl group.
  • a 1-ethylpentyl group or a 1-propyl butyl group more preferably a butyl group, an isobutyl group, a s-butyl group, a t-butyl group or a 1-ethylpentyl group, and particularly preferably a t-butyl group or a 1-butylpentyl group.
  • R 5 and one C 6 alkyl group in the definition of the substituent group A are ⁇ the rc, one C 7 alkyl group '' of the straight or branched C 1 to C 6 alkyl group.
  • the alkyl group of R 4 or R 5 is preferably a C, -C alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group, and particularly preferably a methyl group.
  • the alkyl group in the S-substituent group A is preferably a C 1, 1C alkyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.
  • the “halogen group, —C 6 alkyl group” in the definition of the substituent group A is the same as or different from the “halogen atom” and is one to three halogen atoms selected from the group consisting of rct-C ⁇
  • An alkyl group ", for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, or a 3-fluorobutyl group.
  • Bil group 3,3,3-Trifluorobutyl mouth group, 4-Fluorobutyl group, Dichloromethyl group, Trichloromethyl group, 2-Chloroethyl group, 2,2,2-Trichloroethyl group, Dibromomethyl group, 2 —Bromoethyl, 2,2-dibromoethyl, 2-bromobutyl, 2-tert-butyl, 5-fluoropentyl, or 4-cyclohexyl And preferably a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group or a 2,2,2-trifluoromethyl group, and more preferably a trifluoromethyl group.
  • Group 4-Fluorobutyl group, Dichloromethyl group, Trichloromethyl group, 2-Chloroethyl group, 2,2,2-Trichloroethyl
  • “mono C 3 —C, .cycloalkyl group” in the definition of R 3 is, for example, a cyclobutyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group, a norbornyl group Or a fused ring such as an adamantyl group It may be a 3-10 shell saturated ⁇ -hydrocarbon group, preferably a cyclopentyl group or a cyclohexyl group, and more preferably a cyclohexyl group.
  • the "C, - C s alkoxy group” in the definition of substituent group A indicates a bonded groups to an oxygen atom, for example, main butoxy group, ethoxy Group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, neopentoxy group, 1-ethylbroboxyl group, Xyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1 -Dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group or 2-ethylbutoxy group, and preferably d-C An alkoxy group, more preferably to the main butoxy group or an oxygen atom, for example, main butoxy group, ethoxy
  • the ⁇ rc, -C alkoxy-alkyl group '' in the definition of the at substitution group A means a group in which the ⁇ C, -C alkoxy group '' is bonded to the rc ⁇ -alkyl group,
  • a methoxymethyl group a 1-methoxyl group, a 2-methoxyl group, a 1-methoxyl group, a 2-methoxyl group, a 3-methloxyl group, a 2-methloxylsopropyl group, a 4-methloxybutyl group, Methoxybutyl, 2-methoxybutyl, ethoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, butoxymethyl, butoxybutyl or t-butoxybutyl, preferably methoxymethyl Or an ethoxymethyl group, and more preferably a methoxymethyl group.
  • the “rd-alkylthio group” in the definition of the substituent group A is, for example, a methylthio group, an ethylthio group, a propylthio group, an isobromothio group, a butylthio group, an isobutylthio group, an s-butylthio group or a t-alkylthio group. It may be a linear or branched alkylthio group having 1 to 4 carbon atoms such as a butylthio group, preferably a methylthio group or an ethylthio group, and more preferably a methylthio group.
  • substituent group A may have 1 to 3 B substituents" C ⁇ - reel group (where the S substituent is halogen, C, -C 4 alkyl or d —
  • C * alkoxy is a carbon violet aromatic group having 6 to 14 carbon atoms which may have 1 to 3 substituents and is the same or different and selected from the group II.
  • the protecting group of the amino group of the “protected amino group” in the definition of the substituent group A can be generally used without particular limitation as long as it is a group used as a protecting group of the amino group. possible, for example, formyl group; Asechiru group, a propionyl group, a butyryl group, an isobutyryl group, Pentanoiru group, pivaloyl group, Bruno, 'Reriru groups, C such as I Sobareriru group or to Kisanoiru group 2 - C Arukanoiru group; Kuroroa Cetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, 3-fluorobutyral pionyl group, 4,4-dichlorobutyryl group, methoxyacetyl group, butoxyacetyl group, ethoxypropionyl group or brobo such as Kishibuchiriru group,
  • the “mono C 3 -C 10 cycloalkylamino group” in the definition of R 3 is a group in which the above rc 3 —C 10 cycloalkyl group is bonded to an amino group. It can be a bilamino group, a cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino group, a cycloheptylamino group, a norbornylamino group or an adamantylamino group, preferably a cyclobentylamino group. Or a cyclohexylamino group, more preferably a cyclohexylamino group.
  • the “carboxy C t -C * alkyl group J” in the definition of the 31-substituent group A is a group in which a carboxy group is bonded to the rc, -C alkyl group, for example, a carboxymethyl group, A carboxyl group, a 2-carboxyethyl group, a carboxybutyl group, a 2-carboxybutyl pill group, a 3-carboxybutyl group, a 2-carboxyisopropyl group, a 4-carboxybutyl group or a 2-carboxymethyl group It may be a t-butyl group, preferably a carboxymethyl group or a 2-carboxyethyl group, and more preferably a carboxymethyl group.
  • the “C 2 -C 5 alkanol group” in the definition of the S-substituent group A is, for example, a carbon such as an acetyl group, a propionyl group, a butyryl group or an isopyryl group. It may be a linear or branched alkanoyl group having a violet number of 2 to 5, and is preferably an acetyl group.
  • the rc 2 -c 5 alkoxycarbonyl group j in the definition of the as substitution group A is a group in which a carbonyl group is bonded to the aforementioned re, -C alkoxy group '', for example, a methoxycarbonyl group, It may be an ethoxycarbonyl group, a propoxycarbonyl group, an isobromoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, an S-butoxycarbonyl group or a t-butoxycarbonyl group, preferably a methoxycarbonyl group or an ethoxy group.
  • a C 6 —C 14 aryl group which may have 1 to 3 S substituents selected from the same or different substituent group A Is an aromatic hydrocarbon group having 6 to 14 carbon violet numbers which may have the substituent, for example, a phenyl group, a fluorophenyl group, a difluorophenyl group, a cyclophenyl group, a dichlorophenyl group, and a bromophenyl group.
  • Methyl, 2 Fluoroethyl, 2,2 —Difluoroethyl, 2,2,2 — Trifluoroethyl, -C alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methyl 1 to 3 members selected from the same or different selected from the group consisting of toxicoxy, hydroxyl, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro
  • a phenyl group or a naphthyl group which may have a substituent, more preferably fluorine, chlorine, C t -C alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluor
  • nitrophenyl group particularly preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2.4-difluorophenyl, 2 , 5-difluorophenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5- A difluorophenyl group, a 3,4-dichlorophenyl group, a p-tolyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group or a 2-methoxyphenyl group, which are very suitable.
  • a phenyl group is a 2,3-difluorophenyl group, a 2,4-difluorophenyl group, a 2,5-difluorophenyl group or a 3,4-dichlorofunyl group, most preferably a phenyl group or Is a 2,4-difluorophenyl group.
  • the aryl group of FT is preferably fluorine, salt purple, C 1 -C 4 alkyl, fluoromethyl, difluoromethyl, trifluormethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-to One to three B substituents selected from the group consisting of rifluoroethyl, monoalkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro
  • a phenyl group which may have a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2,3-difluorophenyl group, and a 2,4-difluorophenyl Group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3.5-
  • C aralkyl group optionally having 1 to 3 substituents, which are the same or different from the following S-substituent group A,” in the definition of R 3 , refers to the substituent may also be the rc e has - from 1-3 C aryl group ", the"(## - group bonded to C 6 alkyl group ", for example, a benzyl group, Furuo port base Njiru group, difluoromethyl O-benzyl, trifluobenzyl, chlorobenzyl, dichlorobenzyl, trichlorobenzyl, bromobenzyl, methylbenzyl, dimethylbenzyl, trimethylbenzyl, Ethylbenzyl group, fluoromethylbenzyl group, difluoromethylbenzyl group, trifluoromethylbenzyl group, fluoroethylbenzyl group, difluoroethylbenzyl group, trifluoroethyl
  • -C alkyl fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2—difluoroethyl, 2,2,2—trifluoromethyl, -C alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 41 Fluorophenyl, 4-methylphenyl, 4-methoxy 1 to 3 substituents selected from the group consisting of cyphenyl, hydroxyl, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro
  • 2-DOO Rifuruoroechiru one C 4 alkoxy, main Tokishimechiru, Mechiruchi O, phenyl, 4 one-fluorophenyl, 4 one-methylphenyl, 4-main Tokishifue sulfonyl, 1 is selected same or different from the group consisting of Shiano and nitro With three fi substitution groups A benzyl group, a benzyl group, a fluorobenzyl group, a cyclobenzyl group, a difluorobenzyl group, a dichlorobenzyl group, a trifluoromethylbenzyl group, A methylbenzyl group, a dimethylbenzyl group, a trimethylbenzyl group, a methoxybenzyl group, a cyanobenzyl group or a nitrobenzyl group, and particularly preferably a benzyl group.
  • a 5-substituted or 6-substituted aromatic compound which may have one substituent selected from the following substituent group A may be combined with a benzene ring,
  • a purple ring group (the double purple ring contains one or two acid purple, nitrogen or sulfur atoms) ”is, for example, a pyrrolyl group, a fluoropyrrolyl group, a cyclopyrrolyl group, a methylpyrrolyl group, a methoxypyrrolyl group, Amyl biaryl group, methoxycarbonyl biaryl group, Imi Dazolyl, Fluoroymidazolyl, Chloroimidazolyl, Promoimidazolyl, Podoimidazolyl, Birazolyl, Methylpyrazolyl, Ethylbirazolyl, Provirvirazolyl, Butylpyrazolyl, Butoxybutylvillazolyl, Oxazolyl Group, fluoroxazolyl group,
  • 2,2-Difluoroethyl, 2,2.2 Trifluoroethyl, monoalkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, phenyl, 4-monofluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl, thiol, amino Pyrrolyl, which may have one g-substituent selected from the group consisting of acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, cyano and nitro.
  • a pyridyl group optionally having one substituent selected from the group consisting of methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro, a virazinyl group ,
  • Ki 3—Ceni Group, 5-chloro-2-phenyl, 3-methyl-2-phenyl, 5-methyl-2-phenyl or 4-methoxy-3-phenyl, most preferably a virazinyl group or a 2-phenyl group. Or a 5-methyl-2-phenyl group.
  • the compound (I) or (II) of the present invention can be converted into a corresponding pharmacologically acceptable salt by treating with an acid according to a conventional method.
  • an acid for example, compound (I) or (II) is treated with a corresponding acid for 5 to 30 minutes at room temperature in a solvent (for example, ethers, esters or alcohols, especially ethers), and the precipitated crystals are collected by tt. Or by distilling off the solvent under reduced pressure.
  • a solvent for example, ethers, esters or alcohols, especially ethers
  • Such salts include, for example, hydrofluoride, hydrochloride, hydrobromide, iodide violet, nitric acid Minerates such as salts, perchlorates, sulfates or phosphates: such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate Sulfonates: Carboxylates such as fumarate, succinate, citrate, tartrate, oxalate or maleate; or or amino acid salts such as glutamate or aspartate. It is preferably a mineral salt, especially a hydrochloride.
  • the compound (I) or (II) of the present invention or a pharmacologically acceptable salt thereof may be left in the air or recrystallized to absorb or adsorb water, It may be a sum, and each of them or a mixture thereof is included in the present invention.
  • the compound (I) or (II) of the present invention has an asymmetric carbon violet in the molecule, and there are stereoisomers each having an R configuration or an S configuration. Any mixture in any proportion is encompassed by the present invention.
  • preferred compounds have a specific rotation of (1).
  • preferred compounds are those having the general formula (I), and more preferably, R 'in the general formula (I) is A group having CO--R 3 or a group having the general formula (III), wherein R 1 and R 2 are formed together with the nitrogen atom to which they are bonded, and Is a group having the general formula (III) in which R 1 and R ′ are formed together with the room purple atom to which they are bonded in the general formula (I).
  • preferred compounds are those wherein X is a methylene group.
  • preferred compounds are those wherein m is an integer of 2 to 4, and more preferred are those wherein m is an integer of 2 or 4. is there.
  • preferred compounds include
  • R 3 force C, 1 -C alkyl group, 1 -methylhexyl group, 1 -ethyl benzyl group, 1 -bromobutyl group; cyclopentyl group, cyclohexyl group; c Rogen, -C alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2.2,2-trifluoroethyl, -C * alkoxy, methoxymethyl, ethoxymethyl, methylthio, ethylthio, Phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, hydroxyl group, thiol, amino, acetylamino, carboxy, carboxymethyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, ethoxylcarbonyl, cyano and nitro
  • R 3 force butyl group, isobutyl group, s-butyl group, t-butyl group, 1-ethylpentyl group; cyclobentyl group or cyclohexyl group; fluorine, salt purple,
  • C-Calkyl fluoromethyl, difluoromethyl, trifluoromethyl, 2—fluoroethyl, 2,2—difluoroethyl, 2,2.2—trifluoroethyl, C alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-fluorophenyl
  • a phenyl group which may have 1 to 3 substituents, which may be the same or different and is selected from the group consisting of methylphenyl, 4-methoxyphenyl, cyano and nitrogen; benzyl, fluorobenzyl and Benzyl group, difluorobenzoyl group, dichlorobenzyl group, trifluoromethylbenzyl group, methylbenzyl group, dimethylbenzyl group, trimethylbenzyl group, methoxybenzyl group, cyanobenzyl group, nitrobenzyl group; Cyclohexylamino group; phenylamino group, Flu
  • R 3 force t-butyl group, 1-ethylpentyl group, cyclohexyl group, phenyl group, fluorophenyl group, chlorophenyl group, difluorophenyl group, dichlorophenyl group, trifluoromethylphenyl Group, tolyl group, xylyl group, mesityl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, benzene Zyl group, phenylamino group, 2,4-difluorophenylamino group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, virazinyl group, 3-methylbirazinyl group, 1-methyl-2-y Drillyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 2-furyl group, 3-furyl group, 2-phenyl group, 3-phenyl group, 5-fluoro-2-pheny
  • R 3 is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluoro Phenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 3,4-dichlorophenyl group, p-tolyl group, 3-trifluoromethyl Phenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-pyridyl, virazinyl, 1-methyl-2-indolyl, 4-quinolyl, 2-phenyl Ryl, 2-Chenyl, 3-Chenyl, 5-Cross-2-Cenyl, 3-Methyl-12-Cenyl, 5-Methyl-2-Cenyl, or 4-Methoxy-3-Cenyl A compound
  • R 3 is a phenyl group, a 2,3-difluorophenyl group, a 2,4-difluorophenyl group, a 2,5-difluorophenyl group, a 3,4-dichlorophenyl group, a birazinyl group, or a 2-phenyl group
  • a general formula (I) which is a 3-, 3-phenyl, 5-chloro-2-phenyl, 3-methyl-2-phenyl, 5-methyl-2-phenyl or 4-methoxy-3-phenyl group;
  • R 1 and 2 together with the nitrogen atom to which they are attached, are a 2,4-dioxo-3-thiazolidyl group, a 5-methyl-2,4-dioxo-3-thiazolidyl group, a 5,5-dimethyl-2, 4-Dioxo 3-thiazolidyl group, 5-methyl-5-ethyl-2,4-dioxo 3-thiazolidyl group, 5-ethyl-2,4-dioxo-1-thiazolidyl group, 5,5-Jethyl-2,4-dioxo 3-
  • R 1 and R 2 together with the nitrogen atom to which they are bonded are 2,4-dioxo-3-thiazolidyl groups, 5,5-dimethyl-2,4-dioxo-3-thiazolidyl groups or 5- A compound having the general formula (I), which is isopropyl-1,4-dioxo-3-thiazolidyl group,
  • R 1 and R 2 are, together with the nitrogen atom to which they are attached, a 5.5-dimethyl-2,4-dioxo-3-thiazolidyl group or a 5-isobrovir-12,4 dioxo-3-thiazolidyl group.
  • a compound having the general formula (I) is, together with the nitrogen atom to which they are attached, a 5.5-dimethyl-2,4-dioxo-3-thiazolidyl group or a 5-isobrovir-12,4 dioxo-3-thiazolidyl group.
  • R 6 forces fluoride purple, salts purple, C, - C lambda alkyl, Furuoromechiru, diphenyl Ruoromechiru, preparative Rifuruoromechiru, 2 Furuoroechiru, 2, 2-Jifuruoro Echiru, 2, 2, 2-preparative Rifuruoroechiru one C It may have 1 to 3 substituents selected from the same or different from the group consisting of alkoxy, methoxymethyl, methylthio, phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, cyano and nitro
  • R e is phenyl group, 2-fluorophenyl group, 3-Furuorofe group, 4 one fluorophenyl group, 2. 3-difluorophenyl group, 2, 4-di-fluorophenyl group, 2, 5- Difluorophenyl group, 2,6-difluorophenyl group, 3,5-difluorophenyl group, 3,4-dichlorophenyl group, A compound having the general formula (II), which is a luyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group or a 2-methoxyphenyl group;
  • Representative compounds of the present invention include, for example, the compounds described in the following table, but the present invention is not limited to these compounds.
  • More preferred compounds include 1-6, 1-11, 1-20, 1-23, 1-12
  • Particularly preferred compounds are 1-23, 1 25, 1 50, 1 55, 1-63, 1-92, 1-248, 1-283.1-285, 1-299, 1 -30 2, 1-30 9, 1-343, 1-345, 1-365, 2-27 or 2-34.
  • the most preferred compounds include
  • R ′, R 2 , R 3 , R 6 , X and m have the same meaning as described above
  • R 7 represents a C, — , 8 aralkyl group
  • R e represents R 9 represents a C, -C alkoxycarbonyl group which may be replaced by a trigen or tri-C alkylsilyl
  • R 9 represents a halogen atom
  • Y and Y ' represent the same or different leaving groups. Shown.
  • C 7 —C ⁇ e aralkyl group of R 7 has the same meaning as described above, and examples thereof include a benzyl group, an ⁇ -phenethyl group, a 0-phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, and an ⁇ -phenyl group.
  • Halogen or Application Benefits C of R 8, - at C alkylsilyl may be IB conversion, C -! C alkoxycarbonyl group, for example, main butoxycarbonyl group, Etoki aryloxycarbonyl group, Bro Po alkoxycarbonyl group, Isopurobo Oxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, chloromethoxycarbonyl group, 2,2,2-trichloromouth ethoxycarbonyl group, 2-fluoroborobo Xycarbonyl group, 2-bromo-t-butoxycarbonyl group, 2,2-dibutene-butoxycarbonyl group, triethylsilylmethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 4-triprovirsilyl Butoxycarbonyl group or t-butyldimethylsilylpropoxycarbonyl group And is preferably
  • the halogen atom for R 9 has the same meaning as described above, and is preferably a salt purple atom or an odor purple atom.
  • the leaving group for Y and Y ′ is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue.
  • a halogen atom such as salt purple, odor purple or iodine purple: methanesulfonyl A C, -C alkanesulfonyloxy group such as methoxy, ethanesulfonyloxy, propanesulfonyloxy or butanesulfonyloxy; trifluoromethansulfonyloxy, 2,2,2-trichloroethanesulfonyloxy, 3,3 Halogeno, such as, 3-, 3-bromopropanesulfonyloxy or 4.4,4-trifluorobutanesulfonyloxy; -C alkanesulfonyloxy group; or benzenesulfonyloxy, ⁇ -naphthylsulfonyloxy C,-, such as xy,
  • Arylsulfonyloxy group preferably chlorine, bromine or iodine atom; methanesulfonyloxy group or ethanesulfonyloxy group; trifluoromethanesulfonyloxy group, 2,2,2-trichloro A mouth ethanesulfonyloxy group or a pentafluoroethanesulfonyloxy group; or a benzenesulfonyloxy group, a ⁇ -toluenesulfonyloxy group or a mesitylenesulfonyloxy group, more preferably chlorine or odor. It is a purple or iodine atom.
  • the compound having the general formula (VI) and the compound having the general formula (VIII), which are the starting material compounds of the present invention, are known compounds or can be produced according to known methods.
  • Journal of Medicinal Chemistry, Vol. 13, pp. 5 16 (1970) [J. Med. Chem., 13, 516 (1970) .1, Indian Journal 'Ob' Chemistry. Volume 7, p. 833 (1969) [Indian J. Chem .. 7.833 (1969).], Indian Journal of Ob. Chemistry, Vol. 13, 4 62 (1975) [Indian J. Chem., 13, 462 (1975).]
  • Japanese Patent Application Laid-Open No. 50-58324 Japanese Patent Publication No. 46-33032, etc.
  • Method A is a method for producing compound (I).
  • Step A1 involves reacting a compound having the general formula (V) with a compound having the general formula (VI) in an inert solvent in the presence or absence (preferably in the presence) of a base. Is a step of producing a compound having the general formula (VII).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aliphatic hydrocarbons such as hexane, hebutane, lignin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as methylene chloride, carbonaceous form, carbon tetrachloride purple, dichloroethane, chlorobenzene or dichlorobenzene
  • Ethers such as isopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether
  • amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide
  • Dimethyl sulfoxide or sulfo It can be a sulfoxide such as an orchid, preferably an ether, an amide or a s
  • the base used is, for example, an alkali gold carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal such as sodium carbonate purple, sodium carbonate carbonate or lithium carbonate purple.
  • Bicarbonates Al hydrides such as lithium hydride, water purple sodium hydride or hydride hydride Gold hydrides: Al hydrides such as sodium hydroxide, hydration power or lithium hydroxide Alkali gold I »alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; methyl mercaptan sodium or ethyl mer Merkabutane alkali metals such as sodium butane; triethylamine, tributylamine, diisoprovirethylamine, N— Tyl morpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N.N-getylaniline,
  • Organic amines such as 4-diazabicyclo [2.2.2] octane (DABC 0) or 1,8-diazabicyclo [5.4.0] pendequat 7-ene (DBU): methyllithium, ethyllithium or butyllithium
  • Alkyllithium such as; lithium diisopropylamide or lithium diisopropyl
  • It can be a lithium alkyl amide such as cyclohexyl amide, preferably, alkali gold bicarbonates, alkali metal bicarbonates, alkali gold bihydrides (particularly sodium purple violet).
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually from 120 to 100, preferably from 0 to 50.
  • the reaction time varies depending on the starting compound, reagent, solvent and reaction temperature, but is usually 10 minutes to 12 hours, preferably 30 minutes to 5 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer is washed with water, and then anhydrous magnesium sulfate, etc.
  • the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, chromatography, or salt formation by adding an acid.
  • the step A2 comprises reacting the compound having the general formula (VII) with the compound having the general formula (VIII) in an inert solvent in the presence or absence (preferably in the presence) of a base.
  • an inert solvent in the presence or absence (preferably in the presence) of a base.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • Examples thereof include aliphatic hydrocarbons such as hexane, heptane, rigoin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; Ethers such as virether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, dimethylformamide, Amides such as dimethyl acetate or hexamethyl phosphate triamide; It may be a sulfoxide such as tyl sulfoxide or sulfolane, preferably an ether, an alcohol or an amide, and more
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal such as sodium carbonate purple, sodium carbonate carbonate or lithium hydrogencarbonate.
  • Bicarbonates Al hydrides such as lithium hydride, sodium violet or hydrogen hydride Gold hydrides: Al hydrides such as sodium hydroxide, hydroxyl hydride or lithium hydroxide Alkali metal hydroxides; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; Such as methyl mercaptan natrium or ethyl mercaptan natrium Merkabutane alkali metals; triethylamine, tributylamine, diisoprovirethylamine; N-meth Tyl morpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline,
  • Organic amines such as 4-diazabicyclo [2.2.2] octane (DABC 0) or 1,8-diazabicyclo [5.4.0] pendec 7-ene (DBU); methyllithium, ethyllithium or butyllithium Or lithium alkyl amides such as lithium diisopropyl amide or lithium dicyclohexyl amide; preferably, alkali metal alkoxides or alkali metal hydrides. And more preferably alkaline gold carbonates (particularly sodium carbonate or potassium carbonate).
  • DABC 0 4-diazabicyclo [2.2.2] octane
  • DBU 1,8-diazabicyclo [5.4.0] pendec 7-ene
  • lithium alkyl amides such as lithium diisopropyl amide or lithium dicyclohexyl amide
  • the anti-15 temperature varies depending on the starting compound, reagent, solvent and the like, but is usually from 0 to 150, preferably from 20 to 100 * C.
  • the reaction time varies depending on the starting compound, reagent, solvent and reaction temperature, but is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method. For example, remove any insoluble matter and remove the solvent, or distill off the solvent, or add water to the residue from which the solvent has been distilled off, and add a water-immiscible solvent (eg, benzene, ether). , Ethyl acetate, etc.) to extract the target compound, wash the extracted organic JB with water, dry over anhydrous magnesium triluate, etc., and distill off the solvent to obtain the target compound.
  • a water-immiscible solvent eg, benzene, ether
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation *, chromatography, or salting with an acid.
  • R 1 is a method of producing compound is a group having the formula one COR 3 and (I a).
  • Step B1 is a compound having the general formula (I) obtained by Method A, wherein R 1 and R 2 form a phthalimidyl group together with the nitrogen atom to which they are bonded (lb).
  • R 1 and R 2 form a phthalimidyl group together with the nitrogen atom to which they are bonded (lb).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aliphatic hydrocarbon purples such as hexane, heptane, rigoin or petroleum ether
  • Aromatic hydrocarbons such as benzene, toluene or xylene
  • halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichloromethane, etc .
  • Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether
  • alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol
  • formamide dimethylformamide
  • Do Amides such as dimethylacetamide or hexamethylphosphate triamide
  • the base used can be, for example, hydrazines such as hydrazine or hydrazine hydrate or organic amines such as methylamine, ethylamine or butylamine, preferably hydrazines (especially hydrazine hydrate). Drazine).
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually 0 to 150 ⁇ :, preferably 20 to 100 ⁇ .
  • the reaction time varies depending on the starting compound, reagent, solvent and reaction temperature, but is usually 30 minutes to 24 hours, preferably 1 hour to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method. For example, remove any insoluble matter and remove the solvent, or distill off the solvent, or add water or alkaline water to the residue from which the solvent has been distilled off, and add a water-immiscible agent (eg, benzene). , Methylene chloride, ether, ethyl acetate, etc.) to extract the target compound, wash the extracted organic layer with water, dry over anhydrous magnesium triluate, etc., and distill off the solvent to obtain the target compound.
  • a water-immiscible agent eg, benzene
  • the desired compound obtained can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation, chromatography or salt formation by adding an acid.
  • the solvent used in the step B2a is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include hexane, heptane, ligroin and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene Ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate triamide Class: Or dimethyl sulfoxide Obtained is de or sulfoxides such as sulfolane, preferably a halogenated hydrocarbons such
  • the base used is, for example, an alkali gold carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal such as sodium carbonate purple, sodium carbonate carbonate or lithium carbonate purple.
  • Bicarbonates Al hydrides such as lithium hydride, water purifying sodium or water purifying power hydrides; Al hydrides such as sodium hydroxide, water hydrating power or lithium hydroxide.
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually from 120 to 100, preferably from 0 to 50.
  • the reaction time varies depending on the starting compound, the reagent, the solvent and the reaction temperature, but is usually from 10 minutes to 12 hours, preferably from 30 minutes to 6 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the target compound precipitated in the reaction solution is destroyed, or the solvent is distilled off, water is added to the residue, and a water-immiscible solvent (eg, benzene, methylene chloride, ether, sulfuric acid)
  • a water-immiscible solvent eg, benzene, methylene chloride, ether, sulfuric acid
  • the target compound is extracted by washing the organic layer with water, dried over anhydrous magnesium phosphate or the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation » chromatography or by adding an acid to make a salt.
  • aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride Halogenated hydrocarbon purples, such as methyl, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; ethers, such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, or diethylene glycol dimethyl ether Amides such as formamide, dimethylformamide, dimethylacetamide or hexamethylphosphoric acid; or sulfoxides such as dimethylsulfoxide or sulfolane, preferably halogen.
  • the condensing agent to be used is not particularly limited as long as it is generally used in the art of organic chemistry.
  • dicyclohexylcarbodiimide (DCC) getyl cyanophosphonate (DEPC)
  • DEPC getyl cyanophosphonate
  • 2-pyridyl) disulfide and triphenyl phosphine
  • 2-chloro-1-methylbiridinyl dimethyl or ethyl carboxylate preferably getyl cyanophosphonate.
  • the base used is, for example, an alkaline metal such as sodium carbonate, potassium carbonate or lithium carbonate; an alkaline metal such as sodium carbonate aqueous purple, sodium carbonate aqueous lithium or lithium hydrogen carbonate.
  • Bicarbonates Alkali hydrides such as lithium-purified lithium, sodium-purified sodium or water-purified lithium hydride; Alkali hydrides such as sodium hydroxide, hydroxylated lithium or lithium hydroxide Metal hydroxides; sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide; alkali metal alkoxides; methyl mercaptan tanium or ethyl mercaptan tan Alkali metal such as mercaptan; or triethylamine, tributylamine, diisopropylethylamine, N Organic amines such as methylmorpholine, pyridine, 4- (N.N-dimethylamino) pyridine, N
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually from 120 to 100, preferably from 0 "C to 50" C.
  • the reaction time varies depending on the starting compound, reagent, solvent and reaction temperature, but is usually from 10 minutes to 24 hours, preferably from 30 minutes to 12 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • the target compound precipitated in the reaction solution is removed, or the solvent is distilled off, water is added to the residue, and a water-immiscible solvent (eg, benzene, methylene chloride, ether, acetic acid)
  • a water-immiscible solvent eg, benzene, methylene chloride, ether, acetic acid
  • the target compound is extracted by washing with water, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off to obtain the target compound.
  • the desired target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, re-sedimentation, chromatography or salting with an acid.
  • Method C is a method for producing compound (II).
  • Step C2 comprises reacting a compound having the general formula (XV) with a compound having the general formula (VIII) in the presence or absence (preferably in the presence) of a base in an inert solvent.
  • This is a step of producing a compound having the general formula (II), and is carried out in the same manner as in Step A2.
  • Method D is a method for producing compound (VIII), which is a raw material of Method A.
  • the desired compound obtained in any step can be optically resolved as desired (preferably, the optical resolution in the D1 step).
  • Step D1 comprises reacting a compound having the general formula (XVI) with a compound having the general formula (XVII) in an inert solvent in the presence of a condensing agent (if necessary, in the presence of a base).
  • a step of producing a compound having the general formula (XVIII) is carried out in the same manner as in Step B2b.
  • the compound having the general formula (XVIII) obtained by this step can be obtained by a method used in the field of ordinary organic chemistry, for example,
  • Natural resolution Natural crystallization
  • a method using asymmetric adsorption a method using silica gel column chromatography or high performance liquid chromatography, etc.
  • a resolving reagent for example, tartaric acid, mandelic acid or 10-
  • Optical resolution can be carried out by a method of producing diastereomer with camphorsulfonate, etc., and preferably by silica gel column chromatography.
  • Step D2 is a step of producing a compound having the general formula (XIX) by reacting the compound having the general formula (XVIII) with a reducing agent in an inert solvent.
  • the solvent to be 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, and chloroform.
  • Halogenated carbohydrate purples such as carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene; or ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether. It is possible and preferably ethers (especially tetrahydrofuran).
  • the reducing agent used is not particularly limited as long as it is used in a normal reduction reaction.
  • Examples thereof include sodium borohydride, lithium borohydride, lithium aluminum water violet, and water.
  • Gold such as diisobutylaluminum violet or water-purified aluminum) K hydride, aluminum isopropoxide, diborane or borane-methyl sulfide, preferably borane-methyl sulfide complex You.
  • the reaction temperature varies depending on the starting compound, the solvent, the reducing agent used and the like, but is usually from 20 to 100, preferably from 0 * C to 50.
  • the reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature, and the like, but is usually 12 hours to 120 hours, and preferably 48 hours to 96 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • an acid preferably hydrochloric acid
  • an acid preferably hydrochloric acid
  • the reaction solution After decomposing the reaction mixture, make the reaction solution alkaline, add a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) to extract the target compound, wash the extracted organic layer with water, and then use anhydrous magnesium sulfate or the like.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • the desired compound is obtained by drying and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step D3 comprises reacting a compound having the general formula (XIX) with a compound having the formula (R 0 or R 8 —Y [preferably a compound having the formula (R e ) 0]) in an inert solvent. This is a step of producing a compound having the general formula (XX).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride; Halogenated hydrocarbons such as form, carbon tetrachloride, dichloroethane, cyclobenzene, or dichlorobenzene; or ethers such as ethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, or diethylene glycol dimethyl ether. And preferably ethers (particularly dioxane).
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually from 120 to 100, preferably from 0 to 50.
  • the reaction time varies depending on the starting compound, reagent, solvent, reaction temperature, etc. It is 10 minutes to 12 hours, preferably 1 hour to 3 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • water is added to the reaction solution, if necessary, alkalinized, and then a solvent immiscible with water (for example, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic B Is washed with water, dried over anhydrous magnesium sulfate and the like, and the solvent is distilled off to obtain the desired compound.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step D4 is a step of reacting the compound having the general formula (XX) with a halogenoacetyl halide in an inert solvent in the presence or absence (preferably in the presence) of a base. This is a step of producing a compound having (XXI).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material K to some extent.
  • aromatic hydrocarbon purples such as benzene, toluene and xylene; methylene chloride, and chloroform.
  • Halogenated hydrocarbons such as mouth form, carbon tetrachloride purple, dichloroethane, cyclobenzene or dichlorobenzene: or ethers such as dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether.
  • ethers particularly tetrahydrofuran).
  • the base used is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal bicarbonate such as sodium carbonate purple, sodium carbonate carbonate or lithium hydrogencarbonate; Alkali metal hydroxides such as sodium hydroxide, hydroxide hydroxide or lithium hydroxide; alkalis such as sodium methoxide, sodium ethoxide, potassium t-butoxide or lithium methoxide Metal alkoxides; mercaptan alkali metals such as methyl mercaptan sodium or ethyl mercaptan sodium; or triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholin, Pyridine, 4- (N, N-dimethylamino) Pyridine, N, N-dimethyl Ruanirin, N, N -..
  • halogenoacetyl halide used can be an amine, preferably an organic amine (especially pyridine).
  • examples of the halogenoacetyl halide used are, for example, chloroacetylheptyl chloride, bromoacetyl chloride, eodoacetyl chloride, chloroacetyl bromide.
  • It can be mido, bromoacetyl bromide or acetyl acetyl chloride, preferably chloroacetyl chloride or bromoacetyl chloride, and particularly preferably chloroacetyl chloride.
  • the reaction temperature varies depending on the starting compound, reagent, solvent and the like, but is usually from ⁇ 20 to 100, preferably from 0 to 50.
  • the reaction time varies depending on the starting compound, reagent, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, preferably 10 minutes to 1 hour.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound obtained in this step can be used in the next step without purification.
  • Step D5 is a step of preparing a compound having the general formula (XXI)
  • the solvent used in Step D5a is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include aromatic hydrocarbons such as benzene, toluene and xylene.
  • Water purple methylene chloride, black form, carbon tetrachloride , Halogenated carbohydrate purples such as dichloroethane, cyclobenzene or dichlorobenzene; or ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether. It is possible and preferably ethers, especially tetrahydrofuran.
  • Acids used are, for example, mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, bromoiodic acid, acetic acid, perchloric acid,izic acid or phosphoric acid; methanesulfonic acid, trifluoic acid and the like.
  • Sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or ⁇ —toluenesulfonic acid; or acetic acid, trifluoroacetic acid, fumaric acid, succinic acid, cunic acid, tartaric acid, oxalic acid or maleic acid
  • It can be a carboxylic acid, preferably carboxylic acid (especially trifluoric acid).
  • the reaction temperature varies depending on the starting compound, reagent, solvent and the like, but is usually -200 to 100, preferably 0 * C to 50.
  • the reaction time varies depending on the starting compound, reagent, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, preferably 10 minutes to 2 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the target compound is obtained by distilling off the solvent.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the compound obtained in this step can be used in the next step without purification.
  • the solvent used in Step D5b is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hexane, heptane, ligroin and petroleum ether.
  • Aliphatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride purple, dichloroethane, cyclobenzene or dichlorobenzene Purples: getyl ether, diisopropyl ether, tetrahydrofuran, di Ethers such as oxane, dimethoxetane or diethylene glycol dimethyl ether: alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, dimethylformamide, dimethylacetamide or hexamethylphosphate It can be an terttert
  • the base used is, for example, an alkaline metal such as sodium carbonate, potassium carbonate or lithium carbonate; an alkaline metal such as sodium hydrogen carbonate, a carbonated aqueous purple rim or an aqueous lithium carbonate.
  • Bicarbonates lithium hydride, sodium hydride or lithium hydride.
  • Alkali hydrides sodium hydroxide, sodium hydride, lithium hydride or lithium hydroxide.
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; such as methyl mercaptan sodium or ethyl mercaptan natrium Merkabutane alkaline metals; or triethylamine, tributylamine, diisoprovirethylamine N one-methylmorpholine, pyridine, 4-(N, N-Jimechiruamino) Pyridine, N, N-dimethyl ⁇ diphosphate, N, N-Jechiruanirin, 1. 5 Jiazabishikuro
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent and the like, but is usually from ⁇ 20 to 150, preferably from 0 to 100.
  • the reaction time varies depending on the starting compound, reagent, solvent, reaction temperature and the like, but is usually 5 minutes to 12 hours, preferably 10 minutes to 2 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method.
  • a water-immiscible solvent eg, benzene , Ether, and ethyl diethyl acid
  • the extracted organic layer is washed with water, dried over anhydrous magnesium phosphate and the like, and the solvent is distilled off to obtain the target compound.
  • the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step D6 is a step of producing a compound having the general formula (XXIII) by reacting the compound having the general formula (XXII) with a reducing agent in an inert solvent. Done in
  • step D7 a compound having the general formula (VIII) is produced by contacting the compound having the general formula (XXIII) with a reducing agent in an inert solvent (if necessary, in the presence of ammonium formate) It is a process.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • examples thereof include aliphatic hydrocarbons such as hexane, heptane, rigoin or petroleum ether; Aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, purple tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene: Jetyl ether, diisopro Ethers such as virether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether; alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol; formamide, dimethylformamide Amides such as dimethyl acetate or hexamethyl phosphate triamide: sulfoxides such as
  • the reducing agent used can be, for example, palladium black, palladium carbon, platinum, Raney nickel, preferably palladium charcoal purple.
  • the reaction temperature varies depending on the starting compound, the solvent, the reducing agent used and the like, but is usually from 0 to 150 "C, preferably from 50 to 100" C.
  • Reaction time varies depending on starting compounds, solvent, reducing agent used, reaction temperature, etc. However, it is usually 10 minutes to 12 hours, preferably 30 minutes to 2 hours.
  • the target compound of this step is collected from the reaction mixture according to a conventional method. For example, after completion of the reaction, the catalyst is removed, and then the solvent is distilled off, or the residue obtained by distilling off the solvent is added with water, and then a water-immiscible solvent (for example, benzene, ether, (Ethyl acetate, etc.) to extract the target compound, wash the extracted organic layer with water, dry over anhydrous magnesium sulfate, etc., and evaporate the solvent to obtain the target compound. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • a water-immiscible solvent for example, benzene, ether, (Ethyl acetate, etc.
  • the hexahydrovirazinoquinoline derivative (I) or (II) or a pharmacologically acceptable salt thereof according to the present invention has excellent 5- HT1A receptor action, sedative action against mental stress or hallucination-suppressing action. With low toxicity and side effects (especially drowsiness etc.), anxiety, B disease, hypertension, schizophrenia, sleep disorders, migraine, sexual dysfunction, motion sickness, dizziness or senile dementia peripheral symptoms It is useful as a therapeutic or preventive (particularly therapeutic) for (such as delirium).
  • the abbreviation nd indicates that the cleavage pattern is unknown due to overlap with a solvent or another signal.
  • Example 13 3- [4-1 (3,4-dichlorobenzamide) butyl] -1,2,3,4,4a, 5,6-hexahidraw 1H-Virazino [1,2, a] quinoline Hydrochloride (Exemplary compound number: 1-9 2)
  • K point 15 5-16 0;
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (solvent: 10% ethanol / methylene chloride solution), and an excess of 10 N hydrochloric acid / methanol solution was added. It was left at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to give the desired compound (230 mg, 61%) as colorless needles.
  • the target compound (1.57 g, 84%) was reacted with mid (1.41 g) and lithium carbonate (0.66 g) in the same manner as in Example 1 (a), followed by post-treatment. ).
  • the target compound (1.21 g, 84 %).
  • Specific rotation (. [Shed] 24): + 8. 2 ° (. C 1 0 0. E t OH); IR spectrum ( ⁇ ⁇ ⁇ ) ⁇ ⁇ , c m- ': 3 2 6 9 . 2 9 3 1, 2 8 5 9
  • (+) 1-3-(2-aminoethyl) 1, 2,3,4,4a, 5,6-hexahydro 1H-birazino [1,2, a] quinoline (0.25 g ), 3-thenoyl acid (0.15 g), getyl cyanophosphonate (0.18 ml) and triethylamine (0.16 ml) were reacted in the same manner as in Example 31 (a). This gave the desired compound (0.27 g, 73%).

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Abstract

Dérivés d'hexahydropyrazinoquinoline de la formule générale (I), présentant d'excellents effets d'agoniste du récepteur de 5-HT1A, et par conséquent utiles en tant que préventif ou remède contre l'anxiété, la dépression ou des symptomes associés à la démence sénile. Dans ladite formule, R1 représente -CO-R3; R2 représente hydrogène; R3 représente alkyle, cycloalkyle, aryle falcutativement substitué, aralkyle facultativement substitué, cycloalkylamino, arylamino facultativement substitué ou un hétérocycle facultativement substitué; ou R1 et R2 forment ensemble avec l'atome d'azote, auquel ils sont liés, 2,4-dioxothiazolidin-3-yl ou phtalimidyle; X représente -CH¿2?- ou -O-; et m représente un nombre entier compris entre 2 et 6.
PCT/JP1996/000194 1995-02-03 1996-02-01 Derives d'hexahydropyrazinoquinoline WO1996023789A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997040015A1 (fr) * 1996-04-23 1997-10-30 Neurogen Corporation Aminoalkylcarboxamides tricycliques, nouveaux ligands specifiques a des sous-types de recepteurs de la dopamine d¿3?
WO2000035922A1 (fr) * 1998-12-17 2000-06-22 American Home Products Corporation Derives de 2,3,4,4a-tetrahydro-1h-pyrazino(1,2-a)quinoxalin-5(6h)one utilises en tant qu'agonistes de 5ht2c
US6231833B1 (en) 1999-08-05 2001-05-15 Pfizer Inc 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine derivatives as ligands for serotonin receptors
WO2001090069A1 (fr) * 2000-05-24 2001-11-29 Centre National De La Recherche Scientifique (Cnrs) Composes possedant une activite calcimimetique
US6372745B1 (en) 1999-12-06 2002-04-16 American Home Products Corporation 2,3,4,4A-tetrahydro-1H-pyrazino[1,2-A]quinoxalin-5(6H)one derivatives
US6476032B2 (en) 1998-12-17 2002-11-05 Wyeth 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)one derivatives
WO2002100350A2 (fr) * 2001-06-13 2002-12-19 The Regents Of University Of Michigan Ligands des recepteurs de dopamine et procedes therapeutiques correspondants
CN105418605A (zh) * 2015-11-23 2016-03-23 东南大学 一种改进的含氮三环类多巴胺d3受体配体的制备方法
CN113381041A (zh) * 2021-06-29 2021-09-10 清华四川能源互联网研究院 一种电极支撑型固体氧化物燃料电池及其制备方法
WO2022223022A1 (fr) * 2021-04-23 2022-10-27 四川海思科制药有限公司 Dérivé hétérocyclique à cycles fusionnés et son application médicale

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JPS5283397A (en) * 1975-12-30 1977-07-12 Erba Carlo Spa 1*44benzoxazine and 1*44benzothiazine cyclic derivatives process for preparing same and medical composition having antiidepression activity containing same

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7220753B2 (en) 1994-09-30 2007-05-22 Pfizer Inc. 2,7-substituted octahydro-1H-pyrido[1,2-a]pyrazine derivatives as ligands for serotonin receptors
WO1997040015A1 (fr) * 1996-04-23 1997-10-30 Neurogen Corporation Aminoalkylcarboxamides tricycliques, nouveaux ligands specifiques a des sous-types de recepteurs de la dopamine d¿3?
US6706714B2 (en) 1998-12-17 2004-03-16 Wyeth Corp 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)one derivatives
WO2000035922A1 (fr) * 1998-12-17 2000-06-22 American Home Products Corporation Derives de 2,3,4,4a-tetrahydro-1h-pyrazino(1,2-a)quinoxalin-5(6h)one utilises en tant qu'agonistes de 5ht2c
US6476032B2 (en) 1998-12-17 2002-11-05 Wyeth 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)one derivatives
US7098338B2 (en) 1998-12-17 2006-08-29 Wyeth 2,3,4,4a-tetrahydro-1H-pyrazino(1,2-a) quinoxalin-5(6H)one derivatives
US6231833B1 (en) 1999-08-05 2001-05-15 Pfizer Inc 2,7-substituted octahydro-1H-pyrido[1,2-A]pyrazine derivatives as ligands for serotonin receptors
US6372745B1 (en) 1999-12-06 2002-04-16 American Home Products Corporation 2,3,4,4A-tetrahydro-1H-pyrazino[1,2-A]quinoxalin-5(6H)one derivatives
FR2809396A1 (fr) * 2000-05-24 2001-11-30 Centre Nat Rech Scient Nouvelles molecules possedant une activite calcimimetique et leur mode de preparation
US7084167B2 (en) 2000-05-24 2006-08-01 Centre National De La Rechereche Scientifique (Cnrs) Calcium receptor active molecules and method for preparing same
WO2001090069A1 (fr) * 2000-05-24 2001-11-29 Centre National De La Recherche Scientifique (Cnrs) Composes possedant une activite calcimimetique
WO2002100350A3 (fr) * 2001-06-13 2003-05-22 Univ Michigan Ligands des recepteurs de dopamine et procedes therapeutiques correspondants
WO2002100350A2 (fr) * 2001-06-13 2002-12-19 The Regents Of University Of Michigan Ligands des recepteurs de dopamine et procedes therapeutiques correspondants
CN105418605A (zh) * 2015-11-23 2016-03-23 东南大学 一种改进的含氮三环类多巴胺d3受体配体的制备方法
WO2022223022A1 (fr) * 2021-04-23 2022-10-27 四川海思科制药有限公司 Dérivé hétérocyclique à cycles fusionnés et son application médicale
CN113381041A (zh) * 2021-06-29 2021-09-10 清华四川能源互联网研究院 一种电极支撑型固体氧化物燃料电池及其制备方法

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