WO1990002119A1 - 1,2,3,4-tetrahydroisoquinoline derivatives - Google Patents

Abstract

The invention relates to 1,2,3,4-tetrahydroisoquinoline derivatives represented by following general formula (I) and antitumor effect potentiators containing said compounds as active ingredients. In the said formula, R2 represents a lower alkyl group or, when combined with R1 or R3, represents a methylene group, one of R?1 and R3¿ represents a lower alkyl group or, when combined with R2, represents a methylene group, and the other represents a lower alkenyl group, a substituted or unsubstituted aryl-lower alkenyl group, a substituted or unsubstituted aryl-lower alkyl group (provided that an unsubstituted phenyl group is omitted), a substituted or unsubstituted aryl group (provided that an unsubstituted phenyl group is omitted) or a group represented by -(CH¿2?)m-A (wherein A represents a halogen atom, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted aryl-lower alkylthio group, a substituted or unsubstituted aryl-lower alkylsulfinyl group, a substituted or unsubstituted aryl-lower alkylsulfonyl group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted arylsulfinyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkyloxy group or a substituted or unsubstituted aryloxy group, an N-benzyl-N-(lower alkyl)amino group, an N-phenyl-N-(lower alkyl)amino group, an N,N-di(lower alkyl)amino group, a di(lower alkyloxy)phosphinoyl group or a dibenzyloxyphosphinoyl group, and m represents 2 to 4), R?4¿ represents a lower alkyl group, Ar represents a phenyl group optionally substituted by 1 to 3 lower alkyloxy groups, and n represents 0 to 2.

Description

 m Itoda «

1,2,3,4-tetrahydroisoquinoline derivative

 Technical field

 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.

 Background art

 At present, so-called chemotherapy using anticancer drugs such as doxorubicin (adriamycin), daunorubicin (daunomycin), and vincristine is widely used as one of the treatment methods for cancer. However, in chemotherapy using these anticancer drugs, cross-resistance (multidrug resistance) to other anticancer drugs having different chemical structures or modes of action occurs frequently in addition to the resistance to the anticancer drug used in the treatment, and this is the cancer. Makes it difficult to treat.

 In certain experimental cancer cells that have acquired multidrug resistance, the mechanism of actively excreting the anticancer drug outside the cell is enhanced as compared to the parental susceptible cancer cell, and as a result, the intracellular concentration of the anticancer drug is increased. Does not rise sufficiently. It has been reported that this is one of the causes of multidrug resistance (Cancer Research, Vol. 39, pp. 2200-12203 (1979)).

In an attempt to overcome this resistance, an attempt is made to increase the intracellular concentration of the anticancer drug to enhance its antitumor effect by using a drug that inhibits the active elimination mechanism of the anticancer drug against resistant cancer cells in combination with the anticancer drug. is are ₌ example made, Tsuruo et al., base Rapamiru inhibits the active excretion mechanism of anticancer agents against multidrug resistant cancer cells It reports that it enhances the antitumor effect (Cancer Research, 41: 1967-1972 (1981)). However, this compound has insufficient activity at the stage of clinical application, and a compound having better activity is desired.

 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.

 Disclosure of the invention

 The present invention has the general formula

[Wherein, R ² represents a lower alkyl group or a methylene group together with R ¹ or R ^3, and R ¹ and R ³ each represent a lower alkyl group or a group together with R ² Represents a methylene group, the other 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 for S) or an aryl lower alkyl. Group (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. However, 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, Ν, Ν-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 group or an aryloxy group (the aryl lower alkylthio group, the aryl lower alkylsulfinyl group, the aryl Lower alkylsulfonyl group, aryloxy group, arylsulfinyl group, arylsulfonyl group, aryl lower alkyloxy group and aryloxy group have a hydrogen atom on the aromatic ring as a halogen atom, a lower alkyloxy group, Nitro group, amino group or N, N-di-lower alkylamino group), N-benzyl-N-lower alkylamino group, N-phenyl-N-lower alkylamino group, N , N-di-lower alkylamino group, di-lower alkyloxyphosphinoyl group or dibenzyloxyphosphinoyl group, and m represents 2 to 4). R ⁴ represents a lower alkyl group; A i represents a phenyl group which may be substituted by 1 to 3 lower alkyloxy groups; and 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. Next, definitions and specific examples of various terms referred to in the description of this specification and included in the scope of the present invention will be described.

 The term "lower" is used to mean that the group or compound modified by this term has no more than 6 carbon atoms.

 Therefore, 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. -Methyl-1-propenyl group, 2-methyl-2-propenyl group, 3-methyl-2-butenyl group, 4-methyl-3-pentenyl group and the like.

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. can be used. 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, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, 2-methyl Benzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-aminobenzyl group, 3-aminobenzyl group Group, 4-aminobenzyl group, 3- (N-benzylmethylamino) benzyl group, 3- (N, N-dimethylamino) benzyl group, 4- (N, N-dimethylamino) benzyl group, 3- (N, N- Dimethylaminomethyl) benzyl group, 3- (N- Benzyl-N-methylaminomethyl) benzyl group, 3-morpholinomethylbenzyl group, 2-nitrobenzyl group, 3-nitrobenzoyl group, 4-nitrobenzyl group, 2-methoxycarbonylbenzyl group, 3-methylbenzene Methoxycarbonylpentyl, 4-methoxycarbonylbenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 3-isopropoxybenzyl, 4-isopropoxybenzyl, 2,3-methylenedioxybenzyl, 3,4-methylenedioxybenzyl group, 2,3-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, 2,4-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,6 -Dimethoxybenzyl, 3,5-dimethoxybenzyl, 4-methoxy-3-methoxycarbonylbenzyl, 4-methoxy-3-dinitrobenzyl, 4-methoxy-3 -Morpholino Chirubenjiru group, 3- (N, N- dimethylamino) -4 - Main Tokishibenji le group, 5- (N, N ^T - Jimechiruamino) -2 main Tokishibenjiru group, 5- (N, N- Jimechirua Minomechiru) - 2-Methoxybenzyl group, 5- (N-benzyl-N-methylaminomethyl) -2-methoxybenzyl group, 2-Methoxy-5-nitrobenzyl group, 2,3,4-trimethy Xybenzyl group, 2,4,6-trimethoxybenzyl group, 3,4,5-trimethoxybenzyl group, 2- (2-methoxyphenyl) ethyl group, 2- (3-methoxyphenyl) ethyl group , 2- (4-Methoxyphenyl) ethyl group, 2- (3,4-Dimethoxyphenyl) ethyl group, 3- (4-Methoxyphenyl) propyl group, 3- (3,4-dimethyl) ethyl group Methoxyphenyl) propyl, 4- (4-methoxyphenyl) butyl, 4- (3,4-dimethylphenyl) butyl, 5- (4-methoxyphenyl) pentyl, 5- (3,4-dimethoxyphenyl) pentyl, 1-naphthylmethyl, 2-naphthylmethyl, (4-methoxy-1-naphthyl) methyl, (3,4-dimethoxy-1) (Naphthyl) methyl group, (1-methoxy-2-naphthyl) methyl group, etc.

 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. 3-, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-amino Phenyl, 2- (ί, Ν-dimethylamino) phenyl, 3- (N, N-dimethylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 2-methoxycarbonylphenyl, 3-- Meth: xycarponylphenyl group , 4-Methoxycarbonylphenyl, 1-naphthyl, 2-naphthyl, 4-methoxy-1-naphthyl, 4- (Ν, Ν-dimethylamino) -1-naphthyl, 4-nitro -1-naphthyl group and 4-chloro-1-naphthyl 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, Ν, Ν-dibutylamino group and the like.

 Ν, Ν-di-lower alkylaminomethyl group means a methyl group substituted by で, Ν-di-lower alkylamino group as defined above, for example, Ν, Ν-dimethylaminomethyl group, Ν- Examples thereof include ethyl-Ν-methylaminomethyl group, Ν, Ν-ethylaminomethyl group, Ν, Ν-dipropylaminomethyl group, Ν, Ν-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. Can be

 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. Jilsulfonyl, 2-phenylethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl, 4-chlorobenzylsulfonyl, 4-methoxybenzylsulfonyl, 4-nitrobenzyl Sulfonyl group, 4-aminobenzylsulfonyl group, 4- (N, N-dimethylamino) benzylsulfonyl group and the like.

 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. For example, a phenylthio group,

1-naphthylthio, 2-naphthylthio, 4-chlorophenylthio, 2-methoxyphenylthio, 3-methoxyphenylthio, 4-methoxyphenylthio,

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

4-, 4-methylphenylsulfinyl, 2-methoxyphenylsulfinyl, 3-methoxyphenylsulfinyl, 4-methoxyphenylsulfinyl, 4-nitrophenylsulfinyl Group, 4-aminophenylsulfinyl group, 4- (N, N-dimethylamino) phenylsulfinyl group and the like. 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. For example, 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. For example, phenoxy, 1-naphthoxy, 2-naphthoxy, 4-chlorophenoxy, 4-methoxyphenoxy, 4-nitrophenoxy, 4-aminophenoxy, 4- (N, N-dimethylamino) phenoxy Motoki is fisted.

An 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.

 An 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.

 The term "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.

 In general, 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 of the methyl group 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

[Wherein, 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, with R ²¹ Represents a methylene group, the other represents a hydrogen atom, R ⁴ represents a lower alkyl group, Ar represents a phenyl group which may be substituted by 1 to 3 lower alkyloxy groups, η Represents 0 to 2] in the presence of a base, and when R ⁵ described below is an aryl group, a base and metallic copper or a monovalent or divalent copper salt In the presence of the general formula

R ^S -X cm]

Wherein 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 lower Arukiruokishi group, nitro group, amino group, N, N-di - lower alkylamino Motomata lower Arukiruokishi It may be substituted with a carbonyl group. However, 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) An aryl lower alkylsulfinyl group, an aryl lower alkylsulfonyl group, an arylthio group, an arylsulfinyl group, an arylsulfonyl group, an aryl lower alkyloxy group or an aryloxy group (the aryl lower alkylthio group) In the aryl lower alkylsulfinyl, aryl lower alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, aryl lower alkyloxy and aryloxy, the hydrogen atom on the aromatic ring is a halogen atom. , 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 phosphite. Eye , Or, if the product has a sulfide group, by oxidation of this group to a sulfinyl group or a sulfonyl group, if desired. Can be. In addition, when the group R ⁵ newly introduced on the isoquinoline ring has a double-ended group, this group can be reduced to a primary amino group, if desired, and further by a reductive alkylation reaction. Can lead to a dimethylamino group.

(Hereinafter the margin)

Next, the production method of the compound [I] of the present invention will be described in more detail. The compound of the present invention represented by the above general formula [I] includes a phenolic compound represented by the general formula [Π] and a phenolic compound represented by the general formula [Π] 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 [ΙΠ] (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. Usually, the reaction is carried out by dissolving compound [Π] in the above solvent, adding an appropriate base, and further adding compound [ΙΠ] 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 [ΠΠ used is from 1 to L0 mol, preferably from 1 to L.2 mol, per 1 mol of the compound [Π]. 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 [Π].

In addition, among the compounds of the present invention represented by the general formula [I], in which R ¹ or R ³ is an aryl group, a phenolic compound [Π] and a compound [ΠΙ] (wherein A compound in which R ⁵ is an aryl group) can be produced by performing a so-called Ullnmnn reaction in a suitable solvent in the presence of a copper catalyst and a base.

Typically, a suitable solvent (eg, pyridine, collidine, quinoline, 90/02119 16 Dissolve compound [Π] in tilformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, diglyme, etc.) and use a suitable inorganic base (eg, alkali metal carbonate, alkali hydroxide) Metal, alkali metal hydride, etc.) and a suitable copper catalyst (eg, copper powder, cuprous halide, cupric halide, cuprous oxide, cupric oxide, copper carbonate, copper acetate, etc.) In addition, 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 [π] ιmol. Among the compounds represented by the general formula [I], a compound represented by the formula wherein R ¹ or R ³ is represented by the formula: 4C¾X ¹ (wherein X ¹ represents a halogen atom and m represents 2 to 4) [Γ] 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, 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 [].

Further, 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. Replace the atom 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 Ν, Ν-di-lower alkylamino groups.よ い -benzyl-Ν-lower alkylamino group, Ν-phenyl-Ν-lower alkylamino group, Ν, Ν-di-lower alkylamino group, di-lower alkyloxyphosphinoyl A dibenzyloxyphosphinoyl group, and m represents 2 to 4).

 Typically, in a suitable solvent (eg, alcohol, dimethylformamide, dimethylsulfoxide, benzene, toluene, tetrahydrofuran or the like) or without a solvent, a thiol compound, a hydroxyl compound, a secondary amine, a trialkyl phosphite is used. If necessary, use a suitable base (eg, alkali metal carbonate, alkali metal hydroxide, alkali metal alkoxide, alkali metal hydride, etc.) It can be obtained by adding the above-mentioned halogen compound [I '] in the coexistence and reacting at 0 ° C to the boiling point of the solvent for 2 to 18 hours.

 The used amount of the nucleophilic reagent is 1 mole to a large excess with respect to 1 mole of the compound [Γ], and the used amount of the base is 1 to 1.5 mole.

Furthermore, among the compounds represented by the general formula [I], 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.

 Typically, in a suitable solvent (eg, dichloromethane, chloroform, carbon tetrachloride, acetic acid, etc.), 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 [] '].

Among the compounds represented by the general formula [I], the compound [Γ ″] 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.

As an example of the reduction reaction, tin chloride (Π) is added to the nitro compound [Γ ″] in an appropriate solvent (eg, alcohol, ethyl acetate), and the mixture is allowed to act at 70 ° C. for 30 minutes to 2 hours. Thus, reduction can be performed. The use amount of tin chloride (III) is 3 to 10 mol, preferably: to 5 mol, per 1 mol of the compound [III,]. The thus obtained compound having a primary amino group is dissolved in a suitable solvent (for example, acetonitrile, acetic acid, tetrahydrofuran, etc.) in formaldehyde and 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. If necessary, 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 [Π] 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

[Wherein .R ¹² and R ²² represent a lower alkyl group or a methylene group together with the rain, and Bn represents a benzyl group.] A phenethylamine derivative [IV] represented by the general formula

Ar (CH ₂ ) nCOX ² [V]

[Wherein, Ar represents a phenyl group which may be substituted with 1 to 3 lower alkyloxy groups, η represents 0 to 2, and X ² represents a halogen atom, a hydroxyl group, or a lower alkyloxy group.] Which is obtained by condensation with a compound represented by the general formula

[Wherein R ¹² , R ²² , Bn, Ar and n have the above-mentioned meanings], and the vicula-Navierski reaction using phosphorus oxychloride or the like. (Bischler-Napieralski reaction)

Wherein, 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 ϋ have the above-mentioned meanings].

 Then, the present compound [Π] is subjected to 低 -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. Further, the phenolic compound represented by the general formula [Π] is obtained through debenzylation by the action of an acid such as hydrochloric acid or catalytic hydrogenation. Alternatively, 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 Ν-alkylation. The phenolic compound represented by the general formula [Π] can be obtained by debenzylation by action or catalytic hydrogenation.

As the raw material compound [ΙΠ], 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. Chem.), 23, 1122 (1980); Journal of Ob'Chemical 'Society, Parkin' Transaction 1 (J. Chem. Soc., Perkin Trans. 1), 1739 (1987); Tetrahedron, 1847 (1987); JP-A-55-53247]. Further, 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.), | ^, 1064 (1978) Journal of the 'American' Chemical 'Society (J. Am. Chem. Soc.), ^, 3159 (1951); JP-A-57-163390].

If the halides have a sulfide group obtained by the above method, 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

 Hereinafter, pharmacological test examples of the compound according to the present invention will be shown, and the usefulness thereof will be specifically described.

Pharmacological test example 1.

Adriamicin (ADR) 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.

 D F =

ADR IC ₆ for drug combination against P388 / ADR. Each test drug alone showed almost no growth inhibition in Η.δ ^ Η. As is clear from Table 1, 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.

Test drug D M F

 Reference 1

 Compound of Example 17.6

 ノ / 2 "7.8

 "3" 7.7

 "4" 7.5

 "5 〃 11.0

 "6" 6.8

 "7" 5.9

 "17 '! 6.2

 // 18 "-10.2

 "19" 8.7

 "21" 5.0

"22>'8.3 Table 1 '(continued) Compound of Example 23 14.0

〃 24 11 9.7

// 25 II 7.4

〃 26 1! 7.4

〃 27 II 9.3

28 I! 8.6

〃 29 〃 8.7

30 n 10.8

〃 31 8.7

// 32 1! 6.0

; / 34 mo 6.5

〃 35 〃 6.2

〃 36 14.3

// 37 11 12.7

〃 38 II 8.8

// 39 II 13.0

// 40 // 12.3

〃 41 // 7.7

// 52 〃 6.6

// 53 // 6.6

; / 54 ;; 5.9

〃 57 mo 5.2

60! '7.2

〃 65 n 7.9

66 "6.1

67 II 10.2

// 68 II 10.0

〃 69! ! 8.4

// 70 II 6.4

// 71 1! 6.4

〃 74 II 7.4

〃 75 11 8.8

// 78! 1 5.9

// 79! , 8.3 Verapamil 2.2 Pharmacological Test Example 2 Enhancing Effect of Intracellular Accumulation of ADR in Multitangle-Resistant Cancer Cells As in Pharmacological Test Example 1, P388 / ADR cells were used. Prepare a cell suspension of 1 X 10 ^s cells / tn ώ, add 0.1 M of the test drug and ADR to this suspension ltn £ so that the reaction becomes, and incubate at 37 ° C for 1 hour. Was. The cells were washed by centrifugation, then disrupted, ADR was extracted by adding tricloacetic acid, and the sedimentation supernatant was measured with a fluorometer. The results are shown in Table 2. As is evident from Table 2, 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

 Intracellular ADR accumulation rate

 (T / C%)

 Control 100

 Example 2 Compound 166

 ! '3 "168

 "4 ,! 157

 "5" 222

 "'17" 224

 "18" 169

 "19" 169

 > '30! ! 165

 "32" 174

 "57" 156

 "60" 225

 "65" 227

 "66" 215

 "67".

 "68" 160

 »69" 173

 "71 '! 184

"74" 205 Table 2 (continued)

 "75 〃 159

 "78 I! 201

 "79 11 205

 Bella Pa S Le 106

From the above pharmacological test results, it is clear that 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. In the present invention, 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. As the administration form of the antitumor effect enhancer or anticancer agent of the present invention, various forms can be selected, for example, 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. Examples of such 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. For example, 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. Can be

 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), and a mixed solution thereof are included.

 In addition, 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. When the antitumor effect enhancer of the present invention and the substance having an antitumor effect are separately administered, the antitumor effect It is necessary to administer the antitumor effect enhancer of the present invention in accordance with the administration schedule of the substance having the following.

(Hereinafter the margin)

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (5-phenylpentyloxy) -1,2,3,4-tetrahydroisoquinoline

 Under a nitrogen atmosphere, 6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,

To a solution of 63 mg of 4-tetrahydroisoquinolin-8-ol (compound 1 0.18 mmol) in dimethylsulfoxide Ι.Οπιβ was added 19 rag (0,28 mmol, 85%) of a hydroxylating power at room temperature, and after stirring for 15 minutes, A solution of 37 mg (0.20 mmol) of 5-methylpentylbenzene in dimethyl sulfoxide l.Omja is added, and the mixture is stirred at room temperature for 15 hours. To the reaction mixture was added 50mJ2 of water, and the mixture was extracted three times with ethyl acetate 50πιβ.

After washing with 50mJ2, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by medium-pressure liquid chromatography (Merck Rover-Column Size B Recrobrup SI60, black-mouthed form (20) Z methanol (1)) to dilute the title compound. 69nig is obtained as a yellow oil. Yield 77%.

IR (neat, cm): 2938 , 2860, 1605, 1585, 1515, 1497, 1314,1245, 1176, 1035, 822 High Resolution FAB-MS (m / e, (C 3, H 39 0 4 N + H) ⁺ ):

 Calculated 490.2957

 Measured 490.2965,

'H-NMRCCDC, δ ppm): 1.48-1.86 (6Η, ι), 2.34 (3H, s), 2.36-2.45 (lH, m), 2.63 (2H, t, J-6.7Hz), 2.73-2.92 ( 4H, m), 3.26-3.36 (lH , m), 3.77 (3H, s), 3.82 (3H 5 s), 3.83 (3H, s), 3.88-3.94 (lH, m), 3.95-4.01 (lH, m), 4.14-4.21 (lH, ni), 6.37 (lH, s), 6.80 (2H, d, J = 8.9Hz), 7.15-7.31 (7H _s ni) O

?

C CD 筚

a "fl-NMRCCDCla, δppra): 2.04 (2H, quin, J = 6.8 Hz), 2.37 (3H, s), 2.40-2.47 (lH, m); 2.73-2.94 (4H, m), 2.96 (3H, s), 3.25-3.35 (lH, ni), 3.56-3.61 (2H, ni), 3.77 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 3.95-4.00 (lH, ni) , 4.05 (lH, td, J = 5.8 Iiz, 9.5 Hz), 4.22 (lH, td, J = 6.3 Hz, 9.5 Hz), 6.38 (lH, s), 6.66-6.81 (5H, m), 7.12 (2H , d, J = 8.8Hz), 7.18-7.28 (2H, m)

Example 4

 6,7-Dimethoxy-l- (4-methoxybenzyl) -2-methyl-8- (4-funinylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 1 and 4-chlorobutylthiobenzene. Yield 83%.

 IR (neat, cm): 2932, 1584, 1515, 1494, 1464, 1437, 1359, 1245, 1119, 1092, 1038,

 738

FAB-MS (m / e, as ^{_{+ (C 3 .H 37 0 4}} NS + H)): 508

'H-NMRCCDCla, δ ppm): 1.83-1.94 (4H, ni), 2.34 (3H, s), 2.36-2.44 (lH ₎ m), 2.72- 2.90 (4H, ni), 3.00 (2fi, t, J = 7.0Hz), 3.24-3.32 (lH, m), 3.78 (3II, s), 3.80

(3H, s), 3.83 (3H, s), 3.89 (lH, dd, J = 4.1Hz, 9.3Hz), 3.98 (lH, td, J = 5.9Hz, 9.2Hz), 4.17 (lH, td, J = 6.2Hz, 9.2Hz), 6.37 (lH, s), 6.80 (2H, d, J = 8.7Hz), 7.14 (2H, d, J = 8.7Hz), 7.18-7.35 (5H, ni)

Example 5

S, 7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (4-phenoxybutoxy) -1,2,3,4-tetrahydroisoquinoline Using 1 and 4-chlorobutoxybenzene, the title compound is obtained as a colorless oil in the same manner as in Example 1. Yield 70%.

 IR (neat, cm): 2938, 1602, 1587, 1515, 1497, 1470, 1344, 1299, 1245, 1176, 1113,

1038,1005,831

High Resolution FAB- MS (m / e, as _{+ (C 3 H 37 0 5} N + H).):

 Calculated 492,2750

 Measured value 492.2762

Luo _{(CDC1 3, δ ppm):} 1.95-2.06 (4H, ni), 2.35 (3H, s), 2.38-2.46 (lH, iii), 2.74- 2.93 (4H, m), 3.26-3.56 (lH, ni ), 3.77 (3H, s), 3.83 (3H, s), 3.84 (3H, s), 3.93 (lH, dd, J = 3.8Hz, 9.3Hz), 4.03-4.10 (3Η, πι), 4.23-4.30 (1Η, πι), 6.39 (lH, s), 6.80 (2H, d, J = 8.4Hz), 6.89-6.96 (3H, m), 7.17 (2H, d, J = 8.4Hz), 7.26-7.32 ( 2H, m)

Example 6

 8- [3- (dibenzyloxyphosphinoyl) propoxy] -6,7-dimethoxy-1-

(4-Methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and dibenzyl = 3-chloropropylphosphonate, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 49%.

 IR (neat, cm): 2938, 1608, 1515, 1497, 1461, 1344, 1245, 1119, 1083, 1035, 999,

 870

High resolution FAB - MS (m / e, as ^{_{+ (C 37 H 44 0 7}} NP + H)):

 Calculated 646.2930

Measured value 646.2932 _{- NMR (CDC1 3, δ ppm} ): 1.90-2.10 (4H, m), 2.33 (3H, s), 2.34-2.45 (lH, m), 2.70- 2.89 (4H, m), 3.21-3.35 (lH, m), 3.72 (3H, s), 3.74 (3H, s), 3.82 (3H, s), 3.80-3.90 (lH, m), 3.91-3.99 (lH, ni), 4.05-4.14 (lH, ra) , 4.93-5.10 (4H, m), 6.37 (iH, s), 6.75 (2H, d, J = 8.8Hz), 7.09 (2H, d, J = 8.8Hz), 7.31-7.41 (10H, in)

Example 7

 6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-8--phenylsulfonylbutoxy) -1,2,3,4-tetrahydroisoquinoline

 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, αη): 2938, 1608, 1584, 1515, 1497, 1452, 1344, 1308, 1269, 1245, 1179,

1146,1119,1086,1035,819

High-resolution FAB-MS (m / e, (C ₃₀ Η ₃₇ Ο _β NS + H) ⁺ ):

 Calculated value 540.2420

 Measured value 540.2406

^-ECCDC ^, δ ppm): 1.78-1.89 (2H, m), 1.91-2.02 (2H, m), 2.34 (3H, s) ₎ 2.35- 2.43 (lH, m), 2.72-2.89 (4H, m ), 3.16-3.33 (3H, in), 3.76 (3H, s), 3,79 (3H, s) 3.83 (3H, s), 3.78-3.85 (lH, m), 3.93 (lH, td, J = 5.9Hz, 9.5Hz), 4.07 (lH, td, J = 6.2Hz, 9.5Hz), 6.37 (lH, s), 6.79 (2H, d, J = 8.9Hz), 7.09 (2H, d, J = 8.9 Hz), 7.52-7.78 (3H, m), 7.91-7.95 (2H, m)

Example 8

_ (4-Dichlorobutoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl

Example 10

 8-(2-Chloroethoxy) -6,7-dimethoxy-1- (4-methoxybenzyl)-2-tyl-1,2,3,4-tetrahydroisoquinoline

 Using 1 and 1-bromo-2-chloroethane, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 43%.

 IR (neat, cm): 2938, 1605, 1515, 1497, 1458, 1344, 1245, 1179, 1119, 1035, 1005, 822

High Resolution FAB-MS (m / e, as ^{_{+ (C 22 H 28 0 4}} NC1 + H)):

 Calculated value 406.1785

 Measured value 406.1787

'H-NMRCCDCla, δ ppm): 2.35 (3H, s), 2.38-2.47 (lH, ni), 2.73-2.94 (4H, m), 3.25-3.36 (lH, m), 3.71-3.81 (2H, m ), 3.79 (3H, s), 3.83 (3H, s) _s 3.84 (3H, s), 4.06 (lH, dd, J = 3.9Hz, 9.0Hz), 4.21-4.29 (lH, m), 4.45-4.52 . (lH, ni), 6.40 (lH, s), 6.81 (2H, d, J = 8.4Hz), 7.17 (2H, d, J = 8.4Hz)

Example 11

 8- (3-bromopropoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroizoquinoline

 The title compound is obtained as a pale yellow oil using Compound 1 and 1,3-dibromopropane in the same manner as in Example 1. Yield 33%.

 IR (neat, cm): 2938, 1611, 1518, 1503, 1467, 1350, 1248, 1182, 1122, 1032, 987, 840

High Resolution FAB-MS (m / e, as ^{_{+ (C 23 H 3o 0 4}} NBr + H)): Calculated value 464.1437

 Measured value 464.1476

_{^{J H - NMR (CDC1 3,}} δ ppni): 2.21-2.33 (2H, ni), 2.38 (3H, s), 2.39-2.48 (lH, ni), 2.73- 2.91 (4H, m), 3.23-3.35 ( lH, ffl), 3.57-3.66 (2H, m), 3.79 (3H, s), 3.83 (3H, s): 3.84 (3H, s), 3.92 (lH, t, J = 6.6Hz), 4.02-4.11 (1Η, ιη), 4.25-4.34 (1Η, πι), 6.40 (lH, s), 6.81 (2H, d, J = 8.7Hz), 7.12 (2H, d, J = 8.7Hz)

Example 12

 6,7-Dimethoxy-8- (2-N, N-dimethylaminoethoxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetradroisoquinoline

 Using 1 and 2-chloro-N, N-dimethylethylamine hydrochloride, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 42%.

IR (neat, cm): 2940, 2840, 1615, 1518, 1467, 1344, 1246, 1121; 1037, 822

FAB-MS (m / e, as _{+ (C 24 H 34 0 4} N 2 + H)): 415

_{^{1 H-NMR (CDC1 3,}} δ ppm): 2.33 (9H, s), 2.34-2.45 (lH, m), 2.67-2.94 (6H, in), 3.26- 3.35 (lH, m), 3.79 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 4.04 (lH, dd, J = 3.5Hz, 9.3Hz), 4.14 (lH, td, J = 5.9Hz, 10.3Hz), 4.26 (lH , td, J = 5.8Hz, 10.3Hz), 6.38 (lH, s), 6.81 (2H, d, J = 8.5Hz), 7.20 (2H, d, J = 8.5Hz)

Example 13

 6,7-Dimethoxy-8- (3-N, N-dimethylaminopropoxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

Performed with Compound 1 and 3-chloro-N, N-dimethylpropylamine hydrochloride

Example 15

 6,7-dimethyloxy-1- (4-methoxybenzyl) -8- (3-methoxybenzyloxy)

2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using Compound 1 and 3-methoxybenzyl chloride. Yield 56%.

 IR (neat, cm): 2938, 1605, 1515, 1497, 1467, 1266, 1245, 1119, 1077, 1035, 795

- High resolution FAB-MS (in / e, as ^{_{+ (C 28 H 33 0 5}} N + H)):

 Calculated value 464.2437

 Measured value 464.2458

 'H-NMRCCDC, δ ppm): 2.18 (3H, s), 2.35-2.43 (lH, m), 2.69-2.90 (4H, m) ^ S-SS lH, !!!), 3.72-3 1Η, πι), 3.76 (6H, s), 3.86 (3H, s), 3.89 (3H, s), 5.01 (lH, d, J = 11.2Hz), 5.20 (lH, d, J = 11.2Hz), 6.40 (lH, s), 6.71 (2H, d, J = 8.7 Hz), 6.86-6.90 (lH, m), 6.96-7.05 (4H, iD), 7.25-7.31 (lH, iii)

Example 16

 β, 7-Dimethoxy-1- (4-methoxybenzyl) -8- (4-Methoxybenzyloxy)

-2-Methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using compound 1 and 4-methoxybenzyl chloride. 85% yield.

IR (neat, cm ¹ ): 2938, 1614, 1518, 1497, 1248, 1176, 1116, 1077, 1035, 822

High resolution FAB-¾S (m / e, as ^{_{+ (C 28 H 33 0 5}} N + H)):

 Calculated value 464.2437

Measured value 464.2452

)-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using compound 1 and 3-methylbenzyl chloride. Yield 50%.

IR (neat, cm ¹ ): 2938, 1605, 1515, 1497, 1467, 1419, 1371, 1245, 1176, 1119, 1080,

1035,83.1,792

High Resolution FAB-MS (m / e, as ^{_{+ (C 2 s H 33 0}} 4 N + H)):

 Calculated 448.2488

 Measured value 448.2468

- Dragon _{R (CDC1 3, δ ppm)} : 2.18 (3H, s), 2.35 (3H, s), 2.36-2.45 (lH s m), 2.69-2.92 (4H, ra), 3.23-3.33 (lH, in ), 3.74-3.80 (lH, ni), 3.77 (3H, s), 3.86 (3H, s), 3.89 (3H, s), 5.00 (lH, d, J = 11.0Hz), 5.20 (lH, d, J = 11.0Hz), 6.41 (lH, s), 6.72 (2H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.4Hz), 7.14-7.28 (4H, ni)

Example 19

 8- (3-chlorobenzyloxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2

-Methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 1 and 3-chlorobenzylbenzene. Yield 80%.

 IR (neat, cm): 2938, 1605, 1515, 1467, 1344, 1245, 1179, 1119, 1080, 1035, 822, 789

High resolution FAB - MS (m / e, as ^{_{+ (C 27 H 3 .0 4}} NCl + H)):

 Calculated value 468.1942

Measured value 468.1971 - title _{R (CDC1 3, δ ppm)} : 2.23 (3H, s), 2.38-2.47 (lH, m), 2.75-2.90 (4H, ni), 3.24- 3.44 (lH, m), 3.73-3.81 (lH , iD), 3.78 (3H, s), 3.86 (6H, s), 5.00 (lH, d, J = 11.5Hz), 5.18 (lH, d, J = 11.5Hz), 6.43 (lH, s) ₅ 6.74 (2H, d, J = 8.6Hz), 7.00 (2H, d, J = 8.6Hz), 7.26-7.34 (3H, in), 7.46 (lH, brs)

Example 20

 6,7-Dimethoxy-8- [3- (N, N-dimethylaminomethyl) benzyloxy] -toluene (4

-Methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 1 and 3-cupromethyl-N, N-dimethylbenzylamine hydrochloride. Yield 65%.

IR (neat ₅ cm): 2938, 1605, 1515, 1467, 1344, 1245, 1176, 1119, 1080, 1035,828,

710

High Resolution FAB-MS (m / e, as _{+ (C 3 H 38 0 4} N 2 + H).):

 Calculated value 49Γ.Ϊ910

 Measured value 491.2905

， δ ppiD):2.20(3H,s),2.23(6H,s),2.39-2.48(lH,m)_>2.70-2.95 (4H，m)，3.23-3.35(lH，m)，3.44(2H，s)，3.76(3H，s)，3.81(lH，dd，J=3.2Hz， 10.0Hz),3.86(3H,s),3.88(3H,s),5.03(lH,d,J=ll.lHz),5.23(lH,d,J= ll.lHz),6.40(lH,s)_}6.69(2H,d,J=8.5Hz),6.96(2H,d,J=8.5Hz),7.30- 7.40(4H₅m)

, Δ ppiD): 2.20 (3H, s), 2.23 (6H, s), 2.39-2.48 (lH, m) _> 2.70-2.95 (4H, m), 3.23-3.35 (lH, m), 3.44 (2H, m s), 3.76 (3H, s), 3.81 (lH, dd, J = 3.2Hz, 10.0Hz), 3.86 (3H, s), 3.88 (3H, s), 5.03 (lH, d, J = ll.lHz ), 5.23 (lH, d, J = ll.lHz), 6.40 (lH, s) _} 6.69 (2H, d, J = 8.5Hz), 6.96 (2H, d, J = 8.5Hz), 7.30-7.40 ( 4H ₅ m)

Example 21

8- [3- (N-benzyl-Ν'-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

. To

 IR (neat, cm): 2938, 1605, 1515, 1458, 1344, 1245, 1176, 1119, 1035, 835, 750, 695

High Resolution FAB-MS (m / e, as ^{_{+ (C 3s H 42 0 4}} N 2 + H)):

 Calculated 567.3223

 Measured value 567.3261

_{'H- MR (CDC1 3, δ} ppin): 2.15 (3H, s), 2.17 (3H, s), 2.34-2.42 (lH, m), 2.68-2.91 (4H, m), 3.22-3.29 (lH, in), 3.49 (2H, s), 3.51 (2H, s), 3.73 (3H, s), 3.77 (lH, dd, J = 2.9Hz, 9.2Hz), 3.86 (3H, s), 3.89 (3H, s), 5.05 (lH, d, J = 11.0Hz), 5.24 (lH, d, J = 11.0Hz), 6.40 (lH, s), 6.68 (2H, d, J = 8.7Hz), 6.96 (2H, d, J = 8.7Hz), 7.20-7.39 (8H, m), 7.42 (lH, brs)

Example 22

 8- [5- (N-benzyl-N-methylaminomethyl) -6,7-dimethoxy-2-methoxybenzyloxy] -1- (4-methoxybenzyl) -2-methyl-1, 2,3,4-tetrahydroy soquinoline

 Using compound 1 and N-benzyl-3-cupromethyl-4-methoxy-N-methylbenzylamine hydrochloride, the title compound is obtained as a colorless oil in the same manner as in Example 1. Yield 36%.

IR (neat, cm): 2936, 1614, 1512, 1466, 1344, 1248, 1118, 1032, 819, 754, 695 High Resolution FAB-MS (m / e, as _{+ (C 37 H 44 0 5} N 2 + H)):

 Calculated 597.3329

 Measured value 597.3334

lH-NMR (CDCl ₃ , δ ppm): 2.11 (3H, s), 2.16 (3H, s), 2.29-2.50 (lH, m), 2.65-2.97 (4H, m) _} 3.24-3.35 (lH, m ), 3.44 (4H, s), 3.73 (3H, s), 3.76 (3H, s) ₃ 3.80-3.90 (lH, ni), 3.85 (3H, s), 3.92 (3H, s), 5.09 (lH, d, J = 11.0Hz), 5.33 (lH, d, J = 11.0Hz), 6.36 (lH, s), 6.67 (2H, d, J = 8.7Hz), 6.85 (lH, d, J = 8.3Hz) , 6.97 (2H, d, J = 8.7Hz), 7.20-7.38 (7H, in)

Example 23

 6,7-Dimethoxy-8- (2,3-dimethoxybenzyloxy) -l- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetradroisoquinoline

 Using compound 1 and 2,3-dimethoxybenzyl chloride, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 75%.

 IR (neat, cm): 2938, 2836, 1584, 1518,1491, 1345, 1250, 1122, 996,753

High Resolution FAB-MS (ni / e, as _{+ (C 23 H 35 0 B} N + H)):

 Calculated 494.2543

 Measured value 494.2538

'H-NMRCGDC, δ ppm): 2.26 (3H, s), 2.37-2.51 (lH, ni), 2.65-3.00 (4H _> ni), 3.23-3.34 (lH, m), 3.75 (3H, s), 3.75-3.90 (lH, iE), 3.81 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 5.04 (lH, d, J = 11.3Hz), 5.36 (lH, d, J = 11.3Hz), 6.41 (lH, s) _r 6.68 (2H, d, J = 8.4Hz), 6.91-6.96 (3H, m), 7.06 (2H, d _! J = 8.4Hz) Example 24

 6,7-Dimethoxy-8- (3,4-dimethoxybenzyloxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

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): 2938, 1515, 1467, 1341, 1245, 1119, 1077, 1029, 813, 759

High-resolution FAB-MS (m / e, (C ₂₃ Η _{350 β} N + H) +):

 Calculated 494.2543

 Measured value 494.2528

-丽_{R (CDC1 3, δ ppm)} : 2.18 (3H, s), 2.37-2.48 (lH, m), 2.68-2.95 (4H, m), 3.23- 3.33 (lH, m), 3.76 (3H, s ), 3.79 (3H, s), 3.80-3.88 (lH, m), 3.87 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 5.03 (lH, d, J = 11.0Hz) , 5.14 (lH, d, J = 11.0Hz), 6.41 (lH, s), 6.72 (2H, d, J = 8.8Hz), 6.83 (lH, d, J = 8.1Hz), 6.92-6.97 (2H, m), 7.01 (2H, d, J = 8.8Hz)

Example 25

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (3,4,5-trimethoxybenzyloxy) -1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 3,4,5-trimethoxybenzyl chloride, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 92%-

IR (neat, cm):. 2938, 1596, 1509, 1470, 1422, 1341, 1248, 1131, 1008, 834, 753 High Resolution FAB-MS (m / e, (C 3 H 37 0 7 N + H) +):

Calculated value 524.2648 f

)) Η6HHΐ6r HsOI ZZ. Example 27

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (2-phenoxyethoxy) -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 1 and 2-chloroethoxybenzene. Yield 75%.

IR (neat, cm ¹ ): 2938, 1605, 1584, 1500, 1458, 1344, 1245, 1122, 1062, 831, 753, 690

High Resolution FAB-MS (m / e, as ^{_{+ (C 28 H 33 0 5}} N + H)):

 Calculated value 464.2437

 Measured value 464.2420

_{- NMR (CDC1 3, δ ppm} ): 2.25 (3H, s), 2.37-2.45 (lH, ni), 2.72-2.95 (4H, ni), 3.24- 3.34 (lH, ra), 3.73 (3H, s) ", 3.84 (3H, s), 3.86 (3H, s), 4.09 (lH, dd, J = 3.2Hz, 9.2Hz), 4.19 (lH, ddd, J = 2.6Hz, 5.6Hz, 10.2Hz), 4.24 -4.31 (lH, ni), 4.38 (lH, ddd, J = 2.6Hz, 6.3Hz, 11.3Hz), 4.64 (lH, ddd, J = 2.6Hz, 5.6Hz, 11.3Hz), 6.40 (lH, s) , 6.66 (2H, d, J = 8.9Hz), 6.89-6.98 (3H, m), 7.14 (2H, d, J = 8.9Hz), 7.25-7.30 (2H, m)

Example 28

 6,7-Dimethoxy-8- (3-dimethylaminobenzyloxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using Compound 1 and 3-octamethyl-N, N-dimethylaniline hydrochloride. 79% yield.

IR (neat, o¾): 2932, 1608, 1494, 1456, 1344, 1242, 1178, 1120, 1080, 1036, 840 High resolution FAB - MS (m / e, as ^{_{+ (C 23 H 3S 0 4}} N 2 + H)): Calculated 477.2753 measured value 477.2800

_{^{I .H-NME (CDC1 3,}} δ ppm): 2.17 (3H, s), 2.35-2.44 (lH, m), 2.68-2.95 (4H, in), 2.91 (6H, s), 3.20-3.31 (lH , M), 3.74-3 · 85 (lH, m), 3.76 (3H, s), 3.86 (3H, s), 3.90 (3H, s), 5.00 (lH, d, J = 10.9Hz), 5.19 ( lH, d, J = 10.9Hz), 6.40 (lH, s), 6.70 (2H, d, J = 8.7H2), 6.70-6.73 (lH, ni), 6.77-6.82 (2H, m), 6.99 (2H , D, J = 8.7Hz), 7.22 (lH, t, J = 7.9Hz)

Example 29

 8- (2-benzyloxyethoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

， δ ppm):2.29(3H,s),2.41-2.51(lH,m),2.75-3.02(4fl,ni),3.25- 3.36(lH，m)，3.76(3H，s)，3.77-3.83(2H，ra)，3.83(6H，sX2)，4.10-4.19(lH: m)_J4.23(lH_Jddd,J=3.3Hz,6.2Hz,ll.lHz),4.42(lH,ddd,J=3.3Hz,5.2Hz, H.lHz),4.59(2H,s),6.39(lH,s),6.72(2H,d,J=8.7Hz),7.17(2H,d,J=8.7 Hz) 7.31-7.34(5H,m) 実施例 30 Using compound 1 and α- (2-chloroethoxy) toluene, in the same manner as in Example 1, to obtain the title compound as a colorless oil. Yield 59%. ^{'IR (neat, cA 1)} : 2938, 1610,1515, 1458, 1344, 1245, 1122, 1083, 1038, 830, 740, 700 High Resolution FAB-MS (m / e, (C 29 H 3B 0 B unto Hiroshi): Calculated 478.2594 Measured 478.2617

, Δ ppm): 2.29 (3H, s), 2.41-2.51 (lH, m), 2.75-3.02 (4fl, ni), 3.25-3.36 (lH, m), 3.76 (3H, s), 3.77-3.83 ( 2H, ra), 3.83 (6H, sX2), 4.10-4.19 (lH: m) _J 4.23 (lH _J ddd, J = 3.3Hz, 6.2Hz, ll.lHz), 4.42 (lH, ddd, J = 3.3Hz) , 5.2Hz, H.lHz), 4.59 (2H, s), 6.39 (lH, s), 6.72 (2H, d, J = 8.7Hz), 7.17 (2H, d, J = 8.7Hz) 7.31-7.34 ( (5H, m) Example 30

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (3-phenyl-2-propyl-2-yloxy) -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using compound 1 and (3-bromo-1-probenyl) benzene. Yield 68%.

 IR (neat, cm): 2932, 1515, 1497, 1455, 1341, 1245, 1176, 1122, 1077, 1038, 831,

753

High Resolution FAB-MS (πl / e, as ^{_{+ (C 23 H 33 0 4}} N + H)):

 Calculated 460.2488

 Measured value 460.2510

^ - s Awakening _{(CDC1 3, δ ppm):} 2.30 (3H, s), 2.35-2.45 (lH, iii), 2.70-2.90 (2H, m), 2.82 (lH, dd, J = 9.3Hz, 14.3Hz) , 2.94 (lH, dd, J = 3.2Hz, 14.3Hz), 3.25-3.35 (lH, ni), 3.74 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 3.98 (lH, dd, J = 3.2Hz, g.3Hz), 4.72 (lH, ddd, J = 1.2Hz, 6.2Hz, 12.2Hz), 4.86 (lH, ddd, J = 1.2Hz, 6.2Hz, 12.2Hz), 6.40 ( lH, s), 6.47 (lH, td, J = 6.2Hz, 15.9Hz), 6.71 (lH, d, J = 15.9Hz), 6.70-6.80 (2H, m), 7.15-7.40 (7H, m)

Example 31

 β, 7-Dimethoxy-l- (4-methoxybenzyl) -2-methyl-8- (3,4-methylenedioxybenzyloxy) -1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 3,4-methylenedioxybenzyl octalide, the title compound is obtained as a pale brown oil in the same manner as in Example 1. Yield 70%.

IR (neat, cm): 2936, 1514, 1448, 1250, 1116, 1076, 1040, 1004, 932, 816, 758 High Resolution FAB-MS (m / e, as ^{_{+ (C 28 H 3, 0}} 6 N + H)):

 Calculated 478.2230.

 Measured value 478.2259

_{- NMR (CDC1 3, δ ppm} ): 2.20 (3H, s), 2.34-2.46 (lH, ni), 2.69-2.88 (4H, ni), 3.21- 3.33 (lH, m), 3.73 (lH, dd, J = 3.2Hz, 9.3Hz), 3.77 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.94 (lH, d, J = 10.9Hz), 5.11 (lH, d, J = 10.9Hz), 5.95 (2H, s ), 6.40 (lH, s), 6.74 (2H, d, J = 8.7Hz), 6.78 (lH, d, J = 7.8Hz), 6.88 (lH 5 dd, J = 1.6Hz, 7.8Hz), 6.91 (lH, d, J = 1.6Hz), 7.00 (2H, d, J = 8.7Hz)

 6,7-Dimethoxy-1- (4-methoxybenzyl) -8- [3- (4-methoxyphenyl) -2-propenyloxy] -2-tyl-1,2,3,4-tetrahydroisoquinoline

 Using 1 and 1- (3-bromo-1-propenyl) -4-methoxybenzene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 57%.

IE (neat, cm): 2938 , 1515, 1467, 1344, 1302, 1248, 1176,1119,1035,840, 756 High Resolution FAB-MS (m / e, (C 30 H 35 0 5 N + H) + As):

 Calculated 490.2594

 Measured value 490.2602

'H-NMRCCDCla, δ ppm): 2.29 (3H, s), 2.35-2.45 (; iH, ni), 2.70-2.90 (3H, ni), 2.93 (lH, dd, J = 3.2Hz, 14.4Hz), 3.25-3.35 (lH, mO, 3.75 ( 3H, s), 3.82 (3H 5 s), 3.85 (3H, s), 3.88 (3H, s) s 3.97 (lH, dd, J = 3.2Hz, 9.3Hz) , 4.70 (lH, ddd, J = 1.2 Hz, 6.5 Hz, 12.0 Hz), 4.83 (lH, ddd, J = 1.2 Hz, 6.5 Hz, 12.0 Hz), 6.33 (lH, td J = 6. Hz, 15.9 Hz ), 6.40 (lH, s), 6.64 (lH, d, J = 15.9Hz), 6.74 (2H, d, J = 8.8 Hz), 6.85 (2H, d, J = 8.8Hz), 7.19 (2H, d, J = 8.8Hz), 7.31 (2H, d, J = 8.8Hz)

Example 33

 S, 7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (3-methyl-2-butenyloxy) -1,2,3,4-tetrahydroisoquinoline

 Using 1 and 1-chloro-3-methyl-2-butene as in Example 1, the title compound is obtained as a pale yellow oil. Yield 77%.

^{IR (neat, cm 1):} 2930, 1515, 1497,1458, 1245, 1176, 1119, 1077, 1035,831, 770 High Resolution FAB-MS (m / e, (C 25 H 33 0 4 N + H) ⁺ ):

 Calculated value 412.2488

 Measured value 412.2481

- Awakening: _{(CDC1 3, δ ppm):} 1.70 (3H, d, J = 1.5Hz), 1.78 (3H, s), 2.30 (3H, s), 2.35- 2.45 (lH, ra), 2.70-2.85 (3H , ni), 2.90 (lH, dd, J = 3.0Hz, 14.3Hz), 3.25-3.35 (lH, ra), 3.79 (3H, s), 3.84 (3H, s), 3.87 (3H, s), 3.92 (lH, dd, J = 3.0Hz, 9.0Hz), 4.59 (lH, dd, J = 7.5Hz, H.3Hz), 4.58 (lH, dd, J = 7.5Hz, 11.3Hz), 5.55-5.64 (lH , m), 6.38 (lH, s), 6.81 (2H, d, J = 8.5Hz), 7.19 (2H, d, J = 8.5Hz)

Example 34

 6,7-Dimethoxy-l- (4-methoxybenzyl) -8- [2- (3-methoxybenzyloxy) ethoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 1 and para- (2-chloroethoxy) -3-methoxytoluene. Yield 57%.

IR (neat, CTi): 2938, 1605, 1515, 1458, 1344, 1269, 1245, 1116, 1038, 834, 786, 759

High Resolution FAB- MS (m / e, as ^{_{+ (C 3 H 37 0 β}} N + H).):

 Calculated value 508.2699

 Measured value 508.2720

iH-MR CDCIa, δppra): 2.29 (3H, s), 2.35-2.43 (lH, ni), 2.69-2.96 (4H, ni), 3.24-3.34 (lH, m), 3.75 (3H, s) , 3.76 (3H, s), 3.77-3.81 (2H, ni), 3.83 (3H, s), 3,84 (3H s s), 4.06 (lH, dd, J = 3.0Hz, 9.2Hz), 4.23 ( lH, ddd, J = 3.4Hz, 6.1Hz, 9.0 Hz), 4.41 (lH, ddd, J = 3.4Hz, 5.7Hz, 9.0Hz), 4.58 (2H, s), 6,38 (lH, s), 6.73 (2H, d, J = 8.8Hz), 6.81 (lH, dd, J = 1.5Hz, 7.7Hz), 6.90-6.93 (2H, m), 7.17 (2H _J d, J = 8.8Hz), 7.23 ( (lH, t, J = 7.7Hz)

Example 35

 6,7-diethoxy-l- (4-methoxybenzyl) -2-methyl-8- [2- (3-nitrobenzyloxy) ethoxy] -1,2,3,4-tetrahydroisoquinoline

 Using 1 and α- (2-chloroethoxy) -3-nitrotoluene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 77%.

IRCneat, αϊί): 938, 1608 , 1533, 1515, 1467, 1353, 1245, 1119, 1038,816,732 High Resolution FAB-MS (m / e, (C 23 H 34 0 7 N 2 + H) as a ^+):

 Calculated value 523.2444

 Measured value 523.2468

HMl CDCls, δ ppm): 2.27 (3H, s), 2.36-2.44 (lH, m), 2.71-2.95 (4H, m), 3.23-3.33 (lH, ra), 3.74 (3H, s), 3.78- 3.90 (2H, ni), 3.84 (6H, sX), 4.02 (lH, dd, J = 3.3Erz, 9.4Hz), 4.28 (lH, ddd, J = 3.2Hz, 6.1Hz, 11.3Hz) _I 4.44 (lH , ddd, J = 3.2Hz, 5.5Hz, 11.3Hz), 4.65 (2H, s), 6.39 (lH, s), 6.70 (2H, d, J = 8.5Hz),

7.14 (2H, d, J = 8.5Hz), 7.46 (lH, t, J = 8.0Hz), 7.61 (lH, dd, J = 1.8Hz, 8.0Hz),

8.11 (lH, d, J = 8.0Hz), 8.17 (lH, d, J = 1.8Hz)

Example 36

 6,7-Dimethoxy-8- (3,5-dimethoxybenzyloxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 3,5-dimethoxybenzyl chloride, the title compound is obtained as a pale brown oil in the same manner as in Example 1. 86% yield.

IR (neat, cm): 2940 , 1602, 1514, 1468, 1344, 1246, 1156, 1122, 1068, 832, 758 High Resolution FAB-MS (m / e, (C 29 H 35 0 B N + H) + As):

 Calculated 494.2543

 Measured value 494.2527

'.Eta.讀_{(CDC1 3, δ ppm):} 2.20 (3H, s), 2.34-2.45 (lH, ra), 2.69-2.92 (4H, m), 3.20- 3.33 (lH, m), 3.74 (6H, s) i, 3.75-3.85 (lH, ni), 3.76 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.98 (lH, d, J = ll, 2Hz), 5.16 (lH , d, J = 11.2Hz), 6.41 (lH, s), 6.43 (lH, t, J = 2.3Hz), 6.59 (2H, d, J = 2.3Hz), 6.72 (2H, d, J = 8.5Hz) ), 7.01 (2H, d, J = 8.5Hz) i

Example 37

 S, 7-Dimethoxy-8- (2,5-methoxybenzyloxy) -l- (4-Methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

As in Example 1 using compound 1 and 2,5-dimethoxybenzyl chloride To give the title compound as a pale brown oil. Yield 80%.

IR (neat, cm): 2938 , 1505, 1467, 1245, 1179,1116, 1077, 1041, 1005, 816, 759 High Resolution FAB-MS (m / e, (C 23 Η 35 0 β Ν + Η) + As):

 Calculated 494.2543

 Measured 494.2513

'H-NMRCCDCla, δ ppm): 2.18 (3H, s), 2.34-2.45 (lH, ni), 2.68-2.94 (4H, m), 3.21- 3.35 (lH, m), 3.72 (6H, s), 3.76 (3H, s), 3.79-3.88 (lH, m), 3.86 (3H, s), 3.90 (3H, s), 5.05 (lH 5 d, J = 11.4Hz), 5.29 (lH, d, J = 11.4Hz), 6.40 (lH, s), 6.70 (2H, d, J = 8.7Hz), 6.80 (lH, d, J = 8.5Hz), 6.85 (lH, dd, J = 2.7Hz, 8.5Hz), 6.98 (2H, d, J = 8.7Hz), 7.03 (lH, d, J = 2.7Hz)

Example 38

 8- (2-benzylthioethoxy) -6,7-diethoxy-1- (4-methoxybenzyl) -2

-Methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and α- (2-chloroethylthio) toluene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 43%.

IR (neat, cm): 2938 , 1515, 1458, 1344, 1245, 1119, 1083, 1029, 1005, 834, 702 High Resolution FAB-MS (m / e, (C 29 H 35 0 4 NS + H) + As):

 Calculated 494.2365

 Measured value 494.2341

_{^{1 H-NMR (CDC1 3,}} δ ppm): 2.32 (3H, s), 2.35-2.45 (1H, m), 2 · 70-2.90 (4H s m), 2.77 (2H, t, J = 7.1Hz) , 3.25-3.35 (lH, ra), 3.75 (2H, s), 3.78 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 3.95 (lH, dd, J = 3.7Hz, 8.8 H2), 4.12 (lH, td, J = 7.1Hz, 10.0Hz),

9

) Ηΐ299 7,90 (lH, d, J = 8.7Hz)

Example 42

 — 6,7-Dimethoxy-8- (2,6-dimethoxybenzyl) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 2,6-dimethoxybenzyl chloride, the title compound is obtained as a pale brown oil in the same manner as in Example 1. Yield 83%.

IR (neat, cm ¹ ): 2938, 1602, 1482, 1344, 1248, 1125, 1038, 942, 834, 756

High Resolution FAB-MS (m / e, as ^{_{+ (C 23 H 35 0 e}} N + H)):

 Calculated 494.2543

 Measured value 494.2523

- Spirit _{(CDC1 3, δ ppm):} 2.19 (3H, s), 2.35-2.45 (lH, m), 2.58-2.91 (4H, m), 3.25- 3.37 (lH, m), 3.72 (6H, s) , 3.75 (3H, s), 3.86 (3H, s), 3.92 (lH, dd, J = 2.5 Hz, 9.9 Hz), 3.99 (3H, s), 5.05 (lH, d, J = 9.6 Hz), 5.51 (lH, d, J = 9.6Hz), 6.39 (lH, s), 6.57 (2H, d, J = 8.5Hz), 6.64 (2H, d, J = 8.9Hz), 6.90 (2H, d, J = 8.9Hz), 7.30 (lH, t, J = 8.5Hz)

Example 43

 6,7-Dimethoxy-1- (4-methoxybenzyl) -8- [3- (4-methoxyphenylsulfinyl) propoxy] -2-methyl-1,2,3,4-tetrahydroisoquino Rin

 Using 1 and 1- (3-chloropropylsulfonyl) -4-methoxybenzene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 61

%. IR (neat, cm): 2932, 1584, 1511, 1464, 1341, 1248, 1179, 1122, 1053, 867, 831, 753

High resolution FAB- ilS (m / e, as ^{_{+ (C 3 H 37 0 B}} NS + H).):

 Calculated value 540.2420

 Measured value 540.2422

'H-NMRCCDCla, δ ppm): 1.93-2.15 (2H, ni), 2.32 + 2.35 (3H, sX2), 2.30-2.46 (lH, m), 2.71-2.90 (4H, m), 2.90-3.08 (2H _f ni) ₅ 3.21-3.33 (lH, m), 3.75 + 3.78 + 3.82 + 3.84 (12H _S SX4), 3.75-3.90 (1H, IH), 3.98-4.11 (1H, III), 4.12-4.28 (1H, m), 6.38 (lH, s) _} 6.75 + 6.76 (2H, dX2, J = 8.9Hz), 7.00 (2H, d, J = 8.9Hz), 7.05 + 7.06 (2H, dX2, J = 8.9Hz), 7.53 + 7.54 (2H, dX2, J = 8.9Hz)

Example 44

 6,7-Dimethoxy-1- (4-methoxybenzyl) -8- [3- (2-methoxyphenylsulfinyl) propoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using Compound 1 and 1- (3-chlorobutyrpyrsulfinyl) -2-methoxybenzene. Yield 22

⁰

 IR (neat, cm): 2938,1584,1515,1458,1343,1242,1180,1121,1069,1038,835,

759

High resolution FAB-MS (m / e, as (C ₃₀ Η ₃₇ Ο _β S + H) ⁺ ):

 Calculated value 540.2420

 Measured value 540.2436

'H-MR CDCla, δ ppm): 1.93-2.08 (lH, m), 2.23-2.38 (lH, m), 2.32 + 2.33 (3H, sX

(θ ^ 丄 ϊ?)

(ZH9'Z, = r ^< 3XP'HI) T8 * + 08'Z _i ⁱ (ZH9'i = f ^ Xl ⁱ HI) 9 ^ * + 5 ^ * ⁱ (ZH9 "A

= f ⁱ 2Xl ^< HT) 6r + 8r ^< (^ H6'8 = f ⁱ 2XP ^< H2) 80 '+ S0 * Z-'(" ^{I <} HI) 26"9-98'9

 '(ZH6'8 = nxP'H2) 9Z 9 + SZ 9' (s'Hl S'9 '(i "' in) 0S '9ΐ' 'Ο'Ηΐ)

ΟΪ ^-6 · '(ω'ιπ) 06 · --- ε'(9χ3'Η2ΐ) ΐ8 · ε + 08 · ε + 8 / _ίε + · ε + ^ · ε '( ^ΐϋ

 H2) SS'S- 0 ε '("ΐ'ίίΐ) 90 · ε-' ('H) 88-69' ('Ηΐ) 9 2-S'

SZ800 / 68df / JOd / c 6IIZ0 / 06OAV Example 45

 6,7-Dimethoxy-1- (4-methoxybenzyl) -8- [3- (4-methoxybenzylsulfinyl) propoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using 1 and α- (3-chloropropylsulfinyl) -4-methoxytoluene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 9

%.

IR (neat, cm): 2938 , 1614, 1515, 1467, 1347, 1248, 1179, 1119, 1086, 834, 757 High Resolution FAB-MS (m / e, (C 31 H 3 S 0 B NS + H) ⁺ ):

 Calculated 554.2576

 Measured value 554.2557

^ -NMRCCDCU, δ ppm): 2.16-2.25 (2H, m), 2.37 (3H, s), 2.37-2.4S (lH, m), 2.60- 2.93 (6H s m), 3.22-3.34 (lH, m ), 3.73-3.79 (lH, ni), 3.75 + 3.76 + 3.77 + 3.78 (9H, sX4), 3.83 (3H, s), 3.80-3.90 (2H, m), 3.99-4.10 (lH, m), 4.16 -4.30 (lH, m), 6.39 (lH, s), 6.79 + 6.80 (2H, dX2, J = 8.9Hz), 6.86 + 6.87 (2H, dX2, J = 8.8Hz), 7.11 + 7.12 (2H, dX2 , J = 8.9Hz), 7.16 + 7.17C2H, dX2, J = 8.8Hz)

Example 46

 6,7-Dimethoxy-l- (4-methoxybenzyl) -2-methyl-8- (4-phenylsulfinylbutoxy) -1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 4-chlorobutylsulfinylbenzene, the title compound is obtained as a colorless oil in the same manner as in Example 1. 82% yield.

IR (neat, cm ¹ ): 2932, 1605, 1584, 1515, 1497, 1452, 1245, 1119, 1089, 1038, 801,

750,693 High Resolution FAB-MS (m / e, as _{+ (C 30 H 37 0 5} NS + H)):

 Calculated 524.2471

 Measured value 524.2457

， δ ppra):1.80-2.05(4H,m),2.34(3H,s),2.37-2.44(lH,ni),2.73- 2.90(6H，ni)，3.22-3.32(lH，m)，3.78(6H，s)，3.83(3H，s)，3.80- 3.89(1Η，ίπ: 3.92-4.01(lH,m),4.05-4.17(lH,m),6.37(lH,s),6.79+6.80(2H,dX2,J= 8.7Hz),7.11+7.12(2H,dX2,J=8.7Hz),7.47-7.62(5H,in)

, Δ ppra): 1.80-2.05 (4H, m), 2.34 (3H, s), 2.37-2.44 (lH, ni), 2.73- 2.90 (6H, ni), 3.22-3.32 (lH, m), 3.78 ( 6H, s), 3.83 (3H, s), 3.80-3.89 (1 (, ίπ: 3.92-4.01 (lH, m), 4.05-4.17 (lH, m), 6.37 (lH, s), 6.79 + 6.80 (2H , dX2, J = 8.7Hz), 7.11 + 7.12 (2H, dX2, J = 8.7Hz), 7.47-7.62 (5H, in)

Example 47

 8- [3- (Jetoxyphosphinoyl) propoxy] -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and getyl = 3-chloropropylphosphonate, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 77%.

IR (neat, cm ¹ ): 2938, 842, 1605, 1584, 1515, 1497, 1458, 1344, 1299, 1245, 1179,

1119,1029,969,825,753

High Resolution FAB-MS (ni / e, as ^{_{+ (C 27 H 4 0 7}} NP + H).):

 Calculated 522.2621

 Measured value 522.2642

^ -N RCCDC, δ ppm): 1.33 (6H, t, J = 6.9 Hz), 1.88-2.19 (4H, m), 2.37 (3H, s), 2.37-2.48 (1Η, ιπ), 2.73- 2.93 ( 4H, m), 3.24-3.35 (lH, m), 3.78 (3H, s), 3.80 (3H, s), 3.83 (3H, s), 3.86-3.97 (1H, in), 3.99-4.25 (6H, ID), 6.38 (1H, S), 6.79 (2H, d, J = 8.5Hz), 7.13 (2H, d, J = 8.5Hz)

W

826

FAB-MS (m / e, as ^{_{+ (C 24 H 3 0 4}} N + H)): 398

'.Eta. grace _{(CDC1 3, δ ppm):} 2.35 (3H, s), 2.36-2.45 (lH, ni), 2.50-2.58 (2H, iii), 2.72- 2.84 (4H, m), 3.24-3.35 ( lH, m), 3.79 (3H, s), 3.83 (6H, s), 3.88-3.g7 (lH, m) _; 4.05 (lH, td, J = 6.8Hz, 9.6Hz-), 4.25 (lH, td, J = 6.8Hz, 9.6Hz), 5.09 (lH, qd, J = 1.7Hz, 10.2Hz), 5.16 (lH, qd, J = 1.7Hz, 17.4Hz), 5.92 (lH, tdd, J = 6.6 Hz, 10.2Hz, 17.4Hz), 6.37 (lH, s), 6.81 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6Hz)

Example 50

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- [3- (4-nitrophenylsulfinyl) propoxy] -1,2,3,4-tetrahydroisoquinoline

 Using 1 and 1- (3-chloropropylsulfinyl) -4-nitrobenzene, the title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 53%.

IR (neat ', o¾): 2944, 1608, 1518, 1464, 1344, 1245, 1179, 1119, 1047, 1008, 852, 750

High Resolution FAB- MS (m / e, as ^{_{+ (C 23 H 34 0 7}} N 2 S + H)):

 Calculated 555.2165

 Measured value 555.2195

'H-MRCCDCla, δ ppm): 1.93-2.ll (lH, m), 2.17-2.36 (lH, m), 2.32 + 2.37 (3H, s X 2), 2.37-2.48 (lH, m), 2.71 -3.00 (5H, m), 3.08-3.32 (2H, in), 3.75 + 3.77 + 3.79 + 3.83 (9H, sX4), 3.75-3.90 (1Η, πι), 4.00-4.31 (2H, DI), 6.40 (1H, S), 6.75 + 6.79 (2H, dX2, J = 8.9Hz), 7.07 + 7.10 (2H, dX2, J = 8.9Hz), 7.70 + 7.71 (2H, dX2, J = 9.1Hz), 8.32 + 8.33 (2H, dX2, J = 9.1Hz) Example 51

 8- [3- (4-aminophenylsulfinyl) propoxy] -6,7-dimethyl-1- (4

-Methoxybenzyl) -2 -Methyl -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using Compound 1 and 4- (3-chloropropylsulfinyl) aniline. Yield 27%.

 IR (neat, cm): 3350, 3225, 2938, 1602, 1503, 1467, 1344, 1245, 1179, 1119, 1029,

828,753

High resolution FAB- iiS (m / e, as ^{_{+ (C 29 H 38 0 5}} N 2 S + H)):

 Calculated 525.2423

 Measured value 525.2447

 'H-NMR CDC, δ ppm): 1.94-2.19 (2H, m), 2.34 + 2.36 (3H, sX2), 2.36-2.46 (lH, m), 2.70-2.89 (4H, m), 2.96 + 2.97 ( 2H, tX2, J = 7.8Hz), 3.20-3.35 (lH, m), 3.76 + 3.78 + 3.82 (9H, sX3), 3.93-4.10 (2H, m), 4.10-4.26 (lH, ni), 6.38 ( lH, s), 6.73 (2H, d, J = 8.3Hz), 6.77 (2H, d, J = 8.4Hz), 7.06 (2H, d, J = 8.4Iiz), 7.39 + 7.41 (2H, dX2, J = 8.3Hz)

Example 52

 6,7-Dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -8- [3- (K-methylanilino) propoxy] -1,2,3,4-tetradoroisoquinoline

6,7-Dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroisoquinolin-8-ol (Compound 2) and Ν- (3-chloropropyl The title compound is obtained as a pale yellow oil using-物 -methylaniline hydrochloride in the same manner as in Example 1. Yield 57%. IR (neat, cm ¹ ): 2962, 2836, 1602, 1518, 1467, 1383, 1344, 1245, 1119, 1038, 825, 747,693

High resolution FAB - MS (m / e, as ^{_{+ (C 32 H 42 0 4}} N 2 + H)):

 Calculated 519.3223

 Measured value 519.3263

- Dragon _{R (CDC1 3, δ ppm)} : 0.90 (3H, d, J = 5.8Hz), 0.92 (3H, d, J = 5.8Hz), 2.01-2.09 (2H, m), 2.28-2.38 (lH, m) _> 2.57-2.68 (lH, m), 2.74-2.89 (4H, ni), 2.97 (3H, s), 3.13-3.26 (lH, m), 3.58 (2H, t, J = 7.3Hz), 3.76 (3H, s), 3.80 (3H, s), 3.83 (3H, s), 3.99 (lH, td, J = 5.8Hz, 9.4Hz), 4.10-4.25 (2H, ni), 6.36 (lH, s) , 6.66 -6.79 (4H, in), 7.02 (2H, d _s J = 8.9Hz), 7.19-7.25 (3H, in)

Example 53

 6,7-Dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -8- (3-methoxybenzyloxy) -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using compound 2 and 3-methoxybenzyl chloride. Yield 59%.

IR (neat, cm ¹ ): 2962, 1605, 1515, 1497, 1467, 1344, 1245, 1173, 1119, 1038, 825, 786

High Resolution FAB-MS (m / e, as ^{_{+ (C 3 H 37 0 5}} + H).):

 Calculated value 492.2750

 Measured 492.2770

_{- NMR (CDC1 3, δ ppm} ): 0.77 (3H, d, J = 6.3Hz), 0.82 (3H, d, J = 6.3Hz), 2.28-2.40 (lH, m), 2.59-2.95 (5H, ra ), 3.16-3.28 (lH, m), 3.76 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 4.03 (lH, dd, J = 5.1Hz, 8.4Hz), 4.95 (lH, d, J = ll.l

Hz), 5.22 (lH, d, J = ll.lHz), 6.39 (lH, s), 6.67 (2H, d, J = 8.8Hz), 6.87-7.08

(5H, m) ₅ 7.30 (lH, t, J = 8.2Hz)

Example 54

 8- [3- (N-benzyl-N-methylamino) propoxy] -6,7-dimethoxy-2-isopropoxy-1- (4-methoxybenzyl) -1,2,3,4-tetrahydro The title compound is obtained as a pale yellow oil in the same manner as in Example 1 by using isoquinoline compound 2 and N- (3-octapropyl) -N-tylbenzylamine hydrochloride. Yield 30%.

IR (chamber t, cm): 2956, 1605, 1584, 1515, 1497, 1344, 1245, 1176, 1122, 1038, 825,

735,699

High Resolution FAB-MS (m / e, as _{+ (C 33 H 44 0 4} N 2 + H)):

 Calculated value 533.3380

 Measured value 533.3347

_{^{1 HN R (CDC1 3, δ}} ppni): 0.89 (3H, d, J = 6.3Hz), 0.91 (3H, d, J = 6.3Hz), 2.03 (2H, quin, J = 7.1Hz), 2.21 (3H , s), 2.25-2.36 (lH, m), 2.56-2.94 (7H, m), 3.16-3.27 (lH, m), 3.51 (2H, s), 3.75 (3H, s), 3.81 (3H, s ), 3.82 (3H, s), 3.94-4.03 (lH, m), 4.09-4.17 (lH, n, 4.20-4.30 (lH, m), 6.34 (lH, s), 6.74 (2H, d, J = 8.6Hz), 7.06 (2H, d, J = 8.6Hz), 7.20-7.34 (5H, m)

Real Willow 55

6,7-Dimethoxy-8- [3- (N, N-dimethylaminomethyl) benzyloxy] -2-izopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroisoquinoline The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 2 and 3-chloromethyl-N, N-dimethylbenzylamine hydrochloride. Yield 39%.

 IR (neat, cm): 2944, 2824, 1605, 1515, 1467, 1344, 1245, 1176, 1119, 1038, 825,

792

High Resolution FAB-MS (m / e, as ^{_{+ (C 32 H 42 0 4}} N 2 + H)):

 Calculated 519.3223

 Measured value 519.3264

'.Eta. employment _{K (CDC1 3, δ ppm)} : 0.76 (3H, d, J = 6.4Hz), 0.82 (3H, d, J = 6.4Hz), 2.24 (6H, s) 2.30-2.38 (lH, m ), 2.60-2.94 (5H, in), 3.18-3.28 (lH, ni), 3.43 (2H, s), 3.76 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 4.05 ( lH, dd, J = 3.5Hz, 8.6Hz), 4.97 (lH, d: J = ll.lHz), 5.25 (lH, d, J = ll.lHz), 6.38 (lH, s), 6.65 (2H, d, J = 8.7Hz), 6.88 (2H, d, J = 8.7Hz), 7.27-7.40 (4H, m)

Example 56

 8- [3- (N-benzyl-N-methylaminomethyl) benzyloxy] -6,7-dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -1,2,3,4-tetrahydro Isoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 2 and N-benzyl-3-culomethyl-N-methylbenzylamine hydrochloride. Yield 82

⁰

 IR (neat, cm): 2938, 2836, 1605, 1515, 1458, 1344, 1245, 1119, 1035, 981, 825,

 741 '

High resolution FAB-MS (ni / e, as (C ₃₈ Η _{4 β} 0 ₄ N ₂ + H) +): 1 Calculated value 595.3536

 Measured value 595.3566

_{- NMR (CDC1 3, δ ppm} ): 0.75 (3H, d, J = 6.3Hz), 0.80 (3H, d, J = 6.3Hz), 2.17 (3H, s), 2.25- 2.36 (lH, m), 2.57- 2.94 (5H, m), 3.16-3.27 (lH, m), 3.51 (2H, s), 3.54 (2H, s) _s 3.72 (3H, s), 3.85 (3H, s), 3.89 (3H, s), 4.04 (lH, dd, J = 3.4Hz, 8.6Hz), 4.97 (lH, d, J = 10.5Hz), 5.25 (lH, d, J = 10.5Hz), 6.38 (lH, s), 6.63 (2H, d, J = 8.6Hz), 6.88 (2H, d, J = 8.6Hz), 7.20-7.46 (9H, ni)

Example 57

 , 7-Dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -8-C3- (morpholinomethyl) benzyloxy] -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 2 and N- (3-culomethylbenzyl) morpholine hydrochloride. Yield 65%.

IR (neat, cni): 2962 , 1611, 1515, 1461, 1344, 1284, 1119, 1086, 1035, 864, 822 High Resolution FAB-MS (m / e, (C 34 H 44 0 6 N 2 + H) ⁺ ):

 Calculated 561.3329

 Measured value 561.3353

_{^{1 H- MR (CDC1 3, δ}} ppm): 0 · 75 (3H, d, J = 6.4Hz), 0.80 (3H, d, J = 6.4Hz), 2.27-2.38 (lH, ra), 2.38-2.47 (4H, m), 2.S0-2.95 (5H, ffl), 3.16-3.27 (1Η, πι), 3.49 (2Η, s), 3.64-3.71 (4H, m), 3.75 (3H, s) , 3.85 (3H, s), 3.89 (3H, s), 4.02 (lH, dd, J = 3.2 Hz, 8.5 Hz), 4.98 (lH, d, J = ll.lHz), 5.25 (lH, d, J = ll.lHz), 6.38 (lH, s) _; 6.64 (2H, d, J = 8.7Hz), 6,87 (2H, d, J = 8.7Hz), 7.30-7.43 (4H, ni) Example 58

 6,7-Dimethoxy-2-isopropyl-1- (4-methoxybenzyl) -8- [4-methoxy-3- (morpholinomethyl) benzyloxy] -1,2,3,4-tetrahydroisoquinolyl

The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 2 and N- (5-chloromethyl-2-methoxybenzyl) morpholine hydrochloride. Yield 40

%.

 IR (neat, cm): 2956, 1611, 1515, 1467, 1341, 1284, 1248, 1176, 1119, 1086, 1035, 869

FAB- S (ni / e, as ^{_{+ (C 3 s Η 4 β}} 0 S N 2 + H)): 591

 (lH, ra), 2.40-2.52 (4H, ffl), 2.60-2.72 (3H, ra), 2.75-2.96 (2H, m), 315-3.27 (lH, m), 3.53 (2H, s) , 3.67-3.72 (4H, m), 3.76 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.88 (3H, s), 3.90-4.00 (lH, m), 4.98 (lH , d, J = 10.6Hz), 5.20 (lH, d, J = 10.6Hz), 6.37 (lH, s), 6.65 (2H, d, J = 8.7Hz), 6.87 (lH, d, J = 8.4Hz ), 6.88 (2H, d, J = 8.7Hz), 7.35 (lH, dd, J = 2.1Hz, 8.4Hz), 7.42 (lH, d, J = 2.1Hz)

Example 59

 7,8-Dimethoxy-l- (4-methoxybenzyl) -2-methyl-6 (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

7,8-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol (Compound 3) and 4-butyl butylthiobenzene The title compound is obtained as a colorless oil in the same manner as in Example 1. Yield 91%. IR (neat, cm): 2938, 1605, 1584, 1515, 1497, 1458, 1344, 1269, 1179, 1116, 1038,

822,738,693

High Resolution FAB- MS (m / e, as ^{_{+ (C 30 H 37 0 4}} NS + H)):

 Calculated value 508.2522

 Measured value 508.2572

 'H-NMRCCDC, δ ppm): 1.82-2.02 (4H, m), 2.33 (3H, s), 2.34-2.42 (lH, ni), 2.71-2.88 (4H, ni), 3.02 (2H, t, J = 7.1Hz), 3.21-3.32 (lH, m), 3.78 (3H, s), 3.80 (3H, s), 3.94 (3H, s), 3.88-3.93 (lH, m), 3.97 (2H, t, J = 6.8Hz), 6.35 (lH, s), 6.81 (2H, d, J = 8.8Hz), 7.14-7.36 (7H, m)

Example 60

 6- [3- (Dibenzyloxyphosphinoyl) propoxy] -7,8-dimethoxy-1-

(4-Methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 3 and dibenzyl = 3-clopropylpropylphosphonate. 85% yield.

 IR (neat, oft): 2938, 1605, 1584, 1515, 1497, 1458, 1344, 1245, 1179, 1116, 1030,

822,735

High Resolution FAB-MS (m / e, as _{+ (C 37 H 44 0 7} NP + H)):

 Calculated 646.2933,

 Measured value 646.2942

'HN RCCDC ^, δ ppm): 1.93-2.15 (4H, m), 2.32 (3H, s), 2.33-2.39 (lH, m), 2.72-2.85 (4H, m), 3.21-3.32 (lH, m ), 3.78 (6H, s), 3.89 (lH, dd, J = 3.9Hz, 6.8Hz), 3.93 (3H, s), 3.95 (2H, d, J = 5.9Hz), 4.98 (2H, dd, J = 8.0Hz, 12.0Hz), 5.07 (2H _: dd, J = 8.8Hz, 12.0Hz), 6, 30 (lH, s), 6.81 (2H, d, J = 8.5Hz), 7.17 (2H, d, J = 8.5Hz), 7.30-7.36 (10H, ni)

Example 61

 6,7-Dimethoxy-8- (2-dimethylaminoethoxy) -1- (4-methoxyphenyl)

2-methyl-1,2,3,4-tetrahydroisoquinoline

 6,7-Dimethoxy-1- (4-methoxyphenyl) -2-methyl-1,2,3,4-tetrahydrido

表 題 The title compound is obtained as a colorless oil in the same manner as in Example 1 using isoquinolin-8-ol (compound 4) and 2-chloro-N, N-dimethylethylamine hydrochloride. Yield 66%.

 IR (neat, cm): 2938, 2830, 1608, 1512, 1458, 1245, 1173, 1122, 1032, 832

FAB-ίίS (In / e, as ^{_{+ (C 23 H 32 0 4}} N 2 + H)): 401

 ^ -NMRCCDC, δ ppm): 2.07 (lH, td, J = 5.6Hz, 13.2Hz), 2.16 (6H, s), 2.30

 (lH, ddd, J = 6.0Hz, 7.3Hz, 13.2Hz), 2.35 (3H, s), 2.54-2.63 (lfl, ni), 2.75 (lH, td, J = 3.5Hz, 5.2Hz), 2.81- 3.02 (3H, m), 3.76 (6H, s), 3.85 (3H, s), 4.04 (lH, ddd, J = 5.6Hz, 7.3Hz, 9.8Hz), 4.88 (lH, s), 6.46 (lH, s), 6.79 (2H, d, J = 8.8Hz), 7.01 (2H, d, J = 8.8Hz)

Example 62

 6,7-Dimethoxy-8- (3-dimethylaminopropoxy) -1- (4-methoxyphenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound is obtained as a colorless oil in the same manner as in Example 1 using Compound 4 and 3-chloro-N, N-dimethylpropylamine hydrochloride. Yield 76%.

Example 64

 8- (3-Butenyloxy)-, 7-dimethoxy-1- (4-methoxyphenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 4 and 4-bromo-1-butene, the title compound is obtained as a colorless oil in the same manner as in Example 1. Yield 41%.

 IR (neat, cm): 2938, 1608, 1497, 1458, 1350, 1245, 1176, 1122, 1083, 1035, 831, 774

High resolution FAB-MS (m / e, (0 ₂₃ Η ₂₉ 0 ₄ Ν + Ν) ⁺ ):

 Calculated value 384.2175

 Measured value 384.2195

lH-NMR (CDCl ₃ , δ ppni): 2.00-2.19 (2H, m), 2.35 (3H, s), 2.56-2.63 (lH, iii), 2.75-3.02 (4H, m), 3.74 (3H, s ), 3.77 (3H, s), 3.85 (3H, s), 3.92 (lH, td, J = 7.2Hz, 9.0Hz), 4.81 (lH, s), 4.94-5.00 (2H, m), 5. ' 65 (lH, tdd, J = 6.6Hz, 9.6Hz, 17.7 Hz), 6.46 (lH, s), 6.7g (2H, J = 8.9Hz), 7.01 (2H, J = 8.9Hz)

Example 65

 6,7-Dimethoxy-1- [2- (4-methoxyphenyl) ethyl] -2-methyl-8- (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

 6,7-Dimethoxy-1- [2- (4-methoxyphenyl) ethyl] -2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (compound 5) The title compound is obtained as a colorless oil in the same manner as in Example 1 using butylthiobenzene. Yield 51 ° /. .

IR (neat, απ ¹ ): 2938, 1584, 1515, 1494, 1341, 1299, 1245, 1179, 1119, 1035, 828, High Resolution FAB- MS (m / e, as _{+ (C 3 H 3 s 0} 4 NS + H)):

 Calculated value 522.2740

 Measured value 522.2709

- Lan _{E (CDC1 3, δ ppra)} : 1.70-1.84 (4H, m), l.85-1.95 (2H, in), 2.35-2, 50 (lH, m), 2.45 (3H, s), 2.65 -2.90 (4H, m), 2.96 (2H, t, J = 7.1Hz), 3.20-3.35 (lH, in), 3.50-3.64 (lH, m), 3.76 (3H, s), 3.77 (3H, s ), 3.82 (3H, s), 3.83-3.90 (lH, m), 4.02-4.11 (lH, ni), 6.37 (lH, s), 6.81 (2H, d, J-8.9Iiz), 7.13-7.38 ( 7H, m)

Example 66

 8- [3- (dibenzyloxyphosphinoyl) propoxy] -6,7-dimethoxy-1- [2- (4-methoxyphenyl) ethyl] -2-methyl-1,2,3 , 4-tetrahydroisoquinoline

The title compound is obtained as a pale yellow oil in the same manner as in Example 1 using compound 5 and dibenzyl = 3-chloropropylphosphonate. Yield 52 ° / ₀ .

IE (neat, αη): 2938 , 1608, 1515, 1497, 1458, 1344, 1245, 1119, 1023, 996,753 High Resolution FAB-MS (m / e, as ^{_{+ (C 38 H 46 0 7}} NP + H)) :

 Calculated 660.3090

 Measured value 660.3054

'H-MRCCDCla, δ ppm): 1.84-2.02 (6H, m), 2.41 (3H, s), 2.42-2.50 (lH, s), 2.61-2.92 (4H, m), 3.19-3.30 (lH, m ), 3.49-3.54 (lH, ni) , 3.73 (6H 5 s), 3.81 (3H, s)! 3.83- 3.90 (1Η, πι), 3.98- 4.06 (lH, m), 4.93-5.09 (4H, ffl ), 6.36 (lH, s), S.76 (2H, d, J = 8.6Hz), 7.10 (2H, d, J = 8.6Hz), 7.29-7.37 (10H, ni) Example 67

 6,7-Dimethoxy-1- (4-isopropoxybenzyl) -2-methyl-8- (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

6,7-Dimethoxy-1- (4-isopropoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (compound 6) and 4-chlorobutylthiobenzene The title compound is obtained as a pale yellow oily substance in the same manner as in Example 1 by using phenol. Yield 57 ^_0/0.

IR (neat, cm ¹ ): 2938, 1605, 1584, 1512, 1497, 1386, 1344, 1269, 1239, 1185, 1119, 753

High resolution FAB - MS (m / e, as ^{_{+ (C 32 H 41 0 4}} NS + H)):

 Calculated 536.2835

 Measurement value 536.2807 '

_{^{1 H - MR (CDC1 3,}} δ ppm): 1.3.1 (6H, d, J = 6.0Hz), i .80-1.98 (4H, m), 2.34 (3H, s), 2.35-2.45 (lH, m), 2.70-2.90 (4H, m), 2.99 (2H, t, J = 7.2Hz), 3.25-3.35 (lH, m), 3.79 (3H, s), 3.83 (3H, s), 3.89 (lH , dd, J = 4.6Hz, 7.9Hz), 3.96 (lH, td, J = 6.1Hz, 9.5Hz), 4.16 (lH, td, J = 6.4Hz, 9.5Hz), 4.49 (lH, sept, J = 6.0Hz), 6.37 (lH, s), 6.78 (2H, d, J = 8.7Hz), 7.12 (2H, d, J = 8.7Hz), 7.15-7.36 (5H, m) '

Example 68;

 6,7-Dimethoxy-1- (3,4-dimethoxybenzene) -2-methyl-8- (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

6,7-Dimethoxy-1- (3,4-dimethoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (compound 7) and 4-butoxybutyl Thiobenzene To give the title compound as a colorless oil in the same manner as in Example 1. Yield 61%.

 IR (neat, cm): 2938, 1587, 1518, 1494, 1458, 1344, 1266, 1236, 1119, 1029, 798, 741

High resolution FAB-¾S (m / e, (C ₃ χΗ ₃₃ 0 ₅ NS + H) +):

 Calculated 538.2627

 Measured value 538.2654

_{^{1 H-NMR (CDC1 3,}} δ ρριη): 1.80-2.00 (4H, a), 2.30-2.45 (1Η, πι) 3 2.38 (3H, s), 2.70- 2.91 (4H, m), 2.99 (2H, t, J = 7.2Hz), 3.17-3.30 (lH, ni) J 3.7g (3H, s), 3.80 (3H i s), 3.83 (3H, s), 3.84 (3H, s), 3.90-3.96 ( lH, m), 3.99 (lH, td, J = 6.0Hz, 9.2Hz), 4.18 (lH, td, J = 6.3Hz, 9.2Hz), 6.37 (lH, s), 6.67 (lH, brs), 6.74 -6.80 (2H, m), 7.13-7.33 (5H, m)

Example 69

 8- (3-benzylthiopropoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Under an argon atmosphere, potassium tert-butoxide (32 mg, 0.26 mmol, 90%) and phenylmethane thiol J2 (0.31 mmol) are added to anhydrous dimethylformamide (0.5 mj) and stirred at room temperature for 30 minutes. The solution thus prepared was treated with 8- (3-clopropoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4

-To a solution of 100 mg of tetrahydroisoquinoline (compound 8, 0.24 mmol) in 0.5 mJ2 of anhydrous dimethylformamide, and stir at room temperature for 18 hours under an argon atmosphere. 20 mJ2 of water was added to the reaction mixture, and extracted three times with 25 mJ2 of ethyl acetate, and the organic layer was saturated. After washing with 20m β of saline, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by medium-pressure liquid chromatography (Merck Mouth-to-Bar column size B Licroblep SI60, Black-mouthed form (60) / Methanol (1)), and the title compound was colorless. 55 mg are obtained as an oil. Yield 46%.

IR (neat, cm):. 2932, 1605, 1515, 1497, 1458, 1344, 1245, 1119, 1086, 1035 High Resolution FAB-MS (m / e, (C 3 H 37 0 4 NS + H) as ⁺ ):

 Calculated value 508.2522

 Measured value 508.2486

'H-NMRiCDC ^, δ ppm): 1.95-2.05 (2H, m), 2.35 (3H, s), 2.36-2.45 (lH, in), 2.55- 2.65 (2H, m), 2.72-2.90 (4H, in), 3.20-3.35 (lH, ni), 3.70 (2H, s), 3.77 (3H, s) _; 3.79 (3H, s), 3.83 (3H, s), 3.89 (lH, dd, J = 4.8Hz , 7.7Hz), 4.01 (lH, td, J = 6.3Hz, 9.3Hz), 4.21 (lH, td, J = 6.3Hz, 9.3Hz), 6.37 (lH, s), 6.80 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.7Hz), 7.15-7.35 (5H, ni)

Example 70

 S, 7-Dimethoxy-8- (4-ethylthiobutoxy) -l- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Ethanethiol and 8- (4-chlorobutoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoxoline (compound 9 )) To give the title compound as a colorless oil in the same manner as in Example 69. Yield 39%.

IR (neat, cm ¹ ): 2938, 1605, 1584, 1497, 1455, 1344, 1302, 1245, 1176, 1119, 1083,

819

FAB-MS (m / e, (C 2 B H 37 0 4 NS + H) + to): 460 'H-NMRCCDCla, δρρπι): 1.26 (3H,, J = 7.3Hz), 1.77-1.90 (4H, m), 2.34 (3H, s), 2.37-2.46 (lH, m), 2.50-2.63 (4H , in), 2.73-2.95 (4H, [n), 3.24-3.35 (lH,! n), 3.79 (3H, s), 3.83 (3H, s), 3.84 (3H, s), 3.85-3.93 (lH , In), 3.99 (lH, t; d, J = 6.0 Hz, 9.3 Hz), 4.18 (lH, td, J = 6.4 Hz, 9.3 Hz), 6.38 (lH, s), 6.80 (2H, d, J = 8.6Hz), 7.15 (2H, d, J = 8.6Hz)

Example 71

 8- (3-benzyloxypropoxy) -6,7-dimethoxymethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline

 Under a nitrogen atmosphere, 10.3 mg (0.258 mmol) of 60% oily sodium hydride was added to a solution of 27.0 ^ & (0.261 mmol) of benzyl alcohol in 0.9 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Next, 80.3 mg of 8- (3-bromopropoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline (compound 10) (0.173 mmol) in 0.6 mfi of anhydrous dimethylformamide is added at 0 ° C, and the mixture is stirred for 3 hours, and further stirred at room temperature for 14 hours. 150 mJ2 of water is added to the reaction mixture, and the mixture is extracted three times with 50 infi of ethyl acetate. The organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. -The solvent is distilled off under reduced pressure, and the residue is separated by medium pressure liquid chromatography (Merck's Roper column size Β poly cloprep SI60, black form (20) / methanol (1)), and the title compound is colorless. Obtain 8.4 rag as an oil. Yield 10%.

IR (neat, cm ¹ ): 2932, 1608, 1515, 1497, 1458, 1344, 1245, 1176, 1122, 1080, 1038, 819, 738

High Resolution FAB- MS (in / e, as _{+ (C 3 H 37 0 5} N + H).): Calculated value 492.2750

 Measurement value 492.2751

'HN RCCDC ^, δ ppni): 2.10 (2H, quin, J = 6.3Hz), 2.34 (3H, s), 2.37-2.43 (lH, ni) 2.73-2.91 (4H, Di), 3.23-3.33 (lH , Di), 3.65-3.71 (2H, m), 3.77 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.91 (lH, dd, J = 3.5Hz, 8.2Hz), 4.09 (lH, td, J = 6.3Hz, 9.6Hz), 4.29 (lH, td, J = 6.3Hz, 9.6Hz), 4.50 (2H, s), 6.37 (lH, s), 6.79 (2H, d _; J = 8.9Hz), 7.14 (2H, d, J = 8.9Hz), 7.27-7.34 (5H, in)

Example 72

 8- [3- (N-benzyl-N-methylamino) propoxy] -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Under a cliff atmosphere, to a 1.5 DI JS solution of 100 mg (0.217 mmol) of Compound 10 in ethanol, add 500 JS (3.87 mmol) of Ν-methylbenzylamine, and heat to reflux for 2 hours. The solvent is distilled off under reduced pressure, and the residue is subjected to medium pressure liquid chromatography (Merck's rover-column size B Recroblep SI60, dichloromethane

(30) / methanol (1)) to give 61ing of the title compound as a pale yellow oil. Yield 56%.

 IR (neat, cm): 2938, 2836, 1605, 1584, 1515, 1497, 1458, 1314, 1245, 1119, 822, 798

FAB - MS (. In / e , as ^{_{+ (C 31 H 4 0 4}} N 2 + H)): 505

- thigh _{(CDC1 3, δ ppm):} 2.02 (2H, quin, J = 6.4Hz), 2.22 (3H, s), 2.40 (3H, s), 2.41 -2.51 (lH, m), 2.62 (2H, t , J = 7.3Hz), 2.77-2.98 (4H, ni), 3.24-3.35 (lH, in), 3.54 (2H, s), 3.7 & (3H, s), 3.81 (3H, s), 3.84 (3H , s), 3.96-4.09 (2H, m), 4.22 (lH, td, J = 6.6Hz, 9.6Hz), 6.38 (lH, s), 6.78 (2H, d, J = 8.6Hz), 7.13 (2H, d, J = 8.6Hz), 7.22-7.38 (5H , M) Example 73

 6,7-Dimethoxy-8- (4-dimethylaminobutoxy) -1- (4-methoxybenzyl)

-2-methyl-1,2,3,4-tetrahydroisoquinoline

Dimethylamine in tetrahydrofuran 2. Add 26.9 mg (0.062 mmol) of compound 9 to the OmJ¾ solution (12%), and heat in a sealed tube at 70 ° C for 15 hours. ₃ Add water 80πιΰ to the reaction mixture, and add ethyl acetate 40πιώ. , And the organic layer is washed with water (80πιβ) and saturated saline (80 mL) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by thin-layer chromatography (Merck, silica gel, chloroform (80) / methanol (8) / triethylamine (3)) to give the title compound as a pale yellow oil. Get 5.8nig as a thing. Yield 21%.

IR (neat, ciS): 2930,2850 , 1613, 1519, 1468, 1350, 1247, 1120, 1032,838,735 FAB-MS (m / e, as _{+ (C 2 s H 3 s} 0 4 N 2 + H) ): 443

'H-NMRCCDC ^, δ ppm): 1.62-1.80 (4H, m), 2.26 (6H, s), 2.31 (3H, s), 2.32-2.42 (lH, m), 2.40 (2H, t, J = 7.3Hz), 2.74-2.89 (4H, m), 3.18-3.29 (lH _} in), 3.74 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 3.84-3.99 (2H, m ), 4.10-4.18 (lH, ni), 6.33 (lH, s), 6.75 (2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz) Example 74

6,7-Dimethoxy-methoxybenzyl) -2-methyl-8- (3-phenylthiopropoxy) -1,2,3,4-tetrahydroisoquinoline Using compound 8 and benzenethiol, the title compound is obtained as a pale-yellow oil in the same manner as in Example 69. Yield 82 ° / ₀ .

 IR (neat, cm): 2938, 1605, 1515, 1497, 1467, 1344, 1299, 1245, 1176, 1119, 1035, 822,738

High Resolution FAB- MS (; n / e, as ^{_{+ (C 23 H 35 0 4}} NS + H)):

 Calculated 494.2365

 Measured value 494.2371

 'H-NMRCCDCla, δ ppm): 2.05-2.11 (2Η, ιπ), 2.35 (3H, s), 2.36-2.45 (1Η, ιη), 2.72- 2.90 (4H, in), 3.09-3.18 (2H, ni ), 3.24-3.32 (lH, ni), 3.77 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 3.87-3.95 (lH, m), 4.06 (lH, td, J = 5.9 Hz, 9.3Hz), 4.27 (lH, td, J = 6.1Hz, 9.3Hz), 6.38 (lH, s), 6.77 (2H, d, J = 8.5Hz), 7.10 (2H, d, J = 8.5Hz) ), 7.14-7.38 (5H, m)

Example 75

 β, 7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (2-phenylthioethoxy) -1,2,3,4-tetrahydroisoquinoline

 Using 8- (2-chloroethoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline (compound 11) and benzenethiol, The title compound is obtained as a pale yellow oil in the same manner as in Example 69. Yield 87

%. .

 IR (neat, cm): 2932, 1608,1515, 1497, 1467,1344, 1245,1119,1035,1002,822,

741,698 ·

High Resolution FAB- MS (m / e, as ^{_{+ (C 28 H 33 0 4}} NS + H)): Calculated value 480.2209

 Measured value 480.2223

 'H-NHRCCDCla, δ ppm): 2.32 (3H, s), 2.37-2.44 (lH, m), 2.74_2.91 (4H, m)' S A-S.SS ^ H'm), 3.78 (3H , S), 3.80 (3H, s), 3.82 (3H, s), 3.99 (lH, dd, J = 3.6 Hz, 8.0 Hz), 4.1-7 (lH, td, J = 6.8 Hz, 10.4 Hz), 4.36 (lH, td, J = 6.3Hz, 10.4Hz), 6.38 (lIi, s), 6.81 (2H, d, J = 8.7Hz), 7.16 (lH, l:, J = 6.0Hz), 7.17 (2H , D, J = 8.7 Hz), 7.23-7.37 (4H, m)

Example 76

 6,7-Dimethoxy-1- (4-methoxybenzyl) -8- [2- (4-methoxybenzylthio) ethoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline-Compound 11 And the title compound is obtained as a pale yellow oil in the same manner as in Example 69, using 4-methoxyphenylmethanethiol. Yield 38%.

IR (neat, cm): 2932, 1611, 1515, 1467, 1344, 1248, 1176, 1119, 1083, 1035, 831 High-resolution FAB-MS (m / _er (C ₃₀ H ₃₇ 0 _S NS + H) ⁺ As):

 Calculated 524.2471

 Measured value 524.2502

'H-NMRCCDC ^, δ ppm): 2.33 (3H, s), 2.34-2.48 (1Η, πι), 2.76 (2H, t, J = 7.1Hz), 2.75-2.95 (4H, ni), 3.24-3.36 (lH, ni) ₎ 3.71 (2H, s), 3.77 (3H, s), 3.78 (3H _J s), 3.82 (3H, s), 3.84 (3H, s), 3.93-4.03 (lH, ni), 4.12 (lH, td, J = 7.1Hz, 10.0Hz), 4.27 (lH, td, J = 7.1Hz, 10.0Hz), 6.39 (lH, s), 6.78 (2H, d, J = 8.8Hz), 6.80 (2H, d, J = 8.7Hz), 7.14 (2H, d, J = 8.7Hz), 7.20 (2H, d, J = 8.8Hz) Example 77

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- [2- (4-ditrophenylthio) ethoxy] -1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale yellow oil in the same manner as in Example 69 using compound 11 and 4-nitrobenzenethiol. Yield 76%.

 IR (neat, cm): 2944, 2836, 1581, 1518, 1460, 1341, 1248, 1120, 841, 743

High Resolution FAB-MS (in / e, as _{+ (C 2 s H 32 0} 8 N 2 S + H)):

 Calculated value 525.2059

 Measured value 525.2040

_{- NMR (CDC1 3, δ ppm} ): 2.34 (3H, s), 2.39-2.47 (lH, in), 2.72-2.90 (4H, ni), 3.23- 3.32 (lH, m), 3.37 (2H, t, J = 6.6Hz), 3.78 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 3.98 (lH, brt, J = 6.0Hz), 4.24 (lH, td, J = 6.6Hz, 10.2Hz), 4.39 (lH, td, J = 6.6Hz, 10.2Hz), 6.41 (lH, s), 6.78 (2H, d, J = 8.5Hz), 7.16 (2H, d, J = 8.5Hz), 7.33 (2H, d, J = 8.7Hz), 8.08 (2H, d, J = 8.7Hz)

Example 78

 , 7-Dimethoxy-l- (4-methoxybenzyl) -8- [2- (4-methoxyphenylthio) ethoxy] -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Using compound 11 and 4-methoxybenzenethiol, the title compound is obtained as a pale-yellow oil in the same manner as in Example 69. 97% yield.

 IR (neat, cm): 2936, 1596, 1512, 1492, 1458, 1344, 1240, 1178, 1122, 1034, 830, 762

High Resolution FAB-MS (m / e, as _{+ (C 23 H 35 0 5} NS + H)): Calculated value 510.2314

 Measured value 510.2320

lH-MR (CDCl ₃ , δ ppm): 2.32 (3H, s), 2.35-2.45 (lH, m), 2.71-2.88 (4H, m), 3.17 (2H, t, J = 7.1Hz), 3.24- 3.35 (lH, m), 3.77 (3H, s), 3.79 (6H, s), 3.82 (3H, s), 3.97 (lH, dd, J = 4.0Hz, 8.8Hz), 4.12 (lH, td, J = 7.1Hz, 10.0Hz), 4.29 (lH, td, J = 7.1Hz, 10.0Hz), 6.37 (lH, s), 6.80 (4H, dX2, J = 8.8Hz), 7.16 (2H, d, J = (8.8 Hz), 7.35 (2H, d, J = 8.8Hz)

Example 79

 8- [2- (4_chlorophenylthio) ethoxy] -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound was obtained as a pale yellow oil in the same manner as in Example 69 using compounds 11 and 4-benzene benzenethiol. 97% yield.

IR (neat, cm ¹ ): 2932, 1611, 1584, 1461, 1344, 1302, 1242, 1179, 1122, 1038, 822,

 756

High resolution FAB-iIS (in / e, as ^{_{+ (C 28 H 32 0 4}} NSC1 + H)):

 Calculated 514.1819

 Measured value 514.1842

讀_{(GDC1 3, δ ppm):} 2.32 (3H, s), 2.37-2.46 (lH, m), 2.74-2.89 (4H, in), 3.25 (2H, t, J = 6.8Hz), 3.25-3.35 ( lH ₅ n), 3.79 (3H, s), 3.80 (3H, s), -3.83 (3H, s), 3.97 (lH, dd, J = 4.9 Hz, 7.3 Hz), 4.15 (lH, td, J = 6.8Hz, 10.0Hz), 4.32 (lH, td, J = 6.8Hz, 10.0Hz) _J 6.38 (lH, s), 6.79 (2H, d, J = 8.6Hz), 7.15 (2H, d, J = 8.6 Hz) 7.20-7.28 (4H, m) Example 80

 6,7-Dimethoxy-8- [2- (4-N, N-dimethylaminobenzylthio) ethoxy] -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydro Droisoquinoline

 The title compound is obtained as a colorless oil in the same manner as in Example 69 using compound 11 and 4-N, N-dimethylaminobenzenethiol. 96% yield.

IR (neat, cm ¹ ): 2932, 1602, 1509, 1455, 1344, 1245, 1176, 1119, 1083, 1035, 816, 757

FAB- S (m / e, ( C 3 H 38 0 4 N 2 S + H) as +.): 523

'.Eta. title _{R (CDC1 3, δ ppni)} : 2.3l (3H, s), 2.35-2.43 (lH, in), 2.70-2.96 (4H, in), 2.92 (6H, s), 3.12 (2H, t, J = 7.1Hz), 3.23-3.35 (lH, ni), 3.78 (3H, s), 3.79 (3H, s), 3.82 (3H, s), 3.99 (lH, dd, J = 3.7Hz, 8.8 Hz), 4.12 (lH, td, J = 7.1 Hz, 10.0 Hz), 4.30 (lH, td, J = 7.1 Hz, 10.0 Hz), 6.36 (lH, s), 6.60 (2H, d, J = 9.1 Hz) ), 6.80 (2H, d, J = 8.9Hz), 7.16 (2H, d, J = 8.9Hz), 7.32 (2H, d, J = 9.1Hz)

 6,7-Dimethoxy-8- (4-ethylsulfinylbutoxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

6,7-Dimethoxy-8- (4-ethylthiobutoxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline 58 mg (0.13 mmol) To a solution of methane 1.3πι in dichloromethane is added dropwise a solution of 31 mg (0.13 mimol, 70%) of metabenzoin perbenzoic acid in 2.7πιβ at 0 ° C and stirred for 2 hours. The reaction mixture is added with dichloromethane (20 mfi), washed with a saturated aqueous sodium hydrogen carbonate solution (20 ID) and a saturated saline solution (20 ml), and dried over anhydrous magnesium sulfate. Under reduced pressure The solvent was distilled off, and the residue was separated by medium-pressure liquid chromatography (Merck Rover Force Ram Size B Licroblep SI60, black-mouthed form (40) / methanol (1)) to give the title compound as a pale yellow oil in 26ra get _g . Yield 44%.

IR (neat, cm ¹ ): 2938, 1605, 1584, 1515, 1497, 1458, 1344, 1245, 1179, 1119, 1035, 835

FAB - MS (m / e, as ^{_{+ (C 2 B H 37 0}} 5 NS + H)): 476

_{^{1 H-NMR (CDC1 3,}} δ ppra): 1.34 (3H, t, J = 7.6Hz), 1 · 87-2.06 (4H, m), 2.37 (3H, s), 2.3S-2.47 (lH, in ), 2.62-2.91 (8H, ni), 3.24-3.36 (lH, nt), 3.79 (3H, s), 3.82 (3H, S), 3.84 (3H, S), 3.86-3.95 (1H, I), 3.97-4.07 (1H, III), 4.13-4.22 (1H, m), 6.34 (lH, s), 6.80 (2H, d, J = 8.5Hz), 7.13 (2H, d, J = 8.5Hz) 82

 8- (3-aminobenzoyloxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

Under an argon atmosphere, 6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (3-nitrobenzyloxy) -1,2,3,4-tetrahydridoisoquinoline 25.0rag ( 65.4 mg (0.290 mmol) of tin chloride (Π) dihydrate is added to an ethanol solution (Ι.Οπιβ) of 0.052 mmol) and stirred at 70 ° C. for 1.5 hours. Add a permanent piece to the reaction mixture, stir, add an aqueous solution of sodium hydrogen carbonate to adjust the pH to 8, and extract three times with ethyl acetate and Omfi. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by thin-layer gel chromatography (manufactured by Merck, silica gel, silica gel form 8 (8) / methanol ( 1)) to give 20.3 mg of the title compound as a colorless oil. 87% yield. IR (neat, cm): 3460 , 2960, 1608, 1516, 1498, 1468, 1246, 1120, 1034, 798 High Resolution FAB-MS (m / e, as ^{_{+ (C 27 H 32 0 4}} N 2 + H) ):

 Calculated 449.2440

 Measured value 449.2451

 'H-NMRCCDCla, δ ppm): 2.23 (3H, s), 2.36-2.47 (lH, m), 2.72-2.94 (4H, m), 3.23-3.35 (lH, m), 3.64 (2H, brs), 3.77 (3H, s), 3.81-3.88 (lH, ra), 3.86 (3H, s), 3.88 (3H, s), 4.93 (lH, d, J = 11.2 Hz), 5.15 (lH, d, J = 11.2Hz), 6.41 (lH, s), 6.45 (lH, td, J = 1.3Hz, 7.8Hz), 6.75 (2H, d, J = 8.5Hz), 6.75-6.80 (2H, ni), 7.02 (2H , d, J = 8.5Hz), 7.13 (lH, t, J = 7.8Hz)

 8- (2-Aminophenoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-titrahydroisoquinoline

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (2-nitrophenoxy) -1,2,3,4-tetrahydroisoquinoline was prepared in the same manner as in Example 82. To give the title compound as a pale yellow oil. Yield 98%.

 IR (neat, cm): 3480, 3375, 2938, 1620, 1500,1461, 1356, 1245, 1194,1116, 1035, 840,750

High Resolution FAB-MS (m / e, as ^{_{+ (s H 3 0 4 N}} 2 + H).):

 Calculated 435.2284

 Measured value 435.2303

'.Eta. dragon _{R (CDC1 3, δ ppm)} : 2.29 (3H, s), 2.49 (lH, ddd, J = 1.7Hz, 5.3Hz, 16.7Hz), 2.76- 2.95 (4H, m), 3.34 (lH , Ddd, J = 5 3Ηζ, 10.3Hz, 13.3Hz), 359 (3H, s), 3.75 (3H, s), 3.74-3.99 (lH, n, 3.85 (3H, s), 6.39 (lH, d, J = 7.5Hz), 6.50-

6.54 (lH, m), 6.55 (lH, s), 6.76 (2H, d, J = 8.9Hz), 6.76-6.80 (2H, in), 7.05 (2H _; d, J = 8.9Hz) Example 84

 6,7-Dimethoxy-8- (2-N, N-dimethylaminophenoxy) -l- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 8- (2-Aminophenoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,4,2,3,4-tetrahydroisoquinoline 49.3 mg (0.114 mmol) of acetate To a nitrile solution (0.5πιβ) is added a 35% aqueous formaldehyde solution 50, sodium cyanoborohydride (11.5 mg, 0.182 mmol) and acetic acid 100 J2 at room temperature, and the mixture is stirred for 4 hours. The reaction mixture is basified with aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to thin layer chromatography (manufactured by Merck, silica gel, chromate form (1) / methanol (1)). To obtain 36.3 rog of the title compound as a pale yellow oil. Yield 69%.

IR (neat, cm): 294 , 1611, 1578, 1500, 1467, 1344,1242, 1116, 1068, 819,756 High Resolution FAB - MS (ra / e, as _{(C 2 s H 34 0 4} N 2):

 Calculated 463.2597

 Measured value 463.2612

'H- RCCDCla, δ ppm): 2.23 (3H, s), 2.45 (lH, ddd, J = 1.7Hz, 4.8Hz, 16.8Hz), 2.72-3.02 (4H, m), 2.95 (6H, s), 3.36 (lH, ddd, J = 4.8Hz, 10.5Hz, 12.9Hz), 3.64 (3H, s), 3.72- 3.76 (lH, m), 3.75 (3H, s), 3.86 (3H, s), 6.47 ( lH, dd, J = 1.5Hz, 8.1Hz), 6.54 (lH, s), 6.73 (2H, d, J = 8.7Hz), 6.73-6.75 (lH, m), 6.91 (lH, dt, J = 1.5Hz, 8.1Hz), 6.99 (lH, dd, J = 1.5Hz, 8.1Hz), 7.11 (2H, d, J = 8.7

(Hz) Example 85

 6,7-Dimethoxy-l- (4-methoxybenzyl) -8- (2-methoxyphenoxy) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 Under a nitrogen atmosphere, 48 mg (0.14 mmol) of compound 1 and 2-bromoanisole 56 & (0.45 mmol) were dissolved in 2 mfi of anhydrous pyridine, and lOOmg of anhydrous carbon dioxide

(0.72 mmol) and heat to 130 ° C. Next, 59 mg (0.74 mmol) of copper oxide (Π) is added, and the mixture is stirred at 14 CTC for 54 hours. The reaction mixture is extracted with 50 mL of form on a black mouth, and the extract is washed with 50 mJ3 of water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to medium pressure liquid chromatography (Merck Mouth Bar Column Size A Licroblep SI60, dichloromethane

(80) / methanol (1)) to give 12 mg of the title compound as a pale yellow oil. Yield 19%. '

^{IR (neat, cm l):} 2938,2836, 1611, 1581, 1506, 1458, 1356, 1251,1176,1122, 1068,

 1029,747

High Resolution FAB-MS (m / e, as ^{_{+ (C 27 H 3 0 5}} N + H)):

 Calculated value 450.2281

 Measured value 450.2246

_{- NMR (CDC1 3, δ ppm} ): 2.23 (3H, s), 2.41-2.50 (lH, m), 2.74-2.97 (4H, in), 3.31- 3.42 (lH, m), 3.70 (3H, s) , 3.75 (3H, s), 3.76-3.84 (lH, m), 3.86 (3H, s), 3.96 (3H, s), 6.54 (lH, s), 6.56 (lfi, dd, J = 1.5Hz, 8.1IIz), 6.74 (2H, d, J = 8.7Hz),

6.72-6.78 (lH, m), 6.93 (lH, dt, J = 1.5 Hz, 8.1 Hz), 6.99 (lH, dd, J = 2.1 Hz, 8.1 Hz), 7.09 (2H, d, J = 8.7 Hz)

Example 86

 6,7-Dimethoxy-l- (4-methoxybenzyl) -2-methyl-8- (2-ditrophenoxy)-1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 1-bromo-2-nitrobenzene, the title compound is obtained as a colorless powder in the same manner as in Example 85. Yield 77%.

^{_{IR (CHC1 3, cm 1)}} : 2938, 1611, 1584, 1525, 1458, 1344, 1317, 1236, 1179, 1113, 1062, 858,747

High Resolution FAB-MS (m / e, as ^{_{+ (C 2 β H 2 s}} 0 8 N 2 + H)):

 Calculated value 465.2025

 Measured value 465.2036

 ^ -N RCCDC, δ ppm): 2.29 (3H, s), 2.49 (lH, ddd, J = 2.3Hz, 5.4Hz, 16.7Hz), 2.76-2.96 (4H, m), 3.34 (lH, ddd, J = 5.4Hz, 10.1Hz, 12.5Hz), 3.69 (3H, s),

3.73- 3.81 (lH, m), 3.75 (3H, s), 3.86 (3H, s), 6.59 (lH, s), 6.74 (2H, d, J = 8.5 Hz), 6.68-6.78 (lH, m) , 7.06 (2H, d, J = 8.5Hz), 7.02-7.10 (lH, ni), 7.36 (lH, ddd _s J = 1.7Hz, 7.2Hz, 8,5Hz), 7.95 (lH, dd, J = 1.7 (Hz, 8.0Hz) 00

LO

/ Rob ^ 0

 O (s gg SH 9 sti 98ε S90 S62S ^ S SI:

 /))) SK≤3

Two Measured value 465.2044

¹ H- negation _{R (CDC1 3, δ ppm)} : 2.29 (3H, s), 2.51 (lH, ddd, J = 2.2Hz, 5.3Hz, 16.9Hz),

 2.76-3.00 (4H, in), 3.32 (lH, ddd, J = 5.3Hz, 10.5Hz, 16.8Hz), 3.65 (3H, s), 3.70 (lH, dd, J = 4.2Hz, 10.6Hz), 3.76 (3H, s), 3.88 (3H, s), 6.61 (lH, s), 6.76 (2H, -d, J = 8.9Hz), 7.02 (2H, d, J = 8.9Hz), 7.16 (lH, ddd , J = l.lHz, 2.2Hz, 8.4Hz), 7.40 (lH, t, J = 8.4Hz), 7.62 (lH, t, J = 2.2Hz), 7.85 (lH, ddd, J = l.lHz, (2.2Hz, 8.4Hz)

Example 89

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (4-nitrophenoxy) -1,2,3,4-tetrahydroisoquinoline

 Using compound 1 and 1-bromo-4-nitrobenzene, the title compound is obtained as a pale yellow powder in the same manner as in Example 85. 85% yield.

IR (KBr, cm ¹ ): 2938, 1611, 1515, 1497, 1461, 1344, 1245, 1164, 1113, 1065, 849, 755 High resolution FAB-MS (in / e, (C _{2 s} H _{2 s} 0 _S N ₂ + H) +):

 Calculated value 465.2025

 Measured value 465.2030

- thigh _{R (CDC1 3, δ ppin)} : 2.28 (3H, s), 2.51 (lH, ddd, J = 2.2Hz, 5.3Hz, 16.9Hz), 2.76-2.99 (4H, m), 3.32 (lH, ddd , J = 5.3Hz, 10.5Hz, 16.8Hz), 3.66-3.70 (lH, m), 3.67 (3H, s), 3.76 (3H, s), 3.88 (3H, s), 6.62 (lH, s), 6.76 (2H, d, J = 8.9Hz), 6.90 (2H, d, J = 9.2Hz), 7.00 (2H, d, J = 8.9Hz), 8.17 (2H, d, J = 9.2Hz) 6,7-Diisopropoxy-1- (4-methoxybenzyl) -2-methyl-8- (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

 6,7-Diisopropoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (compound 13) and 4-chlorobutylthiobenzene The title compound is obtained as a yellow oil using the same method as in Example 1. yield

44 ^_0/0.

IR (neat, cm ¹ ): 2932, 1602, 1515, 1488, 1443, 1344, 1248, 1116, 1038, 966, 822, 741,698

High Resolution FAB-MS (m / e, as ^{_{+ (C 34 H 45 0 4}} NS + H)):

 Calculated 564.3147

 Measured value 564.3182

- negation _{R (CDC1 3, δ ppm)} : l.25 (3H, d, J = 6.1Hz), 1.26 (3H, d, J = 6.1Hz), 1.32 (3H, d, J = 6.1Hz), 1.36 (3H, d, J = 6.1Hz), 1.79-1.91 (4H, m), 2.42 (3H, s), 2.40-2.48 (lH, ni), 2.77-2.93 (4H, m), 2.97 (2H, t , J = 7.1Hz), 3.23-3.34 (lH, in), 3.76 (3H, s), 3.93 (lH, td, J = 6.1Hz, 9.2Hz), 3.97-4.05 (lH, m), 4.17 (lH , td, J = 6.4Hz, 9.2Hz), 4.32 (lH, sep, J = 6.1Hz), 4.49 (lH, sep, J = 6.1Hz), 6.35 (lH, s), 6.76 (2H, d, J = 8.5Hz), 7.09 (2H, d, J = 8.5Hz), 7.13-7.34 (5H, ni)

Example 91

 1- (4-Methoxybenzyl) -2-methyl-7,8-methylenedioxy-6- (4-phenylthiobutoxy) -1,2,3,4-tetrahydroisoquinoline

1- (4-Methoxybenzyl) -2-methyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-6-ol (compound 12) and 4-chlorobutylthiobenzene The title compound is obtained as colorless crystals in the same manner as in Example 1 using the same. Yield 60%.

rap.81.0-81.5 ° C

^{IR (KBr, cm 1):} 2932, 1611, 1515, 1479, 1353, 1311, 1242, 1131, 1050, 740, 695 High Resolution FAB-MS (m / e, (C 23 H 33 0 4 S + H) ⁺ ):

 Calculated value 492.2209

 Measured 492.2207

_{- R (CDC1 3, δ ppin} ): 1.80-1.97 (4H, ni), 2.40 (3H, s), 2.43-2.47 (lH> ni), 2.65- 2.78 (2H, m), 2.94 (2H, d, J = 5.9Hz), 2.g9 (2H, t, J = 7.1Hz), 3.09-3.19 (lH, m), 3.76 (3H, s), 3.81 (lH, t, J = 5.9Hz), 4.05 ( 2H, t, J = 6.1Hz), 5.85 (lH, d, J = 1.5Hz), 5.87 (lH, d, J = 1.5Hz), 6.20 (lH, s), 6.76 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.7Hz), 7.14-7.35 (5H, m)

Example 92

 1- (4-Methoxybenzyl) -6- (3-Methoxybenzyloxy) -2-methyl-7,8-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as colorless crystals in the same manner as in Example 1 using compound 12 and 3-methoxybenzyl chloride. Yield 62%.

mp. 96-97 ° C.

IE (KBr, cm ¹ ): 2932, 1605, 1515, 1473, 1440, 1269, 1245, 1116, 1050, 1035, 822, 798

High Resolution FAB-MS (m / e, as ^{_{+ (C 27 H 23 0 s}} N + H)):

Calculated 448.2124 Measured value 448.2126

'.Eta. dragon _{R (CDC1 3, δ ppin)} : 2.34-2.47 (lH, in), 2.41 (3H, s), 2.61-2.76 (2H 5 iii), 2.95 (2H, d, J = 6.1Hz), 3.09-3.19 (lH, m), 3.77 (3H, s), 3.81 (3Η, s), 3.83 (lH, t, J = 6.1Hz), 5.11 (2H, s), 5.86 (lH, d, J = 1.4Hz), 5.89 (lH, d, J = 1.4Hz), 6.28 (lH _; s), 6.76 (2H, d, J = 8.5Hz), 6.83-6.86 (lH, m), 6.98-7.01 (2H, ni), 7.07 (2H, d, J = 8.5Hz), 7.28-7.32 (lH, m)

Example 93

6,7 dimethyl butoxy-l-(4-menu Tokishibenjiru) -8- (2-main butoxycarbonyl Hue phenoxy) - 2-methyl-1,2, ^{3, 4} - tetrahydroisoquinolin key 'Norin

 Using compound 1 and methyl 2-bromobenzoate, the title compound is obtained as a colorless oil in the same manner as in Example 85. 96% yield.

 IR (neat, cm): 2940, 1725, 1610, 1580, 1491, 1458, 1344, 1242, 1116, 1038, 840, 753

High Resolution FAB-MS (. M / e , 0 β N + H) + and (C ₂₈ H ₃₁ to):

 Calculated value 478.22,30

 Measured value 478.2249

 ^-MRCCDC ^, δ ppm): 2.26 (3H, s), 2.43 (lH, ddd, J = 2.4Hz, 5.7Hz, 16.9Hz),

2.76-2.95 (4H, in), 3.26 (lH, ddd, J = 5.7Hz, 10.8Hz, 13.5Hz), 3.70 (3H, s), 3.68-3.78 (lH, m), 3.75C3H, s), 3.85 (3H, s), 3.87 (3H, s), 6.55 (lH, s), 6.59 -6.65 (lH, m), 6.73 (2H, d, J = 8.8Hz), 6.97-7.12 (3H, ni), 7.30 (lH, dt, J = 1.7 Hz, 6.7Hz), 7.92 (lH, dd, J = 1.7Hz, 6.7Hz) , 7-Dimethoxy-1- (4-methoxybenzyl) -8- (4-methoxycarbonylphenoxy) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale brown oil in the same manner as in Example 85 using compound 1 and methyl 4-butamobenzoate. Yield 92%.

 IRCneat, cm): 2938, 1719, 1611, 1503, 1463, 1344, 1230, 1161, 1104, 1071, 846, 762

High resolution FAB-MS (m / e, as (C ₂₈ Η ₃₁ 0 _β Ν + Η) ⁺ ):

 Calculated 478.2230

 Measured value 478.2271

 'H-NMRCCDC, δ ppm): 2.25 (3H, s), 2.48 (lH, ddd, J = 2.4Hz, 5.7Hz, 16.8Hz), 2.76-2.98 (4H, m), 3.33 (lH, ddd, J = 5.7Hz, 10.8Hz, 13.5Hz), 3.65-3.70 (lH, m), 3.66 (3H, s), 3.76 (3H, s), 3.87 (6H, sX2), 6.59 (lH, s), 6.72 ( 2H, d, J = 8.9Hz), 6.88 (2H, d, J = 9.1Hz), 7.01 (2H, d, J = 8.9Hz), 7.97 (2H, d, J = 9.1Hz)

Example 95.

8 - (3-aminophenoxy) -6 ^¾, 7- dimethyl butoxy-1- (4-menu Tokishibenjiru) -2 - methyltransferase 1,2,3,4-tetrahydro Sokinorin

6,7 - dimethyl butoxy-1- (4-menu preparative ^ Shibenjiru) one 2 - methyl - ₈ - In the same manner as ₍₃ twelve Torofuenoki Shi) -1,2,3,4 Tetorahidoroi quinoline Example 82 To give the title compound as a pale yellow oil. Yield 76%.

IR (neat, ofi): 3450, 3375, 3225, 2938, 1629, 1581, 1497, 1461, 1419, 1344, 1245, 1176, 1149, 1116, 1068, 1035, 840, 753 High resolution? ! ₄ - (1 1/6, ((: ₂₈ 11 _3.0 ^ ₂ +11) as ^+):

 Calculated 435.2284

 Measured value 435.2287

_{- NMR (CDC1 3, δ ppm} ): 2.26 (3H, s), 2.43-2.52 (lH, ra), 2.76-2.96 (4H, iii), 3.27- 3.38 (lH, m), 3.69 (3H, s) , 3.74-3.80 (lH, in), 3.76 (3H, s), 3.86 (3H, s), 6.19 -6.22 (lH, m), 6.26 (lH, dd, J = 2.5Hz, 8.4Hz), 6.31 ( lH, dd, J = 1.6Hz, 8.0Hz), 6.54 (lH, s), 6.76 (2H, d, J = 8.2Hz), 7.01 (lH, t, J = 8.0Hz), 7.05 (2H, d, J = 8.2

Hz) Example 96

 8- (4-aminophenoxy) -6,7-dimethoxy-1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 6,7-Dimethoxy-1- (4-methoxybenzyl) -2-methyl-8- (4-ditrophenoxy) -1,2,3,4-tetrahydroisoquinoline is reduced in the same manner as in Example 82. To give the title compound as a pale yellow oil. Yield 69%.

IR (neat, cm ¹ ): 3376, 3010, 2938, 1611, 1584, 1506, 1458, 1344, 1245, 1122, 1071, 1032, 753

High Resolution FAB-MS (m / e, as ^{_{+ (C 26 H 3 0 4}} N 2 + H).):

 Calculated 435.2284

 Measured value 435.2277

'H-NMlUCDCls, δ ppni): 2.25 (3H, s), 2.43-2.51 (lH, ra), 2.75-2.96 (4H, m), 3.27-3.38 (lH, m), 3.66 (3H, s), 3.73- 3.80 (lH, ni), 3.76 (3H, s), 3.85 (3H, s), 6.52 (lH, s), 6.59 (2H, d, J = 8.8 Hz), 6.69 (2H, d, J = 8.8Hz), 6.76 (2H, d, J = 8.3Hz), 7.05 (2H, d, J = 8.3Hz)

Example 97

 6,7-dimethyl-1- (3-methoxybenzyl) -2-methyl-8- (4-phenylthiobutoxy) -1,2,3,4-tetrahydridoisoquinoline

 Use 6,7-dimethoxy-1- (3-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinolin-8-ol (compound 14) and 4-chlorobutylthiobenzene The title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 40%.

I (neat, can ¹ ): 2938, 1605, 1494, 1458, 1347, 1266, 1152, 1119, 1083, 1047, 745,

698

High Resolution FAB- MS (m / e, as ^{_{+ (C 3 H 37 0 4}} NS + H).):

 Calculated value 508.2522

 Measurement value 508.2531

-Ni'ffi (CDCl ₃ , δ ppm): 1.80-1.96 (4H, m), 2.35 (3H, s), 2.38-2.47 (lH, ni), 2.73-2.92 (4H, m), 2.98 (2H, t, J = 6.8Hz), 3.22-3.32 (lH, ni), 3.75 (3H 5 s), 3.79 (3H! s), 3.83 (3H, s), 3.95-4.03 (2H, m), 4.16 (lH , td, J = 6.4Hz, 9.3Hz), 6.38 (lH, s), 6.72 (lH, ddd, J = 0.9Hz, 2.5Hz, 7.3Hz), 6.77-6.80 (lH, m), 6.84 (lH, td, J = 0.9H, 7.3Hz), 7.12-7.36 (6H, m)

Example 98

 6,7-Dimethoxy-8- (3,4-dimethoxybenzyloxy) -1- (3-methoxybenzyl) -2-methyl-1,2,3,4-tetradoroisoquinoline

As in Example 1 using compound 14 and 3,4-dimethoxybenzyl chloride To give the title compound as a pale yellow oil. Yield 64%. IR (neat, cm): 2938 , 1602, 1498, 1467, 1341, 1266, 1158, 1116, 1077, 1029,852, 760 High Resolution FAB- MS (m / e, ( C 23 H 35 0 B N + H ) ⁺ As): Calculated 494.2543 Measured 494.2519

'H-NMRCCDC ^, δ ppm): 2.16 (3H, s), 2.35-2.44 (lH, m), 2.70-2.92 (3H, m), 2.93 (lH, dd, J = 2.8Hz, 14.2Hz), 3.21-3.33 (lH, m), 3.71 (3H, s), 3.77 (3H, s), 3.80-3.95 (lH, m) _> 3.87 (3H, s), 3.88 (3H, s), 3.90 (3H, s), 5.04 (lH, d, J = 10.8Hz), 5.14 (lH, d, J = 10.8Hz), 6.41 (lH, s), 6.67-6.75 (3H, (n), 6.81 (lH, d _; J = 8.3Hz), 6.92-6.97 (2H, m), 7.10 (lH, t, J = 8.0Hz)

Example 99

8- (3-butynyloxy) -6,7-dimethoxy-1- (3-methoxybenzyl) -2-methyl-1,2,3, -tetrahydroisoquinoline. Compound 14 and 4-bromo-1- The title compound is obtained as a colorless oil using butene in the same manner as in Example 1. Yield 27%.

IR (neat, ατί): 2938, 1605, 1584, 1437, 1344, 1263, 1152, 1119, 1083, 1050, 1008, 775 ί.

 I

High Resolution FA $ - MS (m / e , as _{+ (C 24 H 3 0 4} N + H)): Calculated 398.2332 measured value 398.2344

UMR CDCls, δ ppm): 2.35 (3H, s), 2.35-2.47 (lH, m), 2.53 (2H, dq-like, J = 1.5 Hz, 6.4Hz), 2.72-2.91 (3H, m), 2.95 (lH, dd, J = 4,0Hz, 15.0Hz), 3.23-3.33

(lH, m), 3.78 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 4.02 (lH, dd, J = 4.0Hz ₅ 8.6

Hz), 4.04 (lH, td, J = 6.9Hz, 9.6Hz), 4.24 (lH, td, J = 6.9Hz, 9.6Hz), 5.08 (lH, ddt, J = 1.5Hz, 9.9Hz, 1.8Hz) , 5.15 (lH, qd, J = 1.5Hz, 15.6Hz), 5.91 (lH, tdd,

J = 6.4Hz, 9.9Hz, 15.6Hz), 6.38 (lH, s), 6.72 (lH, dd, J = 1.9Hz, 7.7Hz), 6.78-

6.83 (1Η, πι), 6.85 (1Η ^ Γ (υ = 7.7Ηζ), 7.18 (1Η ₅ ΐ ^ = 7.7Ηζ)

Example 100

 6,7-diisopropoxy-8- (3,4-dimethoxybenzyloxy) -1- (4-methoxybenzyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a colorless oil using Compound 13 and 3,4-dimethoxybenzyl chloride in the same manner as in Example 1. Yield 23%.

IRCneat, cm): 2932, 1611,1515 , 1470, 1377,1242, 1110, 1032,858, 811,765 High Resolution FAB-MS (ro / e, (C 33 H 43 0 e N + H) as a ^+):

 Calculated value 550.3168

 Measured value 550.3185

'H-NMRCCDC ^, δ ppi): 1.33 (3H, d, J = 6.2 Hz), 1.34 (3H, d, J = 6.2 Hz), 1.35 (3H, d, J = 6.2 Hz), 1.39 (3H, d _s J = 6.2Hz), 2.14 (3H, s), 2.31-2.41 (lH, in), 2.65-2.91 (4H, m), 3.18-3.28 (lH, ni), 3.71 (lH, dd, J = 3.2Hz, 5.3Hz), 3.76 (3H, s) _} 3.77 (3H, s), 3.88 (3H, s) _i 4.42 (lH, sep, J = 6.2Hz), 4.53 (lH, sep, J = 6.2Hz ), 5.01 (lH, d, J = 11.0Hz), 5.16 (lH, d ₅ J = 11.0Hz), 6.38 (lH, s), 6.70 (2H, d, J = 8.4 Hz), 6.82 (lH, d , J = 8.0Hz), 6.89 (lH, d, J = 1.7Hz), 6.92 (lH, dd, J = 1.7Hz, 8.0Hz), 6.99 (2H, d, J = 8.4Hz) Tri (4-methoxybenzyl) -8- (3-methoxybenzyloxy) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

1- (4-Methoxybenzyl) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolin-8-ol and 3-methoxybenzyl The title compound is obtained as a pale yellow oil in the same manner as in Example 1. Yield 39%. IR (neat, cm ¹ ): 2925, 1620, 1515, 1473, 1371, 1248, 1176, 1122, 1044, 825, 795 High resolution FAB-MS (ni / e, (C ₂₇ H _2a 0 ₅ N + H) as ^+): calculated 448.2124 measured 448.2094 - negation _{R (CDC1 3, δ ppm)} : 2.23 (3H, s), 2.32-2.43 (lH, m), 2.68-2.92 (4H, ni), 3.20- 3.43 ( lH, m), 3.75 (3H, s), 3.76 (3H, s), 3.89 (lH, dd, J = 2.9Hz, 9.6Hz), 5.27 (2H, s), 5.91 (2H, s), 6.32 ( lH, s), 6.71 (2H, d, J = 8.9Hz), 6.88 (lH, dd, J = 2.3 Hz, 7.9Hz), 6.97-7.06 (2H, in), 7.01 (2H, d, J = 8.9Hz) Hz), 7.27 (lH, t, J = 8.1Hz)

Example 102

6,7-Dimethoxy-1- (4-methoxybenzyl) -8- (3-methoxyphenoxy) -2-'methyl-1,2,3,4-tetrahydroisoquinoline Compound 1 and 3-bromoanisole And the title compound i in the same manner as in Example 85.

~

Is obtained as a light brown powder. Yield 93%. IR (KBr, cm ¹ ): 2938, 1608, 1584, 1515, 1497, 1416, 1284, 1245, 1188, 1116, 1041, 762 High Resolution FAB- MS (m / e, as ^{_{+ (C 27 H 3 0 5}} N + H)):

 Calculated value 450.2281

 Measured value 450.2251

'H-NMRCCDC, δ ppm): 2.25 (3H, s), 2.42-2.50 (lH, m), 2.74-2.98 (4H, m) ^ T-S-SSClH, !!!), 3.69 (3H, s ), 3.70-3.77 (lH, m), 3.76 (6H, s), 3.86 (3H, s), 6.42 (lH, ddd, J = l. LHz, 2.1 Hz, 8.3 Hz), 6.46 (lH, dd, J = 2.1Hz, 2.5Hz), 6.54 (lH, and ddd _s J = l.lHz, 2.5Hz, 8.3Hz), 6.55 (lH, s), 6.76 (2H, d, J = 8.9Hz), 7.05 ( 2H, d _s J = 8.9Hz), 7.13 (lH, t, J = 8.3Hz)

Example 103

 6, 7-Dimethoxy -l- (4-methoxybenzyl) -8-(4-Methoxyphenoxy) -2-tyl-1,2,3,4-tetrahydroisoquinoline

 The title compound is obtained as a pale brown powder in the same manner as in Example 85 using compound 1 and 4-bromoanisole. 94% yield.

 IR (KBr, cm): 2938, 1615, 1506, 1464, 1419, 1245, 1206, 1179, 1116, 1068, 1035,

 825,740

High Resolution FAB-MS (m / e, as ^{_{+ (C 27 H 3 i 0}} 5 N + H)):

 Calculated value 450.2281

 Measured value 450.2311

_{- NMR (CDC1 3, δ ppm} ): 2.25 (3H, s), 2.46 (lH, ddd 5 J = 1.0Hz, 5.1Hz, 15.7Hz),

 2.74-2.98 (4H, m), 3.33 (lH, ddd, J = 5.1Hz, H.3Hz, 13.4Hz), 3.66 (3H, s),

3.70-3.80 (lH, in), 3.76 (3H, s), 3.77 (3H, s), 3.89 (3H, s), 6.53 (lH, s), 6.76 (2H, d, J = 8.8Hz), 6.79 (4H, s), 7.05 (2H, d, J = 8.8Hz) Example 104

 90% ethanol 3 πιβ 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 £. And Example 105

 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 '

Claims

Claims  (1) General formula

Wherein, R ² represents a methylene group Te summer together with or R ¹ or R ³ or a lower alkyl group, R ¹ and R ³ or indicates either a lower alkyl group: R ² and Taken together represent a methylene group, the other being 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), Aryl lower alkyl group (where the hydrogen atom on the aromatic ring is a lower alkyl group, a lower alkyloxy group, an N-benzylmethylamino group, a halogen atom, an amino group, an N-di-lower alkylamizo group) Group, (N, N-di-lower alkylamino) methyl group, (N-benzyl-N-methylamino) methyl group, morpholinomethyl group, nitro group, methylenedioxy group and lower alkyloxycarbonyl group May be substituted with the same or different 1 to 3 substituents selected from the group consisting of the following, provided that an unsubstituted benzyl group is excluded, an aryl group (the aryl group is a hydrogen atom on an aromatic ring) The atom 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, provided that the unsubstituted phenyl group is Or-(CH ₂ ) m-A (where A is a halogen atom, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, an aryl lower alkylthio group, an aryl lower alkyl) O 90/02119 sulfinyl group, aryl lower alkylsulfonyl group, arylaryl group, arylsulfinyl group, arylsulfonyl group, aryl lower alkyloxy group or aryloxy group (the aryl lower alkylthio group, aryl) Lower alkylsulfinyl, aryl lower alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, aryl lower alkyloxy and aryloxy have a hydrogen atom on the aromatic ring as a halogen atom. , Lower alkyloxy, nitro, amino or N, N-di-lower alkylamino), N-benzyl-N-lower alkylamino, N-phenyl-N-lower An alkylamino group, an N, N-di-lower alkylamino group, a di-lower alkyloxyphosphinoyl group or Represents a dibenzyloxyphosphonyl group, in represents 2 to 4), R ⁴ represents a lower alkyl group, and Ar represents 1 to 3 lower alkyloxy groups. Represents a phenyl group which may be substituted, and η represents 0 to 2], or a pharmaceutically acceptable acid addition salt of 1,2,3,4-tetrahydroisoquinoline. (2 and R ² are both a lower alkyl group, or both are a methylene group together, and R ³ is a lower alkenyl group, a phenyl lower alkenyl group (the phenyl lower alkenyl group has a hydrogen atom on the benzene ring A lower alkyloxy group which may be substituted with a lower alkyloxy group; a phenyl lower alkyl group wherein the hydrogen atom on the benzene ring is a lower alkyl group, a lower alkyloxy group, an N-benzyl-N-methylamino group, a halogen atom, Amino group, N, N-di-lower alkylamino group, (N, N-di-lower alkylamino) methyl group, (N-benzyl-N-methylamino) methyl group, morpholinomethyl group, nitro group, Same or different, selected from the group consisting of a methylenedioxy group and a lower alkyloxycarbonyl group May be substituted with 1 to 3 substituents. However, an unsubstituted benzyl group is excluded), and the hydrogen atom on the benzene ring is replaced with a halogen atom, lower alkyloxy group, nitro group, amino group, N, N-di-lower alkylamino group or lower alkyloxycarbonyl group. Or a formula:-(CH ₂ ) m-A ² (where A ² is a halogen atom, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a phenyl lower alkylthio group, a phenyl lower alkyl) Sulfinyl group, phenyl-lower alkylsulfonyl group, phenylthio group, phenylsulfinyl group, phenylsulfonyl group, phenyl-lower-alkyloxy group or phenoxy group (the phenyl-lower-alkylthio group, phenyl-lower-alkylsulfinyl group, phenyl-lower group) Alkylsulfonyl group, phenylthio group, phenyl In the sulfinyl group, phenylsulfonyl group, phenyl lower alkyloxy group, and phenoxy group, the hydrogen atom on the benzene ring is substituted with a halogen atom, lower alkyloxy group, nitro group, amino group, or N, N-di-lower alkylamino group. N-benzyl-N-lower alkylamino group, N-phenyl-N-lower alkylamino group, N, N-di-lower alkylamino group, di-lower alkyloxyphosphino 1, 2, 3, 4, 4-tetraquinone diisoquinoyl according to claim 1, which is a group represented by the formula: A phosphorus derivative or a pharmaceutically acceptable acid addition salt thereof. (3) An antitumor effect enhancer comprising the 1,2,3,4-tetrahydroisoquinoline derivative or the acid addition salt thereof according to claim 1.  (4) An anticancer agent comprising the 1,2,3,4-tetrahydroisoquinoline derivative or the acid addition salt thereof according to claim 1, and a substance having an antitumor effect. (5) The 1,2,3,4-tetrahydroisoquinoline derivative or the acid thereof according to claim 1 A method for enhancing the antitumor effect of an anticancer drug, which comprises administering an addition salt to a patient.  (6) Use of the 1,2,3,4-tetrahydroisoquinoline derivative or the acid addition salt thereof according to the first claim for enhancing the antitumor effect of an anticancer agent.