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WO1996020191A1 - Derives d'indole - Google Patents

Derives d'indole Download PDF

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Publication number
WO1996020191A1
WO1996020191A1 PCT/JP1995/002709 JP9502709W WO9620191A1 WO 1996020191 A1 WO1996020191 A1 WO 1996020191A1 JP 9502709 W JP9502709 W JP 9502709W WO 9620191 A1 WO9620191 A1 WO 9620191A1
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WO
WIPO (PCT)
Prior art keywords
group
methyl
indole
quinolin
methylamine
Prior art date
Application number
PCT/JP1995/002709
Other languages
English (en)
Japanese (ja)
Inventor
Shunji Naruto
Kazuo Koyama
Yasushi Ueda
Shinji Marumoto
Keiichi Matsuda
Jun Harada
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 AU43552/96A priority Critical patent/AU4355296A/en
Publication of WO1996020191A1 publication Critical patent/WO1996020191A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a nerve growth factor (NGF), which comprises an indole derivative and an indole having an active ingredient for promoting the production or secretion of an nerve growth factor (NGF). It relates to a production promoter or a secretagogue.
  • NGF nerve growth factor
  • NGF neurotrophic factor
  • catechol analogs such as adrenaline and noradrenaline and similar tecole compounds also have an effect of promoting the production of NGF, but at the same time, these compounds have side effects. (Especially neuroexcitation).
  • W092-077829 includes indole derivatives, for example, compounds ⁇ , ⁇ , and C, as therapeutic or therapeutic agents for improving hyperglycemia, hyperinsulinemia, obesity, and hyperlipidemia. It is described as being useful as a prophylactic.
  • the compounds described in Production Examples 1, 2, 3 and 4 described below are the chemical 'Abstract' Registry 'number (C hem.A bsts., Registry No.) are 5 35 5-42-0, 53 79-9 4-2. 1 6 08 7-95-9.5 5 7 9-88-4 respectively. Is given Although it is a known compound, the NGF production or secretagogue ffl of these known compounds is not known.
  • Me and Bn represent a methyl group and a benzyl group, respectively.
  • the inventor of the present invention has conducted extensive research on the synthesis of indole derivatives and their pharmacological actions over many years with the aim of developing an excellent drug for treating Alzheimer's dementia, and as a result, an indole derivative having a specific structure has been obtained. It has a strong NGF production or secretion promoting effect, and has a therapeutic or preventive (particularly therapeutic) effect on neurological diseases such as Alzheimer's dementia and cerebral ischemia pathological models (particularly Alzheimer's dementia). And completed the present invention.
  • the present invention relates to an indole derivative having an excellent NGF production promoting action or secretion promoting action, a process for producing the same, and an NGF production promoting agent or secretion promoting action comprising an indole as an active ingredient.
  • an enhancer Provide an enhancer.
  • the indole bath of the present invention has the general formula ( ⁇ )
  • R ′ and R 2 are the same or different and each represent a hydrogen atom or a d-C ⁇ alkyl group
  • R 3 represents a hydrogen atom, a halogen atom, a C, -C alkyl group, a halogeno C
  • -Re represents a C alkyl group, -C alkoxy group or C 2 -C alkoxy carbonyl group, and represents halogen, C, -C 6 alkyl, nordogeno C [-
  • the active ingredient of the NGF production / secretion enhancer of the present invention is an indole having the general formula (II).
  • R ′, R 2 and R have the same meanings as described above, and R s is a C 1 -C alkyl group and C 3 —C 3 .
  • a 5- or 6-membered heterocyclic methyl group which may have one or two different S substituents and may be fused to a benzene ring (the double purple ring is an oxygen, nitrogen or sulfur atom
  • R 7 is a hydrogen atom, which is an unsaturated ⁇ or saturated ring containing one or two hetero atoms selected from the group consisting of
  • CC alkyl group, Nono Rogeno C, - C alkyl group, C 2 - C alkenyl le group, C 2 - have a C alkynyl group, or below the same from Substituent group A or different 1 to 2 selected substituents May represent a C 7 —C ⁇ e aralkyl group, or may be fused to a benzene ring together with the nitrogen atom to which R 6 and R 7 are attached in combination.
  • Substituent group A is halogen, -C alkyl, halogeno, 1 C alkyl, -C alkoxy, CC alkoxycarbonyl, 1 to
  • C e -C aryl which may have three substituents (the substituent is fluorine, chlorine, methyl or methoxy), and a five- to six-membered double-purple ring (the double-purple ring)
  • the ring is unsaturated with one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • a ring or a saturated ring may have three substituents (the substituent is fluorine, chlorine, methyl or methoxy), and a five- to six-membered double-purple ring (the double-purple ring)
  • the ring is unsaturated with one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • a ring or a saturated ring may have three substituents (the substituent is fluorine, chlorine, methyl or methoxy), and a five- to six-membered double-purple ring (the double-purple ring)
  • the ring is unsatur
  • the substituents contained in R ′, R 2 , R 3 , R 4 , R 5 , R s , R 7 and the ⁇ C, -C 6 alkyl group '' in the definition of the substituent group A include, for example, Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, Hexyl, 4-methylbentyl, 3-methylbentyl, 2-methylpentyl, 1-methylpentyl, 3.3-dimethylbutyl, 2.2-dimethylbutyl, 1,1-dimethylbutyl, A straight or branched alkyl group having 1 to 6 carbon atoms such as 1,2-dimethylbutyl, 1,3-
  • R 5 or R 7 is preferably a C 1, -C alkyl group, more preferably an ethyl group, a bromo group, an isopropyl group, an isopropyl group or a t-butyl group.
  • the substituents contained in R 3 and R 4 , R 5 , R 7, and the “hacogeno C, -C 6 alkyl group” in the definition of the substituent group A include the above “halogen atom J is the above rc-C 6 "Alkyl group” means, 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 port.
  • Bil group 3,3,3-Trifluorov mouth building group, 41-Fluorobutyl group, Dichloromethyl group, Trichloromethyl group, 2-Chloroethyl group, 2.2.2-Trichloroethyl group, Dibromomethyl Group, 2-bromoethyl group, 2,2-dibromoethyl group, 2-bromobutyl group, 2-iodo-t-butyl group, 5-fluorobentyl group or (4) The substituent group contained in H 1.
  • ⁇ may be a cyclohexyl group
  • the substituent group H is preferably a trifluormethyl group, a 2.2.2-trifluorethyl group, It is a 3-fluoro-substituted bil group or a 3.3.3-trifluoro-substituted bil group, and more preferably a trifluoromethyl group.
  • R or R 7 is preferably a trifluoromethyl group, a 2.2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 3-fluorobutyl building group, or a 3.3,3-trimethyl group.
  • the “-C alkoxy group” refers to a group in which the above “C-C alkyl group” is bonded to an oxygen atom, and is, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group.
  • the ⁇ C-C alkoxycarbonyl group '' in the definition of the substituents and the substituent group A contained in R 3 and R 4 represents a group in which the -C alkoxy group is bonded to a carbonyl group, for example, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, Isobenoxycarbonyl group, 2-methylbutoxycarbonyl group, neopentoxycarbonyl group, hexyloxy Carbonyl ⁇ , 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylbenzyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2.2-dimethylbutoxycarbonyl, 1.1-dimethylbuty It may be a toxicoxycarbonyl group, a toxicoxycarbony
  • C 3 —C [.cycloalkyl group” in the definition of R 6 means, for example, a cyclobutyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a norbornyl group or an adamantyl group And may be a 3- to 10-membered saturated cyclic hydrocarbon group which may be condensed, preferably a cyclobentyl group, a cyclohexyl group or an adamantyl group, and particularly preferably an adamantyl group.
  • the “C 2 -C alkenyl group” in the definition of R 5 and R 7 includes, for example, vinyl group, 1-propenyl group, aryl group, 1-methyl-1-proenyl group, 1-methyl-2-butanol group Benenyl group, 2-methyl-1-propenyl group, isopropenyl group, arenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-benthenyl group, isobrenyl group, 5-hexenyl Or a straight-chain or branched alkenyl group having 2 to 6 carbon atoms having 1 to 2 double bonds such as a 1,4-hexagenenyl group, preferably a vinyl group, A benzyl group, an aryl group, a 1-methylenyl 1-propenyl group, an isobutenyl group, a 2-butenyl group or a 3-butenyl group, and more preferably an aryl group, an
  • the “C 2 -C 6 alkynyl group” in the definition of R 5 and R 7 includes, for example, an ethynyl group, a 1-propyl group, a propargyl group, a 1-methyl-2-propyl group, a 2-methyl-2-brovinyl group, 2-Ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 3 It may be a straight-chain or branched alkynyl group having 2 to 6 carbon atoms such as a butynyl group, a 2-benthynyl group, a 5-hexynyl group or a 2-methyl-4-pentynyl group, preferably an ethynyl group. And a propargyl group, a 2-butynyl group or a 3-butynyl group, and more preferably a bropargyl group.
  • the substituent contained in R 4 and the C s —C, aryl group which may have 1 to 3 a substituents in the definition of the S substituent group A (the substituent may be fluorine, chlorine, ) Is defined as the same or different from the group consisting of fluorine, chlorine, methyl and methoxy, and may have 1 to 3 carbon atoms which may have 1 to 3 S-substituents.
  • a phenyl group which may have 1 or 2 substituents selected from the same or different, more preferably a phenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, 2, 4 —A dichlorophenyl group, a 4-methylphenyl group or a 4-methoxyphenyl group, particularly preferably a phenyl group.
  • Benzyl fluorobenzyl, cyclobenzyl, dichlorobenzyl, bromobenzyl, methylbenzyl, trimethylbenzyl, trifluoromethylbenzyl, methoxybenzyl, methoxycarbonylbenzyl, biphenyl Methyl group, pyridylbenzyl group, naphthylmethyl group, chloronaphthylmethyl group, indenylmethyl group, phenanthrenylmethyl group, methoxycarbonylphenanthrenyl Butyl group, Ann Bok Rasenirumechiru group, preparative Rifuruoroan Bok racemate two Rumechi group, Jifuenirumechiru group, preparative rutile group, dimethyl Bok alkoxy preparative rutile group, phenethyl group , Fluorophenethyl, cyclophenethyl, methylphenethyl, trifluoromethylphenethyl, meth
  • a benzyl group or a 2-phenethyl group which may have 1 to 3 substituents selected from the same or different, more preferably a benzyl group, a 3-fluorobenzyl group, a 4-fluorobenzyl group, —Black mouth benzyl Group, 2.4-dichlorobenzyl group, 4-bromobenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2,4,6-trimethylbenzyl group, 3-methoxybenzyl group, 4- Methoxybenzyl, 2-phenethyl, 3-fluoro-2-phenethyl, 4-fluoro-2-phenethyl, 3-chloro-2-phenethyl, 4-chloro-2-phenethyl, 4-methyl-2-phenethyl or 4-methoxy 2-phenethyl group, and even more preferably benzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 3-chlorobenzyl group, 41
  • the term “5- to 6-membered heterocyclic group” in the definition of the substituent, R 6 and the substituent group A includes 1 to 2 selected from the group consisting of oxygen, nitrogen and sulfur atoms.
  • the term "isoxazolyl group, benzoisoxazolyl group, thiazolyl group, benzothiazolyl group or quinolyl group which may have a g-substituted group" in the definition of R 4 means, for example, Isoxazole-5-yl group, 3-phenylisosoxazole-5-yl group, 5-methyl-3-phenyl-2-soxazole-4-yl group, 3,5-dimethylisoxazole-4-yl group, benzoisosoxazolu-3 —Yl group, thiazo-1-yl 4-yl group, 2,4-dimethylthiazo-1-yl 5-yl group, 2-bromothiazo-1-yl 4-yl group, 2-pyridine-13 —ylthiazole-4-yl group, benzothiazol — 2 —yl group, quinoline-1 2 —yl group, 6—cycloquinoline-1 2 —yl group, 8
  • a quinolyl group which may have two substituents, more preferably a g-substituent group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy and phenyl;
  • a quinolin-12-yl group, a quinolin-13-yl group or a quinolin-14-yl group which may have 1 or 2 substituents and which are the same or different from Particularly preferred are quinolin-12-yl, 6-chloroquinolin-2-yl, 8-trifluoromethylquinolin-12-yl and quinolin-13 -Yl group, 6-fluoroquinoline 1 3-yl group, 6 —cloquinoline 1-3-yl group, 5.7—dichroquinoline-3-yl group, 7-methylquinoline-3-yl group, 6,7—dimethylquinoline-3-yl group, 7 — Trifluoromethylquinolin-3-yl, 6, 7 —Dimethoxyquinolin
  • a 5- or 6-membered heterocyclic ring which may have a substituent selected from 1 to 2 identical or different from the S-substituent group A and may be fused to a benzene ring
  • the “methyl group” is a group in which the “5- or 6-membered heterocyclic group” which may have one or two substituents is bonded to a methyl group, or A 5- or 6-membered heterocyclic group fused to a benzene ring, which is bonded to a methyl group; for example, it may have one or two such substituents Good, furylmethyl group, pyrrolylmethyl group, chenylmethyl group, imidazolylmethyl group, pyrazolylmethyl group, thiazolylmethyl group, isothiazolylmethyl group, oxazolylmethyl group, isoxazolylmethyl group, pyridylmethyl group, virazinylmethyl group, pyridylmethyl group Mi Din
  • Chlorine, bromine, C, -C. Al'alkyl, trifluoromethyl, 2,2,2—trifluorethyl Is the same or different from the substituent group consisting of, 3-fluorobutyl building block, 3.3.3-trifluorov pill, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, fuunyl and pyridyl 1 to 2 chenylmethyl group, indolylmethyl group which may have 2 substituents , Lee Seo old Kisazorirumechiru group, benzoyl Soo hexa benzotriazolyl methyl group, a thiazolylmethyl group, benzothiazolyl methyl or keno Rirumechiru group, and more preferably, fluorine, salts purple, bromine, C, one C 4 alkyl, Trifluoromethyl, 2,2,2—Trifluoroethyl, 3—Fluorov mouth building, 3,3,3—Tri
  • a quinolylmethyl group which may be the same or different, and more preferably one or more selected from the same or different S substituent groups consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy and phenyl
  • a quinolin-12-methyl group, a quinolin-3-ylmethyl group or a quinolin-4-ylmethyl group which may have two substituents, and particularly preferably quinoline -2 -ylmethyl group, 6-chloroquinoline-2 -ylmethyl group, 8 -trifluoromethylquinoline- 1-2-methyl group, quinolin-1-3 -methylmethyl group, 6-fluoroquinoline 3-ylmethyl group, 6-chloroquinolin-3-ylmethyl group, 5.7-dichroquinoline-3-ylmethyl group, 7-methylquinolin-13-ylmethyl group, 6.7-dimethylquinolyl group Nichi 3 Methyl group, 7-trifluoromethylquinoline-1-ylmethyl
  • R 6 and R 7 in combination with R 6 , together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic group which may be fused to a benzene ring (the A heterocyclic group may contain, in addition to the nitrogen atom to which R 6 and R 7 are attached, one more oxygen, nitrogen or sulfur atom).
  • 1-vinylidinyl Group 1-pyrrolinyl group, 1-imidazolidinyl group, 1-imidazolinyl group, 2-birazolidinyl group, 3-birazolin-2-yl group, biberidino group, 1-piperazinyl group, morpholino group, 3-benzothiazolyl group , 2-benzoisoxazolyl group, 1-indolinyl group, 2-isoindolinyl group or 1,2,3.4-tetrahydroisoquinoline-12-yl group, preferably 1-pyrrolidinyl group , Biberidino group, mole Reno group or 1, 2, 3, 4 Tetorahi Doroi Sokino Li down one 2 - I le group.
  • the compound (I) or (II) of the present invention can be converted into a salt according to a conventional method.
  • the compound (I) or (II) is treated with a corresponding acid in a solvent (for example, ethers, esters or alcohols, particularly ethers) at room temperature for 5 minutes to 30 minutes, and the crystal is deposited.
  • a solvent for example, ethers, esters or alcohols, particularly ethers
  • Such salts include, for example, mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate; methanesulfone Sulphonates such as sulphate, trifluorosulphonate, ethanesulphonate, benzenesulphonate or p-toluenesulphonate: fumarate, succinate, citrate, tartaric acid Salt, carboxylate such as oxalate or maleate: or amino acid salt such as glutamate or aspartate, preferably mineral acid salt (especially hydrochloride).
  • mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate or phosphate
  • methanesulfone Sulphonates such as sulphate, trifluorosulphonate, ethanesulphonate, benzen
  • the compound (I) or (II) of the present invention or their tfi may have an asymmetric carbon in the molecule, and each may have an R-coordination or S-coordination stereoisomer.
  • the compound (I) or (II) or a salt thereof of the present invention absorbs water, becomes adsorbed water, or becomes a hydrate when left in the air or recrystallized.
  • Compound salts containing such water may be included in the present invention.
  • preferred compounds include
  • R is a hydrogen atom or a C, -C alkyl group
  • R 'force A compound that is a hydrogen atom or a methyl group
  • R lambda force a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, C, - C alkyl group, preparative Rifuruoromechiru group, C, one alkoxy group, compounds menu Tokishikarubo alkenyl group or an ethoxycarbonyl group,
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group
  • R 4 force fluorine, chlorine, bromine, C, - C * alkyl, preparative Rifuruoromechiru, 2, 2, 2-preparative Rifuruoroechiru, 3
  • Furuorobu port buildings 3, 3, 3-Bok riff Ruorobu opening pill Methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, phenyl and pyridyl, which may have 1 to 2 substituents, which may be the same or different from each other, isoxazolyl group, benzoiso Compounds that are oxazolyl, thiazolyl, benzothiazolyl or quinolyl;
  • R 4 is fluorine, chlorine, bromine, C, - C * alkyl, preparative Rifuruoromechiru, 2, 2, 2-preparative Rifuruoroechiru, 3 Furuorobu port buildings, 3, 3, 3-Bok riff Ruorobu port pills, Having one or two substituents which are the same or different from the substituent group consisting of methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, phenyl, 3-pyridyl and 4-pyridyl; Compounds that are good quinolyl groups,
  • R 4 force It may have one or two substituents selected from the same or different from the substituent group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy and phenyl.
  • a compound that is a quinolyl group
  • R 4 has one or two substituents selected from the same or different from the substituent group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy and phenyl.
  • R 5 is a hydrogen atom, a C, -C alkyl group, a trifluoromethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 3_fluoroborovir group, a 3,3,3 —Trifluorov mouth building group, chloromethyl group, 2,2.2—Trichloro mouth ethyl group, aryl group, isoprobenyl group, 2-butenyl group, bromopargyl group, 2-butynyl group or 3-butynyl A compound that is a group,
  • R 5 is methyl group, Echiru group, Purobiru group, Lee Soburobiru group, butyl group, i Sobuchiru group, s- butyl, t one-butyl group, 2, 2-Jifuruoroechiru group> 2, 2.2 — Trifluoroethyl, 3-fluoropropyl pill, 3,3.3—trifluorov bil, aryl or propargyl,
  • R 5 is an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a t-butyl group or a 2,2.2-trifluoroethyl group;
  • preferred compounds include:
  • R 1 is a hydrogen atom or a C 1, C 4 alkyl group
  • R 2 is a hydrogen atom or a C, -C.alkyl group
  • R 2 force represent hydrogen atom or a methyl group
  • R 3 force A compound that is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C, —C 4 alkyl group, a trifluoromethyl group, a C 4 alkoxy group, a methoxycarbonyl group or an ethoxycarbonyl group.
  • R 3 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group
  • RS is the same or different from the group consisting of methyl group or ethyl group: cyclobentyl group, cyclohexyl group or agmantyl group; fluorine, chlorine, bromine, methyl, ethyl, methoxy and ethoxy.
  • a benzyl group or a 2-phenethyl group which may have 1 to 3 substituents: a pyrrolyl group, a pyridyl group or a virazinyl group
  • R 6 force adamantyl group, benzyl group, 3-fluorobenzyl group, 4-phenyl Benzoyl radical, 3-benzylbenzene, 4-chlorobenzene, 4-bromobenzyl, 3-methylbenzyl, 4-methoxybenzyl, 2-phenethyl, 3-fluoro 2-phenethyl group, 4-fluoro-2-phenyl group, 3-pyridyl group or 4-pyridyl group: or fluorine, chlorine, bromine, C, -C alkyl, trifluoromethyl, 2,2.
  • Trifluoroethyl 3 — Fluorovrovir, 3.3, 3 — Trifluorov mouth building blocks, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, phenyl and pyridyl
  • R 6 is fluorine, chlorine, bromine, C, -C alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3-fluorov mouth building, 3,3.3-trifluorofurov mouth building, Having one or two substituents selected from the same or different from the substituent group consisting of toxic, ethoxy, methoxycarbonyl, ethoxycarbonyl, phenyl, 3-pyridyl and 4-pyridyl A compound that is a good quinolylmethyl group,
  • (11) RS force Even if it has one or two substituents selected from the same or different substituents from the substituent group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy and phenyl.
  • R 6 is, keno re down one 2-Irumechiru group, 6- black port Kino Li down one 2-I methyl group, 8-preparative Riffle O b methylquinoxaline-Li emissions - 2 Irumechiru group, keno Li 3-ylmethyl group, 6-fluoroquinoline-3-ylmethyl group, 6-chloroquinolin-3-ylmethyl group, 5,7-cycloquinoline-3-ylmethyl group, 7-methyl Tyrquinoline-1-3-ylmethyl S, 6.7—Dimethylquinoline-1-3-ylmethyl group, 7—Trifluoromethylquinoline-1-3-ylmethyl group, 6,7 — Dimethoxyquinolin-1-ylmethyl group, quinolin-4-ylmethyl group, 6-chloroquinolin-14-ylmethyl group, 7-ethylquinolin-1-ylmethyl group or 5-methoxyquinoline A compound which is one 4-ylmethyl group,
  • R 7 force a hydrogen atom, C, - C alkyl group, Application Benefits Furuoromechiru group, 2, 2-Jifuruoroechiru group, 2, 2.2 - Application Benefits Furuoroechiru group, 3 full silo Burobiru group, 3.3,3-Trifluorobutyl chloro group, chloromethyl group, 2.2,2-Trichloroethyl group, aryl group, isobrobenyl group, 2-butenyl group, propargyl group, 2-butynyl A compound which is a group, 3-butynyl group or benzyl group,
  • R 7 is a methyl group, an ethyl group, a propyl group, an isobrovir group, a butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a 2.2-difluoroethyl group, 2.2.2. -Compounds that are trifluorethyl group, 3-fluorov mouth building group, 3,3,3-trifluorov mouth building group, aryl group, provalgyl group or benzyl group
  • R 7 is an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a t-butyl group or a 2,2.2-trifluoroethyl group,
  • R 6 and R 7 cooperate together with the nitrogen atom to which they are attached to a 1-vinylidinyl group, a biperidino group, a morpholino group or a 1,2,3,4-tetrahedral A compound that is a di-soquinolin-1-yl group,
  • Representative compounds of the present invention include, for example, the compounds listed in the following table; the present invention is not limited to these compounds.
  • Preferred compounds for the indole derivative having the general formula (I) of the present invention include, for example, 118, 119, 111, 110, 1-111, 1-112, 1-116, 1 1 1 7 1 1 1 8 1 1 1 9 1 1 2 0 1 1 2 1 1 1 2 2 1 1 2 3 1 1 24 1
  • More preferred compounds are> 1-1 2 6 1 1 2 7-1 2 8. 1 1 3
  • Particularly preferred compounds include
  • Suitable compounds for the indole having the general formula (II), which is an active ingredient of the nerve growth factor production promoter or secretion promoter of the present invention include 118, 119, 110, 1-1 1, 1 1 1 2, 1 1 16, 1 1 1 7, 1-1 8, 1-1 9, 1 1 2 0, 1-2 1, 1 1 2 2, 1 1 2 3, 1-124, 1-132, 1-133, 1-34, 1-135, 1-141, 1-143, 1-144, 1-145, 1-46, 1-49, 1-50, 1-51, 1-51, 1-52, 1-53, 1-63, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70 , 1 1 7 3, 1 1 84, 1 1 85, 1 1 86, 1-87, 1-88, 1-89, 1-90, 1-92, 1-94,
  • Even more preferred compounds include 1-126, 1-165-166.1- 1 6 7. 1-1 6 8. 1-1 7 1 .1-1 7 3.1-1 7 5> 1-1 76.1-
  • Particularly preferred compounds include
  • R ′, R 2 , R 3 , R 4 , R 6 and R 7 have the same meanings as those described above, and R 6 , from the aforementioned RS, has R s in combination with R 7.
  • R 7 is a hydrogen atom, C [C 1 -C s alkyl group, halogeno C, -C 5 alkyl group, C 2 -C alkenyl group, C 2 -C alkynyl group, or 1 or 2 substituents which are the same as or different from the above-mentioned substituent A.
  • C 6 have a group - a C Ariru group from R 7 b the foregoing R 7, together with the nitrogen atom to which and R 7 are hydrogen atoms are bonded them jointly with R s
  • R 7 has the same meaning as that except for those forming a 5- or 6-membered heterocyclic group which may be fused to benzene.
  • R 7 Those from the foregoing R 7, except those that form a heterocyclic group of jointly fusion also may 5- to 6-membered ring to a benzene ring together with the nitrogen atom to which they are attached R 7 is A And X is a leaving group.
  • the compound having the general formula (I) Manufacturing methods are included.
  • R 7 is, for example, a hydrogen atom; methyl, ethyl, propyl> isopropyl, butyl, isobutyl.
  • the leaving group for X is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue.
  • a halogen atom such as chlorine, bromine or iodine: methanesulfonyloxy, ethanesulfonylo C, -C, such as xy, propanesulfonyloxy or butanesulfonyloxy; alkanesulfonyloxy group: trifluorometansulfonyloxy, 2,2,2-trichloroethanesulfonyloxy, 3,3,3— Tribromobromosulfonyloxy or 4.4.4-trifluorobutanesul , Such as honyloxy, no, logeno C, -C, alkane sulfonyloxy: or benzenesulfonyloxy, ⁇ -naphthylsulfonyloxy, ii-naphthylsulf
  • the compounds (III), (V), (XVII) and (XXI), which are starting material compounds of the present invention, are known compounds or can be prepared according to known methods.
  • Method ⁇ ⁇ is a method for producing compound (II).
  • Step A1 comprises reacting a compound having the general formula (III) with formaldehyde and a compound having the general formula (IV) in an inert solvent under the conditions of a Mannich reaction to obtain a compound of the general formula (II) )).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene: methylene chloride
  • Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene glycol dimethyl ether.
  • Alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol
  • fatty acids such as himenoic acid or acetic acid: or water, preferably aromatic Hydrocarbons (especially benzene or toluene), c Hydrogenated hydrocarbons (especially methylene chloride), ethers (especially tetrahydrofuran).
  • aromatic Hydrocarbons especially benzene or toluene
  • c Hydrogenated hydrocarbons especially methylene chloride
  • ethers especially tetrahydrofuran
  • Ethanol especially methanol, ethanol is blobanol
  • fatty acids especially acetic acid
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 30 ° C. to 50 ° C., preferably from 10 ° C. to 30 ° C.
  • the reaction time varies depending on the starting compound, the reagent, the reaction temperature and the type of the solvent used, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 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, add water to the reaction solution, 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, etc. Then, the target compound is obtained by distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • Method B is a method for separately producing compound (IIa) in which R 6 is R 6 and R 7 is R 7 in compound (II).
  • step B1 a compound having the general formula (V) and a compound having the general formula (VI) are
  • the condensing agent used in the step B1a is not particularly limited as long as it is generally used in the art of synthetic organic chemistry. Examples thereof include dicyclohexacarbimide and getylphosphorocyanide. Can be date (DEPC;), pyridine-12-thione and triphenylphosphine or ethyl chlorocarbonate.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene: methylene chloride, chloroform Halogenated hydrocarbons such as oral form, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene: or, getyl ether. Diisopropyl ether, tetrahydrofuran, dioki.
  • ether such as sun, dimethyloxetane or diethylene glycol dimethyl ether, preferably aromatic hydrocarbons (especially benzene or toluene)-halogenated hydrocarbons (especially methylene chloride) or ethers. 3 ⁇ 4 (especially tetrahydrofuran).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 30 ° C. to 50 ° C., preferably from 10 to 30 ° C.
  • the reaction time varies depending on the starting compound, the reagent, the reaction temperature and the type of the solvent used, but is usually 30 minutes to 48 hours, preferably 1 hour to 24 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, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water, and then dried over anhydrous magnesium sulfate. Then, 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.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the halogenating agent used in the step B1b is not particularly limited as long as it is generally used in the art of organic synthetic chemistry, and examples thereof include oxalyl chloride, thionyl chloride, oxychloride and the like. It can be phosphorus pentachloride.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene: methylene chloride, chloroform Halogenated hydrocarbons such as oral form, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene: or getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane or diethylene.
  • Ethers such as glycol dimethyl ether, preferably aromatic hydrocarbons (particularly benzene or toluene), halogenated hydrocarbons (particularly methylene chloride) or ethers (particularly tetrahydrofuran) ).
  • the reaction temperature varies depending on the starting compounds, reagents and the like, but is usually from ⁇ 30 ° C. to 50 ′ C, preferably from ⁇ 10 to 30 ° C.
  • the reaction time Rii is a raw material compound, a reagent, a reaction temperature, and a force that varies depending on the type of solvent used; usually, 30 minutes to 48 hours, preferably 1 hour to 24 hours. After completion of the reaction.
  • 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.
  • water is added to the reaction solution
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the extracted organic layer is washed with water, and then dried over anhydrous magnesium sulfate.
  • 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 step B2 is a step of producing a compound having the general formula (VIII) by reacting the compound having the general formula (VIII) with a reducing agent in an inert solvent.
  • the reducing agent to be used is not particularly limited as long as it is used in a normal reduction reaction. If it is clear, sodium borohydride, lithium borohydride, lithium aluminum hydride, hydrogen hydride It can be a metal hydride, such as disobutylaluminum hydride, aluminum isopropoxide or diborane, preferably lithium aluminum hydride or disobutylaluminum hydride.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride; Halogenated hydrocarbons such as form, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene: or like acetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether.
  • aromatic hydrocarbons particularly benzene or toluene
  • halogenated hydrocarbons particularly methylene chloride
  • ethers particularly tetrahydrofuran
  • 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.
  • Reaction time varies depending on starting compounds, solvent, reducing agent used, reaction temperature, etc. However, it is usually 5 minutes to 24 hours, preferably 10 minutes to 18 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, water is added to the reaction solution, and a water-immiscible solvent (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound. After the extracted organic layer is washed with water, anhydrous magnesium sulfate, etc. Then, 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.
  • a water-immiscible solvent eg, benzene, ether, ethyl acetate, etc.
  • step B3 a compound having the general formula (IXa) is reacted with a compound having the general formula (IX) in the presence of a base in an inert solvent to produce a compound having the general formula (IIa) This is the step of performing
  • Examples of the base to be used include alkali metal such as sodium carbonate, potassium carbonate and lithium carbonate.
  • Carbonates sodium carbonate such as sodium hydrogen carbonate, lithium hydrogen carbonate and lithium hydrogen carbonate.
  • Organics such as non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABC 0) or 1,8-diazabicyclo [5.4.0] pendeco 7-ene (DBU) Amines, preferably Organic amines (particularly viridin).
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene or xylene: methylene chloride
  • Halogenated hydrocarbons such as form, carbon tetrachloride, dichloroethane, cyclobenzene or dichlorobenzene: or of getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane or diethylene glycol dimethyl ether
  • Such ethers are preferred, and are preferably aromatic hydrocarbons (particularly benzene or toluene), halogenated hydrocarbons (particularly methylene chloride) or ethers (particularly tetrahydrogen). Mouth franc).
  • the reaction temperature varies depending on the starting compound, the reagent, the solvent used and the like, but is usually from 180 to 150, preferably from 120 to 80.
  • the reaction time varies depending on the starting compound, solvent, reagent, reaction temperature and the like, but is usually 30 minutes to 48 hours, preferably 1 hour to 30 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, and a solvent immiscible with water (for example, benzene, ether, ethyl ethyl ester, etc.) is added to extract the target compound, and the extracted organic layer is washed with water and dried over anhydrous magnesium sulfate.
  • the desired compound can be obtained by drying under reduced pressure 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.
  • Method C is a method for separately producing a compound having the general formula (Ila).
  • Step C1 comprises producing a compound having the general formula (VIII) by reacting a compound having the general formula (III) with formaldehyde and a compound having the general formula (VI) in an inert solvent. This step is performed under the same conditions as in the first step A1.
  • a compound having the general formula (IIa) is produced by reacting a compound having the general formula (VIII) with a compound having the general formula (IX) in the presence of a base in an inert solvent. And performed under the same conditions as in Step B3.
  • R 6 is R s
  • R 7 is R 7 in the compound (II). Is a method for separately producing a compound having the general formula (lib).
  • Step D1 comprises combining a compound having the general formula (V) with a compound having the general formula (X)
  • Step B a step of producing a compound having the general formula (XI) by reacting in an inert solvent in the presence of a halogenating agent, which is carried out under the same conditions as in Step B1.
  • 5 D 2: [f3 is a step of producing a compound having the general formula (X [I]) by reacting the compound having the general formula (I) with a compound in the ⁇ activity. It is performed under the same conditions as in the process.
  • step D3 the compound having the general formula (lib) is reacted with the compound having the general formula (XIII) in the presence of a base in an inert solvent to produce a compound having the general formula (lib)
  • step D3 the compound having the general formula (lib) is reacted with the compound having the general formula (XIII) in the presence of a base in an inert solvent to produce a compound having the general formula (lib)
  • Method E is a method for separately producing a compound having the general formula (lib).
  • Step E1 comprises reacting a compound having the general formula (III) with a compound having the general formula (X) in an inert solvent in the presence of formaldehyde to produce a compound having the general formula (XII). This is performed under the same conditions as in step A1.
  • a compound having the general formula (Xlb) is reacted with a compound having the general formula (XIII) in an inert solvent in the presence of a base to form a compound having the general formula (Ilb).
  • This is a manufacturing step, which is performed under the same conditions as in the step B3.
  • Method F is a method for producing a compound having the general formula (XVI) wherein R s is —CH 2 R * and R 7 is R 7 C in compound (II).
  • Step F1 comprises the step of converting a compound having the general formula (XII) into
  • the step F2 is a step of producing a compound having the general formula (XVI) by reacting the compound having the general formula (XV) with a reducing agent in an inert solvent. It is performed under similar conditions.
  • Method G the compound (II) is one CH 2 R 4 At a is a method for the preparation of a compound having the general formula R 7 is R 7 b and (XVI a).
  • Step G1 comprises reacting a compound having the general formula (XVII) with a compound having the general formula (XVIII) in an inert solvent, and then reacting the compound with the reducing agent to convert the general formula (XIX)
  • This is a step of separately producing a compound having the same.
  • the reduction performed is not particularly limited as long as it is used in a normal reduction reaction. Examples thereof include sodium boron hydride, lithium boron hydride, lithium aluminum hydride, and lithium aluminum hydride. It can be a gold hydride such as sodium butyl aluminum hydride, aluminum isopropoxide or diborane, preferably lithium aluminum hydride or diisobutyl aluminum hydride.
  • the solvent used is not particularly limited as long as it inhibits the reaction and dissolves the starting material 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 such as getyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane, diethylene glycol dimethyl ether Ethers: alcohols such as methanol, ethanol, propanol, isopropanol, butanol or isobutanol: fatty acids such as diacid or acetic acid; or water, preferably aromatic carbonized Hydrogens (particularly benzene or toluene , Halogenation hydrocarbons (particularly Mechirenkurori de), ethers (particularly Te Bok Rahi Dorofu run),
  • the reaction temperature varies depending on the starting compound, the solvent, the reducing agent used, and the like, but is usually from ⁇ 20 T) to 100 ° C., and preferably from 0 to 50 ° C.
  • the reaction time varies depending on the starting compound, the solvent, the reducing agent used, the reaction temperature and the like; it is generally 5 minutes to 24 hours, preferably 10 minutes to 18 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, water is added to the reaction solution, a solvent immiscible with water (eg, benzene, ether, ethyl acetate, etc.) is added to extract the target compound, and the extracted organic layer is washed with water, and then dried over anhydrous magnesium sulfate. Then, the target compound is obtained by distilling off the solvent.
  • a solvent immiscible with water eg, benzene, ether, ethyl acetate, etc.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • Step HI comprises reacting a compound having the general formula (XVII) with a compound having the general formula (X) in an inert solvent and then reacting with a reducing agent to obtain a compound of the general formula (XIla)
  • This is a step of producing a compound having the following formula: and is carried out under the same conditions as in Step G1.
  • step H2 the compound having the general formula (XIIa) is reacted with the compound having the general formula (XIII) in an inert solvent in the presence of a base to form a compound having the general formula (IIc).
  • This is a manufacturing step, which is performed under the same conditions as in the step B3.
  • Method J is a method for separately producing a compound having the general formula (IIa).
  • Step J1 comprises reacting a compound having the general formula (XXI) with a compound having the general formula (VI) in an inert solvent, followed by reacting with a reducing agent to obtain a compound having the general formula (VIII). And performed under the same conditions as in the G1 step.
  • Step J2 is a step of reacting the compound having the general formula (VIII) with the compound having the general formula (IX) in an inert solvent in the presence of a base to produce a compound having the general formula (IIa) This step is performed under the same conditions as in step B3.
  • Method K is a method for separately producing a compound having the general formula (lib).
  • Step K1 comprises reacting a compound having the general formula (XXI) with a compound having the general formula (X) in an inert solvent and then reacting the compound with the reducing agent to form the compound represented by the general formula (XII). This is a step of producing a compound having the same conditions as the step G1.
  • Step L1 is a step of reacting the compound having the general formula (X ⁇ ) obtained from Step D2, Step E1, Step # 1 or Step K1 in an inert solvent with a compound of the formula (XVIII) And then reacting with a reducing agent to produce a compound having the general formula (XVI), which is performed under the same conditions as in Step G1.
  • the indole derivative (I) or (II) of the present invention has an excellent nerve growth factor production promoting action or secretion promoting action and has low toxicity, so that the recovery of peripheral nerve damage can be accelerated. It is useful as a therapeutic or prophylactic agent (especially a therapeutic agent) for central dysfunction, especially Alzheimer's dementia and cerebral ischemic pathology.
  • Kffl of the present invention is not limited to these.
  • the R f values of the compounds are the values obtained by thin-layer chromatography on mercury (Merck) ⁇ ⁇ (TLC).
  • N-ethyl (indole-3-yl) methylamine (2.5 g) and triethylamine (1.49 g) were dissolved in methylene chloride (20 ml), and the mixture was treated with 5-bromoethylisoxazole ( A solution of 2.8) in methylene chloride (10 ml) was added dropwise over 10 minutes while stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was added with saturated aqueous layer water, extracted with ethyl acetate, and the organic layer was dried using anhydrous sodium sulfate.
  • the solvent is distilled off under reduced pressure, and the obtained residue is purified using silica gel column chromatography (elution solvent: mixed solvent of n-hexane and ethyl ethoxide) to give the target compound (2. 6 g) was obtained as an oil.
  • N-Ethyl (indol-3-yl) methylamine and 5-bromomethyl-3-phenylisoxazole are reacted in the same manner as in Example 1 and post-treated to obtain the desired compound as an oil.
  • Example 1 N-Ethyl (indol-3-yl) methylamine and 5-bromomethyl-3-phenylisoxazole are reacted in the same manner as in Example 1 and post-treated to obtain the desired compound as an oil.
  • N-Ethyl (indole-3-yl) methylamine and 3-bromomethylbenzoisosoxazole were reacted in the same manner as in Example 1 and worked up to give the target compound as an oil.
  • Example 3 The compound (0.3 g) obtained in Example 3 was dissolved in 5 ml of methylene chloride, and 4 N dioxane hydrochloride (0.3 ml) was added under ice cooling. The solvent was distilled off under reduced pressure to obtain the desired compound (0.31 g) as an amorphous substance.
  • N-ethyl (indole-3-yl) methylamine and 4-bromomethyl-5-methyl-3-phenylisosoxazole are reacted in the same manner as in Example 1 and post-processed to give the target compound as an oil. Obtained.
  • N-Ethyl- (indole-3-yl) methylamine and 5-bromomethyl-2.4-dimethylthiazole were reacted in the same manner as in Example 1 to obtain a target compound. As obtained.
  • N-ethyl (indole-3-yl) methylamine (1.46 g), quinolin-41-aldehyde (1.57 g) and sodium cyanoborohydride (1.0) It was dissolved in ethanol (20 ml). After adding 6 N hydrochloric acid while maintaining the pH at 3 under ice-cooling stirring, the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, a saturated aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate, and the organic layer was dried using anhydrous sodium sulfate.
  • N-ethyl- (indole-3-yl) methylamine and quinolin-13-aldehyde were reacted in the same manner as in Example 9 and worked up to give the target compound as an oil.
  • N-ethyl (indole-3-yl) methylamine and 4-bromomethyl-3,5-dimethylisoxazole were reacted in the same manner as in Example 1 and worked up to give the target compound as an oil. .
  • N-Ethyl (5-methoxyxindole-3-yl) methylamine and 3-bromomethylbenzoyl soxazole are reacted in the same manner as in Example 1 and post-treated to give the target compound as an oily substance. As obtained.
  • N-ethyl (5-fluoro-3-yl) methylamine and 3-bromomethylbenzoisosoxazole were reacted in the same manner as in Example 1 and post-treated to obtain the target compound.
  • N-Ethyl (5-methylindole-3-yl) Methylamine and quinolin-13-aldehyde are reacted in the same manner as in Example 9 and post-treated to give the target compound as an oil. Obtained as material.
  • the solvent was distilled off under reduced pressure, and the obtained residue was purified using silica gel column chromatography (elution solvent: mixed solvent of ethyl acetate and methanol), and the target compound (44 mS) was converted to an oily substance. Obtained.
  • N-isoprovir-1-N- (quinolin-3-yl) methyl- (indul-3-yl) methylamine was reacted in the same manner as in Example 4 and post-treated. The desired compound was obtained.
  • N-methyl- (indole-3-yl) methylamine and quinolin-13-aldehyde are reacted in the same manner as in Example 9 and post-treated to give the target compound as an oily substance Obtained.
  • N-Provir-1 (quinolin-3-yl) methylamine and indole were reacted in the same manner as in Example 16 and worked up to give the target compound as an oil.
  • R f 0.26 (developing solvent: ethyl diacid).
  • N-Isopropyl-1 (quinolin-3-yl) methylamine and 1-methylindole are reacted in the same manner as in the Reference Example, and the target compound is converted into an oily substance by post-treatment. I got it.
  • N-Isobutyl- (indole-3-yl) methylamine and quinolin-13-aldehyde were reacted in the same manner as in Example 9 and worked up to give the target compound as an oil. .
  • N-Isopropyl-1 (5-methylindole-3-yl) Methylamine and quinolin-1-3-aldehyde were reacted in the same manner as in Example 9 and post-treated to give the target compound as an oily substance. As obtained.
  • N-Isopropyl-1- (5-methoxyindole-3-yl) methylamine and quinolin-3-aldehyde are reacted in the same manner as in Example 9 and post-treated to give the target compound as an oil. Obtained as material.
  • N-Isobrovir-1- (indole-3-yl) methylamine and 6-chloroquinolin-13-ylaldehyde were reacted in the same manner as in Example 9 and post-treated to give the target compound as a glass. Obtained as a solid.
  • Example 4I (Exemplary compound number: 3-13) 1.2-Dimethylindole and pyrrolidine were reacted in the same manner as in Example 4I. Post-treatment gave the target compound as an oil.
  • Example 41 1-Methylindole and morpholine were reacted in the same manner as in Example 41, and worked up to give the target compound as an oil.
  • the target compound was obtained by reacting indole with benzyl (indole-3-ylmethyl) amine in the same manner as in Example 41, followed by post-treatment.
  • Benzylmethylamine (1.3 g) is dissolved in a 2N aqueous solution of sodium hydroxide (30 ml) and, with stirring, 3-trimethylammoniummethylindoleide ( 3.2 g) was added. After stirring at room temperature for 2 hours, the mixture was extracted with methylene chloride, and the organic layer was dried using potassium carbonate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate Z hexane Z triethylamine-20Z20-1), and the target compound (1 9 g) was obtained.
  • the target compound was obtained as an oily substance by reacting benzylbutyrviramine with 3-trimethylammonium methylindole iodide in the same manner as in Example 55, followed by post-treatment.
  • Benzylethylamine and 1-methyl-3-trimethylammonium methylindole iodide were reacted in the same manner as in Example 55, followed by post-treatment to obtain the target compound as an oil.
  • Example 5 By reacting 5-chloro-1-methyl-3- (N-benzyl-ethyl) aminomethylindole obtained in Example 1 in the same manner as in Example 4 and performing post-treatment, the object was obtained. The compound was obtained.
  • Example 61 1-Methylindole-3-carboxylic acid was reacted with ethylamine in the same manner as in Example 61, followed by post-treatment to give the target compound as an oil.
  • the desired compound was obtained as an oily substance by reacting 1-methylindole-3-carboxylic acid and 3-aminoviridine in the same manner as in Example 61, followed by post-treatment.
  • Example 61 1-Methylindole-13-butyric acid and 4-aminoviridine were reacted in the same manner as in Example 61, followed by post-treatment to obtain the target compound as an oil.
  • the target compound was obtained as an oily substance by reacting 1-methylindole-3-carboxylic acid and 11-aminoaminodamantane in the same manner as in Example 61, followed by post-treatment.
  • the target compound was obtained by reacting indole-3-carboxylic acid and (N-phenylmethyl-N-brovir) amine in the same manner as in Example 61, followed by post-treatment. Melting point: 72-73.
  • the target compound was obtained as an oily substance by reacting indole-3 -capillonic acid and (N-phenylethyl-N-ethyl) amine in the same manner as in Example 61, followed by post treatment.
  • indole-3 -capillonic acid and (N-phenylethyl-N-ethyl) amine in the same manner as in Example 61, followed by post treatment.
  • Example 2-16 Indole-3-carboxylic acid and benzylamine were reacted in the same manner as in Example 61 and worked up to give the target compound as an oil.
  • the target compound was obtained as an oily substance by reacting indole-3-carboxylic acid and 2-tenylamin in the same manner as in Example 61, followed by post-treatment.
  • the target compound was obtained by reacting indole and viridin in the same manner as in Example 41 and performing post-treatment.
  • the target compound was obtained as an oily substance by reacting indole and pyrrolidine in the same manner as in Example 41 and performing post-treatment.
  • Example 41 1-Methylindole and pyrrolidine were reacted in the same manner as in Example 41 and worked up to give the target compound as an oil.
  • L-M cells For culture of L-M cells, 199 medium containing 0.596 peptone was used. Approximately 5 ⁇ 10 4 L-M cells were seeded in a 24-well culture plate at each hole and cultured in a carbon monoxide incubator (37, 5% carbon dioxide) until confluent. After removing the culture solution, the cells were washed once with a 199 medium containing 0.5% bovine serum albumin (Fraction V, manufactured by Sigma). The test compound was contained in a 199 medium containing 0.5% bovine blood albumin at a specified concentration, and 0.5% L-M cells were treated. After culturing the L-M cells in a carbon dioxide incubator for 24 hours, the culture solution was recovered and NGF in the culture solution was quantified.
  • a carbon monoxide incubator 37, 5% carbon dioxide
  • the NGF is a member of the Brothings' Ob 'The National' Academy 'Ob' Science. Natl. Acad. Sci. USA, 80, 3513 (1983).]] And the enzyme immunoassay (the method of Korsching and Thoenen et al.).
  • An anti-mouse 0-NGF antibody manufactured by Hopkins Mannheim
  • 0.3 jugZm l. PH 9.6 was dispensed into a 96-well plate made of polystyrene in 75 tx l portions of each well. Released for 1 hour at room temperature. After removing the antibody, each well was washed three times with a washing solution. Standard
  • Test compound dose NGF production increasing effect (Example number) (ug / m1) (%. Control)
  • the indole derivative (I) or (II) of the present invention has an excellent nerve growth factor production promoting action or secretion promoting action and has low toxicity, so that it can accelerate recovery of peripheral nerve damage, It is useful as a therapeutic agent for central dysfunction, especially for Alzheimer's dementia and cerebral ischemic disease models.
  • the compound (I) or (II) of the present invention or a pharmacologically acceptable salt thereof is used as a therapeutic or prophylactic agent for the above-mentioned neurological disease
  • the compound itself or an appropriate pharmacologically acceptable salt is used.
  • Excipients, diluents and the like and can be administered orally by tablets, capsules, granules, powders or syrups, or parenterally by injections or suppositories.
  • These preparations contain excipients (eg, lactose, white sugar, glucose, mannite, sugar derivatives such as sorbite: corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyldene)
  • Starch derivatives such as bun: Cellulose derivatives such as crystalline cellulose, low S-substituted hydroxypropyl cellulose, hydroxymethyl virmethyl cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked carboxymethylcellulose sodium.
  • the amount used depends on the symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably l O mg) per day and the upper limit is 200 mg (preferably 4 mg / day). 0 0 mg) for intravenous administration, 1 1 mg / day (preferably 1 mg / day), upper limit 500 mg / day (preferably 300 mg / day) for adults 1 to 6 times / day depending on symptoms It is desirable to do so.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivé d'indole de formule générale (I) ou sel pharmaceutiquement acceptable dudit dérivé; formule dans laquelle R1 et R2 sont chacun hydrogène ou alkyle; R3 est hydrogène, halogéno, alkyle éventuellement substitué, alcoxy ou alcoxycarbonyle; R4 est isoxazolyle éventuellement substitué, benzisoxazolyle éventuellement substitué, thiazolyle éventuellement substitué, benzothiazolyle éventuellement substitué ou quinolyle éventuellement substitué; et R5 représente hydrogène, alkyle éventuellement substitué, alcényle ou alcynyle. Ledit composé possède un excellent effet promoteur sur la production ou la sécrétion des facteurs de croissance de tissus nerveux et il est utile comme remède ou agent prophylactique des maladies nerveuses telles que la démence de type Alzheimer ou les modèles pathologiques d'ischémie cérébrale (en particulier la démence de type Alzheimer).
PCT/JP1995/002709 1994-12-28 1995-12-27 Derives d'indole WO1996020191A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003068741A1 (fr) * 2002-02-13 2003-08-21 Meiji Dairies Corporation Derives d'indole substitues avec des alcools a longue chaine et medicaments contenant ceux-ci
WO2004047840A1 (fr) * 2002-11-22 2004-06-10 Merck Patent Gmbh Derives de pyridinalkyl-aminoalkyl-1h-indole inhibant les recepteurs 5-ht et la recapture de la serotonine, pouvant servir d'antidepresseurs et d'anxiolytiques
US6821962B2 (en) 1997-05-28 2004-11-23 Aventis Pharmaceuticals Inc. Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and /or p56lck tyrosine kinases
WO2010007972A1 (fr) 2008-07-14 2010-01-21 参天製薬株式会社 Nouveau dérivé d'indole comportant un groupe carbamoyle, un groupe uréido et un groupe oxy substitué
US8193237B2 (en) 2007-01-15 2012-06-05 Santen Pharmaceutical Co., Ltd. Indole derivative having IκB kinase β inhibitory activity
CN111153848A (zh) * 2020-01-17 2020-05-15 成都睿智化学研究有限公司 一种非催化Mannich反应合成3-氨甲基吲哚类化合物的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641070A (ja) * 1992-03-23 1994-02-15 Sankyo Co Ltd インドール誘導体
JPH06199784A (ja) * 1991-08-13 1994-07-19 Adir 新規なアリールエチアミン化合物、その製法、及びこれを含有する医薬組成物。

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06199784A (ja) * 1991-08-13 1994-07-19 Adir 新規なアリールエチアミン化合物、その製法、及びこれを含有する医薬組成物。
JPH0641070A (ja) * 1992-03-23 1994-02-15 Sankyo Co Ltd インドール誘導体

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6821962B2 (en) 1997-05-28 2004-11-23 Aventis Pharmaceuticals Inc. Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and /or p56lck tyrosine kinases
US6852712B2 (en) 1997-05-28 2005-02-08 Aventis Pharmaceuticals Inc. Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases
WO2003068741A1 (fr) * 2002-02-13 2003-08-21 Meiji Dairies Corporation Derives d'indole substitues avec des alcools a longue chaine et medicaments contenant ceux-ci
US7407983B2 (en) 2002-02-13 2008-08-05 Meiji Dairies Corporation Indole derivatives substituted with long-chain alcohols and medicaments containing them
US7902249B2 (en) 2002-02-13 2011-03-08 Meiji Dairies Corporation Indole derivatives substituted with long-chain alcohols and medicaments containing them
WO2004047840A1 (fr) * 2002-11-22 2004-06-10 Merck Patent Gmbh Derives de pyridinalkyl-aminoalkyl-1h-indole inhibant les recepteurs 5-ht et la recapture de la serotonine, pouvant servir d'antidepresseurs et d'anxiolytiques
US7432282B2 (en) 2002-11-22 2008-10-07 Merck Patent Gesellschaft Mit Beschrankter Haftung Pyridinalkyl-aminoalkyl-IH-indole derivatives having an inhibitory action on 5-HT and serotonin reuptake as antidepressants and anxiolytics
US8193237B2 (en) 2007-01-15 2012-06-05 Santen Pharmaceutical Co., Ltd. Indole derivative having IκB kinase β inhibitory activity
WO2010007972A1 (fr) 2008-07-14 2010-01-21 参天製薬株式会社 Nouveau dérivé d'indole comportant un groupe carbamoyle, un groupe uréido et un groupe oxy substitué
US8445529B2 (en) 2008-07-14 2013-05-21 Santen Pharmaceutical Co., Ltd. Indole derivative having, carbamoyl group, ureido group and substituted oxy group
CN111153848A (zh) * 2020-01-17 2020-05-15 成都睿智化学研究有限公司 一种非催化Mannich反应合成3-氨甲基吲哚类化合物的方法
CN111153848B (zh) * 2020-01-17 2023-07-28 成都睿智化学研究有限公司 一种非催化Mannich反应合成3-氨甲基吲哚类化合物的方法

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