WO1990002119A1 - Derives de 1,2,3,4-tetrahydro-isoquinoline - Google Patents

Derives de 1,2,3,4-tetrahydro-isoquinoline Download PDF

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Publication number
WO1990002119A1
WO1990002119A1 PCT/JP1989/000825 JP8900825W WO9002119A1 WO 1990002119 A1 WO1990002119 A1 WO 1990002119A1 JP 8900825 W JP8900825 W JP 8900825W WO 9002119 A1 WO9002119 A1 WO 9002119A1
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group
phenyl
substituted
compound
methyl
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PCT/JP1989/000825
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English (en)
Japanese (ja)
Inventor
Kiyofumi Ishikawa
Takashi Hayama
Takehiro Fukami
Ikuko Takahashi
Keiko Miura
Akira Okuyama
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Banyu Pharmaceutical Co., Ltd.
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Publication of WO1990002119A1 publication Critical patent/WO1990002119A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Definitions

  • the present invention relates to a novel 1,2,3,4-tetrahydroisoquinoline derivative having an effect of enhancing the antitumor effect of an anticancer agent on various cancer cells including multidrug-resistant cancer cells and useful for treating cancer It is about.
  • the present inventors have conducted intensive studies on compounds that enhance the antitumor effect of anticancer drugs against various cancer cells including multidrug-resistant cancer cells. As a result, the compounds represented by the following general formula [I] showed excellent antitumor effects. (4) The present invention has been completed by discovering that it exhibits strong action.
  • the present invention has the general formula
  • R 2 represents a lower alkyl group or a methylene group together with R 1 or R 3
  • R 1 and R 3 each represent a lower alkyl group or a group together with R 2
  • the aryl lower alkyl group is a group in which a hydrogen atom on an aromatic ring is a lower alkyl group, a lower alkyloxy group, an N-benzyl-N-methylamino group, a halogen atom, an amino group, an N, N-di-lower alkylamino Group, (N, N-di-lower alkylamino) methyl group, (N-benzyl-N-methylamino) methyl group, morpholinomethyl group, nitro group, It may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a tylenedioxy group and a lower alkyloxycarbonyl group.
  • an unsubstituted benzyl group is excluded, and an aryl group (where the hydrogen atom on the aromatic ring is a halogen atom, lower alkyloxy group, nitro group, amino group, ⁇ , ⁇ -di-lower) It may be substituted with an alkylamino group or a lower alkyloxycarbonyl group, provided that an unsubstituted phenyl group is excluded, or a compound represented by the formula:-(CHjm-A (where A is a halogen atom, a lower alkylthio group) Group, lower alkylsulfinyl group, lower arylsulfonyl group, aryl lower alkylthio group, aryl lower alkyl sulfinyl group, aryl lower alkylsulfonyl group, arylaryl, arylsulfinyl group, arylsulfonyl group, arylyl A lower alkyloxy
  • R 4 represents a lower alkyl group
  • a i represents a phenyl group which may be substituted by 1 to 3 lower alkyloxy groups
  • II represents 0 to 2].
  • 4-tetrahydroisoquinoline derivatives or It is intended to provide a pharmaceutically acceptable acid addition salt thereof and a use thereof as an agent for enhancing the antitumor effect of the anticancer agent.
  • a lower alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. -Butyl, tert-butyl, pentyl, hexyl, etc.
  • the lower alkenyl group means a linear or branched alkenyl group having 1 to 6 carbon atoms, for example, a vinyl group, an aryl group, an isopropyl group, a 2-butenyl group, a 3-butenyl group, a 2-butenyl group.
  • An aryl lower alkenyl group refers to a lower alkenyl group in which a hydrogen atom on an aromatic ring is substituted with an aromatic hydrocarbon group which may be substituted with a lower alkyloxy group, for example, a styryl group, a cinnamyl group, or a 4-phenyl- 3-butenyl group, 5-phenyl-4-pentenyl group, 3- (1-naphthyl) -2-propenyl group, 2-methoxycinnamyl group, 3-methoxycinnamyl group, 4-methoxycinnamyl group, 4-ethoxycinnamyl group, 4- (4-methoxyphenyl) -3-butenyl group, etc.
  • An aryl lower alkyl group is a group in which a hydrogen atom on an aromatic ring is a lower alkyl group, a lower alkyloxy group, an N-benzyl-N-methylamino group, a halogen atom, an amino group, an N, N-di-lower alkylamino group, (N , N-di-lower alkylamino) methyl group, (N-benzyl-N-methylamino) tyl group, morpholinomethyl group, nitro group, methylenedioxy group and lower alkyloxycarponyl group
  • a lower alkyl group (excluding an unsubstituted benzyl group) substituted with an aromatic hydrocarbon group which may be substituted with the same or different 1 to 3 substituents, for example, 1- Phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group
  • An aryl group is an aromatic group in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group, an N, N-di-lower alkylamino group or a lower alkyloxycarbonyl group. It means a hydrocarbon group (excluding an unsubstituted phenyl group), for example, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methoxyphenyl group.
  • a lower alkyloxy group is a straight-chain or branched alkyl having 1 to 6 carbon atoms. It means a methoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the N, N-di-lower alkylamino group means an amino group substituted with two same or different lower alkyl groups, such as N, N-dimethylamino group, N-ethyl-N-methylamino group, , N-ethylamino group, N-ethyl-N-propylamino group, N, N-dipropylamino group, ⁇ , ⁇ -dibutylamino group and the like.
  • ⁇ , ⁇ -di-lower alkylaminomethyl group means a methyl group substituted by ⁇ , ⁇ -di-lower alkylamino group as defined above, for example, ⁇ , ⁇ -dimethylaminomethyl group, ⁇ - Examples thereof include ethyl- ⁇ -methylaminomethyl group, ⁇ , ⁇ -ethylaminomethyl group, ⁇ , ⁇ -dipropylaminomethyl group, ⁇ , ⁇ -dibutylaminomethyl group and the like.
  • the lower alkyloxycarbonyl group means an alkyloxycarbonyl group having 2 to 7 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like.
  • the lower alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, and a butylthio group.
  • the lower alkylsulfinyl group means a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms, such as a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, And a tylsulfinyl group.
  • the lower alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, for example, mesyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group. Groups and the like.
  • An aryl lower alkylthio group is an aromatic hydrocarbon group in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group, or an N, N-di-lower alkylamino group.
  • a substituted lower alkylthio group means, for example, benzylthio, 2-phenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 4-chlorobenzylthio, 2-methoxybenzylthio, etc. And 3-methoxybenzylthio, 4-methoxybenzylthio, 4-nitrobenzylthio, 4-aminobenzylthio, 4- (N, N-dimethylamino) benzylthio and the like.
  • An aryl lower alkylsulfinyl group is an aromatic carbon atom in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group or an N, N-di-lower alkylamino group.
  • a lower alkylsulfinyl group substituted with a hydrogen group such as benzylsulfinyl group, 2-phenylethylsulfinyl group, 3-phenylpropylsulfinyl group, 4-phenylbutylsulfinyl group, Benzylsulfinyl, 4-methoxybenzylsulfinyl, 4-nitrobenzylsulfinyl, 4-aminobenzylsulfinyl, 4- (N, N-dimethylamino) benzylsulfinyl, etc. It is.
  • An aryl lower alkylsulfonyl group is a hydrogen atom on an aromatic ring which is Lower alkylsulfonyl group substituted by an aromatic hydrocarbon group which may be substituted by a substituent, a lower alkyloxy group, a nitro group, an amino group or an N, N-di-lower alkylamino group.
  • An arylthio group refers to a phenyl or naphthylthio group in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group or an N, N-di-lower alkylamino group.
  • a phenylthio group refers to a phenyl or naphthylthio group in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group or an N, N-di-lower alkylamino group.
  • 2-nitrophenylthio group, 3-nitrophenylthio group, 4-nitrophenylthio group, 4-aminophenylthio group, 4- (N, N-dimethylamino) phenylthio group and the like can be used.
  • Arylsulfinyl group is phenyl or naphthyls in which a hydrogen atom on the aromatic ring may be replaced by a halogen atom, lower alkyloxy group, nitro group, amino group, N, N-di-lower alkylamino group Luffinyl group, such as enylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfi
  • An arylsulfonyl group refers to a phenyl or naphthylsulfonyl group in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, lower alkyloxy group, nitro group, amino group, N, N-di-lower alkylamino group.
  • phenylsulfonyl 1-naphthylsulfonyl, 2-naphthylsulfonyl, 4-chlorophenylsulfonyl, 4-methoxyphenylsulfonyl, 4-nitrophenylsulfonyl, 4- Aminophenylsulfonyl group, 4- (N, N-dimethylamino) phenylsulfonyl group and the like can be used.
  • An aryl lower alkyloxy group is an aromatic hydrocarbon in which a hydrogen atom on an aromatic ring may be substituted with a halogen atom, a lower alkyloxy group, a nitro group, an amino group, an N, N-di-lower alkylamino group.
  • a lower alkyloxy group substituted with a group such as benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-chlorobenzyloxy, 2-methoxybenzyloxy, 3 -Methoxybenzyloxy, 4-methoxybenzyloxy, 3-nitrobenzyloxy, 4-nitrobenzyloxy, 4-aminobenzyloxy, 4- (N, N-dimethylamino) benzyloxy, etc. Is mentioned.
  • An aryloxy group means a phenoxy or naphthoxy group in which a hydrogen atom on the aromatic ring may be represented by a halogen atom, a lower alkyloxy group, a nitro group, an amino group, an N, N-di-lower alkylamino group.
  • a hydrogen atom on the aromatic ring may be represented by a halogen atom, a lower alkyloxy group, a nitro group, an amino group, an N, N-di-lower alkylamino group.
  • phenoxy, 1-naphthoxy, 2-naphthoxy, 4-chlorophenoxy, 4-methoxyphenoxy, 4-nitrophenoxy, 4-aminophenoxy, 4- (N, N-dimethylamino) phenoxy Motoki is fisted.
  • N-benzyl-N-lower alkylamino group means an amiso group which is S-substituted with a benzyl group or a lower alkyl group, such as an N-benzyl-N-methylamino group, -Benzyl-N-ethylamino group, N-benzyl-N-propylamino group and the like.
  • N-phenyl-N-lower alkylamino group means an amino group substituted with a phenyl group and a lower alkyl group, for example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N- A phenyl-N-propylamino group, an N-butyl-N-phenylamino group and the like.
  • di-lower alkyloxyphosphinoyl group means a dialkyloxyphosphinoyl group having two identical lower alkyloxy groups, such as dimethoxyphosphinoyl group and diethoxyphosphinoyl group. And dipropoxyphosphinoyl groups, dibutoxyphosphinoyl groups and the like.
  • the leaving group that can be substituted with an aryloxy group includes a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an alkylsulfonyloxy group such as a methanesulfonyloxy group, or a phenylsulfoninoleoxy group, P -Arylsulfonyloxy groups such as trisulfonyloxy groups.
  • Hue optionally substituted with 1 to 3 lower alkyloxy groups examples include a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 3,4-dimethoxyphenyl group, a 3,4,5-trimethoxyphenyl group, 4-ethoxyphenyl group, 4_propoxyphenyl group, 4-isopropoxyphenyl group and the like.
  • the method for producing the compound according to the present invention is described below.
  • the compound of the present invention [1] has the general formula
  • R 21 represents the combined such connexion methylene group or with R 11 or R 31 or a lower alkyl group
  • R 11 and R 31 indicate carded is either a lower alkyl group
  • R 4 represents a lower alkyl group
  • Ar represents a phenyl group which may be substituted by 1 to 3 lower alkyloxy groups
  • R 5 described below is an aryl group, a base and metallic copper or a monovalent or divalent copper salt
  • R 5 is a lower alkenyl group, an aryl lower alkenyl group (the aryl lower alkenyl group may have a hydrogen atom on the aromatic ring substituted by a lower alkyloxy group), an aryl lower alkyl group (the aryl lower alkyl group)
  • the hydrogen atom on the aromatic ring is a lower alkyl group, lower alkyloxy group, N-benzyl-N-methylamino group, halogen atom, amino group, N, N-di-lower alkylamino group, (N, N-di- 1 to 3 identical or different substituents selected from the group consisting of lower alkylamino) methyl, (N-benzylmethylamino) methyl, morpholinomethyl, nitro, methylenedioxy and lower alkyloxycarbonyl (Except for unsubstituted benzyl groups), aryl groups (where the hydrogen atom on the aromatic ring is halogen) Child, a
  • an unsubstituted phenyl group is excluded, or a compound represented by the formula: (CH 2 ) mA (where A is a halogen atom, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aryl lower alkylthio group)
  • A is a halogen atom, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an arylthio group
  • an arylsulfinyl group, an arylsulfonyl group, an arylthio group, an arylsulfinyl group, an arylsulfonyl group, an aryl lower alkyloxy group or an aryloxy group the aryl lower alkylthio group
  • Lower alkyloxy group, nitro group, amino group May be substituted with an N, N-di-lower alkylamino group), N-benzyl-N-lower alkylamino group, N-phenyl-N-lower alkylamino group, N, N- X represents a di-lower alkylamino group, di-lower alkyloxyphosphinoyl group or dibenzyloxyphosphinoyl group, and m represents 2 to 4); in general, it can be prepared by reacting a compound represented by] a leaving group substitutable by Ariruokishi group, and a group R 5 which is introduced into the new on isoquinoline ring elimination or substitution If it has a possible halogen atom, it may be dehydrohalogenated by treatment with a base, if desired, or a thiol compound, hydroxyl compound, secondary amine, trialkyl phosphite, dialkyl phosphite, dibenzyl
  • the compound of the present invention represented by the above general formula [I] includes a phenolic compound represented by the general formula [ ⁇ ] and a phenolic compound represented by the general formula [ ⁇ ] except for a compound in which R 1 or R 3 is an aryl group.
  • the compound can be produced by subjecting a compound represented by the formula [ ⁇ ] (excluding a compound in which R 5 is an aryl group) to a condensation reaction in the presence of a base.
  • the condensation reaction is preferably performed using a suitable solvent, and examples of the solvent include acetone, acetonitrile, methanol, benzene, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and the like.
  • Examples of the base used in the reaction include inorganic bases such as alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydroxides, alkali metal hydrides, and alkali metal alkoxides.
  • the reaction is carried out by dissolving compound [ ⁇ ] in the above solvent, adding an appropriate base, and further adding compound [ ⁇ ] at 0 ° C to the boiling point of the solvent, preferably at room temperature to 6 CTC for 30 minutes to 24 hours. It can be performed by reacting.
  • the amount of the compound [ ⁇ used is from 1 to L0 mol, preferably from 1 to L.2 mol, per 1 mol of the compound [ ⁇ ].
  • the amount of the inorganic base to be used is 1 to 10 mol, preferably 1 to 2.4 mol, per 1 mol of compound [ ⁇ ].
  • a phenolic compound [ ⁇ ] and a compound [ ⁇ ] can be produced by performing a so-called Ullnmnn reaction in a suitable solvent in the presence of a copper catalyst and a base.
  • a suitable solvent eg, pyridine, collidine, quinoline, 90/02119 16 Dissolve compound [ ⁇ ] in tilformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, diglyme, etc.
  • a suitable inorganic base eg, alkali metal carbonate, alkali hydroxide
  • a suitable copper catalyst eg, copper powder, cuprous halide, cupric halide, cuprous oxide, cupric oxide, copper carbonate, copper acetate, etc.
  • the reaction can be carried out by reacting compound [m] at locrc to the boiling point of the solvent for 1 hour to 3 days.
  • the amount of each compound used is 1 to 5 moles, preferably 1 to 2 moles, for each of the inorganic base, the copper catalyst, and the compound [based on the compound [ ⁇ ] ⁇ mol.
  • a compound represented by the formula wherein R 1 or R 3 is represented by the formula: 4C3 ⁇ 4X 1 (wherein X 1 represents a halogen atom and m represents 2 to 4) [ ⁇ ] can be converted to a compound in which R 1 or R 3 is a lower alkenyl group such as a vinyl group, an aryl group or a 3-butenyl group through dehydrogenation by treatment with a base. it can.
  • the dehydrohalogenation reaction is carried out using a solvent that does not adversely affect the reaction, for example, an alcohol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene, benzene, or the like, using a suitable base such as alkali metal hydroxide,
  • a suitable base such as alkali metal hydroxide
  • the reaction is carried out by allowing a base such as an alkali metal alkoxide, triethylamine, 1,8-diazabicyclo [5.4.0] -7-pentadecene to act at 0 to the boiling point of the solvent, preferably at room temperature to 60 ° C for 30 minutes to 10 hours. be able to.
  • the amount of the base to be used is 1-10 mol, preferably 1-1.5 mol, per 1 mol of compound [].
  • the compound of the present invention [[] having the above halogen atom can be used as a nucleophilic reagent such as a thiol compound, a hydroxyl group compound, a secondary amine, a trialkyl phosphite, a dialkyl phosphite, or a dibenzyl phosphite.
  • a nucleophilic reagent such as a thiol compound, a hydroxyl group compound, a secondary amine, a trialkyl phosphite, a dialkyl phosphite, or a dibenzyl phosphite.
  • R 1 or R 3 is a group represented by the following formula: ⁇ cH 2 ) i A 1 (where A 1 is a lower alkylthio group, an aryl lower alkylthio group, an arylthio group, an aryl lower alkyloxy group, or an aryloxy group (the aryl lower alkylthio group) , Arylthio, aryl lower alkyloxy and aryloxy groups have hydrogen atoms on the aromatic ring substituted by halogen atoms, lower alkyloxy groups, nitro groups, amino groups or ⁇ , ⁇ -di-lower alkylamino groups.
  • a suitable solvent eg, alcohol, dimethylformamide, dimethylsulfoxide, benzene, toluene, tetrahydrofuran or the like
  • a thiol compound eg., a hydroxyl compound, a secondary amine, a trialkyl phosphite
  • a suitable base eg, alkali metal carbonate, alkali metal hydroxide, alkali metal alkoxide, alkali metal hydride, etc.
  • the used amount of the nucleophilic reagent is 1 mole to a large excess with respect to 1 mole of the compound [ ⁇ ], and the used amount of the base is 1 to 1.5 mole.
  • the compound [I ′ ′] in which the group represented by R 1 or R 3 has a sulfide group is obtained by converting this group to a sulfinyl group using an oxidizing agent. Or a sulfonyl group.
  • a suitable oxidizing agent eg, methax oral perbenzoic acid, hydrogen peroxide
  • Water, tetrabutylammonium-oxone, etc. can be added, and the reaction can be carried out at 0 to 60 ° C, preferably at 0 ° C to room temperature for 1 hour to 2 days to oxidize.
  • the amount of the oxidizing agent to be used is 1 to 1.2 moles for sulfinylation and 2 to 3 moles for sulfonylation with respect to 1 mole of the compound [] '].
  • the compound [ ⁇ ′′] in which the group represented by R 1 or R 3 has a double- ended group is converted to a primary amino group using a reducing agent. This can be reduced to a group, and further reduced to a dimethylamino group by a reductive alkylation reaction.
  • tin chloride ( ⁇ ) is added to the nitro compound [ ⁇ ′′] in an appropriate solvent (eg, alcohol, ethyl acetate), and the mixture is allowed to act at 70 ° C. for 30 minutes to 2 hours.
  • an appropriate solvent eg, alcohol, ethyl acetate
  • the use amount of tin chloride (III) is 3 to 10 mol, preferably: to 5 mol, per 1 mol of the compound [III,].
  • a suitable solvent for example, acetonitrile, acetic acid, tetrahydrofuran, etc.
  • a suitable reducing agent for example, sodium borohydride, sodium borohydride, formic acid.
  • the amino group can be converted to a dimethylamino group by adding the compound at room temperature to the solvent for 2 to 10 hours.
  • the amount of formaldehyde used is 2 to 10 moles per mole of primary amino compound, and the amount of reducing agent used is 3 to 10 moles.
  • the product obtained in each of the above steps can be purified by a known purification method such as chromatography, recrystallization, solvent extraction, precipitation, or distillation alone or in an appropriate combination. It can be separated and purified.
  • the phenolic compound [ ⁇ ] as a raw material is produced according to a known method [for example, see Chemical 'and Pharmaceutical' Brutin ((:) 1601.?1131> 111.8111.), (6), 879 (1967)). That is, the general formula
  • Ar represents a phenyl group which may be substituted with 1 to 3 lower alkyloxy groups, ⁇ represents 0 to 2, and X 2 represents a halogen atom, a hydroxyl group, or a lower alkyloxy group.
  • R 23 represents a connexion methylol alkylene group with a lower alkyl group, or R 13 or R 33, or R 13 and R 33 represents any one of a lower alkyl group, with P, Z3 A methylene group and the other a benzyl group, and Ar and ⁇ have the above-mentioned meanings].
  • the present compound [ ⁇ ] is subjected to ⁇ -alkylation with a lower alkyl halide, and then the imidium salt is reduced with a reducing agent such as sodium borohydride to give a 1,2,3,4-tetrahydro 1 isoquinoline derivative.
  • the phenolic compound represented by the general formula [ ⁇ ] is obtained through debenzylation by the action of an acid such as hydrochloric acid or catalytic hydrogenation.
  • the compound is reduced with a reducing agent such as sodium borohydride, and the resulting 1,2,3,4-tetrahydroisoquinoline derivative is reacted with an alkyl halide to undergo ⁇ -alkylation.
  • the phenolic compound represented by the general formula [ ⁇ ] can be obtained by debenzylation by action or catalytic hydrogenation.
  • the raw material compound [ ⁇ ] a commercially available compound can be used. However, if necessary, the hydroxyl group of a commercially available alcohol or an alcohol obtained by a known method can be removed by an ordinary method. It is also possible to use a compound converted to a leaving group [Journal of the American Chemical Society] (J. Am. Chem. Soc.), ⁇ , 2540 (1938)]. Alcohols that can be used as a raw material include, for example, reducing the corresponding carboxylic acids commercially available or produced by a known method with a reducing agent such as aluminum hydride, or reducing the carboxylic acids after converting them into esters. [Journal of Medicine 'Chemistry'-(J. Med.
  • dihaloalkanes can be used as they are, or can be converted to various halides by substituting one of the halogen atoms with a nucleophilic reagent in the presence of an appropriate base, and then use them! : Ger. (East) DD202, 690, Chemical 'Chemical Abstracts, 101, 6798S (1984); Jar-Nal' ob 'Organic' Chemistry (J. 0rg. Chem.),
  • the sulfide group can be converted to a sulfinyl group or a sulfonyl group with an appropriate oxidizing agent and used. Vol., P. 642 (1963); Journal 'Ob di American' Chemical 'Society (J. Am. Chem. Soc), 111, 258 (1989)] B
  • Adriamicin potentiates the antitumor effect of multidrug-resistant cancer cells P388 / ADR, a multidrug-resistant cancer cell that has acquired resistance to anti-cancer drugs such as adriamycin, daunomycin, vincristine, vinblastine, and actinomycin D, for 3 days with 0.5AM of each test drug and a prescribed amount of ADR Cultured. The cell number is then measured and ADR IC 5 . The value (the concentration of ADR that inhibits the growth of cancer cells by 50%) was determined, and the dose modifying factor (hereinafter abbreviated as DMF), which is an index of the antitumor effect enhancing effect, was calculated according to the following formula. The result is first 3 '. One - P388 / ilDi this pair for ADR single IC S.
  • DMF dose modifying factor
  • ADR IC 6 for drug combination against P388 / ADR Each test drug alone showed almost no growth inhibition in ⁇ . ⁇ ⁇ ⁇ .
  • the compound of the present invention increased the sensitivity of multidrug-resistant cancer cells to ADR at 0.5%, and the effect was superior to that of the control drug, verapamil.
  • the compound according to the present invention exhibited ADK in multidrug-resistant cancer cells even at a low concentration at which the control drug verapamil had no significant effect, that is, at 0.1 iM. Has the effect of increasing intracellular accumulation of. Table 2
  • the compound of the present invention has an excellent antitumor effect enhancing effect on multidrug-resistant cancer cells as compared with known compounds. On the other hand, it is expected to provide more effective treatment.
  • a substance having an antitumor effect and a 1,2,3,4-tetrahydroisoquinoline derivative having an antitumor effect enhancing effect on multidrug-resistant cancer cells can be administered separately from each other. It is also possible to mix both in advance and to administer them simultaneously.
  • oral preparations such as tablets, capsules, powders, granules or liquids, or solutions or suspensions, for example.
  • Sterile liquid parenteral preparations Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives.
  • additives include sugars such as lactose and glucose, flours such as corn, wheat and rice, fatty acids such as stearic acid, inorganic salts such as magnesium aluminate metasilicate and calcium phosphate calcium phosphate, and the like.
  • synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol, for example, fatty acid salts such as calcium stearate or magnesium stearate, for example, stearyl alcohol or benzyl alcohol Alcohols such as coal, synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose, and other commonly used additives such as water, gelatin, talc, vegetable oil, and arabia gum.
  • fatty acid salts such as calcium stearate or magnesium stearate
  • stearyl alcohol or benzyl alcohol Alcohols such as coal
  • synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose
  • other commonly used additives such as water, gelatin, talc, vegetable oil, and arabia gum.
  • Solid tablets such as tablets, capsules, granules and powders generally contain from 0.1 to 100% by weight, preferably from 5 to 100% by weight of active ingredient.
  • Liquid preparations can be prepared by using appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil or sesame oil, and suspensions, syrups or injections. It is manufactured in the form of an agent or the like.
  • Suitable solvents for parenteral intramuscular, intravenous or subcutaneous injection include, for example, distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological saline, and glucose.
  • An aqueous solution, ethanol, a liquid for intravenous injection for example, an aqueous solution such as sodium citrate and sodium ⁇ :]
  • an electrolyte solution for intravenous drip infusion and intravenous injection
  • a mixed solution thereof are included.
  • these injections may be in the form of a powder which has been dissolved in advance or a powder to which an appropriate additive has been added, which is dissolved at the time of use.
  • These injections usually contain 0.1 to 10% by weight, preferably 1 to 5% by weight, of the active ingredient.
  • Liquid preparations such as suspensions or syrups for oral administration contain 0.5 to 10% by weight of active ingredient.
  • the dosage of the antitumor effect enhancer of the present invention varies depending on the age, health condition, body weight, or symptoms of the patient, but is 0.1 to 10 mg / kg per day for adults by parenteral administration, or oral.
  • the dose is 0.5 to 50 ing / kg for adults per day after administration.
  • the title compound is obtained as a colorless oil in the same manner as in Example 1, using Compound 1 and 4-butyl butylsulfonylbenzene. Yield 64%.
  • IR (neat, cm 1 ): 2938, 1605, 1515, 1497, 1467, 1419, 1371, 1245, 1176, 1119, 1080,
  • Example 1 8- [3- (N-benzyl- ⁇ '-methylaminomethyl) benzyloxy] -6,7-dimethyl
  • Example 1 was prepared using 1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline compound 1 and N-benzyl-3-culomethylmethylbenzylamine hydrochloride. To give the title compound as a colorless oil. Yield 79
  • the title compound is obtained as a pale yellow oil in the same manner as in Example 1 using compound 1 and 3,4-dimethoxybenzyl chloride. Yield 45 ° / 0 .
  • IR (neat, cm 1 ): 2932, 1605, 1584, 1515, 1497, 1452, 1245, 1119, 1089, 1038, 801,
  • IR (neat ', o3 ⁇ 4): 2944, 1608, 1518, 1464, 1344, 1245, 1179, 1119, 1047, 1008, 852, 750
  • IR (chamber t, cm): 2956, 1605, 1584, 1515, 1497, 1344, 1245, 1176, 1122, 1038, 825,
  • IR (neat, cm 1 ): 2932, 1611, 1584, 1461, 1344, 1302, 1242, 1179, 1122, 1038, 822,
  • IR (CHC1 3, cm 1) 2938, 1611, 1584, 1525, 1458, 1344, 1317, 1236, 1179, 1113, 1062, 858,747
  • IRCneat, cm 2938, 1719, 1611, 1503, 1463, 1344, 1230, 1161, 1104, 1071, 846, 762
  • Example 105 90% ethanol 3 ⁇ was added to the compound lg of Example 67, and distilled water for injection containing 12 in J2 of propylene glycol, 2 g of citric acid and 0.3 g of sodium citrate was added thereto, and the total amount of the injection was 600 ID £.
  • Example 105 90% ethanol 3 ⁇ was added to the compound lg of Example 67, and distilled water for injection containing 12 in J2 of propylene glycol, 2 g of citric acid and 0.3 g of sodium citrate was added thereto, and the total amount of the injection was 600 ID £.
  • Example 105 90% ethanol 3 ⁇ was added to the compound lg of Example 67, and distilled water for injection containing 12 in J2 of propylene glycol, 2 g of citric acid and 0.3 g of sodium citrate was added thereto, and the total amount of the injection was 600 ID £.
  • Example 105 90% ethanol 3 ⁇ was added to the compound lg of Example 67, and distilled water
  • Example 67 The ingredients of Example 67 were mixed in a ratio of 100 g of the compound of Example 67, lactose 200 g, Avicel 50 g, corn starch 46 g and magnesium stearate 4 g, and compression-molded according to a conventional method. Make tablets. Industrial applications
  • the 1,2,3,4-tetrahydroisoquinoline derivative of the present invention has a stronger antitumor effect on various types of cancer cells, including multidrug-resistant cancer cells, than known compounds. It is expected to be very useful in '

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Abstract

Dérivés de 1,2,3,4-tétrahydro-isoquinoline représentés par la formule (I) et agents de potentialisation de l'effet antitumoral contenant ces composés en tant qu'ingrédients actifs. Dans la formule, R2 représente un groupe alkyle inférieur ou, lorsqu'il est combiné avec R1 ou R3, il représente un groupe méthylène, un élément parmi R1 ou R3 représente un groupe alkyle inférieur ou, lorsqu'il est combiné avec R2, il représente un groupe méthylène, et l'autre représente un groupe alcényle inférieur, un groupe alcényle inférieur-aryle substitué ou non substitué, un groupe alkyle inférieur-aryle substitué ou non substitué (à condition que l'on omette un groupe phényle non substitué), un groupe aryle substitué ou non substitué (à condition que l'on omette un groupe phényle non substitué), ou un groupe représenté par -(CH¿2?)m-A (où A représente un atome d'halogène, un groupe alkylsulfonyle inférieur, un groupe alkylthio inférieur-aryle substitué ou non substitué, un groupe alkylsulfinyle inférieur-aryle substitué ou non substitué, un groupe alkylsulfonyle inférieur-aryle substitué ou non substitué, un groupe arylthio substitué ou non substitué, un groupe arylsulfinyle substitué ou non substitué, un groupe arylsulfonyle substitué ou non substitué, un groupe alkyloxy substitué ou non substitué ou un groupe aryloxy substitué ou non substitué, un groupe N-benzyle-N(alkyle inférieur)amino, un groupe N,N-di(alkyle inférieur)amino, un groupe di(alkyloxy inférieur)phosphinoyle ou un groupe dibenzyloxyphosphinoyle, et m représente 2 ou 4), R?4¿ représente un groupe alkyle inférieur, Ar représente un groupe phényle éventuellement substitué par 1 à 3 groupes alkyloxy inférieur, et n représente 0, 1 ou 2.
PCT/JP1989/000825 1988-08-18 1989-08-15 Derives de 1,2,3,4-tetrahydro-isoquinoline WO1990002119A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501693A1 (fr) * 1991-02-27 1992-09-02 Banyu Pharmaceutical Co., Ltd. Dérivés d'isoquinoleine
US5362736A (en) * 1991-02-27 1994-11-08 Banyu Pharmaceutical Co., Ltd. Isoquinoline derivatives
US5446164A (en) * 1993-02-25 1995-08-29 Banyu Pharmaceutical Co., Ltd. Process for preparing 6,7-dialkoxy-3,4-dihydroisoquinolin-8-ol
WO2002051842A1 (fr) * 2000-12-23 2002-07-04 F. Hoffmann-La Roche Ag Derives de tetrahydropyridine, leur preparation et leur utilisation en tant qu'inhibiteurs de proliferation cellulaire
WO2003077874A2 (fr) * 2002-03-13 2003-09-25 The University Of Tennessee Research Foundation Composes tetrahydroisoquinoleine substitues, procedes de preparation et utilisation de ceux-ci
JP2007528877A (ja) * 2004-03-12 2007-10-18 アナリットコン エス アー Ｉｇｆ−１ｒ阻害剤としてのテトラヒドロイソキノリンおよびテトラヒドロベンゾアゼピン誘導体

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US4491665A (en) * 1979-10-19 1985-01-01 Burroughs Wellcome Co. Method of preparing isomers of bis isoquinolinium compounds

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US4491665A (en) * 1979-10-19 1985-01-01 Burroughs Wellcome Co. Method of preparing isomers of bis isoquinolinium compounds

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CHEMICAL ABSTRACTS, Vol. 103, No. 9, see Abstract No. 71575X; & US,A,4491665 (Burroughs Wellcome Co.), 1 January 1985 (01.01.85). *
CHEMICAL ABSTRACTS, Vol. 61, No. 2, see Abstract Nos. 1829e, 1830c, YAKUGAKU ZASSHI, Vol. 84, No. 4, 329-33 (1964). *
CHEMICAL ABSTRACTS, Vol. 65, No. 5, see Abstract Nos. 7230b, 7230c; & JP,B,41 007 591 (Dainippon Pharmaceutical Co. Ltd.), 23 April 1966 (23.04.66). *
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501693A1 (fr) * 1991-02-27 1992-09-02 Banyu Pharmaceutical Co., Ltd. Dérivés d'isoquinoleine
US5362736A (en) * 1991-02-27 1994-11-08 Banyu Pharmaceutical Co., Ltd. Isoquinoline derivatives
US5446164A (en) * 1993-02-25 1995-08-29 Banyu Pharmaceutical Co., Ltd. Process for preparing 6,7-dialkoxy-3,4-dihydroisoquinolin-8-ol
US5498717A (en) * 1993-02-25 1996-03-12 Banyu Pharmaceutical Co., Ltd. 6,7-dialkoxy-3,4-diydroisoquinolin-8-yl compounds
WO2002051842A1 (fr) * 2000-12-23 2002-07-04 F. Hoffmann-La Roche Ag Derives de tetrahydropyridine, leur preparation et leur utilisation en tant qu'inhibiteurs de proliferation cellulaire
US6800638B2 (en) 2000-12-23 2004-10-05 Hoffman-La Roche Inc. Tetrahydropyridine derivatives, their preparation and their use as cell proliferation inhibitors
WO2003077874A2 (fr) * 2002-03-13 2003-09-25 The University Of Tennessee Research Foundation Composes tetrahydroisoquinoleine substitues, procedes de preparation et utilisation de ceux-ci
WO2003077874A3 (fr) * 2002-03-13 2004-08-05 Univ Tennessee Res Foundation Composes tetrahydroisoquinoleine substitues, procedes de preparation et utilisation de ceux-ci
JP2005526770A (ja) * 2002-03-13 2005-09-08 ザ ユニバーシティ オブ テネシー リサーチ ファウンデイション 置換テトラヒドロイソキノリン化合物、調製方法、およびその使用
US7241774B2 (en) 2002-03-13 2007-07-10 University Of Tennessee Research Foundation Substituted tetrahydroisoquinoline compounds, methods of making, and their use
AU2003230665B2 (en) * 2002-03-13 2010-02-18 University Of Tennessee Research Foundation Substituted tetrahydroisoquinoline compounds, methods of making, and their use
JP2007528877A (ja) * 2004-03-12 2007-10-18 アナリットコン エス アー Ｉｇｆ−１ｒ阻害剤としてのテトラヒドロイソキノリンおよびテトラヒドロベンゾアゼピン誘導体

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