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WO1995006032A1 - Inhibiteur de la tyrosine kinase - Google Patents

Inhibiteur de la tyrosine kinase Download PDF

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Publication number
WO1995006032A1
WO1995006032A1 PCT/JP1994/001368 JP9401368W WO9506032A1 WO 1995006032 A1 WO1995006032 A1 WO 1995006032A1 JP 9401368 W JP9401368 W JP 9401368W WO 9506032 A1 WO9506032 A1 WO 9506032A1
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Prior art keywords
group
lower alkyl
dihydroxyphenyl
furanone
alkyl group
Prior art date
Application number
PCT/JP1994/001368
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English (en)
Japanese (ja)
Inventor
Hajime Morishima
Kagari Fujita
Masato Nakano
Seiichi Tanaka
Yuzo Kato
Hiroshi Kawamoto
Teruyuki Nishimura
Eisaku Yoshida
Shinya CHIEDA
Akira Okura
Original Assignee
Banyu Pharmaceutical Co., Ltd.
OKURA, Ikuyo
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Publication date
Application filed by Banyu Pharmaceutical Co., Ltd., OKURA, Ikuyo filed Critical Banyu Pharmaceutical Co., Ltd.
Priority to AU74672/94A priority Critical patent/AU7467294A/en
Publication of WO1995006032A1 publication Critical patent/WO1995006032A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
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    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention is useful in the field of medicine, and more specifically, relates to a novel compound that inhibits the growth of tumor cells and exhibits an antitumor effect, and a use thereof.
  • the present inventors have screened a wide range of microbial metabolites and found that a novel compound BE-23372M [(E) -3- (3,4-dihydroxy) having tyrosine kinase inhibitory activity and antitumor activity Benzylidene) -5- (3,4-dihydroxyphenyl-2 (3H) -furanone] was disclosed [see Japanese Patent Application Laid-Open No. 4-275284].
  • HMPA Hexamethylphosphate triamide HOBT ⁇ H 2 0 1 - hydroxy - 1H-Benzotoriazo Ichiru monohydrate
  • the term “lower” means no more than 6 unless the carbon number of the group to which the term is attached is specifically stated.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group.
  • a methyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group.
  • Tert-butyl group pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group and the like.
  • the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, a 1-propeninole group, an aryl group, a 1-butenyl group, and a 2-butenyl group. , 3-butenyl group, 1-methylvinyl group, 2-methyl-1-butenyl group and the like.
  • the lower alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, for example, ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group Group, 2-hexynyl group and the like.
  • the cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.
  • the cycloalkyl lower alkyl group means a cycloalkylalkyl group having 4 to 14 carbon atoms in which the lower alkyl group is substituted by the cycloalkyl group, for example, a cyclopropylmethyl group, a 1-cyclopropylethyl group, 2-cyclopro Pyrethyl, cyclobutylmethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl And a 2-cyclohexylethyl group.
  • the aryl group means a group having 6 to 12 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a 4-nitrophenyl group, a 4-carboxyphenyl group, and a 4-methoxyphenyl group. .
  • ⁇ reel lower alkyl group means an arylalkyl group having 7 to 14 carbon atoms in which the aryl group is substituted for the lower alkyl group, for example, benzyl group, phenethyl group, 3-phenylpropyl group, Examples thereof include a 4-methoxybenzyl group, a 4-hydroxybenzyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.
  • the protected hydroxy group means a hydroxy group protected by a commonly used protecting group.
  • the used protecting group include a lower alkyl group such as a methyl group and an ethyl group; for example, a trimethylsilyl group and a t-butyldimethyl group.
  • a lower alkylsilyl group such as a silyl group; a lower alkoxymethyl group such as a methoxymethyl group and a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; a benzyl group, a P-methoxybenzizole group, and a 2,4-dimethoxy group;
  • Aryl lower alkyl groups such as benzyl group, 0-nitropentenyl group, p-nitropentenyl group, and trityl group; lower alkanol groups such as formyl group and acetyl group; t-butoxycarbonyl group; Lower alkyloxy such as 2-odoethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl Rubonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-
  • the hydroxy lower alkyl group means a hydroxyalkyl group having 1 to 6 carbon atoms in which the lower alkyl group is substituted by 1 to 2 hydroxy groups. Droxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3 -Dihydroxypropyl group and the like.
  • the protected hydroxy lower alkyl group means the lower alkyl group having 1 to 6 carbon atoms which is substituted by 1 to 2 protected hydroxy groups, for example, methoxymethyl group, benzyl group.
  • an isopropylidene group, a cyclohexylidene group, a benzylidene group, or the like can be used as a protecting group, and specifically, a 1,3-di-0-isopropylidene pentyl group, 1,2 -Di-0-cyclohexylideneethyl group, 2,3-di-0-isopropylidene oryl group.
  • the lower alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy.
  • the lower alkenyloxy group means a linear or branched alkenyloxy group having 3 to 6 carbon atoms, such as an aryloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 4-pentenyloxy group, and the like. Is mentioned.
  • the lower alkynyloxy group means a linear or branched alkynyloxy group having 3 to 6 carbon atoms, such as a propynyloxy group, a 2-butynyloxy group, a 3-butynyloxy group, and a pentynyloxy group.
  • the cycloalkyl lower alkoxy group means a cycloalkyl alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the cycloalkyl group, for example, a cyclopropyl methoxy group, a 1-cyclopropyl ethoxyquin group.
  • An aryloxy group means one having 6 to 12 carbon atoms, such as phenoxy, 4-methoxyphenyl, 4-carboxyphenoxy, 1-naphthyl And a 2-naphthyloxy group.
  • the aryl lower alkoxy group refers to an aryl lower alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the aryl group.
  • Examples thereof include a benzyloxy group, a phenethyloxy group, and a 4-methyl
  • Examples include a toxicbenzyloxy group, a 4-carboxybenzyloxy group, a 1-naphthylmethyloxy group, and a 2-naphthylmethyl group.
  • the lower alkanoyl group means an alkanoyl group having 1 to 6 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group, hexanoyl group and the like.
  • a lower alkanoyloxy group means an alkanoyloxy group having 1 to 6 carbon atoms. And the like.
  • the lower alkenyloxy lower alkyl group means the lower alkyl group substituted with the alkenyloxy group, such as a formyloxymethyl group, an acetyloxymethyl group, a 1-acetyloxyxethyl group. , 2-acetyloxyethyl, propionyloxymethyl, 1-propionyloxyethyl, 2-propionyloxyethyl, and the like.
  • the lower alkoxy lower alkyl group means an alkoxyalkyl group in which the lower alkyl group is substituted by the lower alkoxy group, and examples thereof include a methoxymethyl group, a methoxethyl group, an ethoxymethyl group, and a propyloxymethyl group.
  • the aryloxy lower alkyl group means the lower alkyl group substituted with the aryloxy group, and examples thereof include a phenokinemethyl group, a 1-naphthyloxymethyl group, and a 2-naphthyloxymethyl group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • lower alkyl group means the lower alkyl group substituted with 1 to 3 halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group.
  • Methyl Group bromomethyl group, dibromomethyl group, tribromomethyl group, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2,3-difluoropropyl group, 2,3-dichloro group And a propyl group and a 2,3-dibromopropyl group.
  • the protected carboxyl group means a carboxyl group protected by a commonly used protecting group.
  • the used protecting group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a t-butyl group.
  • a lower alkyl group for example, a halo-lower alkyl group such as a 2,2,2-trichloroethyl group or a 2,2,2-trifluoroethyl group; for example, an acetooxymethyl group, a propionyloxymethyl group, a vivaloyloxy group; Methyl-, 1-acetoxityl,;!-Loweralkanoyloxyalkyl, such as propionyloxyethyl, etc .; for example, 1- (methoxycarboxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1 -(Isopropoxycarbonyloxy) lower alkyl group such as ethyl group such as 2-ethyl group; for example, 2-propininole group Lower alkenyl groups such as 2-chloro-2-propyninole group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-propeny
  • Aryl lower alkyl group for example, (5-substituted-2-oxo-1, 3-dioxol-4-yl) such as (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group; Yl) methyl group; for example, lower alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like.
  • 5-substituted-2-oxo-1, 3-dioxol-4-yl such as (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group
  • Yl) methyl group for example, lower alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like.
  • the carboxy lower alkyl group means the above-mentioned lower alkyl group substituted by a carboxy group, and examples thereof include a carboxymethyl group, a 2-carboxyethyl group, and a 3-carboxypropyl group.
  • the protected carbonyloxy lower alkyl group means the above lower alkyl group substituted by a carboxy group protected by the above protecting group, for example, methoxycarbonylmethyl group, benzyloxycarbonylmethyl group, Methoxycarbonylethyl group, 3-benzyloxycarbonylpropyl group, etc.
  • a carboxy group protected by the above protecting group for example, methoxycarbonylmethyl group, benzyloxycarbonylmethyl group, Methoxycarbonylethyl group, 3-benzyloxycarbonylpropyl group, etc.
  • a carboxy lower alkenyl group means the above-mentioned lower alkenyl group substituted by a carboxy group, such as a 1-carboxyvinyl group, a 2-carboxyvinyl group, a 3-carboxy-2-propenyl group, etc. Is mentioned.
  • the protected carboxy lower alkenyl group means the above lower alkenyl group substituted by a carboxy group protected by the above protecting group, for example, an I-methoxycarbonylvinyl group, a 2-methyl A methoxycarbonylvinyl group and a 3-benzyloxycarbonyl-2-propininole group.
  • the protected amino group means an amino group protected by a commonly used protecting group, and examples of the protecting group include an aryl lower alkylidene group such as a benzylidene group and a P-methoxybenzylidene group; Aryl lower such as p-methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis (P-methoxyphenyl) methyl group and trityl group Alkyl group; for example, lower alkanol group such as formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, and vivaloyl group; for example, phthalyl group; for example, chloroacetyl group, dichloroacetyl group, trichloroacetyl group Halo-substituted lower alkanol groups such as trifluor
  • the amino lower alkyl group means the lower alkyl group substituted with an amino group, for example, an aminomethyl group, a 1-aminoethyl group, a 2-aminoethynole group, a 1-aminopropyl group, a 2-aminopropyl group, Examples thereof include a 3-aminopropyl group, a toamino-1-methylethyl group, a 2-amino-tomethylethynole group, a 1-aminobutyl group, a 2-aminobutyl group, a 3-aminobutyl group, and a 4-aminobutyl group.
  • the protected amino lower alkyl group means the above lower alkyl group substituted by the amino group protected by the above protecting group, for example, benzyloxycarbonylaminomethyl group, 1-t-butoxycarbonyl group.
  • examples include a minethyl group, a 2-benzyloxycarbonylaminoethyl group, a 1-N-p-nitrobenzyloxycarbonyl-Nt-butyldimethylsilylaminopropyl group, and the like.
  • the aryloxy group means an aryloxy group having 7 to 13 carbon atoms, and examples thereof include a benzoyloxy group, a 4-methoxybenzoyloxy group, a 1-naphthoyloxy group and a 2-naphthoyloxy group.
  • N-mono-lower alkyl rubamoyl means a carbamoyl group substituted with one of the above-mentioned lower alkyl groups, such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl. , N-butylcarbamoyl group and the like.
  • ⁇ , ⁇ -di-lower alkyl group refers to a group that is substituted with two identical or different lower alkyl groups, for example, ⁇ , ⁇ -dimethylcarbamoyl group, ⁇ -ethyl- ⁇ -methylcarbamoyl group, ⁇ , ⁇ -getylcarbamoyl group, ⁇ -ethynole- ⁇ -propylcanolebamoinole group and the like.
  • the lower alkoxycarbonyl group means an alkoxycarbonyl group having the lower alkoxy group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group.
  • the lower alkenyloxycarbonyl group means an alkenyloxycarbonyl group having the lower alkenyloxy group, for example, aryloxyl. Examples include a bonyl group and a butenyloxycarbonyl group.
  • the aryloxycarbonyl group means an aryloxycarbonyl group having the above-mentioned aryloxy group, for example, phenoxycarbonyl group, 1-naphthoxycarbonyl group, 2-naphthoxycarbonyl group and the like. Is mentioned.
  • the aryl lower alkoxycarbonyl group means an aryl alkoxycarbonyl group having the aryl lower alkoxy group, such as a benzyloxycarbonyl group, a 1-naphthylmethoxycarbonyl group, and a 2-naphthylmethoxycarbonyl group.
  • the lower alkylsulfonyloxy group means an alkylsulfonyloxy group having the lower alkyl group, for example, a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, Butanesulfonyloxy group and the like.
  • the perylsulfonyloxy group means an arylsulfonyloxy group having the aryl group, and examples thereof include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.
  • the di-lower alkoxyphosphoryloxy group means a dialkoxyphosphoryloxy group having two of the above-mentioned lower alkyl groups, and examples thereof include a dimethoxyphosphoryloxy group and a ethoxyphosphoryloxy group.
  • the N-mono lower alkylamino group means an amino group substituted with the lower alkyl group, such as an N-methylamino group, an N-ethylamino group, an N-propylamino group, an N-butylamino group, and the like. .
  • the protected N-mono-lower alkylamino group means a protected amino group substituted with the lower alkyl group, for example, an N-methyl-Np-nitrobenzyl amino group, an N-acetyl-N-ethylamino group. And the like.
  • ⁇ , ⁇ -di-lower alkylamino group means an amino group substituted with the same or different two lower alkyl groups, for example, ⁇ , ⁇ -dimethylamino group, ⁇ -ethyl- ⁇ -methylamino group. , ⁇ , ⁇ -ethylamino group, ⁇ -ethyl- ⁇ -propylamino group, ⁇ , ⁇ -dipropylamino group, ⁇ , ⁇ -dibutylamino group and the like.
  • the lower alkanoyl group means an amino group substituted with the lower alkanoyl group, for example, an acetylamino group, a propionylamino group, a butylamino group. A lumino group, a vivaloylamino group and the like.
  • the aroylamino group means an amino group substituted with the aroyl group, and examples thereof include a benzoylamino group, a 1-naphthoylamino group, and a 2-naphthoylamino group.
  • the N-lower alkylaminocarbonyloxy group means an aminocarboxy group substituted by the lower alkyl group, specifically, N-methylaminocarbonyl group, N-ethylaminocarbonyloxy group. And the like.
  • the N, N-di-lower alkylaminocarbonyloxy group means an aminocarbonyl group substituted by the same or different two above-mentioned lower alkyl groups, specifically, ⁇ , ⁇ -dimethylaminocarbonyl And a ⁇ , ⁇ -dimethylaminocarbonyloxy group, a ⁇ -ethyl- ⁇ -methylaminocarbonyloxy group, a ⁇ , ⁇ -dipropylaminocarbonylcarbonyl group, and the like.
  • the protected amidino group means an amidino group protected by a commonly used protecting group, and examples of the protecting group include a t-butoxycarbonyl group, a 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And the like.
  • the protected guanidino group means a guanidino group protected by a commonly used protecting group.
  • the protective group include t-butoxycarbonyl group, 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And a mouth group.
  • Leaving groups are those commonly used in organic synthetic chemistry, and specifically include halogen atoms, tri-lower alkylammonium groups, methanesulfonyloxy groups, trifluoromethanesulfonyloxy groups, p- And a toluenesulfonyloxy group.
  • the compound of the present invention represented by the above formula [1] may be, for example, an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, perchlorate or phosphate; Acid addition salts such as organic acid salts such as P-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate or maleate Or an alkali metal salt such as sodium salt, potassium salt, potassium salt or the like, or an alkaline earth metal salt, and particularly preferably a pharmaceutically acceptable non-toxic salt.
  • the compound of the formula [1] may have stereoisomers depending on the mode of the substituent, but the present invention also includes all of these stereoisomers and a mixture thereof.
  • the compounds represented by [la] to [Id] can be synthesized, for example, according to the following scheme.
  • R 'in [Deprotection] Scheme represents a hydrogen atom, a lower alkyl group, lower alkenyl group, a lower ⁇ Rukiniru group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a Ariru group or Ariru lower alkyl group
  • R 3 It is a hydrogen atom, a lower alkyl group, lower-grade alkenyl group, lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Ariru group, Ariru lower alkyl group, a Arukanoiru group or a lower Aroiru group
  • R 4 is claim Has the same meaning as 1, and
  • R 5 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an
  • ⁇ 3 and ⁇ 3 are the same or different and are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, Cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, pager Child, halo-lower alkyl group, a force Rubamoi Le group, Nyu- mono-lower alkyl force Rubamoiru group, New, Nyu- di-lower alkyl force Rubamoi , Lower
  • a protecting group for a functional group other than the above as a protecting group for a glycol, a normal group such as an isopropylidene group, a cyclohexylidene group, or a benzylidene group may be selected and used according to the reaction conditions. Can be.
  • a usual one such as a methylene group, an isopropylidene group or a cyclohexylidene group can be selected and used according to the reaction conditions.
  • Examples of the carbonyl protecting group include lower alkyl acetal groups such as an ethylene acetal group, a dimethyl acetal group, and a dimethyl ether group, a 1,3-dithiolan-2-yl group, and a 1,3-dithiane-2 group.
  • An ordinary group such as -yl group can be selected and used according to the reaction conditions.
  • the compound of the general formula [la] can be prepared by adding 1,3-dicarbonyl disulfide compound [2] and 1 to 5 equivalents of hydroxylamine or a hydrogen halide salt of hydroxylamine to water or methanol, ethanol, or propanol according to a conventional method.
  • an inert solvent such as lower alcohols or water-containing lower alcohols, etc.
  • the reaction is carried out at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, and the ring is closed.
  • the compound of the general formula [lb] can be prepared according to a conventional method by mixing 1,3-dicarboniuihide compound [2] with 1 to 5 equivalents of hydrazine or hydrazine hydrate without solvent, or water, or methanol, ethanol, propanol or the like.
  • aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as THF, DME and getyl ether, lower fatty acid amides such as DMA.
  • ethers such as THF, DME and getyl ether
  • lower fatty acid amides such as DMA.
  • secondary amine alkali metal salts such as LDA, LHMDS and KHMDS
  • alkali metal hydrides such as lithium hydride, sodium hydride and hydrogenation hydride in an inert solvent.
  • an inorganic base such as sodium methoxide, sodium ethoxide, lower alkali metal alkoxide such as t-butoxycali, or an alkali metal such as sodium carbonate, carbon dioxide rim, etc.
  • an inorganic base such as sodium methoxide, sodium ethoxide, lower alkali metal alkoxide such as t-butoxycali, or an alkali metal such as sodium carbonate, carbon dioxide rim, etc.
  • the compound [lb] is prepared by adding 1 to 10 equivalents of the substituted hydrazine compound of the general formula [4] to a 1,3-dicarbonitrile compound [2] without solvent or water or a lower compound such as methanol, ethanol or propanol.
  • a 1,3-dicarbonitrile compound [2] without solvent or water or a lower compound such as methanol, ethanol or propanol.
  • an inert solvent such as alcoholic or hydrated lower alcoholic, ethers such as THF, 1,4-dioxane and DME, lower fatty acid amides such as DMA. DMF or hydrated lower fatty acid amides. It can be obtained by reacting at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, followed by deprotection if necessary.
  • the compound represented by the general formula [lc] is a glycine ester in an amount of 1 to 5 equivalents to the carboxylic acid compound represented by the general formula [5].
  • the solvent, methylene chloride, in an inert solvent such as a halogenated hydrocarbon, such as black hole Holm, to the boiling point of 0 ° Celsius to solvents, preferably 2 days 30 minutes 10 ° C ⁇ 50 e C is 1 3 equivalents of DPPA, DCC, EDCI ⁇ HC1, after condensation in the usual manner as required condensing agent CDI, etc.
  • the compound of the general formula [7] is converted into 1 to 100 equivalents of a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or the like.
  • a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or the like.
  • Inorganic bases or sodium methoxides such as ⁇ 5 equivalents of secondary amialkali metal salts such as LDA, LHMDS, KHMDS, etc., and 1 ⁇ 5 equivalents of lithium metal hydrides such as lithium hydride, sodium hydride and lithium hydride.
  • alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, t-butoxycali, etc.
  • a lower alcohol solvent such as methanol, ethanol, propanol, isopropanol, t-butanol
  • the reaction is carried out at a temperature of from 0 ° C to the boiling point of the solvent for 30 minutes to 2 hours, and if necessary, deprotected.
  • Y 4 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkynole lower alkyl group, an aryl group, an aryl lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, an aryloxy group
  • a phenyl group optionally having 1 to 3 substituents, or 1 to 3 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents.
  • R 8 and R 9 are the same or different and represent a lower alkyl group or an aryl lower alkyl group;
  • R 10 has the same meaning as R 5 except for a hydrogen atom; and L represents a leaving group.
  • the compound of the general formula [Ie] is obtained by combining the compound of the general formula [20] with 1 to 5 equivalents of the compound of the general formula [8] and 1 to 30 equivalents of a lower fatty acid ammonium salt such as ammonium formate or ammonium acetate. 1 hour to 2 hours at room temperature to the boiling point of the reaction solvent in a lower fatty acid such as formic acid, acetic acid, propionic acid or the like at a temperature of 60 ° C to 110 ° C. React for days and deprotect if necessary.
  • a lower fatty acid ammonium salt such as ammonium formate or ammonium acetate.
  • the compound of the general formula [Ie] may be deprotected, if necessary, from the compound of the general formula [20] to obtain 3 to 30 equivalents of a lower carboxylic anhydride such as acetic anhydride or propionic anhydride at 0 ° C to 100 ° C. C.
  • a lower carboxylic anhydride such as acetic anhydride or propionic anhydride
  • the reaction is carried out at 20.degree. 0 to 80 to 1 hour to 12 hours, and the compound of the general formula [21] is obtained by dehydration and ring closure to obtain a compound of the general formula [21].
  • the compound of the general formula [K] can be obtained by converting the compound of the general formula [20] to a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or butyric anhydride in an amount of 1 to 20 equivalents, preferably in an inert gas atmosphere.
  • a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or butyric anhydride in an amount of 1 to 20 equivalents, preferably in an inert gas atmosphere.
  • the starting compound 7-keto acid derivative [20] can be obtained, for example, by the Friedel-Crafts reaction of the compound [18] and the compound [19].
  • Inorganic bases such as hydrides, or alkaline metal such as t-butyne hydride
  • an inert solvent such as DMF, benzene, toluene, THF, or DME at 0 ° C. to the boiling point of the solvent, preferably 10 ° C.
  • the mixture was reacted at 30 ° C. to 70 ° C.
  • reaction is carried out at 0 ° C. to the boiling point of the solvent, preferably at 10 ° C. to 100 ° C. for 30 minutes to 2 days to obtain a compound of the general formula [16]. For 2 days at 30 ° C to 120 ° C, preferably at 50 ° C to 100 ° C.
  • R 5 when R 5 is a hydrogen atom, it can be produced under the same reaction conditions as described above, except for the step of reacting compound [13] with compound R 1QL .
  • the compound of the general formula [13] is According to the method of N. Cohen et al. [J. Org. Chem. 38, pp. 3229-3239], compound [11] is converted to a compound of the general formula 3-20 equivalents according to the method of J. Org. [12] with 1 to 5 equivalents, preferably 1 to 3 equivalents of an alkali metal hydride such as lithium hydride, sodium hydride, or lithium hydride; or an alkali metal hydride such as t-butoxycali. It can also be obtained by reacting for 1 hour to 2 hours at 50 ° C to the boiling point of the reaction solution in the presence of a metal lower alkoxide or the like.
  • the compound of general formula [lg] can be obtained, for example, by the following method. According to the method of A ⁇ Kosak et al. [J. Am. Chem. Soc., Vol. 76, 4450-4454 (1954)], the general formula [20] was converted. The compound together with 1 to 3 equivalents of diphosphorus pentasulfide and 10 to 30 equivalents of an organic base such as pyridine, picoline, collidine, lutidine, etc., in a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride, etc.
  • the product obtained in each of the above steps can be obtained by a known purification method, such as Purification or isolation can be achieved by single or appropriate combination of chromatography, high performance liquid chromatography, thin layer chromatography, recrystallization, solvent extraction, precipitation, or distillation.
  • the tyrosine kinase inhibitory activity of the compound according to the present invention was measured as follows.
  • A431 cells human epidermoid carcinoma cells, were seeded at a concentration of 5 x 10 4 cells / 0.5 ml Z-well in a 24-well plate using a modified Dulbecco's MEM medium supplemented with 10% fetal bovine serum. % C0 2 in the presence 37 ° C and cultured for 6 days Ru to form a cell layer.
  • the compound according to the present invention inhibits the growth of tumor cells and has an anticancer effect.
  • various forms can be selected as the administration form when the compound of the present invention is used as an antitumor agent, which is known in the art.
  • Pharmaceutical preparations include, for example, liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.
  • these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants.
  • the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.
  • the dose of the compound of the present invention as a tyrosine kinase inhibitor differs depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like.
  • a typical administration method for an adult is oral administration or non-administration.
  • the precipitated pale yellow solid is collected by filtration, dissolved in 100 ml of 1N sodium hydroxide solution, washed twice with 50 ml of diethyl ether, and adjusted to pH 2 with concentrated hydrochloric acid at 0 ° C. Analysis The resulting colorless solid is washed twice with 100 ml of water and then twice with 100 ml of ethanol, and dried under reduced pressure to obtain 11.7 g of 3- (3,4-dimethoxybenzoyl) propionic acid as a colorless solid.
  • the aqueous layer is adjusted to pH 2 with 6N hydrochloric acid, extracted twice with 50 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate.
  • 6-Hydroxynicotinic acid 500 mg
  • silver oxide 1.84 g
  • toluene 30 ml
  • benzyl bromide 1.07 ml
  • the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.
  • reaction mixture again - a 78 e C acetic acid Echiru 40ml and 0.01N HCl 10ml and added to separate liquid cooled to a residue after concentration under reduced pressure was added methanol 0.5ml organic layer was washed with water and saturated brine, anhydrous magnesium sulfate The residue obtained by drying and concentration under reduced pressure is purified by Sephadex TM LH-20 column chromatography (methanol) to obtain 13.8 mg of the title compound as white crystals.
  • the reaction solution was cooled again to -78 ° C, 0.5 ml of methanol was added, and the mixture was concentrated under reduced pressure.40 ml of ethyl acetate and 10 ml of 0.01 N hydrochloric acid were added to the residue, and the mixture was separated. The organic layer was washed with water and saturated saline, and then anhydrous magnesium sulfate And concentrated under reduced pressure to give a residue, which is purified by Sephadex TM LH-20 column chromatography (methanol) to obtain 12.4 mg of the title compound as white crystals.
  • Examples 3 to 8 are synthesized by synthesizing a 1,3-diketone compound as a raw material in the same manner as in Reference Example 1, and cyclizing to a pyrazole derivative with hydrazine and deprotecting in the same manner as in Example 2. .
  • Example 22 the compounds of the following Examples 22 to 86 were prepared by condensing a corresponding carbonyl compound of the general formula [8] and a 7-keto acid derivative of the general formula [21] in the presence of a base, followed by ring closure. It is synthesized by a method of treating with boron halide.
  • Example 91 the compound was synthesized from 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone and 4-hydroxy-3-hydroxymethylbenzaldehyde.
  • Example 97 to 115 were obtained in the same manner as in Example 96 by obtaining a 5-substituted-2 (3H) -thiophenone derivative and then condensing each with the corresponding carbonyl compound of the general formula (8) under acidic conditions. And, if necessary, deprotected with boron tribromide.
  • Example 117 to 123 The compounds of Examples 117 to 123 are synthesized in the same manner as in Example 116.
  • the methyl ester 136mg was dissolved in methanol 5 ml, addition of 2N hydroxide sodium ⁇ anhydrous solution lml, stirred for 30 minutes at room temperature, adjust the P H of the reaction solution to 2-3 with ice-cooling under 1N hydrochloric acid, acetic Echiru Extract with 80 ml.
  • the organic layer is washed with a small amount of saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 130 mg of 4-oxo-4- (1-phenyl-2-pyridone-5-yl) butyric acid. .

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Abstract

L'invention concerne un composé représenté par la formule (I) et ses utilisations. Ce composé inhibe fortement une tyrosine kinase et supprime la croissance des cellules tumorales, ce qui le rend utile dans les applications médicinales, avec des perspectives intéressantes d'emploi comme agent antitumoral.
PCT/JP1994/001368 1993-08-20 1994-08-18 Inhibiteur de la tyrosine kinase WO1995006032A1 (fr)

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EP0713869A3 (fr) * 1994-11-25 1996-06-19 Lonza Ag
WO1998056756A1 (fr) * 1997-06-12 1998-12-17 Cheil Jedang Corporation Derives acides des catecholamines et compositions pharmaceutiques les contenant
KR100332273B1 (ko) * 1995-07-26 2002-06-20 디. 제이. 우드, 스피겔 알렌 제이 엔-(아로일)글리신하이드록삼산유도체및이와관련된화합물
US6410540B1 (en) 1998-08-28 2002-06-25 Scios, Inc. Inhibitors of p38-αkinase
US6541477B2 (en) 1999-08-27 2003-04-01 Scios, Inc. Inhibitors of p38-a kinase
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US7163945B2 (en) 2004-04-29 2007-01-16 Pharmix Corp. Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
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US7199126B2 (en) 2004-04-29 2007-04-03 Pharmix Corporation Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
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US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
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EP0713869A3 (fr) * 1994-11-25 1996-06-19 Lonza Ag
US5760236A (en) * 1994-11-25 1998-06-02 Lonza, Ltd. Di and trisubstituted pyridines
KR100332273B1 (ko) * 1995-07-26 2002-06-20 디. 제이. 우드, 스피겔 알렌 제이 엔-(아로일)글리신하이드록삼산유도체및이와관련된화합물
WO1998056756A1 (fr) * 1997-06-12 1998-12-17 Cheil Jedang Corporation Derives acides des catecholamines et compositions pharmaceutiques les contenant
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US6869969B2 (en) 1998-08-07 2005-03-22 Chiron Corporation Estrogen receptor modulators
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US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
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US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
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US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
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JP2017518345A (ja) * 2014-06-17 2017-07-06 サントル ナスィオナル ド ラ ルシェルシュ スィアンティフィク（セ．エン．エル．エス．） がん及び過剰な血管新生に関連する疾患を治療するための新規の３−アリール−４−カテコール−ピロール−ｎ−プロパノール化合物及びその誘導体の使用

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