JP2003506358A - Isoquinoline derivatives, pharmaceutical compositions containing the derivatives and methods for producing active substances - Google Patents

Abstract

  (57) [Summary] The present invention relates to a novel isoquinoline derivative represented by the general formula (I), a pharmaceutical composition containing the derivative, and a method for producing an active ingredient. The novel compounds have an effect on the central nervous system, in particular an anxiolytic effect.

Description

Detailed Description of the Invention

The present invention relates to a novel isoquinoline derivative, a pharmaceutical composition containing the derivative, and a method for producing the active ingredient. The novel compounds have effects on the central nervous system, in particular anxiolytic effects.

[0002]   More specifically, the present invention provides a compound of general formula (I)

[Chemical 17] (In the formula, R₁, R₂And R₃Are independently hydrogen atom, halogen atom, hydroxy
Group or C_1-4Represents an alkoxy group or R₁Is R₂With methylenedioxy
Form a group or an ethylenedioxy group; R_FourIs a hydrogen atom, C_1-4An alkoxy group or
Represents a trifluoromethyl group; R₇Is a hydrogen atom or C_1-4Represents an alkyl group; R ₈ Is a hydrogen atom or C_1-4An alkyl group; R_Five, R₆And R₉Independently, water
Represents an elementary atom or R_FiveIs R₆Forms a valence bond with R, and at the same time, R₈Is
R₉Forms a valence bond with R;_TenAnd R₁₁Are independently hydrogen atom, halo
Gen atom, nitro group, C_1-4Alkoxy group, trifluoromethyl group or cyano group
Represents; X₁And X₂Each independently represents a hydrogen atom or X₁Is X₂along with
Forming an valence bond), and an isoquinoline derivative represented by
A sharp acid addition salt, and general formula (I ')

[Chemical 18] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above. R ′ ₈ represents a C _1-4 alkyl group; and A represents a residue of an inorganic acid or an organic acid represented by the formula HA), a quaternary derivative represented by:
Or, in the general formula (I), R ₁ and R ₂ are as described above; R ₃ , R ₆ and R ₇ independently represent a hydrogen atom; R ₈ is an atom together with R _9. R ₄ represents a hydrogen atom, a C _1-4 alkoxy group or a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ represent a valence bond; Independently represents a hydrogen atom, a halogen atom, a nitro group, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ represents X. An isoquinoline derivative which forms a valence bond with _2, and a pharmaceutically suitable acid addition salt thereof, or in the general formula (I ′), R ₁ and R ₂ are as described above; R ₃ , R ₅ , R ₆ and R ₇ independently represent a hydrogen atom; R ₈ forms a valence bond with R ₉ ;
R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represents a hydrogen atom, or X ₁ forms a valence bond together with X ₂ ; R ′ ₈ represents a C _1-4 alkyl group; and A represents It relates to a quaternary derivative which represents a residue of an inorganic acid or an organic acid represented by the formula HA.

A 1-styrylisoquinoline derivative having an anxiolytic effect is disclosed in French Patent Publication No. 2,71.
Known by issue No. 9,586.

The aim of the present invention is to produce new isoquinoline derivatives which have a more favorable activity than the known compounds.

The object of this is to provide compounds of the general formulas (I) and (I ′) which, in contrast to the known 1-styrylisoquinolines, have a marked anxiolytic effect in the so-called “light-dark transition” test. It was found that such activity can be achieved by the derivative). Furthermore, the novel compounds do not induce or hardly induce key enzymes of metabolism in the liver involved in drug metabolism.

In the description and claims, with respect to the definition of substituents, halogen atom generally means fluorine, chlorine, bromine or iodine, preferably chlorine atom.

The C _1-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl, tertiary-butyl or isobutyl group, preferably
It is a methyl group.

A C _1-6 alkyl group, in addition to what is listed above in the definition of a C _1-4 alkyl group, also represents, for example, an n-pentyl or n-hexyl group.

A C _1-4 alkoxy group is generally methoxy, ethoxy, n-propoxy or n
-Butoxy group, preferably methoxy group.

The pharmaceutically suitable acid addition salt means a pharmaceutically suitable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or formic acid, acetic acid, fumaric acid, maleic acid, lactic acid, malic acid. Acid addition salts formed with pharmaceutically suitable organic acids such as tartaric acid, succinic acid, citric acid, methanesulfonic acid and the like.

In the definition of A, the acid of formula HA is preferably hydrochloric acid, hydrobromic acid,
An inorganic acid such as hydroiodic acid.

[0012]   A subgroup of compounds of the invention are represented by the general formula (Ia)

[Chemical 19] (Wherein R ₁ , R ₂ and R ₃ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is methylenedioxy. Form a group or an ethylenedioxy group; R ₄ represents a hydrogen atom or a C _1-4 alkoxy group; R ₇ represents a hydrogen atom or a C _1-4 alkyl group; R ₈ represents a hydrogen atom or C It is a _1-4 alkyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ are independently A hydrogen atom or X ₁ forms a valence bond with X ₂ ) 1
, 2,3,4-Tetrahydroisoquinoline derivative, pharmaceutically suitable acid addition salt thereof, and general formula (I'a)

[Chemical 20] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above. ; R _'8 represents a C _1-4 alkyl group; and, a is
(Representing a residue of an inorganic acid or an organic acid represented by the formula HA)).

[0013]   Suitable 1,2,3,4-tetrahydroisoquinoline derivative represented by the general formula (Ia)
The body is R₁And R₂Each independently represents a methoxy group, or R₁Is R₂along with
Forms a methylenedioxy group or an ethylenedioxy group; R₃Represents hydrogen; R_FourBut
Represents a hydrogen atom; R₇Is a hydrogen atom; R₈Represents a hydrogen atom or a methyl group; R _Ten Represents a halogen atom, a trifluoromethyl group or a methoxy group; R₁₁But water
Represents an elementary atom or a methoxy group; X₁And X₂Independently represent a hydrogen atom, or
Is X₁Is X₂Forming a valence bond together with the pharmaceutically acceptable acid
In addition salts and in the general formula (I'a), R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R ₈ , R₉, R_Ten, R₁₁, X₁And X₂Is as defined above; R '₈Is a methyl group
And A is a quaternary derivative in which A represents a halide ion.

[0014]   Another subgroup of compounds of the invention is compounds of general formula (Ib)

[Chemical 21] (In the formula, R₁, R₂And R₃Are independently hydrogen atom, halogen atom, hydroxy
Group or C_1-4Represents an alkoxy group or R₁Is R₂With methylenedioxy
Form a group or an ethylenedioxy group; R_FourIs a hydrogen atom, C_1-4An alkoxy group or
Represents a trifluoromethyl group; R₇Is a hydrogen atom or C_1-4Represents an alkyl group; R _Ten And R₁₁Are independently hydrogen atom, halogen atom, nitro group, C_1-4Arcoki
Represents a Si group, a trifluoromethyl group or a cyano group; X₁And X₂Independently, water
Represents an elementary atom or X₁Is X₂Form a valence bond with
Soquinoline derivative, further pharmaceutically suitable acid addition salt thereof, and general formula (I'b)

[Chemical formula 22] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above; R ′ ₈ is a C _1-4 alkyl group. And A represents a residue of an inorganic acid or an organic acid represented by the formula HA).

Suitable isoquinoline derivatives represented by the general formula (Ib) are those in which R ₁ , R ₂ and R ₃ are
Independently, represents a hydrogen atom or a methoxy group, or R ₁ together with R ₂ forms a methylenedioxy group or an ethylenedioxy group; R ₄ is a hydrogen atom, a C _1-4 alkoxy group or Represents a trifluoromethyl group; R ₇ represents a hydrogen atom or a methyl group;
R ₁₀ represents a hydrogen atom, a halogen atom, a nitro group, a methoxy group, a trifluoromethyl group or a cyano group; R ₁₁ represents a hydrogen atom or a methoxy group; X ₁ and X ₂ are independently hydrogen. or represents an atom, or those wherein X ₁ to form a valence bond together with X _2, further a pharmaceutically suitable acid addition salt, and in the general formula (I'b), R _1,
R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above; R
' ₈ represents a methyl group; and A is a quaternary derivative which represents a halide ion.

[0016]   Another sub-group of compounds of the invention is the general formula (XIV)

[Chemical formula 23] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or ethylene. Forms a dioxy group; R ₄ is a hydrogen atom, a C _1-4 alkoxy group or C _1-6
Represents an alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, a nitro group, a C _1-4 alkoxy group or a trifluoromethyl group. X ₁ and X _{2 each} independently represent a hydrogen atom, or X ₁ forms a valence bond together with X _2, and a 3,4-dihydroisoquinoline derivative, , A pharmaceutically suitable acid addition salt thereof.

A preferred 3,4-dihydroisoquinoline derivative represented by the general formula (XIV) is R ₁
And R ₂ independently represents a hydrogen atom, a chlorine atom, a hydroxy group or a methoxy group, or R ₁ together with R ₂ forms a methylenedioxy group or an ethylenedioxy group; R ₄ is _Represents a hydrogen atom or a C _1-6 alkyl group; R ₅ represents a hydrogen atom;
R ₁₀ and R ₁₁ independently represent a hydrogen atom, a fluorine atom, a methoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ is X. Those which form a valence bond with _2, and further a pharmaceutically suitable acid addition salt thereof.

A particularly preferred 3,4-dihydroisoquinoline derivative represented by the general formula (XIV) is
R ₁ forms a methylenedioxy group together with R ₂ ; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ represent Independently, it represents a hydrogen atom, a methoxy group or a trifluoromethyl group; X ₁ forms a valence bond together with X _2, and a pharmaceutically suitable acid addition salt thereof.

[0019]   Yet another subgroup of compounds of the invention is compounds of general formula (XI)

[Chemical formula 24] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or ethylene. A dioxy group is formed; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R 4
' ₈ represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ are ,
Independently, represent a hydrogen atom, or X ₁ forms a valence bond with X ₂ ; A
Represents a residue of an inorganic acid or an organic acid represented by the formula HA) and is a 3,4-dihydroisoquinolinium derivative.

[0020]   Suitable 3,4-dihydroisoquinolinium derivative represented by the general formula (XI) is
R₁And R₂Independently represent a hydroxy group, a chlorine atom or a methoxy group, or
Is R₁Is R₂Forming a methylenedioxy group or an ethylenedioxy group together with R; _Four Is a hydrogen atom or C_1-3Represents an alkyl group; R '₈Represents a methyl group; R_Tenas well as
R₁₁Each independently represents a hydrogen atom, a halogen atom or a trifluoromethyl group;
X₁And X₂Each independently represents a hydrogen atom, or X₁Is X₂Valence with
And A represents a residue of an inorganic acid represented by the formula HA.

[0021]   Particularly preferred 3,4-dihydroisoquinolinium derivative represented by the general formula (XI)
Is R₁Is R₂Forming a methylenedioxy group or an ethylenedioxy group together with R; _Four Is a hydrogen atom or C_1-3Represents an alkyl group; R '₈Represents a methyl group; R_Tenas well as
R₁₁Each independently represents a hydrogen atom, a fluorine atom or a trifluoromethyl group; X ₁ And X₂Each independently represents a hydrogen atom, or X₁Is X₂Valence bond with
And A represents bromide or iodide.

The compounds of the present invention are prepared as follows. a) in the general formula (Ib), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ and R ₁₁ are as defined in relation to the general formula (I); X ₁ is X To prepare an isoquinoline derivative that forms a valence bond with ₂ , a compound of general formula (II)

[Chemical 25] (Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₇ are as described above) 1-
Methyl isoquinoline is represented by the general formula (III)

[Chemical formula 26] (Wherein R ₁₀ and R ₁₁ are as defined in relation to general formula (I)) condensed with an aldehyde; or b) in general formula (Ib), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to general formula (I) for the preparation of isoquinoline derivatives of general formula (IV)

[Chemical 27] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as described above; R ₁₃ represents a hydrogen atom). Subjecting the 3,4-dihydroisoquinoline derivative to catalytic dehydrogenation; or c) in the general formula (Ia), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ Is as defined in relation to general formula (I); R ₈ represents a hydrogen atom 1
In order to prepare a 1,2,3,4-tetrahydroisoquinoline derivative, in the general formula (IV), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are As described above; hydrogenating a 3,4-dihydroisoquinoline derivative in which R ₁₃ represents a hydrogen atom; or d) in the general formula (Ia), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ and R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to general formula (I); and R ₁ , a 1,2,3,4-tetrahydroisoquinoline derivative wherein C ₈ is a C _1-4 alkyl group. For the preparation, the general formula (V)

[Chemical 28] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as described above; R ₁₂ represents a C _1-4 alkyl group; A is as defined in relation to general formula (I ′)), and a 3,4-dihydroisoquinolinium derivative represented by general formula (I ′) is reacted with a reducing agent; or e) in general formula (Ib) , R ₁ , R ₂ , R ₃ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to general formula (I); R ₄ is a trifluoromethyl group. In order to prepare the represented isoquinoline derivative, in the general formula (IV), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as described above; R ₁₃ A 3,4-dihydroisoquinoline derivative in which is a C _1-4 alkoxy group is reacted with an alkali metal hydroxide; or f) in the general formula (Ib), R ₁ , R ₂ , R _{2 3} , R ₇ , R ₁₀ and R ₁₁ are represented by the general formula (
As defined in connection with I); R ₄ represents a trifluoromethyl group; X _{1 in} the presence of a condensing agent to prepare an isoquinoline derivative in which X ₁ forms a valence bond with X ₂ . General formula (VI)

[Chemical 29] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₇ are as described above; R ₁₃ represents a C _1-4 alkyl group.) 1-methyl-3,4- Reacting dihydroisoquinoline with an aldehyde of the general formula (III) in which R ₁₀ and R ₁₁ are as defined above; or g) in the general formula (XIV), R ₁ , R ₂ , R ₄ , R ₅ , R _{5 10} , R ₁₁ , X ₁ and X ₂
To prepare a 3,4-dihydroisoquinoline derivative as defined in relation to general formula (I)

[Chemical 30] (In the formula, R ₁ , R ₂ , R ₄ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as described above; R ₃ represents a hydrogen atom; and R ₁₃ represents a hydrogen atom or tri Represents a fluoromethyl group)
Or) cyclize the acid amide represented by: or in the general formula (XI), R ₁ , R ₂ , R ₄ , R ′ ₈ , R ₁₀ , R ₁₁ , X ₁ and X ₂
Is as defined in relation to general formula (I); for preparing a 3,4-dihydroisoquinoline derivative wherein A represents a residue of an inorganic acid of formula HA, general formula (XII)

[Chemical 31] (Wherein R ₁ , R ₂ , R ₄ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above), and the 3,4-dihydroisoquinoline derivative represented by the general formula R '(wherein, R ₈ -A' ₈ and a are the same as described above) is reacted with a reagent represented by; or i) the general formula _{(XI), R 1, R} 2, R 4, R ' ₈ , R ₁₀ , R ₁₁ , X ₁ and X ₂
Is as defined in relation to general formula (I); to prepare a 3,4-dihydroisoquinolinium derivative in which A is the residue of an inorganic acid of formula HA (XIII)

[Chemical 32] (Wherein R ₁ , R ₂ , R ₄ , R ′ ₈ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as described above), 1,2,3,4-tetrahydroiso Reacting the quinolinium derivative with an oxidizing agent; and, if desired, in the general formula (I) R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R _{1 0} and R ₁₁ are as defined in relation to general formula (I); the resulting compound in which X ₁ forms a valence bond with X ₂ is subjected to catalytic hydrogenation to give Formula (I)
In the formula (Ia), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ and X ₁ are converted into corresponding compounds in which X ₁ and X ₂ each represent a hydrogen atom; And X ₂
Is as defined in relation to general formula (I); reaction of the resulting 1,2,3,4-tetrahydroisoquinoline derivative in which R ₈ represents a hydrogen atom with a C _1-4 alkyl halide According to the formula (Ia), R ₈ is a C _1-4 alkyl group; or the obtained compound represented by the formula (I) is converted into a pharmaceutically suitable acid adduct. The compound represented by the general formula (I) is converted into the compound represented by the general formula R ′ ₈ -A (wherein R ′ ₈ and A are as described below). R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , in the general formula (I ′) by a reaction with a compound represented by
R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to general formula (I); R
' ₈ represents a C _1-4 alkyl group; A is converted to a quaternary derivative which is a residue of an inorganic acid or an organic acid represented by the formula HA; or in the general formula (I′b), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to general formula (I); R ′ ₈ is C _1-4 Represents an alkyl group; A represents a residue of an inorganic acid or an organic acid represented by the formula HA, and the resulting quaternary isoquinoline derivative is reacted with a reducing agent to give R ₁ in the general formula (Ia). ,
R < ₂ >, R < ₃ >, R < ₄ >, R < ₇ >, R < ₁₀ >, R <_11> , X < ₁ > and X < ₂ > are as described above; and R _{< 8 >} is converted to a _C1-4 alkyl group.

In process a) according to the invention, 1-methylisoquinoline of the general formula (II) is represented by the general formula (III) using the method known from French patent publication 2,719,586. Condensation with aldehyde.

In the process b) according to the invention, the literature (Heterocyclic Compounds, 38 , 386-387, E
d. John Wiley and Sons, Inc, New York, (1994)), and the 3,4-dihydroisoquinoline derivative represented by the general formula (IV) is dehydrogenated in the same manner as known.

In the process c) according to the invention, the literature (Houben-Weyl: Meth. Org. Chem., 4 / 1c , 1
21, 271-281, 365, 401, Georg Thieme Verlag, Stuttgart, (1981)) is used to hydrogenate a 3,4-dihydroisoquinoline derivative.

In the process d) of the present invention, the 3,4-dihydroisoquinolinium derivative represented by the general formula (V) is used by using the method described in the literature cited in relation to the process c). Make a reduction.

In the process e) of the present invention, the 4-position alkoxy group is replaced with an alkali metal hydroxide,
Preferably it is removed with potassium hydroxide.

The process f) according to the invention is carried out in the same way as the process a). As the condensing agent, carboxylic acid anhydrides, preferably acetic anhydride, are preferably used.

In the process g) according to the invention, the literature (Heterocyclic Compounds, Ed. J. Wiley a
nd Sons, Inc, 38/3 , 85-89 (1994); 38/1 , 173-175 (1994)),
The acid amide represented by the general formula (VIII) is cyclized.

In the process h) of the present invention, the reagent represented by the general formula R ′ _8- A is preferably a C _1-4 alkyl halide, suitably,
Using methyl iodide or methyl bromide in the presence of different organic solvents, generally 10-
The reaction is carried out at 160 ° C. The organic solvent is non-polar such as benzene, toluene, xylene and dichloromethane, or polar such as methanol and ethanol.

The process i) according to the invention is described in the literature (Houben-Weyl: Meth. Org. Chem., Georg Thi.
eme Verlag, Stuttgart, 4 / 1c , 517-518 (1981)) in the same manner as the known method.

The obtained isoquinoline derivative is converted into another compound represented by the general formula (I) by a known method.

For example, a styryl derivative in which X ₁ forms a valence bond together with X ₂ is subjected to catalytic hydrogenation (Houben-Weyl: Meth. Org. Chem., 4 / 1d , 580-581, Georg Thieme Verlag, S
by tuttgart, (1981)), in the general formula (I), X ₁ and X ₂ are converted to a compound in which a hydrogen atom is represented.

In the general formula (Ia), the nitrogen atom of the 1,2,3,4-tetrahydroisoquinoline derivative in which R ₈ represents a hydrogen atom is alkylated by a known method using, for example, an alkyl halide. To be done.

The compound represented by the general formula (I) is reacted with a compound represented by the general formula R ′ ₈ -A, preferably a C _1-4 alkyl halide to give the compound represented by the general formula (I ′). The quaternary compound represented is obtained. The reaction is carried out at 10 to 160 ° C. in a nonpolar solvent such as benzene, toluene, xylene, dichloromethane or the like, or a polar protic solvent such as alkanol.

The quaternary isoquinoline derivative represented by the general formula (I′b) is reduced to give the general formula (Ia
The corresponding 1,2,3,4-tetrahydroisoquinoline represented by) is obtained. The reaction is carried out using the methods described in the literature cited in connection with process c).

The 1-methylisoquinoline derivative represented by the general formula (II) is a known compound in part. In the general formula (II), the compound in which R ₄ represents a trifluoromethyl group is
Prepared by reacting 1-methyl-1,2-dihydroisoquinoline with potassium hydroxide.

[0038]   1-methyl-1,2-dihydroisoquinoline of the general formula (VI) has the general formula (VII)

[Chemical 33] (Wherein R ₁ , R ₂ and R ₃ are as defined in relation to the general formula (I);
R ₄ represents a trifluoromethyl group; R ₁₃ represents a C _1-4 alkoxy group) and is prepared by cyclizing an acid amide. The cyclization reaction is described in literature (Heterocy
clic Compounds, Ed. J. Wiley and Sons, Inc, 38/3 , 65-89 (1994); 38/1 , 173
-175 (1994)) by a known method.

The aldehyde represented by the general formula (III) is a known compound that is commercially available.

The 1,2-dihydroisoquinoline derivative represented by the general formula (IV) is a novel compound, and in the general formula (VIII), R ₁ , R ₂ , R ₃ , R ₄ , R ₁₀ and R _{11 are represented.} , X ₁ and X ₂ are as defined in relation to general formula (I); prepared by cyclizing an acid amide wherein R ₁₃ represents a C _1-4 alkoxy group. The cyclization reaction can be performed by the general formula (
It is carried out in the same manner as the cyclization of the acid amide represented by VII).

The acid amide represented by the general formula (VIII) can be prepared by using the literature (Houben-Weyl: Meth. Org. Chem.
., E5 / 2 , 993-1100, Georg Thieme Verlag, Stuttgart, (1981)), with the general formula (IX)

[Chemical 34] (Wherein R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in relation to the general formula (I)), the acid derivative represented by the general formula (X)

[Chemical 35] (Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined in relation to the general formula (I); R ₁₃ represents a C _1-4 alkoxy group) It is prepared by reacting with.

The acid derivative represented by the general formula (IX) and phenylethylamine represented by the general formula (X) are commercially available.

[0043]   The trifluoromethyl derivative represented by the general formula (X) has the general formula (XV)

[Chemical 36] Prepared by reduction from the corresponding cyanohydrin of formula where R ₁ , R ₂ , R ₄ and R ₅ are as defined above. The cyanohydrin represented by this general formula (XV) has the general formula (XVI)

[Chemical 37] Prepared by reacting the corresponding acetophenone of the formula where R ₁ and R ₂ are as defined above with an alkali metal cyanide.

The 1,2-dihydroisoquinolinium derivative represented by the general formula (V) has a general formula of R ₁₂ -A (wherein R ₁₂ represents a C _1-4 alkyl group; By reaction with an alkylating agent represented by HA) which is a residue of an inorganic acid or an organic acid represented by HA.
-Prepared from dihydroisoquinoline.

The 3,4-dihydroisoquinoline derivative represented by the general formula (XII) has the general formula (VI
It is prepared by cyclizing the acid amide represented by II). The cyclization reaction is carried out by the method described for the cyclization of the acid amide represented by the general formula (VII).

[0046]   The pharmacological action of the compounds of the present invention is demonstrated by the following experiments.

1. Light-dark transitions Male NMRI mice weighing 18-38 g were used for the experiment. Animals were maintained in a reverse light-dark cycle in polycarbonate cages for 2 weeks prior to the experiment. Two
Behavioral tests were carried out in compartment (illuminated and dark) automated test chambers, and horizontal and vertical activity was recorded with infrared blocking. The test compound was suspended in a 0.4% methylcellulose solution and administered intraperitoneally 30 minutes before the test. Under test conditions, animals tend to explore new environments but are anxious about aversive stimuli (lights) in illuminated areas. Therefore, the search for new environments is limited. Anxiolytic compounds reduce the time spent exploring in dark areas and / or increase exploratory activity in illuminated compartments. The tested compounds, compared to untreated controls,
In one or both compartments, it is judged to be effective when the time spent for searching changes statistically significantly.

The minimum effective dose (ie, the lowest dose producing a statistically significant effect) was determined for each compound studied (Costall, B. et al., Pharm. Biochem. Behav., 32 ,
777-785 (1989); Young, R. and Johnson, DN, Pharm. Biochem. Behav., 40 ,
739-743 (1991)).

1- (4-trifluoromethylstyryl) -6,7-methylenedioxyisoquinoline described in French Patent Publication No. 2,719,586 was used as a reference compound. The results obtained are shown in Table 1.

Table I Compound (Example No.) Minimum Effective Dose (mg / kg (intraperitoneal administration)) 21 10 47 10 51 30 30 53 10 55 55 3 82 10 83 30 84 11 1- (4-trifluoromethylstyryl) -6,7-Methylenedioxyisoquinoline 30 or more

The data in Table 1 clearly show that the tested compounds of the invention exert a significant effect in the “light-dark transition” test, whereas the known control compounds are ineffective.

2. Measurement of locomotor activity Each group consisted of 30 animals (15 male and 15 female) weighing 20-25 g. Animals were treated with test compound or vehicle (control group). The compound to be tested was suspended in 0.4% methylcellulose solution and orally administered at a treatment volume of 20 ml / kg 60 minutes before the start of the test. This method provides general information on the effect of test compounds on the intrinsic locomotor activity of experimental animals, in particular on the sedative effect. For anxiolytic compounds, the presence or absence of sedative effects is crucial for subsequent development (preferably no sedative effects are present). The measurements were carried out on a 10-channel "digital automatic movement meter". The locomotor activity of 3 mice per channel was measured by recording the number of 3 infrared blocks for 30 minutes. The value of ID ₅₀ (50% inhibitory dose) was calculated for each test compound (Borsy, I. et al., Arch. Int. Pharmacodyn., 124 , 180-190 (1960); St.
ille, G. et al., II Farmaco Ed. Pr., 26 , 603-625 (1971)).

The obtained results are shown in Table 2. As a control compound, diazepam (7-chloro-1
, 3-Dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-
2-on) was used.

Table II Compounds (Example No.) ID ₅₀ (mg / kg (oral)) 10 Greater than 100 21 Greater than 100 45 Greater than 100 47 100 Greater than 53 100 Greater than 55 100 Greater than 82 100 Greater than 100 Greater than 83 100 Greater than 84 100 Diazepam 18.4

The data in Table 2 clearly show that the compounds of the invention do not affect the locomotor activity of the animals, even at doses of 5 times or more the dose of diazepam having an ID ₅₀ value. .

3. Measurement of enzyme induction Wistar rats weighing 140-160 g were used in the experiment. The compounds to be tested were suspended in 0.4% methylcellulose solution and orally administered at a dose of 100 mg / kg per day for 3 consecutive days. As a positive control, 25 mg / kg (oral administration) of β-naphthoflavone treatment was used. A typical reaction for the CYP1A isoenzyme was monitored by measuring ethoxyresorufin deethylase (EROD) activity according to the method of Pohl, RJ and Fouts, JR, Anal. Biochem., 107 , 150-155 (1980). . Values from untreated animals were taken as 100% and EROD activity was expressed as a percentage of untreated controls. The results obtained are shown in Table 3. 1- (4-trifluoromethylstyryl) -6,7-methylenedioxyisoquinoline was used as a control compound.

Table III Compounds (Example Number) Relative EROD activity (% of control) 10 99 21 87 87 45 103 47 47 102 51 133 133 53 74 74 55 111 82 82 114 83 97 84 75 1- (4-trifluoromethylstyryl)- 6,7-Methylenedioxyisoquinoline 570 β-naphthoflavone 550

The data in Table 3 show that treatment with a control isoquinoline derivative resulted in a more than 5-fold increase in enzyme activity (similar to β-naphthoflavone used as a positive control).
On the other hand, the results obtained with the compounds of the invention clearly show that they are almost untreated control values.

According to the above experimental results, the compounds of the invention exert a pronounced CNS, especially anxiolytic effect. The anxiolytic activity is prominent in the "light-dark transition" test, while
The known 1-styrylisoquinoline derivative was found to be substantially ineffective in this test. Furthermore, the novel compounds do not affect locomotor activity at doses ≧ 5 times the ID ₅₀ value of the control compound diazepam.

Unlike the known anxiolytic 1-styrylisoquinoline derivatives, the compounds of the invention do not affect the key enzymes of drug liver metabolism. The low and insignificant enzyme-inducing ability of new compounds is very important in terms of drug safety.

Thus, the novel isoquinoline derivative represented by the general formula (I) is used as an active ingredient in a pharmaceutical composition.

The pharmaceutical composition of the present invention comprises a therapeutically active amount of a compound represented by general formula (I) or a pharmaceutically suitable acid addition salt thereof or a quaternary compound represented by general formula (I ′). It contains a derivative and one or more conventional carriers.

The pharmaceutical composition of the present invention is suitable for oral, parenteral or rectal administration, or topical treatment, and is solid or liquid.

Solid pharmaceutical compositions suitable for oral administration are powders, capsules, tablets, film-coated tablets, microcapsules and the like, with the carrier serving as gelatin, sorbitol,
Binders such as poly (vinylpyrrolidone); lactose, glucose, starch,
Fillers such as calcium phosphate; magnesium stearate, talc, poly (
Tablet-forming aids such as ethylene glycol), silica and the like; wetting agents such as sodium lauryl sulfate and the like can be contained.

Liquid pharmaceutical compositions suitable for oral administration are solutions, suspensions or emulsions,
As carriers, for example, suspending agents such as gelatin and carboxymethyl cellulose; emulsifiers such as sorbitan monooleate; solvents such as water, oil, glycerin, propylene glycol, ethanol; preservation such as methyl p-hydroxybenzoate. Agents can be included.

[0066]   Pharmaceutical compositions suitable for parenteral administration generally consist of sterile solutions of the active ingredient.

The above-exemplified dosage forms are known per se together with other dosage forms (eg Remi
ngton's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (
1990)).

The pharmaceutical composition of the present invention generally comprises the compound represented by the general formula (I) or a pharmaceutically suitable acid addition salt thereof, or the quaternary derivative 0.1 represented by the general formula (I ′). ˜95.0% by mass. A typical dose for an adult patient is of the general formula (I
) Is a compound represented by 0.1) to 1000 mg. This dose can be administered in single or divided doses. The actual dosage depends on many factors and is determined by the physician.

The pharmaceutical composition of the present invention comprises a compound represented by the general formula (I) or a pharmaceutically suitable acid addition salt thereof or a quaternary derivative represented by the general formula (I ′) as one or more carriers. And the resulting mixture is converted into a pharmaceutical composition by a known method. Methods available may be found in the literature, eg Remington's Pharmaceutical S, supra.
Known from ciences.

One subgroup of the pharmaceutical composition of the present invention is represented by the general formula (Ia)
3,4-Tetrahydroisoquinoline or a pharmaceutically suitable acid addition salt thereof or the general formula (I
It contains a quaternary derivative represented by'a).

Another subgroup of the pharmaceutical composition of the present invention is an isoquinoline derivative represented by the general formula (Ib) or a pharmaceutically suitable acid addition salt thereof, or a fourth group represented by the general formula (I′b). Contains a grade derivative.

Still another subgroup of the pharmaceutical composition of the present invention comprises a 3,4-dihydroisoquinoline derivative represented by the general formula (XIV) or a pharmaceutically suitable acid addition salt thereof.

Still another subgroup of the pharmaceutical composition of the present invention is represented by the general formula (XI) 3
It contains a 4,4-dihydroisoquinolinium derivative.

The present invention provides a non-toxic dose of the 3,4-dihydroisoquinoline derivative represented by the general formula (I) or a pharmaceutically suitable acid addition salt thereof or the general formula (I It also relates to a therapeutic method characterized by administering a quaternary derivative represented by ').

In addition, the present invention relates to the general formula (II) in the preparation of a pharmaceutical composition having anxiolytic activity.
I) an isoquinoline derivative or a pharmaceutically suitable acid addition salt thereof or a general formula (
It also relates to the use of quaternary derivatives of I ′).

[0076]   The invention is further described by the following examples.

[0077]   Production of acid amides of general formula (VII)

1) N-acetyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

^{3. In} a solution prepared by dissolving 12.46 g (50 mmol) of 3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) -propylamine in 90 cm ³ of ethyl acetate. 91 cm ³ (5.31 g; 52 mmol) of acetic anhydride was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then poured into 90 cm ³ of water. The two phases were separated. It was extracted twice with 60 cm ³ of ethyl acetate each. The combined organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. In this way 14.50 g (98%) of the colorless title compound was obtained.

Melting point: 74-75 ° C. (2-propanol-water) Analysis: C ₁₃ H ₁₆ F ₃ N0 ₃ (291.27) Calculation: C53.61%, H5.54%, N4.81% Result: C53 0.48%, H5.50%, N4.75%

IR (KBr, cm ⁻¹ ): 3330, 1613, 1119 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.34 (1H, t, J = 8.3H)
z), 7.03 (2H, m), 6.93 (1H, s), 5.79 (1H, s),
4.13 (1H, dd, H = 14.8Hz, J = 5.4Hz), 3.90 (1H
, Ddd, J = 14.8 Hz, J = 5.4 Hz, J = 1.4 Hz), 3.83 (
3H, s), 3.35 (3H, q, J = 0.9Hz), 1.99 (3H, s)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 170.1, 159.9, 13
5.0, 129.8, 124.9 (q, ¹ J _CF = 288.8 Hz), 119.6
, 114.5, 113.9, 80.7 (q, ² J _CF = 26.3 Hz), 55.4.
, 52.7, 41.0, 23.2.

2) N-acetyl-3,3,3-trifluoro-2-methoxy-2- (3,4
-Methylenedioxyphenyl) propylamine The procedure described for the preparation of starting compound 1 was carried out to give the title compound.

Yield: 98% Melting point: 119-120 ° C (2-propanol-water) Analysis: C ₁₃ H ₁₄ F ₃ NO ₄ (305.25) Calculation: C 51.15%, H 4.62%, N 4. 59% Result: C51.38%, H4.67%, N4.69%

IR (KBr, cm ⁻¹ ): 3340, 1679, 1111 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 6.97 (1 H, s), 6.93 (
1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz), 6.0
0 (1H, d, J = 1.4Hz), 5.99 (1H, d, J = 1.4Hz), 5
． 86 (1H, bs), 4.09 (1H, dd, J = 14.8 Hz, J = 5.3
Hz), 3.69 (1H, ddq, J = 14.8Hz, J = 5.3Hz, J = 1
． 2Hz), 3.33 (3H, s), 1.99 (3H, s)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 170.0, 148.2, 1
26.8, 124.7 (q, ¹ J _CF = 288.0 Hz), 121.1, 108.
² , 107.8, 101.4 (q, ² J _CF = 26.6 Hz), 52.2, 40.
7,23.1

3) 1-Methyl-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline

2 in 4.46 cm ³ (7.67 g, 50 mmol) of phosphorus (V) trichloride oxide
． 91 g (10 mmol) of N-acetyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine was stirred at 85 ° C. for 16 hours. The reaction mixture cooled to room temperature was poured onto 40 cm ³ of ice water. The pH was adjusted to 11 with concentrated ammonia water and the solution was extracted three times with 30 cm ³ of ethyl acetate each. The combined organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was recrystallized from acetonitrile. In this way 2.22 g (81%) of the colorless title compound was obtained.

Melting point: 203-204 ° C. (acetonitrile) Analysis: C ₁₃ H ₁₆ F ₃ N0 ₂ (273.25) Calculation: C57.14%, H5.16%, N5.13% Result: C57.27%, H5.26%, N5.11%

IR (KBr, cm ⁻¹ ): 1609, 1178 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.56 (1 H, d, J = 8.7 H)
z), 7.19 (1H, dd, J = 0.8 Hz), 7.00 (1H, dd, J =
2.6 Hz), 4.12 (1H, dq, J = 17.5 Hz, J = 1.5 Hz),
4.02 (1H, dq, J = 17.5Hz, J = 1.5Hz), 3.88 (3H
, S), 3.27 (3H, s), 2.39 (3H, J = 1.7 Hz)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 162.7, 161.5, 13
1.2, 127.8, 125.1 (q, ¹ J _CF = 287.2 Hz), 123.2
, 114.7, 112.4, 74.9 (q, ² J _CF = 27.9 Hz), 55.3.
, 52.1, 48.9, 23.0

4) 1-Methyl-6,7-methylenedioxy-4-methoxy-4-trifluoromethyl-3,4-dihydroisoquinoline Recrystallized from acetonitrile by performing the method described in the preparation of starting compound 3. To give the title compound.

Yield: 75% Melting point: 203-204 ° C (acetonitrile) Analysis: C ₁₃ H ₁₂ F ₃ N0 ₃ (2877.23) Calculation: C 54.36%, H 4.21%, N 4.88% Results: C54.19%, H4.27%, N4.79%

IR (KBr, cm ⁻¹ ): 1606, 1286, 1173 ¹ H-NMR (CDCl ₃ 400 MHz) δ: 7.13 (1H, d, J = 0.9H)
z), 7.07 (1H, s), 6.06 (1H, d, J = 0.9 Hz), 6.0
6 (1H, d, J = 1.3Hz), 4.01 (1H, ddd, J = 16.8Hz)
, J = 3.0 Hz, J = 1.5 Hz), 4.00 (1H, dd, J = 16.8H)
z, J = 1.5 Hz), 3.24 (3H, s), 2.37 (3H, t, J = 1.
7Hz)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 162.4, 148.9.1
25,2 (q, ¹ J _CF = 287.3 Hz), 125.1, 107.3 (q, ³ J _CF = 1.9 Hz), 106.4, 102.0, 75.2 (q, ² J) _CF = 27.6H
z), 52.1, 49.1, 23.6.

[0096]   Production of 1-methylisoquinoline of the general formula (II) 5) 1-methyl-6-methoxy-4-trifluoromethylisoquinoline   20 cm³2.73 g (10 mmol) of 1-methyi in 2-isopropanol
Ru-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquino
Add 0.84 g (15 mmol) of potassium hydroxide powder to the solution in which phosphorus is dissolved.
did. The reaction mixture was stirred at 50 ° C. for 2 hours and then evaporated. 5 cm residue ³ Washed with water. The crude product was regenerated from petroleum ether (b.p .: 80-100 ° C).
It crystallized. In this way 2.05 g (85%) of the colorless title compound was obtained.

Melting point: 95-96 ° C. (petroleum ether) Analysis: C ₁₂ H ₁₉ F ₃ N 0 (241.21) Calculation: C 59.75%, H 4.18%, N 5.81% Result: C 59.57%, H 4.13%, N 5.76%

IR (KBr, cm ⁻¹ ): 1624, 1256, 1165, 1126 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 8.64 (1 H, d, 0.7 Hz)
, 8.10 (1H, d, J = 9.0 Hz), 7.35-7.20 (2H, m),
3.98 (3H, s), 2.96 (3H, s)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 162.7, 161.5, 14
0.8 (q, ³ J _CF = 6.7 Hz), 133.7, 128.0, 124.7 (q
, ¹ J _CF = 272.4 Hz), 122.6, 120.2, 118.0 (q, ² J _CF = 28.9 Hz), 102.1, 55.4, 22.8.

6) 1-Methyl-6,7-methylenedioxy-4-trifluoromethylisoquinoline The method described for the preparation of starting compound 5 was carried out to give the title compound as a colorless solid.

Yield: 90% Melting point: 139-141 ° C (petroleum ether, bp: 80-100 ° C) Analysis: C ₁₂ H ₈ F ₃ N0 ₂ (255.196) Calculation: C 56.48%, H 3.16 %, N 5.49% Result: C 56.33%, H 3.14%, N 5.45%

IR (KBr, cm ⁻¹ ): 1477, 1167, 1112 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 8.58 (1 H, s), 7.44 (
1H, s), 7.40 (1H, q, J = 1.8Hz), 6.17 (2H, s),
2.91 (3H, s), 2.96 (3H, s)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 161.1, 151.8, 1
48.6, 139.3 (q, ³ J _CF = 6.5 Hz), 130.1, 124.7 (
q, ¹ J _CF = 273.1 Hz), 124.6, 118.6 (q, ² J _CF = 30.
5Hz), 102.2, 100.6, 23.3

Production of Acid Amide of General Formula (VIII) 7) N-Cinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-
Methoxyphenyl) propylamine

12.46 g (50 mmol) of 3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propionitrile, 30 cm ^{3 of} diethyl ether, 5.30 g (50 mmol) of sodium carbonate, To a suspension of 50 cm ³ of water and 50 cm ³ of water, a solution of 8.33 g (50 mmol) of cinnamoyl chloride in 50 ml of diethyl ether was added at 0 ° C.
At room temperature, and the reaction mixture was stirred for 2 hours. The precipitated crystals are filtered,
It was washed with 20 ml of diethyl ether. In this way the title compound 16.3
Obtained 9 g (90%).

Melting point: 72-73 ° C. (2-propanol, water) Analysis: C ₂₀ H ₂₀ F ₃ N0 ₃ (379.38) Calculation: C63.32%, H5.31%, N3.69% Result: C63 .12%, H5.27%, N3.76%

IR (KBr, cm ⁻¹ ): 1662, 1630, 1179 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.63 (1 H, d, J = 15.6)
Hz), 7.55-7.45 (2H, m), 7.40-7.30 (4H, m),
7.10-7.05 (2H, m), 6.99-6.90 (1H, m), 6.39
(1H, d, J = 15.6 Hz), 5.89 (1H, bs), 4.27 (1H,
dd, J = 15.0 Hz, J = 5.4 HZ), 4.08 (1 H, dd, J = 15)
． 0 Hz, J = 5.4 Hz), 3.83 (3H, s), 3.39 (3H, q, J
= 0.8Hz)

¹³ C-NMR (CDCl ₃ 50.3 MHz) δ: 165.7, 159.8, 14
1.7, 135.0, 134.6, 129.8, 129.7, 128.8, 12
7.8, 124.9 (q, ¹ J _CF = 288.3 Hz), 120.1, 119.5
, 114.5, 113.6, 80.6 (q, ² J _CF = 26.3 Hz), 55.3.
, 52.6, 40.9.

8) N- (4-Fluorocinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine By performing the method described in the preparation of starting compound 7. The title compound was obtained as a colorless solid.

[0110] Yield: 75% mp: 100-101 ° C. (2-propanol, water) _{Analysis: C 20 H 19 F 4 N0} 3 (379.37) calculated: C60.45%, H4.82%, N3 . 52% Result: C60.31%, H4.80%, N3.55%

IR (KBr, cm ⁻¹ ): 3293, 1661, 1628, 1227, 1149
¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.59 (1 H, d, J = 15.6)
Hz), 7.51-7.44 (2H, m), 7.40-7.30 (1H, m),
7.10-7.00 (4H, m), 7.00-6.91 (1H, m), 6.31
(1H, d, J = 15.6 Hz), 5.88 (1H, bs), 4.27 (1H,
dd, J = 14.9 Hz, J = 5.4 HZ), 4.06 (1 H, ddd, J = 1)
4.9 Hz, J = 5.4 Hz, J = 1.3 Hz), 3.83 (3H, s), 3.
39 (3H, s)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 163.5, (d, ¹ J = 24)
9.2 Hz), 159.7, 140.4, 134.8, 130.7, 119.6.
, (Q, ² J _CF = 8.8 Hz), 129.3 (q, ¹ J = 289.1 Hz), 12
2.4, 119.6, 119.4, 117.8, 115.8, (d, ² J _CF = 2
2.6 Hz), 114.3, 113.5, 80.5 (q, ² J _CF = 27.2 Hz
), 55.2, 52.5, 40.9

9) N- (4-trifluoromethylcinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine The method described in the preparation of starting compound 7 was used. Performed to give the title compound as a colorless solid.

Yield: 72% Melting point: 85-86 ° C (2-propanol, water) Analysis: C ₂₁ H ₁₉ F ₆ NO ₃ (447.38) Calculation: C 56.38%, H 4.28%, N 3. 13% Result: C56.45%, H4.32%, N3.18%

IR (KBr, cm ⁻¹ ): 3436, 1672, 1133 ¹ H-NMR (CDCl ₃ 400 MHz) δ: 7.64 (1 H, d, J = 15.6)
Hz), 7.64-7.60 (4H, m), 7.35 (1H, t, J = 8.2H).
z), 7.10-7.06 (2H, m), 6.97-6.92 (1H, m), 6
． 46 (1H, d, J = 15.6 Hz), 5.92 (1H, bs), 4.27 (
1H, dd, J = 14.9Hz, J = 5.4HZ, 4.05 (1H, ddq,
J = 14.9 Hz, J = 5.4 Hz, J = 1.1 Hz), 3.83 (3H, s)
3.40 (3H, s)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 165.0, 159.9, 1
40.1, 138.1, 134.9, 131.4 (d, ² J _CF = 32.8z),
129.8, 128.0, 126.5 (q, ¹ J _CF = 278.9 Hz), 125
． 8 (q, ³ J _CF = 3.8 Hz), 124.8 (q, ¹ J _CF = 288.0 Hz),
122.5, 119.5, 114.5, 80.7 (q, ² J _CF = 26.7 Hz)
, 55.4, 52.7, 41.2

10) N- (4-nitrocinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine By performing the method described in the preparation of starting compound 7. The title compound was obtained as a pale yellow solid.

[0118] Yield: 64% mp: 80-81 ° C. (2-propanol, water) _{Analysis: C 20 H 19 F 3 N} 2 0 5 (424.38) calculated: C56.61%, H4.51%, N6.60% Result: C56.36%, H4.52%, N6.60%

IR (KBr, cm ⁻¹ ): 1659, 1515, 1345, 1168, 1120
. ¹ H-NMR (CDCl ₃ 200 MHz) δ: 8.23 (2H, d, J = 8.8H
z), 7.67 (1H, d, J = 15.6Hzx), 7.65 (2H, d, J =
8.8 Hz), 7.37 (1H, t, J = 8.2 Hz), 7.15-7.03 (
2H, m), 7.00-6.90 (1H, m), 6.55 (1H, d, J = 15)
． 6 Hz), 6.02 (1 H, t, J = 5.2 Hz), 4.30 (1 H, dd,
J = 15.0 Hz, J = 5.5 HZ), 4.04 (1 H, ddq, J = 15.0)
Hz, J = 5.5 Hz, J = 1.6 Hz), 3.84 (3H, s), 3.40 (
3H, s).

[0120]¹³ C-NMR (CDCl₃50.3 MHz) δ: 164.7, 159.9, 14
0.9, 139.2, 134.8, 129.9, 128.5, 124.9 (d, ¹ J_CF= 288.8 Hz), 124.3, 124.2, 119.5, 113.6.
, 80.7 (q,²J_CF= 26.3 Hz), 55.3, 52.7, 41.3

11) Performed the method described for the preparation of starting compound 7 to give the title compound as a colorless solid.

Yield: 85% Melting point: 104-106 ° C (2-propanol, water) Analysis: C ₂₁ H ₁₇ F ₆ NO ₄ (461.36) Calculation: C 54.67%, H 3.71%, N 3. 04% Result: C54.46%, H3.70%, N3.05%

IR (KBr, cm ⁻¹ ): 3310, 1665, 1630, 1326, 1170
, 1125 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 7.66 (1 H, J = 15.4 Hz)
), 7.61 (4H, m), 7.05-6.95 (2H, m), 6.85 (1H)
, D, J = 7.7 Hz), 6.48 (1H, d, J = 15.4 Hz), 6.01
(2H, s), 5.96 (1H, bs), 4.24 (1H, dd, J = 14.9)
Hz, J = 5.1 Hz), 4.04 (1 H, d, J = 14.9 Hz, J = 5.
1 Hz), 3.36 (3H, s).

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 165.1, 148.4, 1
48.2, 140.1, 138.0 (d, ⁴ J _CF = 1.5 Hz), 131.3 (
q, ² J _CF = 32.4 Hz), 128.0, 126.8, 125.7 (q, ³ J _CF = 3.8 Hz), 124.8 (q, ¹ J _CF = 288.0 Hz), 123 .8 (q
, ¹ J _CF = 274.3 Hz), 122.5, 121.2, 121.2, 108.
3, 107.9, 101.48, 80.4 (q, ² J _CF = 26.7 Hz), 52
． 4, 42.1

12) N / 2- (3,4-methylenedioxyphenyl) ethyl / -4-trifluoromethylcinnamic acid amide

A solution of 4.6 g (0.023 mol) of (3,4-methylenedioxyphenyl) ethylamine chlorohydrate in 20 cm ³ of ether was added to 30
To a solution prepared by dissolving 4.1 g (0.2 mmol) of sodium hydroxide in cm ³ of water was added dropwise with stirring at 10 ° C. Then add 20 cm ³ to this mixture.
4.2 g (0.02 mol) of 4-trifluoromethylcinnamoyl chloride in ether was added dropwise over 35 minutes and the reaction mixture was stirred at 5 ° C. for 30 minutes. The precipitated carboxamide was filtered and dried. In this way 4.3 g (63%) of the title compound was obtained. Melting point: 206-208 ° C.

13) N / 2- (3,4-methylenedioxyphenyl) ethyl / -4-fluorocinnamic acid amide

A mixture consisting of 4.84 g (0.029 mol) of (3,4-methylenedioxyphenyl) ethylamine, 4.98 g (0.03 mol) of 4-fluorocinnamic acid and 10 cm ³ of decalic acid. Was stirred at 180 ° C. for 1 hour. Into the cooled mixture,
Chloroform was added and the mixture was stirred at 10 ° C. to crystallize out the carboxamide. The precipitated crystals were filtered and recrystallized from ethanol. In this way 4.9 g (53%) of the title compound was obtained. Melting point: 160-162 [deg.] C.

14) N / 3- (4-trifluoromethylphenyl) propanoyl / 3,3,3
3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

1.25 g (5 mmol) of 3,3,3-trifluoro-2-methoxy-2- (
3-methoxyphenyl) propylamine and 1.09 g (5 mmol) of 3- (4
A suspension of -trifluoromethylphenyl) propionic acid was reacted at 150 ° C for 4 hours. The crude product was recrystallized from aqueous ethanol. In this way 1.55 g (69%) of the colorless title compound was obtained.

Melting point: 58-59 ° C. (ethanol-water) Analysis: C ₂₁ H ₂₁ F ₆ NO ₃ (449.40) Calculation: C 56.13%, H 4.71%, N 3.12% Result: C 56.16% , H4.74%, N3.09%

IR (KBr, cm ⁻¹ ): 3309, 1650, 1338, 1279 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 7.52 (2H, J = 8.1 Hz)
, 7.35-7.25 (3H, m), 7.04-6.68 (3H, m), 5.6.
2 (1H, bs), 4.10 (1H, dd, J = 14.9Hz, J = 5.3Hz
), 3.85 (1H, ddJ = 4.4Hz), 3.82 (3H, s), 3.24.
(3H, s), 3.00 (2H, t, J = 7.3Hz), 2.50 (2H, t,
J = 7.3Hz)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 171.7, 159.8, 1
44.7, 134.7, 129.7, 128.7, 128.6 (q, ² J _CF = 3
2.3 Hz), 125.4 (q, ³ J _CF = 3.7 Hz), 124.7 (q, ¹ J _CF = 288.6 Hz), 124.2 (q, ¹ J _CF = 271.9 Hz), 119.4
, 114.3, 113.5, 80.5 (q, ² J _CF = 26.4 Hz), 55.3
, 52.5, 41.0, 37.6, 31.0

15) N / 3- (4-Fluorophenylpropanoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine The method described in the preparation of starting compound 14. According to, the title compound was obtained as a colorless solid.

Yield: 79% Melting point: 59-61 ° C (ethanol-water) Analysis: C ₂₁ H ₂₁ F ₄ NO ₃ (339.39) Calculation: C 60.15%, H 5.30%, N 3.51% Results : C59.93%, H5.28%, N3.52%

IR (KBr, cm ⁻¹ ): 3305, 1649, 1511, 1280 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 7.38-7.25 ( ¹ H, m),
7.18-7.06 (2H, m), 7.05-6.87 (5H, m), 5.60
(1H, bs), 4.09 (1H, dd, J = 14.8Hz, J = 5.1Hz)
3.86 (1H, dd, J = 14.8 Hz, J = 4.0 Hz), 3.82 (3
H, s), 3.26 (3H, s), 2.90 (2H, t, J = 7.5 Hz), 2
． 46 (2H, t, J = 7.5Hz)

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 171.7, 161.5 (d
, ¹ J _CF = 244.2 Hz), 159.8, 136.2 (d, ⁴ J _CF = 3.4 Hz)
), 134.8, 129.7 (d, ³ J _CF = 8.0 Hz), 129.7,124
． 8 (q, ¹ J _CF = 288.6 Hz), 119.4, 115.2 (d, ² J _CF = 2)
1.0 Hz), 114.4, 113.5 (q, ⁴ J _CF = 1.1 Hz), 80.5
(Q, ² J _CF = 26.3 Hz) 55.3, 52.5, 40.8, 38.2, 30
． 5

16) N / 3- (4-trifluoromethylphenyl) propanoyl / -3,3
, 3-trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propylamine

Following the procedure described for the preparation of starting compound 14, the title compound was obtained as a colorless solid.

[0140] Yield: 84% mp: 75-76 ° C. (ethanol over water) _{Analysis: C 21 H 19 F 6 N0} 4 (463.36) calculated: C54.43%, H4.13%, N3.02 % Result : C54.52%, H4.19%, N3.05%

IR (KBr, cm ⁻¹ ): 3317, 1620, 1334, 1247 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 7.53 (2H, d, J = 7.7H)
z), 7.30 (2H, d, J = 7.7Hz), 7.00-6.80 (3H, m
), 6.00 (2H, s), 4.06 (1H, dd, J = 14.9 Hz, J = 5)
． 1Hz), 3.84 (1H, dd, J = 14.9Hz, J = 5.1Hz), 3
． 21 (3H, s), 3.01 (2H, t, J = 7.5Hz), 2.51 (2H
, T, J = 7.5 Hz).

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 171.4, 148.3, 1
48.1, 144.7, 126.7 (q, ² J _CF = 32.4 Hz), 128.7
, 125.4 (q, ³ J _CF = 3.7 Hz), 124.7 (q, ¹ J _CF = 288.4)
Hz), 124.2 (q, ¹ J _CF = 271.7 Hz), 121.1, 108.2
, 107.8, 101.5, 80.3 (q, ² J _CF = 26.4 Hz), 52.2.
, 40.7, 37.731.1

17) N / 3- (4-Fluorophenyl) propanoyl / -3,3,3-trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propylamine Preparation of starting compound 14 The title compound was obtained as a colorless solid according to the method described in.

[0144] Yield: 83% mp: 92-94 ° C. (ethanol - water) _{Analysis: C 20 H 19 F 4 N0} 4 (413.37) calculated: C58.11%, H4.63%, N3.39 % Result: C58.29%, H4.67%, N3.41%

[0145] IR (KBr, cm^-1): 3325, 1658, 1510, 1217¹ H-NMR (CDCl₃200 MHz) δ: 7.18-7.10 (2H, m),
7.02-6.75 (5H, m), 6.00 (2H, s), 5.61 (1H, b
s), 4.06 (1H, dd, J = 14.7 Hz, J = 5.9 Hz), 3.85
(1H, dd, J = 14.7Hz, J = 4.2Hz) 3.23 (3H, 1, J
= 0.7 Hz), 2.92 (2H, t, J = 7.5 Hz), 2.52 (2H, t
, J = 7.5 Hz).¹³ C-NMR (CDCl₃50.3 MHz) δ: 171.7, 161.6 (d, ² J_CF= 244.1 Hz), 148.3, 148.1, 136.2 (d,^FourJ_CF=
3.4 Hz), 129.7 (d,^FourJ_CF= 3.4 Hz), 129.7 (d,³J_CF = 7.6 Hz), 126.8, 124.7 (q,¹J_CF= 288.4 Hz), 1
21.2, 115.2 (d,²J_CF= 21.4 Hz), 108.2, 107.8
, 101.5, 80.3 (q,²J_CF= 26.5 Hz), 52.2, 40.6,
38.2, 30.5

18) N / 2- (3,4-methylenedioxyphenyl) ethyl / -4-trifluoromethylcinnamic acid amide

A solution of 4.6 g (0.023 mol) of (3,4-methylenedioxyphenyl) ethylamine chlorohydrate in 50 cm ³ of ether was added to 30
To a solution of 4.1 g (0.2 mmol) of sodium hydroxide in cm ³ of water was added dropwise at 10 ° C. with stirring. Then add 20 cm ³ to this mixture.
4.2 g (0.02 mol) of 4-trifluoromethylcinnamoyl chloride in ether was added dropwise over 35 minutes and the reaction mixture was stirred at 5 ° C. for 30 minutes. The precipitated carboxamide was filtered and dried. In this way 4.3 g (63%) of the title compound was obtained. Melting point: 206-208 ° C.

[0148]   19) N / 2- (3,4-methylenedioxyphenyl) ethyl / cinnamic acid amide

To a solution of 8.5 g (0.037 mol) of (3,4-methylenedioxyphenyl) ethylamine in 50 cm ³ of dichloromethane was added 5 g of sodium hydrogen carbonate, then 20 cm ³ of 6.2 g (0.03) in dichloromethane
A solution of cinnamoyl chloride (7 mol) dissolved therein was added over 30 minutes. The reaction mixture was stirred at 40 ° C. for 2 hours, then filtered and the dichloromethane was evaporated. In this way, 10.6 g (96%) of the oily title compound was obtained.

20) N / 2- (3,4-ethylenedioxyphenyl) ethyl / -3- (4-
Trifluoromethylphenyl) propionylamide

20 cm of 14.3 g (0.08 mol) of (3,4-ethylenedioxyphenyl) ethylamine and 14.3 g (0.08 mol) of 3- (4-trifluoromethylphenyl) propionic acid. Heat to 160-170 ° C. in ³ decalin and stir the reaction mixture at this temperature for 4 hours. The water produced was distilled off. The mixture was cooled to 60 ° C. and 50 cm ³ of ethanol was added with vigorous stirring. The suspension cooled to 10 ° C. was filtered and washed with cold ethanol. In this way 17.2 g (56%) of the title compound was obtained as a crude product. Melting point: 161-1
63 ° C.

21) N / 2- (3,4-ethylenedioxyphenyl) ethyl / -4-fluorocinnamic acid amide

4.84 g (0.029 mol) of (3,4-methylenedioxyphenyl) ethylamine, 4.98 g (0.03 mol) of 4-fluorocinnamic acid, and 10 cm ^3.
The mixture with decalin was stirred at 180 ° C. for 1 hour. Chloroform was added to the cooled mixture and the mixture was stirred at 5-10 ° C to crystallize the carboxylic acid amide. The precipitated crystals were filtered and recrystallized from ethanol. In this way
Obtained 4.9 g (53%) of the title compound. Melting point: 160-162 [deg.] C.

22) N / 2- (4-chlorophenylethyl) -3- (4-trifluoromethylphenyl) propionylamide

7.8 g (0.05 mol) of (4-chlorophenyl) ethylamine and 10.5
g (0.05 mol) of 4-trifluoromethylcinnamic acid was heated to 180 ° C. in 25 cm ³ of decalin and the reaction mixture was stirred at this temperature for 14 hours. The mixture was cooled to room temperature and 50 cm ³ of diethyl ether ethanol was added. The crystalline carboxylic acid amide obtained was filtered and washed with ether. In this way
14 g (79%) of the title compound was obtained as a crude product. Melting point: 167-168 ° C
.

23) N / 2- (3,4-ethylenedioxyphenyl) -2-propylethyl / 3- (4-trifluoromethylphenyl) propionylamide

11.0 g (0.05 mol) of 2- (3,4-ethylenedioxyphenyl)-
2-Propylethylamine and 10.9 g (0.05 mol) of 3- (4-trifluoromethylphenyl) propionic acid were heated to 160 ° C. and the resulting melt was stirred at this temperature for 4 hours. The water formed was distilled off. This mixture was added to 0-5
Cooled to ° C and filtered the precipitated crystalline product. The crude product was purified by column chromatography. Thus, 10 g (47%) of the title compound was obtained as a yellow resin.

24) N / 2- (3,4-methylenedioxyphenyl) ethyl / -3- (4-
Trifluoromethylphenyl) propionylamide

A solution of 3.63 g of N / 2- (3,4-methylenedioxyphenyl) ethyl / -4-trifluoromethylcinnamic acid amide in 100 cm ³ of acetic acid was added until hydrogen was consumed. Hydrogenation under atmospheric pressure in the presence of parajum / carbon catalyst. The catalyst was filtered off and the solution was evaporated to dryness. The crude product was recrystallized from acetone.

25) N / 2- (3,4-ethylenedioxyphenyl) -2-propylethyl / -4- (trifluoromethylphenyl) cinnamic acid amide

12.3 g (55 mmol) of 2- (3,4-ethylenedioxyphenyl) -2
- 4-trifluoromethyl cinnamic acid propylethylamine and 12.0 g (55m mol) was heated to 160-165 ° C. in decalin of 100 cm ^3.
The mixture was heated at a temperature above 160-165 ° C. for 2 hours and then cooled to room temperature. The solvent was removed by decantation. 50 cm ³ of toluene were distilled off from the residue. The brown crude product was purified by column chromatography. In this way 12.1 g (52%) of the title compound was obtained. This title compound is
It was a sticky oil but solidified.

Preparation of Starting Compound of Formula (VII) 26) 6,7-Ethylenedioxy-1- / 2- (4- (trifluoromethylphenyl) ethyl / -3,4-dihydroisoquinoline

14.2 g (0.037 mol) of 2- (3,4-ethylenedioxyphenyl)
Ethyl-N- / 3- (4-trifluoromethylphenyl) / propionylamide was dissolved in 80 cm ³ of toluene. 12 cm ³ of phosphorus oxychloride (
V) was added dropwise and the reaction mixture was heated to 80 ° C. and heated at this temperature for 2.5 hours. The precipitated crystalline dihydroisoquinoline was filtered and recrystallized from ethanol.
The product obtained (12 g) is dissolved in 90 cm ³ of methanol, the pH is adjusted to 9 by addition of 20% aqueous sodium hydroxide solution, the precipitated material is filtered off and extracted with aqueous methanol (5: 1). It was washed with water and recrystallized from a mixture of ethanol and water. In this way 1.44 g (41%) of the title compound was obtained.

Melting point: 85 ° C. Analysis: C ₂₀ H ₁₈ F ₁₈ N0 ₂ (361.37) Calculation: C66.48%, H5.02%, N3.88% Result: C66.34%, H5.94%, N 3.90%

¹ H-NMR (CDCl ₃ 400 MHz) δ: 7.61 (2H, d, J = 8.0H)
z), 7.47 (2H, d, J = 8.0Hz), 7.10 (1H, s), 6.7.
4 (1H, s), 4.24 (4H, m), 3.48 (2H, t, J = 7.4Hz
), 2.96 (4H, m), 2.47 (2H, t, J = 7.1Hz)

27) 1- (2-phenylethyl) -6,7-methylenedioxy-3,4-dihydroisoquinoline

In 70 cm ³ of anhydrous benzene, 10 g (0.033 mol) of N- / 2- (3
, 4-methylenedioxy-3,4-dihydroisoquinoline tolylenedioxyphenyl) ethyl / -3-phenylpropionylamide and 30 cm ³ of phosphorus oxychloride (
The solution of V) was boiled for 1.5 hours, then cooled to 50 ° C. and the precipitated crystals were filtered. Water 200 cm ³ and dissolved in a mixture of the crude hydrochloride salt of methanol 200 cm ^3, with the addition of 20% aqueous solution of sodium hydroxide, the pH of the solution 1
Adjusted to 3. The white crystalline substance which precipitated was filtered, washed with cold water, dried and recrystallized from a mixture of ethanol and water. In this way 5.4 g (58%) of the title compound was obtained. Melting point: 112-115 ° C

[0168]   Preparation of starting compound of general formula (XVI)

28) α, α, α-trifluoro-3-methoxyacetophenone A solution of 35.52 g (0.15 mmol) of ethyl trifluoroacetate in 100 cm ³ of tetrahydrofuran was added to 46.76 g ( A solution of 3-methoxyphenylmagnesium bromide prepared by the usual method from 0.25 mol) 3-bromoanisole, 6.32 g (0.26 mol) magnesium, and 200 cm ³ tetrahydrofuran is slowly added at -70 ° C. Was added as a drip.
The reaction mixture was stirred at -70 ° C for 1 hour and warmed to 0 ° C. Then
100 cm ³ of 2N hydrochloric acid was slowly added dropwise to the reaction mixture. The reaction mixture was stirred for 30 minutes and the two phases were separated. The tetrahydrofuran phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The crude product was fractionated under reduced pressure.
Fractions were collected from 83-85 ° C at a pressure of 1600Pa. In this way, 39
． 81 g (785) of the title compound were obtained. ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.70-7.20 (4 H, m)
3.88 (3H, s) Literature value: ¹ H-NMR δ: 7.72-7.16 (4H, m), 3.81 (3H,
s)

[0170]   29) α, α, α-trifluoro-3,4-methylenedioxyacetophenone

The title compound was prepared in the same manner as starting compound 28. The crude product was fractionated under reduced pressure. Fractions were collected from 84-85 ° C at a pressure of 373 Pa.

Yield: 63% Analysis: C ₉ H ₅ F ₃ 0 ₃ (218.134) Calculation: C 49.56%. H2.31% Result: C49.43%, H2.20%

IR (KBr, cm ⁻¹ ): 1702, 1614, 1364. ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.68 (1 H, d, J = 8.3 H)
z, J = 1.2 Hz), 7.45 (1H, d, J = 1.2 Hz), 6.90 (1
H, d, J = 8.3 Hz), 6.10 (2H, s).

Preparation of Starting Compound of General Formula (XV) 30) 3,3,3-Trifluoro-2-methyl-2- (3-methoxyphenyl) propionitrile

25 g (0.3 mol) of α, α, α-trifluoro-3,4-methoxyacetophenone, 150 cm ³ of 1,2-dimethoxyethane and 32.56 g (0.
A suspension of 50 mol) potassium cyanide was stirred for 15 minutes at room temperature. To this reaction mixture, 50.45 g (38.0 cm ³ , 0.40 mol) dimethyl sulfate was added dropwise and the mixture was stirred at 60 ° C. for 5 minutes. Then left overnight. The mixture was filtered and the solvent was distilled off from the mother liquor. The crude product was fractionated under reduced pressure. Fractions were separated from 80-82 ° C at a pressure of 933 Pa. In this way, 60
． Obtained 0 g (82%) of the title compound.

Analysis: C ₁₁ H ₁₀ F ₃ NO ₂ (245.20) Calculation: C 53.88%. H4.11%, N5.71%. Results: C53.50%, H4.10%, N5.51%.

IR (KBr, cm ⁻¹ ): 2850, 1190. ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.41 (1 H, t, J = 8.0 H
z), 7.30-7.00 (3H, m), 3.83 (3H, s), 3.49 (3).
H, s).

31) 3,3,3-Trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propionitrile

32.72 g (0.15 mol) of α, α, α-trifluoro-3,4-methylenedioxacetophenone are dissolved in 330 cm ³ of 1,2-dimethoxyethane, and 14.70 g of the solution are obtained. Stir for 15 minutes with (0.30 mol) sodium cyanide. To the suspension formed was added 20.73 g (0.15 mol) potassium carbonate and to the reaction mixture was 42.7 cm ³ (56.76 g, 0.45 mol).
Of dimethylsulfate was added dropwise and the mixture was stirred at room temperature for 3 hours. Then 42 cm ³ of 25% aqueous ammonia solution was added dropwise to the mixture cooled to 0 ° C. This mixture is diluted with 330 cm ³ of water, then 160
It was extracted twice with cm ³ of ethyl acetate. The combined organic phases were washed twice with cm ³ each of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulphate. The solvent was distilled off. The residue contained about 20% starting material acetophenone, so the above steps were repeated using the same amount of the same material to achieve full conversion. The crude product was fractionally purified using a Vigreux column under reduced pressure.
Fractions were collected at 78-88 ° C at 40Pa. In this way, 27.6
0 (71%) of the title compound was obtained.

Analysis: C ₁₁ H ₈ F ₃ NO ₃ (259.19) Calculation: C 50.98%. H 3.11%, N 5.40%. Results: C50.75%, H3.17%, N5.45%.

IR (KBr, cm ⁻¹ ): 2909, 2248, 1492, 1254, 1189
． ¹ H-NMR (CDCl ₃ 200 MHz) δ: 7.17 (1 H, dd, J = 8.1)
Hz, J = 1.8 Hz), 7.05 (1H, d, J = 1.8 Hz), 6.89 (
1H, d, J = 8.1 Hz), 6.05 (2H, s), 3.48 (3H, s).

Preparation of Starting Compounds of General Formula (X) 32) 3,3,3-Trifluoro-2-methoxy-2- (3-methoxyphenyl) amine

24.52 g (0.10 mol) of 3,3,3-trifluoro-2-methoxy-
In a suspension consisting of 2- (3-methoxyphenyl) propionitrile, 23.78 g (0.10 mol) of cobalt (II) chloride hexahydrate and 250 cm ³ of methanol, 3.78 g (0.10 mol). ) Sodium tetraborate (III) was added at 0 ° C. in several batches. The reaction mixture was stirred at room temperature and left overnight. The solvent was distilled off and the residue was suspended with 500 cm ³ of water. Unreacted sodium (III) tetraborate was hydrolyzed with 2N hydrogen chloride solution. Then, the pH was adjusted to 13 with a 20% aqueous solution of sodium hydroxide. This mixture
Extraction was carried out three times using 300 cm ³ of dichloroethane each. The combined organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was separated under reduced pressure. Fractions were collected at 103-104 ° C. at 533 Pa. In this way 15.20 g (61%) of the title compound was obtained.

Analysis: C ₁₁ H ₁₄ F ₃ NO ₂ (249.23) Calculation: C53.01%. H5.66%, N5.62%. Results: C52.65%, H5.52%, N5.78%.

IR (KBr, cm ⁻¹ ): 2800, 1174, 1119 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 7.33 (1H, t, J = 8.2H)
z), 7.05 (2H, m), 6.90 (1H, ddd, J = 8.2 Hz, J =
2.5 Hz, J = 0.8 Hz), 3.82 (3H, s), 3.42 (3H, s)
3.36 (1H, d, J = 14.6 Hz), 3.13 (1H, d, J = 14.
6 Hz), 1.20 (2H, s).

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 159.7, 135.8, 12
9.4, 125.4 (q, ¹ J _CF = 289.6 Hz), 119.2, 113.5
, 82.2 (q, ² J _CF = 24.8 Hz), 54.9, 52.5, 45.7.

Preparation of the hydrochloride salt A solution obtained by dissolving 12.46 g (50 mol) of the substrate 3,3,3-trifluoro-2- (3-methoxyphenyl) propylamine in 125 cm ³ of diethyl ether. And (60 mol, 25.3 g / 100 cm ³ ) of hydrogen chloride.
6 cm ³ of 2-propanol was added dropwise. The precipitated crystals were filtered and washed with 30 cm ³ of diethyl ether. In this way 12.26 g, 86%) of the title compound was obtained.

Analysis: C ₁₁ H ₁₅ ClF ₃ NO ₂ (285.69) Calculation: C 46.25%. H 5.29%, Cl 12.41%, N 4.90%. Results: C 45.92%, H 5.15%, Cl 12.72%, N 4.98%.

IR (KBr, cm ⁻¹ ): 2945, 1130 ¹ H-NMR (DMSO-d ₆ 250 MHz) δ: 8.47 (3 H, t, J = 7.9 Hz)
), 7.10 (3H, m), 3.96 (1H, t, J = 14.8Hz), 3.8.
0 (3H, s), 3.61 (1H, t, J = 14.8Hz), 3.30 (3H,
s).

33) 3,3,3-Trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propylamine

The title compound was prepared by repeating the same method as for the starting compound 32. The crude product was fractionated under reduced pressure. Fractions were collected from 114-116 ° C at a pressure of 147Pa. Yield: 68%. The title compound was a colorless oil.

Analysis: C ₁₁ H ₁₂ F ₃ NO ₃ (263.22) Calculation: C 50.19%. H4.60%, N5.32%. Results: C49.96%, H4.58%, N5.34%.

IR (KBr, cm ⁻¹ ): 2951, 1167 ¹ H-NMR (CDCl ₃ 200 MHz) δ: 6.97 (1 H, m), 6.93 (
1H, ddd, J = 8.2 Hz, J = 1.8 Hz, J = 0.4 Hz), 6.83
(1H, ddJ = 8.2Hz, J = 0.4Hz), 5.97 (2H, s), 3.
39 (3H, 1, J = 1.2Hz), 3.26 (1H, d, J = 14.6Hz)
3.12 (1H, dq, J = 14.6Hz, J = 1.6Hz), 1.28 (2
H, bs).

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 147.9, 127.8, 1
25.3 (q, ¹ J _CF = 289.5 Hz), 120.8 (q, J = 1.5 Hz)
, 108.0, 107.7 (q, J = 1.5 Hz), 101.2, 82.0 (q
, ² J _CF = 24.8 Hz), 52.3 (q, J = 289.6 Hz), 45.3 (
q, ³ J _CF = 1.1 Hz)

Preparation of Hydrochloride The same procedure as for starting compound 32 was repeated to prepare the title compound.
Yield: 81%, melting point: 248-249 ° C.

Analysis: C ₁₁ H ₁₃ ClF ₃ NO ₃ (299.68) Calculation: C44.09%. H 4.37%, Cl 11.83%, N 4.67%. Results: C44.31%, H4.40%, Cl11.81%, N4.65%.

IR (KBr, cm ⁻¹ ): 2925, 1112, 1076 ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.55 (3 H, bs), 7.1
(1H, s), 7.05-7.02 (2H, m), 6.10 (2H, s), 3.
90 (1H, d, J = 14.9Hz), 3.57 (1H, d, J = 14.9Hz)
), 3.29 (3H, s).

[0198]   Example 1   6-methoxy-1-styryl-4-trifluoromethylisoquinoline

Method A) 1.19 g (3 mmol) of 4,6-dimethoxy-in 10 cm ³ of methanol
To a solution of 1-styryl-4-trifluoromethyl-3,4-dihydroisoquinolinium chloride, 0.42 g (7.5 mmol) of powdered potassium hydroxide was added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated and the residue was stirred with 10 cm ³ of water and then filtered. The crystals were washed with 5 cm ³ of water and then with 3 cm ³ of ethanol each twice at 0 ° C. In this way, 0.94 g (95%) of the pale yellow title compound was obtained. Melting point: 202-203 ° C (chloroform)

Method B) 2.73 g (10 mol) of 1-methyl-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline, 1.17 g (11 mol) of benzaldehyde, and 1. A suspension consisting of 33 g (13 mol) of acetic anhydride,
The reaction was carried out at 100 ° C for 16 hours. The precipitated crystals were filtered and washed twice with 5 cm ³ of ethanol each at 0 ° C. In this way 2.14 g (65%) of the title compound was obtained. Melting point: 202-203 ° C (chloroform)

Method C) 2.41 g (10 mol) of 1-methyl-4,6-methoxy-4-trifluoromethylisoquinoline, 1.17 g (11 mol) of benzaldehyde, and 1.3.
A suspension consisting of 3 g (13 mol) of acetic anhydride was reacted at 100 ° C. for 16 hours. The precipitated crystals were filtered and washed twice with 5 cm ³ of ethanol each at 0 ° C. In this way 1.98 g (60%) of the title compound was obtained. Melting point: 202-203 ° C (chloroform)

Analysis: C ₁₉ H ₁₄ F ₃ NO (329.32) Calculation: C 69.20%. H4.28%, N4.25%. Results: C69.02%, H4.25%, N4.20%.

IR (KBr, cm ⁻¹ ): 1619, 1411, 1318, 1221, 1100
¹ H-NMR (CDCl ₃ 200 MHz) δ: 8.79 (1 H, s), 8.36 (
1H, d, J = 9.5 Hz), 8.07 (1H, d, J = 15.8 Hz), 7.
92 (1H, d, J = 15.8Hz), 7.75-7.65 (2H, m), 7.
45-7.30 (5H, m), 3.99 (3H, s).

¹³ C-NMR (CDCl ₃ 50.3 MHz) δ: 161.7, 157.8, 14
1.1 (q, ³ J _CF = 6.5 Hz), 138.7, 136.3, 135.0, 1
29.3, 128.9, 127.7, 127.1, 124.8 (q, ¹ J = 27
3.1 Hz), 121.8, 120.5, 117.8 (q, ² J _CF = 30.1H
z), 101.1, 55.6.

MS (m / z,%): 329 (37), 328 (100), 314 (7), 31.
0 (3), 298 (8), 286 (10), 285 (37), 252 (7).

6-Methoxy-1-styryl-4-trifluoromethylisoquinolinium chloride 0.99 g (3 mmol) of the above-mentioned base was added to 3.6 mmol (25.3 g / 100c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 0.74 g (67%) of the pale yellow title compound was obtained. Melting point: 189-190 ° C (ethanol, diisopropyl, decomposition)

Analysis: C ₁₉ H ₁₅ ClF ₃ NO (365.78) Calculation: C 62.39%. H 4.13%, Cl 9.68%, N 3.83%. Results: C62.21%, H4.17%, Cl9.60%, N3.86%.

IR (KBr, cm ⁻¹ ): 1618, 1249 ¹ H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.92 (1 H, d, J = 9.4 H)
z), 8.76 (1H, s), 8.28 (1H, d, J = 15.7 Hz), 8.
15 (1H, d, J = 15.7Hz), 7.93-7.89 (2H, m), 7.
58 (1H, d, J = 9.4 Hz), 7.50-7.40 (3H, m), 7.3.
2 (1H, s), 4.00 (3H, s).

Example 2 1- (4-Fluorostyryl) -6-methoxy-4-trifluoromethylisoquinoline

Method A) 1.14 g (3 mmol) of 1- (4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline were added to 20 cm ³
It was dissolved in a mixture of toluene and 10 cm ³ of methanol. To the resulting solution was added 0.25 g (4.5 mmol) potassium hydroxide powder at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then filtered. The crystals were washed with 5 cm ³ of water and then twice with 3 cm ³ of ethanol each at 0 ° C. In this way, 0.92 g (93%) of the pale yellow title compound was obtained. Melting point: 187-188 ° C (chloroform)

[0211]   Method B)   Method B of Example 1 was repeated. Yield: 64%, melting point: 188-189 ° C (chloroform)

[0212]   Method C)   Method C of Example 1 was repeated.

Yield: 64%, Melting point: 188-189 ° C (chloroform) Analysis: C ₁₉ H ₁₃ F ₁₃ NO (347.32) Calculation: C 65.71%. H3.77%, N4.03%. Results: C65.84%, H3.79%, N4.08%.

IR (KBr, cm ⁻¹ ): 1618, 1510, 1321, 1275, 1130
¹ H-NMR (CDCl ₃ 250 MHz) δ: 8.77 (1 H, s), 8.31 (
1H, d, J = 9.1 Hz), 8.01 (1H, d, J = 15.5 Hz), 7.
81 (1H, d, J = 15.5Hz), 7.70-7.63 (2H, m), 7.
35-7.29 (2H, m), 7.11 (2H, t, J = 8.7Hz), 3.9
8 (3H, s)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 165.2, 161.5, 1
59.5 (d, ¹ J _CF = 221.5 Hz), 141.3 (q, ³ J _CF = 6.6 Hz)
), 136.9, 134.8, 132.6, 129.3, 129.2, 126.
8, 124.8 (q, 1J = 273.6 Hz), 121.8, 120.3, 11
7.7 (q, ² J _CF = 29.3 Hz), 115.8 (d, ² J _CF = 21.0 Hz)
102.1, 55.4.

MS (m / z,%): 347 (34), 346 (100), 332 (10), 3
28 (4), 316 (9), 304 (10), 303 (34), 252 (8).

6-Methoxy-1-styryl-4-trifluoromethylisoquinolinium chloride 0.99 g (3 mmol) of the above-mentioned base was added to 3.6 mmol (25.3 g / 100c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 0.74 g (67%) of the pale yellow title compound was obtained. Melting point: 189-190 ° C (ethanol, diisopropyl, decomposition)

Analysis: C ₁₉ H ₁₅ ClF ₃ NO (365.78) Calculation: C 62.39%. H 4.13%, Cl 9.68%, N 3.83%. Results: C62.21%, H4.17%, Cl9.60%, N3.86%.

IR (KBr, cm ⁻¹ ): 1618, 1249 ¹ H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.92 (1 H, d, J = 9.4 H)
z), 8.76 (1H, s), 8.28 (1H, d, J = 15.7 Hz), 8.
15 (1H, d, J = 15.7 Hz), 7.93-7.89 (2H, m), 7.
58 (1H, d, J = 9.4 Hz), 7.50-7.40 (3H, m), 7.3.
2 (1H, s), 4.00 (3H, s).

1- (4-Fluorostyryl) -6-methoxy-4-trifluoromethylisoquinolium chloride

1.04 g (3 mmol) of the above base was mixed with 3.6 mmol (25.3 g / 100 c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 0.63 g (72%) of the title hydrochloride salt was obtained.

Melting point: 189-190 ° C. (ethanol decomposition) Analysis: C ₁₉ H ₁₄ ClF ₄ NO (383.77) Calculation: C 59.46%. H 3.68%, Cl 9.24%, N 3.65%. Results: C 59.19%, H 3.72%, Cl 9.10%, N 3.58%.

IR (film, cm ⁻¹ ): 3437, 1615, ”1228, 11621 ¹ H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.95 (1 H, d, J = 9.5 H)
z), 8.77 (1H, s), 8.29 (1H, d, J = 15.6 Hz), 8.
18 (1H, d, J = 15.6Hz), 8.04 (1H, d, J = 5.6Hz)
, 8.00 (1H, d, J = 5.6 Hz), 7.56 (1H, dd, J = 9.4)
Hz, J = 2.4 Hz), 7.33 (2H, t, J = 8.8 Hz), 7.29 (
1H, s), 4.02 (3H, s)

Example 3 6-Methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) isoquinoline

Method A) Method A of Example 1 was performed to give the pale yellow title compound. Yield: 90%, melting point: 160-161 ° C (chloroform)

Method B) Method B of Example 1 was performed to give the pale yellow title compound. Yield: 62%, melting point: 160-161 ° C (chloroform)

[0227]   Method C)   The method C of Example 1 was performed to obtain the pale yellow title compound.

[0228] Yield: 70% mp: 160-161 ° C. (chloroform) _{Analysis: C 20 H 13 F 6 NO} (397.32) calculated: C60.46%. H3.30%, N3.53%. Results: C60.70%, H3.27%, N3.63%.

IR (KBr, cm ⁻¹ ): 1620, 1409, 1324, 1121 ¹ H-NMR (CDCl ₃ 250 MHz) δ: 8.80 (1 H, s), 8.34 (
1H, d, J = 9.7 Hz), 8.08 (1H, d, J = 15.6 Hz), 7.
98 (1H, d, J = 15.6Hz), 7.78 (2H, d, J = 8.3Hz)
, 7.68 (2H, d, J = 8.3Hz), 7.37 (1H, s), 35 (1H
, Dd, J = 9.7 Hz, J = 2.5 Hz), 4.00 (3H, s)

¹³ C-NMR (CDCl ₃ 62.9 MHz) δ: 161.7, 157.2, 1
41.4 (q, ³ J _CF = 6.5 Hz), 139.8, 136.5, 135.0,
130.1 (q, ² J _CF = 32.5 Hz), 127.8, 126.8, 125.
8 (q, 3J = 4.6 Hz), 124.8 (q, ¹ J _CF = 271.8 Hz), 1
24.5, 124.2 (q, ¹ J _CF = 271.0 Hz), 122.6, 120.
8, 118.5 (q, ² J _CF = 27.8 Hz), 102.1, 55.6

MS (m / z,%): 397 (57), 396 (100), 332 (11), 3
78 (9), 366 (12), 354 (10), 353 (36), 328 (6)
285 (11), 252 (16), 69 (8).

6-Methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) isoquinolinium chloride

1.19 g (3 mmol) of the above base was mixed with 3.6 mmol (25.3 g / 100 c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 0.72 g (68%) of the yellow title hydrochloride salt was obtained.

Melting point: 189-190 ° C. (ethanol decomposition) Analysis: C ₂₀ H ₁₄ ClF ₆ NO (433.78) Calculation: C 55.38%. H3.25%, C18.17%, N3.23%. Results: C55.62%, H3.37%, Cl8.29%, N3.19%.

IR (film, cm ⁻¹ ): 3433, 1613, ”13129, 1132 ¹ H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.92 (1 H, d, J = 9.5 H)
z), 8.83 (1H, s), 8.47 (1H, d, J = 15.5Hz), 8.
20-8.13 (3H, s), 7.81 (2H, d, J = 8.2Hz), 7.5
4 (1H, dd, J = 9.5 Hz, J = 2.4 Hz), 7.29 (1H, s),
4.00 (3H, s)

2-Methyl-6-methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) isoquinolium chloride

A mixture of 1.00 g (2.5 mmol) of the above base and 10 cm ³ of methyl iodide was boiled for 40 hours. The precipitated crystals were filtered and the crude product was recrystallized from ethanol. Thus, the title quaternary salt of an orange-yellow solid 0.7.
8 g (58%) were obtained.

Melting point: 213-215 ° C. (ethanol decomposition) Analysis: C ₂₁ H ₁₆ F ₆ NO (53.26) Calculation: C 46.77%. H 2.99%, N 2.60%. Results: C 46.55%, H 2.97%, N 2.64%.

IR (KBr, cm ⁻¹ ): 3035, 1616, 1324, 1249, 1170
, 1130 ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.29 (1 H, s), 8.69 (
1H, d, J = 9.5 Hz), 8.12 (2H, d, J = 8.2 Hz), 7.9
4 (1H, d, J = 16.4 Hz), 7.92 (2H, d, J = 8.2 Hz),
7.94 (1H, d, J = 16.4 Hz), 7.92 (2H, d, J = 8.2H)
z), 7.78 (1H, dd, J = 9.5 Hz, J = 2.9 Hz), 7.47 (
1H, d, J = 8.2 Hz), 7.46 (1H, s), 4.36 (3H, s),
4.14 (3H.s).

¹³ C-NMR (DMSO-d ₆ , 100.6 MHz) δ: 166.5, 160.0, 1
44.7, 138.5, 137.5 (q, ³ J _CF = 6.9 Hz), 135.3
134.5, 130.4 (q, ² J _CF = 31.9 Hz), 129.3, 126.
0 (q, ³ J = 3.8 Hz), 124.1 (q, ¹ J _CF = 272.1 Hz), 12
3.5, 122.9 (q, ¹ J _CF = 273.7 Hz), 122.7, 119.8
, 119.4 (q, ² J _CF = 32.8 Hz), 103.0, 57.1, 46.6.

MS (m / z,%): 397 (48), 396 (74), 382 (18), 37.
8 (10), 366 (18), 354 (12), 353 (33), 328 (4)
285 (10), 252 (15), 142 (100), 127 (39), 69.
(5).

Example 4 6-Methoxy-1- (4-nitrostyryl) -4-trifluoromethylisoquinoline

Method A) Method A of Example 1 was performed to give the title compound as a lemon yellow solid. yield:
92%, melting point: 232-224 ° C (chloroform)

Method B) Method B of Example 1 was carried out to obtain the title compound. Yield: 62%. Melting point: 160
-161 ° C (chloroform)

[0245]   Method C)   Perform Method C of Example 1 to obtain the title compound. Yield: 70%

Melting point: 222-223 ° C. (chloroform) Analysis: C ₁₉ H ₁₃ F ₃ N ₂ O ₃ (374.32) Calculation: C 60.97%. H3.50%, N7.48%. Results: C60.78%, H3.46%, N7.46%.

[0247] ^{IR (KBr, cm -1):} 1619,1327,1106 1 H-NMR (DMSO-d 6, 2400MHz) δ: 8.92 (1H, d, J = 9.3Hz
), 8.87 (1H, s), 8.56 (1H, d, J = 15.3 Hz), 8.2
9 (2H, d, J = 8.7Hz), 8.21 (2H, d, J = 8.7Hz), 8
． 18 (1H, d, J = 15.3Hz), 7.56 (1H, d, J = 9.3Hz)
), 7.30 (1H, s), 4.00 (3H, s)

¹³ C-NMR (CDCl ₃ 50.3 MHz) δ: 161.9, 157.4, 1
47.5, 142.8, 135.7, 134.2, 129.3, 128.7, 1
27.0, 126.2, (q, ¹ J _CF = 274.3 Hz), 124.1,121
． 8, 120.7, 116.4 (q, ² J _CF = 32.7 Hz), 101.7, 5
5.9

MS (m / z,%): 374 (100), 373 (99), 359 (12), 3
55 (7), 344 (12), 343 (28), 328 (27), 327 (68)
), 326 (15), 313 (15), 285 (29), 284 (23), 28
3 (16), 252 (26), 216 (12), 215 (19).

6-Methoxy-1- (4-nitrostyryl) -4-trifluoromethylisoquinolinium chloride

1.12 g (3 mmol) of the above base was mixed with 3.6 mmol (25.3 g / 100 c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 0.86 g (70%) of the title hydrochloride salt was obtained as a pale yellow solid.

Melting point: 250 ° C. or higher (ethanol) Analysis: C ₁₉ H ₁₄ ClF ₃ N ₂ O ₃ (410.78) Calculation: C 55.56%. H3.44%, C18.63%, N6.82%. Results: C55.87%, H3.29%, Cl8.56%, N6.84%.

IR (film, cm ⁻¹ ): 2440, 1646, 1345, 1262 ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.96 (1H, d, J = 9.5H)
z), 8.86 (1H, s), 8.57 (1H, d, J = 15.4 Hz), 8.
36-8.14 (5H, m), 7.57 (1H, dd, J = 9.5Hz, J = 2
． 2Hz), 7.30 (1H, s), 3.85 (3H, s).

Example 5 6,7-Methylenedioxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) isoquinoline

Method A) Method A of Example 1 was performed to give the title compound as a pale yellow solid. Yield: 92%,
Melting point: 180-182 ° C (chloroform)

Method B) Method B of Example 1 was carried out to obtain the title compound. Yield: 64%. Melting point: 180
-182 ° C (chloroform)

[0257]   Method C)   Perform Method C of Example 1 to obtain the title compound. Yield: 68%

Melting point: 180-182 ° C. (chloroform) Analysis: C ₂₀ H ₁₁ F ₁₁ NO ₂ (411.30) Calculation: C 58.40%. H2.70%, N3.41%. Results: C58.22%, H2.73%, N3.35%.

IR (KBr, cm ⁻¹ ): 1615, 1478, 1324, 1104 ¹ H-NMR (CDCl _3, 200 MHz) δ: 8.72 (1 H, s), 8.04 (1
H, d, J = 15.4 Hz), 7.84 (1H, d, J = 15.4 Hz), 7.
76 (2H, s), 7.69 (2H, s), 7.66 (1H, s), 7.43 (
1H, q, J = 1.8 Hz).

¹³ C-NMR (CDCl ₃ 100.6 MHz) δ: 155.8, 152.0,
149.0, 138.8 (q, ⁴ J _CF = 1.5 Hz), 136.7, 136.2
, 131.5, 130.6 (q, ² J _CF = 32.8 Hz), 127.7, 125
． 8 (q, ³ J _CF = 3.8 Hz), 124.6, 124.6 (q, ¹ J _CF = 273)
． 1Hz), 124.0 (q, ¹ J _CF = 272.0Hz), 124.0, 102
． 4, 101.1, 100.5 (q, ³ J _CF = 2.7 Hz)

MS (m / z,%): 411 (37), 410 (100), 392 (10), 3
82 (13), 382 (2), 380 (2), 353 (11), 352 (7),
284 (7), 283 (7), 266 (28), 240 (3), 171 (16)
.

6,7-Methylenedioxy-4-trifluoromethyl-1- (4-trifluoromethylcytyryl) isoquinolium chloride

1.23 g (3 mmol) of the above base was mixed with 3.6 mmol (25.3 g / 100 c).
m ³ ) was reacted with 0.5 cm ^{3 of} 2-propanol containing hydrogen chloride. In this way 1.03 g (77%) of the title hydrochloride salt was obtained as a pale yellow solid.

Melting point: 259-260 ° C. (methanol, diisopropyl ether, decomposition) Analysis: C ₂₀ H ₁₂ ClF ₆ NO ₂ (447.77) Calculation: C 53.65%. H2.70%, C17.92%, N3.13%. Results: C53.82%, H2.63%, Cl7.87%, N3.16%.

IR (film, cm ⁻¹ ): 1630, 1482, 1320, 1180, 1134.
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.73 (1 H, s), 8.41
(1H, s), 8.38 (1H, d, J = 15.4Hz), 8.16 (2H, d
, J = 8.2 Hz), 8.11 (1H, d, J = 15.4 Hz), 7.80 (2
H, d, J = 8.2 Hz), 7.34 (1H, q, J = 1.4 Hz), 6.36
(2H, s).

Example 6 1- / 2- (4-Trifluoromethylphenyl) ethyl / -6,7-ethylenedioxyisoquinoline 5.5 g (0.015 mol) of 1- (4-trifluoromethylstyryl) -6
, 7-Ethylenedioxyisoquinoline was dissolved in 100 cm ³ of methanol. The solution obtained was hydrogenated in the presence of 1 g of palladium / catalyst at a pressure of 15 bar. The catalyst was filtered. The pH was adjusted to 9 by adding concentrated ammonia water to the residue. The precipitated crystals were filtered and recrystallized from ethanol. In this way 2.4 g (44%) of the title compound was obtained.

Melting point: 110-111 ° C. _{Analysis: C 20 H 16 F 3 NO} 2 (359.35) calculated: C66.85%. H 4.49%, N 3.90%. Results: C 66.34%, H 4.42%, N 4.03%.

IR (KBr, cm ⁻¹ ): 1509, 1292, 1168, 1096, 1066 ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.27 (1 H, d, J = 5.8 Hz)
), 7.53 (2H, d, J = 8.1Hz), 7.47 (1H, s), 7.36
(3H, m) 7.21 (1H, s), 4.37 (4H, m), 3.46 (2H,
dd, J ₁ = 7.6 Hz, J ₂ = 8.6 Hz), 3.25 (2H, dd, J = 7.
6 Hz, J = 8.6 Hz).

Example 7 1- / 2- (Trifluoromethylphenyl) ethyl / 2-methyl-6,7-ethylenedioxy-1,2,3,4-tetrahydroisoquinoline fumarate

2.2 g (0.004 mol) of 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolium iodide Was dissolved in 150 cm ³ of methanol. 1 in the resulting solution
g of sodium tetrahydroboride were added with stirring. The reaction mixture was stirred at room temperature for 2 hours and then evaporated. To the residue was added 100 cm ³ of water, the aqueous phase was extracted with dichloromethane, dried over anhydrous sodium sulphate and evaporated. The oily residue was dissolved in ethanol and an equimolar amount of fumaric acid dissolved in ethanol was poured. The precipitated crystals were filtered and recrystallized from aqueous acetone. In this way 1.33 g (67%) of the title compound was obtained.

Melting point: 192-194 ° C. Analysis: C ₂₅ H ₂₆ F ₃ NO ₂ (493.48) Calculation: C 60.85%. H5.31%, N2.84%. Results: C60.12%, H5.28%, N2.82%.

¹ H-NMR (DMSO-d _6, 400 MHz) δ: 7.60 (2H, d, J = 8.1H)
z), 7.39 (2H, d, J = 8.1Hz), 6.64 (1H, s), 6.6
1 (2H, s) 6.56 (1H, s), 4.18 (4H, bs), 3.40 (1
H, t, J = 5.2 Hz), 3.06 (1H, m), 2.80-250 (5H,
m), 2.39 (3H, s), 2.00 (2H, m).

Example 8 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-ethylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

5.0 g (12 mol) of 1- / 2- (4-fluorophenyl) ethyl / 2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolium iodide was added to 370 cm ³ Dissolved in methanol. To the resulting solution was added 1 g (24 mmol) sodium tetraborohydride with stirring. The reaction mixture was stirred at room temperature for 3 hours, then evaporated to half its volume and 200 cm ³ of water was added. The residual methanol was evaporated off and the aqueous phase was extracted with dichloromethane. The organic solution was dried and evaporated under reduced pressure. The residue was dissolved in diethyl ether and pH was adjusted to 1 by adding 2-propanol containing hydrogen chloride. The hydrochloride salt that precipitated was filtered and recrystallized from 2-propanol. In this way, the title compound 3
． 63 g (82%) were obtained.

Melting point: 175-177 ° C. Analysis: C ₂₀ H ₂₃ ClFNO ₂ (363.86) Calculation: C 66.02%. H 6.37%, N 3.85%. Results: C65.45%, H6.35%, N3.95%.

¹ H-NMR (DMSO-d _6, 400 MHz) δ: 11.36 (1 H, bs), 7.2
9 (2H, dd, J ₁ = 5.8Hz, J ₂ = 8.2Hz), 7.10 (2H, t,
J = 8.8 Hz), 6.76 (1H, s), 6.74 (1H, s) 4.30 (1
H, m), 4.23 (4H, m), 3.65-3.15 (2H, m), 2.98.
(2H, m), 2.79 (5H, m), 2.44 (1H, m), 2.05 (1H
, M).

Example 9 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

5.94 g (0.02 mol) of 1- / 2- (4-fluorophenyl) ethyl /
-6,7-methylenedioxy-3,4-dihydroisoquinoline was dissolved in acetone 50 cm ^3. To the resulting solution was added 14.1 g of methyl iodide,
The reaction mixture was left at room temperature for 24 hours. The precipitated quaternary isoquinolinium salt was filtered, then dissolved in 150 cm ³ of methanol and 3.5 g of sodium tetraborohydride was added in portions at 25-30 ° C. The reaction mixture was stirred for 2 hours and then evaporated to dryness. 200 cm ³ of water was added to the residue and the solution was extracted with dichloromethane. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from ethanol. In this way the title compound 3.7
g (52%) was obtained.

Melting point: 208-211 ° C. Analysis: C ₁₉ H ₂₁ ClFNO ₂ (349.83) Calculation: C 65.23%. H 6.95%, N 4.00%. Results: C 64.80%, H 6.00%, N 4.07%.

¹ H-NMR (DMSO-d _6, 400 MHz) δ: 11.53 (1 H, bs), 7.3
1 (2H, dd, J ₁ = 6.0 Hz, J ₂ = 8.1 Hz), 7.1 (2H, t, J
= 8.8 Hz), 6.83 (2H, s), 6.2 (2H, s) 4.43 (2H,
t, J = 5.6 Hz), 3.49 (1H, m), 3.24 (1H, m), 2.7.
-3.1 (3H, m), 2.78 (3H, s), 2.45 (1H, m), 2.8
(1H, m).

Example 10 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-4-propyl-6,7-methylenedioxyisoquinolinium iodide

4.0 g (0.01 mol) of 1- / 2- (4-trifluoromethylphenyl)
Ethyl / 2-methyl-4-propyl-6,7-methylenedioxy-isoquinoline, it was dissolved in nitromethane 100 cm ^3. To the resulting solution was added 14.1 g methyl iodide and the reaction mixture was boiled for 3 hours. The mixture was cooled to room temperature and the crystalline isoquinolinium salt was filtered. The crude product was recrystallized from a mixture of acetonitrile and ether. In this way 2.7 g (49%) of the title compound was obtained.

Melting point: 214-216 ° C. Analysis: C ₂₄ H ₂₅ F ₃ NO ₂ (5433.73) Calculation: C 53.05%. H4.64%, N2.58%. Results: C52.83%, H4.69%, N2.60%.

¹ H-NMR (DMSO-d _6, 400 MHz) δ: 8.29 (1 H, s), 7.78 (
1H, s), 7.62 (1H, s), 7.53 (2H, m), 7.42 (2H,
m), 4.5 (4H, m), 4.38 (3H, s), 3.87 (2H, t, J =
7.8 Hz), 3.26 (2H, t, J = 7.8 Hz), 3.4 (2H, t, J)
= 7.8 Hz), 1.8 (3H, t, J = 7.4 Hz)

Example 11 1- (4-Trifluoromethylstyryl) -4-propyl-6,7-ethylenedioxyisoquinolinium chloride

6.2 g (0.015 mol) of N- / 2- (3,4-ethylenedioxyphenyl) ethyl / -4-trifluoromethylcinnamide were dissolved in 90 cm ³ of anhydrous benzene. To the resulting solution was added 25 cm ³ of phosphorus oxychloride (V), was boiled and the reaction mixture 4 hours. To the still hot solution was poured 100 cm ³ of methanol and then evaporated to dryness. The addition and evaporation of methanol was repeated 3 times, using 50 cm ³ of methanol each. A methanolic solution of isoquinoline chloride was then passed through an acidic ion exchange "Amberlite 46" and the product was precipitated with diisopropyl ether. In this way, 1.3 g (31%) of the title compound was obtained.

Melting point: 188-190 ° C. Analysis: C ₂₃ H ₂₁ ClF ₃ NO ₂ (435.87) Calculation: C 63.38%. H 4.86%, N 3.21%. Results: C63.39%, H4.85%, N3.19%.

¹ H-NMR (DMSO-d _6, 400 MHz) δ: 8.48 (1 H, s), 8.22 (
1H, d, J = 16.2 Hz), 8.16 (4H, m), 7.86 (2H, d,
J = 8.3 Hz), 7.71 (1H, s), 4.56 (2H, m), 4.52 (
2H, m), 3.05 (2H, d, t, J = 7.6Hz), 1.7 (2H, hx
, J = 7.4 Hz), 0.99 (3H, t, J = 7.3 Hz)

Example 12 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline 4.89 g (0.01 Mol) of 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium iodide in 80 cm ³ of methanol. 2.1 g of sodium tetrahydridoborate is added to the dissolved and formed solution in portions. The solution is stirred at room temperature for 3 hours and then evaporated to dryness. To the residue, water was added 150 cm ^3, and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate, evaporated under reduced pressure and the residual white solid recrystallized from ethanol. In this way, 2.
8 g (77%) of the title compound are obtained. M. p. : 51-52 ° C. _{Analysis: C 20 H 20 F 3 NO} 2 (363.3) calculated for: C66.11%, H5.55%, N3.85 %. Results: C66.08%, H5.53%, N3.86%. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.5 (2H, d, J = 8.2H)
z), 7.27 (2H, d, J = 8.2Hz), 6.54 (1H, s), 6.5
3 (1H, s), 5.88 (2H, s), 3.38 (1H, t, J = 5.4Hz)
), 3.1 (1H, m), 2.55-2.84 (5H, m), 2.45 (3H,
s), 2.3 (2H, m).

Example 13 1- (4-Trifluoromethylstyryl) -6,7-methylenedioxy-1,2,3,
4-Tetrahydroisoquinoline 3.4 g (0.01 mol) of 1- (4-trifluoromethylstyryl) -3,4-
Dihydroisoquinoline is dissolved in 150 cm ³ of methanol. To the solution formed, 1.4 g of sodium tetrahydridoborate are added in portions under stirring, and the solution is stirred for 3 hours at room temperature. The mixture is evaporated to 1/4 of its original volume, and to the residue 200 cm ³ of water are added and any methanol present is distilled off, the solid material is filtered off and water is neutralized. Wash with. The product is recrystallized from ethanol. In this way 2.6 g (74%) of the title compound are obtained. M. p. : 124-125 ° C Analysis: Calculated for C ₁₉ H ₁₉ F ₃ NO ₂ (347.34): C 65.70%, H 4.64%, N 4.03%. Results: C65.90%, H4.67%, N4.06%. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 7.56 (2H, d, J = 8.5)
Hz), 7.48 (2H, d, J = 8.5Hz), 6.61 (1H, d, J = 1)
5.8 Hz), 6.6 (1H, s), 6.58 (1H, s), 6.4 (1H, d)
, J = 15.8 Hz), 5.89 (2H, s), 4.58 (1H, d, J = 7.
7 Hz), 3.3-3.0 (2H, m), 2.9-2.6 (2H, m).

Example 14 1- / 2- (4-Trifluoromethylphenyl) ethyl / 2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisochirinium iodide 5 1 g (0.01 mol) of 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-methylenedioxy-1,2,3,4-tetradihydroisoquinoline, Dissolve in 60 cm ³ of acetone. To the solution formed, 8 cm ³ of methyl iodide are added and the reaction mixture is stirred at room temperature for 24 hours. The precipitated material is filtered and recrystallized from ethanol. In this way, 4.2 g (
83%) of the title product is obtained. M. p. : 229-231 ° C Analysis: Calculated for C ₂₁ H ₂₃ F ₃ INO ₂ (505.32): C49.92%, H4.59%, N2.77% Result: C49.01%, H4.61%, N2 0.73% ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.66 (2 H, d, J = 8.
8Hz), 7.44 (2H, d, J = 8.8Hz), 6.89 (1H, s), 6
． 82 (1H, s), 6.06 (2H, s), 4.55 (1H, m), 3.77
(2H, m), 3.62 (2H, m), 3.33 (2H, s), 3.29 (3H
, S), 3.09-3.05 (2H, m), 2.88-2.86 (1H, m), 2
． 69-2.68 (1H, m).

Example 15 1- (4-Trifluoromethylstyryl) -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolinium iodide In Example 14 The title compound is obtained according to the procedure described. Yield: 5
9%. M. p. : 256-258 ° C. Analysis: For C ₂₁ H ₂₁ FINO ₂ (503.30) Calculation: C 50.31%, H 4.21%, N 2.78% Result: C 49.88%, H 4.25%, N 2.87%

Example 16 1- / 2- (4-Fluorophenyl) ethyl / -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolinium iodide 2 0.93 g (6.5 mmol) of 1- / 2- (4-fluorophenyl) ethyl / -2
1,2-Dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2.8 cm ³ of methyl iodide are boiled under stirring for 3 hours in 40 cm ³ of nitromethane. The mixture is cooled to room temperature and then left in the refrigerator. The crystalline material is filtered, washed with cold acetone and recrystallized from ethanol. In this way 1.3 g (43%) of the title compound is obtained. M. p. : 213-215 ° C. Analysis: C ₂₀ H ₂₃ FINO calculated for _{2 (455.31): C52.76%,} H5.09%, N3.08%; Result: C53.11%, H5.21%, N3.15 %. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.28 (2H, m), 6.99
(2H, m), 6.78 (1H, s), 6.7 (1H, s), 6.02 (2H,
s), 4.85 (1H, m), 3.83 (2H, m), 3.45 (3H, s),
3.21 (3H, s), 3.15-3.1 (2H, m), 2.86-2.61 (2
H, m), 2.52-2.0 (2H, m).

Example 17 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-methylenedioxy
-Isoquinolinium iodide 5.9 g (0.02 mol) of 1- / 2- (4-fluorophenyl) ethyl / -2-methyl-6,7-methylenedioxy-isoquinoline in 250 cm ³ of acetone And 6
． A 1 cm ³ solution of methyl iodide is left at room temperature for 20 hours. The resulting suspension is cooled to 0 ° C., filtered, washed with cold acetone and the product recrystallized from methanol. In this way 4.7 g (54%) of the title compound is obtained. M. p. : 224-227 ° C. Analysis: Calculated for C ₁₉ H ₁₇ FINO ₂ (437.25): C52.19%, H3.92%, N3.20%; Results: C52.24%, H3.99%, N3.29%. IR (KBr, cm ^-1 ): 1031, 932 ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.58 (1 H, d, J = 6.
8 Hz), 8.19 (1H, d, J = 6.8 Hz), 8.05 (1H, s), 7
． 71 (1H, s), 7.41 (2H, dd, J ₁ = 8.5Hz, J ₂ = 5.7H
z), 7.14 (2H, t, J = 8.5Hz), 6.46 (2H, s), 4.3
8 (3H, s), 3.78 (2H, t, J = 8.1Hz), 3.04 (2H, J
= 8.1 Hz).

Example 18 1- / 2- (4-Fluorophenyl) ethyl / -2,3-dimethyl-6,7-methylenedioxy-isoquinolinium iodide 3.0 g (0.0097 mol) 1- / 2- (4-fluorophenyl) ethyl / -2
3,3-Dimethyl-6,7-methylenedioxyisoquinoline and 3.2 cm ³ of methyl iodide are dissolved in 25 cm ³ of nitromethane. The reaction mixture is boiled for 1.5 hours, then 1.6 cm ³ of methylene iodide are added and the reaction mixture is boiled for another hour. The reaction mixture is cooled to room temperature, 50 cm ³ of diethyl ether are poured into it, stirred for 2 hours and then filtered. The product is recrystallized from dimethylformamide. In this way 2.19 g (50%) of the title compound is obtained. M. p. : 271-273 ° C. Analysis: C ₂₀ H ₁₉ FINO calculated for _{2 (451.28): C53.23%,} H4.24%, N3.10%; Result: C53.28%, H4.12%, N3.14 %. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.09 (1 H, s), 7.9
2 (1H, s), 7.53 (1H, s), 7.40 (2H, m), 7.13 (2
H, m), 6.40 (2H, s), 4.22 (3H, s), 3.83 (2H, t)
, J = 8.0 Hz), 3.00 (2H, t, J = 8.0 Hz), 2.80 (3H
, S).

[0296]   Example 19   1- (4-fluorostyryl) -6,7-methylenedioxy-1,2,3,4-tetrahi
Droisoquinoline   200 cm³4.4 g (0.015 mol) of 1- (4-fluor in methanol of
Rostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline solution,
1.6 g of sodium tetrahydridoborate are added under stirring in 3 portions
It The reaction mixture was stirred for 2 hours at 25-30 ° C (TLC benzene: methanol.
Le 8: 2, R_f= 0.46 UV), then evaporated to dryness under reduced pressure. In the residue,
150 cm³Water is added and the mixture is extracted three times with dichloromethane. Mixed
The combined organic phases are dried over anhydrous sodium sulphate, evaporated and the residue is treated with diethyl ether.
To crystallize. The product is filtered and recrystallized from ethanol. like this
This gives 2.7 g (82%) of the title compound. M. p. : 112-1
13 ° C. Analysis: C₁₈H₁₆FNO₂About (217.33) Calculation: C72.71%, H5.42%, N4.71%; Results: C72.37%, H5.41%, N4.51%.¹ H-NMR (CDCl₃, 200 MHz) δ: 7.32 (2H, m), 6.96
(2H, m), 6.93 (1H, s), 6.55 (1H, s), 6.53 (1H
, S), 6.47 (1H, d, J = 15.8Hz), 6.18 (1H, dd, J ₁ = 15.8Hz, J₂= 8.0 Hz), 5.8 (2H, s), 4.51 to 4.4
8 (1H, m), 3.24-3.17 (1H, m), 3.02-2.99 (1H,
m), 2.99-2.68 (2H, m).

Example 20 1- / 2- (4-Trifluoromethylphenyl) ethyl / -2-methyl-6,7-methylenedioxyisoquinolinium iodide 5.1 g (0.015 mol) of 1 -/ 2- (4-Trifluoromethylphenyl) ethyl / -2-methyl-6,7-methylenedioxyisoquinoline and 5 cm ³ of methyl iodide were boiled in 25 cm ³ of nitromethane for 30 minutes and the mixture was brought to room temperature. Cool, pour into 250 cm ³ of acetone and stir. The crystalline solid which precipitates is filtered off, washed with cold acetone and the crude isoquinolinium salt is recrystallized from a mixture of hexane and ethanol in the ratio 4: 1. In this way, 5.4 g (
75%) of the title compound is obtained. M. p. : 258-260 ° C. Analysis: C ₂₀ H ₁₇ F ₃ INO calculated for _{2 (487.26): C49.30%,} H3.52%, N2.87%; Result: C48.62%, H3.44%, N2.93 %. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.61 (2 H, d, J = 6.
8 Hz), 8.20 (2H, d, J = 6.8 Hz), 8.05 (2H, s), 7
． 71-7.61 (2H, m), 6.44 (2H, s), 4.43 (3H, s)
3.83 (2H, t, J = 8.0Hz), 3.14 (2H, t, J = 8.0H)
z).

Example 21 1- (4-Trifluoromethylstyryl) -2-methyl-6,7-methylenedioxy-
Isoquinolium iodide 6.8 g (0.02 mol) of 1- (4-trifluoromethylstyryl) -2-methyl-6,7-methylenedioxyisoquinoline were dissolved in 40 cm ³ of dichloromethane and formed. 9.95 g (0.065 mol) of methyl iodide are added to the solution obtained. The reaction mixture is boiled for 1.5 hours, then evaporated to dryness, the residue is stirred with diethyl ether, cooled to 5 ° C., filtered, washed with cold ether and recrystallized from methanol. In this way 5.9 g (61%) of the title compound are obtained. M. p. : 233-235 ° C. Analysis: For C ₂₀ H ₁₅ F ₃ INO ₂ (485.25) Calculation: C 49.51%, H 3.12%, N 2.89% Result: C 49.05%, H 3.18%, N 2.82% ¹ H -NMR (CDCl ₃ , 400 MHz) δ: 8.77 (1H, d, J = 11H)
z), 8.12 (1H, d, J = 11.0Hz), 7.80 (3H, m), 7.
63 (2H, d, J = 13.2Hz), 7.58 (1H, s), 7.44 (1H
, S), 7.31 (1H, m), 6.29 (2H, s), 4.62 (3H, s)
.

Example 22 1- (4-Trifluoromethylstyryl) -2-methyl-6,7-methylenedioxy-
1,2,3,4-Tetrahydroisoquinoline 5.6 g (0.012 mol) of 1- (4-trifluoromethylstyryl) -2-methyl-6,7-methylenedioxyisoquinolinium iodide, Dissolve in 110 cm ³ of methanol and add 0.8 g of sodium tetrahydridoborate in two portions to the solution formed. The solution is stirred for 1 hour and then evaporated under reduced pressure. 100 cm ³ of water are added to the residue, and the mixture is extracted 3 times with 50 cm ³ of dichloromethane each time. The organic phase is dried over anhydrous sodium sulfate,
Then it is evaporated and dried. The residue is recrystallized from ethanol. In this way 2.5 g (57%) of the title compound is obtained. M. p. : 85-88 ° C. Analysis: C ₂₀ H ₁₈ F ₃ INO calculated for _{2 (361.37): C66.48%,} H5.02%, N3.88%; Result: C66.60%, H5.13%, N3.91 %. IR (KBr, cm ^-1 ): 2844, 1166, 1121, 957. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.69 (4 H, m), 6.7
8 (1H, d, J = 8.7 Hz), 6.69 (1H, s), 6.56 (1H, s)
), 6.34 (1H, d, J = 8.7 Hz), 5.93 (2H, m), 3.86.
(1H, m), 3.29 (3H, s), 3.1-2.9 (4H, m).

Example 23 1- (4-Fluorostyryl) -2-methyl-6,7-methylenedioxyisoquinolinium iodide 38.1 g (0.13 mol) of 1- (4-fluorostyryl) -2-methyl-6,7-
Methylenedioxyisoquinoline is dissolved in 200 cm ³ of nitromethane.
To the solution formed is added 98.4 g of methyl iodide. The reaction mixture is 120
Stir at 1.5 ° C. for 1.5 hours. The precipitated crystalline solid is filtered to give 50.9 g of crude product. 12 g of crude product are recrystallized from 70 ml of methanol. In this way 7.4 g (62 title compound is obtained. Mp: 228-23
0 ° C. Analysis: Calculated for C ₁₉ H ₁₅ FINO ₂ (435.25): C52.43%, H3.47%, N3.22%: Results: C52.05%, H3.38%, N3.25%. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.62 (1 H, d, J = 6.
0 Hz), 8.21 (1H, d, J = 6.0 Hz), 7.93 (2H, m), 7
． 80 (1H, s), 7.75 (1H, m), 7.62 (1H, d, J = 12.
4 Hz), 7.38-7.32 (3H, m), 6.44 (2H, s), 4.34
(3H, s).

Example 24 1- (4-Fluorostyryl) -2-methyl-6,7-methylenedioxy-1,2,3,
4-Tetraisoquinolinium chloride 30 g (0.07 mol) of 1- (4-fluorostyryl) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoli Thallium iodide
It is dissolved in 00 cm ³ of methanol and to the solution formed 4.7 g of sodium tetrahydroborate are added in portions at 20 ° C. The solution is stirred at room temperature for 1 hour and then evaporated under reduced pressure. 500 cm ³ of water is added to the residue. The aqueous solution is extracted with a total of 440 cm ³ of dichloromethane. The organic phase is dried over anhydrous sodium sulfate. After addition of 20 cm ³ of ethanol containing hydrogen chloride, the solution is evaporated to dryness. The residue is crystallized from benzene to give 18.7 g of crude product, which is recrystallized from 110 cm ³ of 2-propanol. In this way, 16.
3 g (76%) of the title compound are obtained. M. p. : 210-213 ° C. Analysis: C ₁₉ H ₁₉ IFNO calculated for _{2 (347.33): C65.61%,} H5.51%, N4.03%: Result: C65.68%, H5.59%, N3.98 %. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 12.1 (1H, bs), 7.3
6 (2H, m), 6.98 (2H, m), 6.59-6.52 (3H, m), 6
． 02 (1H, m), 5.85 (2 × 1H, 2 × s), 3.78-3.75 (1
H, m), 3.01-2.4 (4H, m), 3.45 (3H, s).

Example 25 1- (4-trifluoromethylstyryl) -2-ethyl-6,7-methylenedioxy-
Isoquinolinium iodide 2.0 g (5.8 mmol) 1- (4-trifluoromethylstyryl) -2-ethyl-6,7-methylenedioxyquinoline were dissolved in 15 cm ³ nitromethane, Then 4.7 cm ³ of ethyl iodide are added to the solution formed. 1 solution
Stir at 20 ° C. for 4 hours, then evaporate under reduced pressure. The residue is crystallized from diethyl ether and the crude product is recrystallized from acetone. In this way, 1.9 g (
65%) of the title compound is obtained. M. p. : 234-236 ° C. Analysis: C ₂₁ H ₁₇ F ₃ INO calculated for _{2 (499.27): C50.52%,} H3.43%, N2.81%: Result: C50.34%, H3.40%, N2.81 %. IR (KBr, cm ^-1 ): 1439, 1462, 1328. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.68 (1 H, d, J = 6.
9 Hz), 8.28 (1H, d, J = 6.9 Hz), 8.06 (2H, d, J =
8.2 Hz), 7.89 (2H, d, J = 8.2 Hz), 7.86 (1H, d,
J = 16.7 Hz), 7.8 (1H, s), 7.76 (1H, s), 7.40 (
1H, d, J = 16.7 Hz), 6.44 (2H, s), 4.70 (2H, q,
J = 7.2 Hz), 1.49 (3H, t, J = 7.2 Hz).

Example 26 1- (4-Cyanostyryl-2-methyl-6,7,8-trimethoxyisoquinolinium iodide 1.8 g (55 mmol) of 1- (4-cyanostyryl-2- Methyl-6,7,8-trimethoxyisoquinoline is dissolved in 15 cm ³ of nitromethane, 3.7 g of methyl iodide are added to the resulting solution and the reaction mixture is stirred at 120 ° C. for 4 hours. The mixture is evaporated down, the residue is crystallized from diethyl ether, the crystals are dissolved in 40 cm ³ of dichloromethane and the product is precipitated by the addition of 10 ml of cyclohexane, thus 1 g (40%) of the title. .M.p compounds are obtained:.. 130-133 ° C. _{analysis: C 23 H 23 iN 2 O} 3 (502.35) calculated for: N5.58%: result:. N5.38% IR (KB ^{, Cm -1):. 3438,2225,1406 1} H-NMR (DMSO-d 6, 200MHz) δ: 8.15 (1H, s), 8.0
2 (1H, d, J = 16.9Hz), 7.91 (4H, m), 7.45 (1H,
s), 6.95 (1H, d, J = 16.8Hz), 4.14 (3H, s), 4.
06 (3H, s), 3.85 (3H, s), 3.68 (3H, s), 2.80 (3
H, s).

Example 27 1-2- (3,4-Dimethoxyphenyl) ethyl / -2-methyl-6,7-dimethoxyisoquinolinium iodide 7.2 g (0.02 mol) of 1- ( 2- (3,4-dimethoxyphenyl) ethyl /-
6,7-Dimethoxyisoquinoline is dissolved in 60 cm ³ of nitromethane. To the solution formed, 14.2 g of methyl iodide were added and the reaction mixture was added to 12
Stir at 0 ° C. for 4 hours. Then the mixture is cooled and 100 cm ³ of diethyl ether are added to precipitate the crystallized product. The crystals are filtered to give 8.7 g of crude product. 5.7 g of crude product are recrystallized from a mixture of water and ethanol. In this way 4.8 g (71%) of the title compound are obtained. M. p
． 188-190 ° C. Analysis: C ₂₂ H ₂₈ INO calculated for ₅ (513.37): N2.73%: Result: N2.63%.

Example 28 1- / 2- (3,4-Dimethoxyphenyl) ethyl / -6,7-dimethoxyisoquinoline 3.51 g (0.01 mol) of 1- (3,4-dimethoxystyryl) -6 The 7,7-dimethoxyisoquinoline is dissolved in 100 cm ³ of acetic acid. In the solution formed,
0.5 g of Pd / C catalyst are added and the mixture is hydrogenated at room temperature and a pressure of 10 bar until the end of hydrogen gas consumption. Remove the catalyst by filtration,
The filtrate is evaporated under reduced pressure. The residue is dissolved in 50 cm ³ of methanol and the base is prepared by addition of about 50 g of crushed ice and 10 cm ³ of 25% aqueous ammonia. The precipitated crystalline product is filtered and washed with cold water. In this way 1.5 g (43%) of the title compound is obtained. M. p. : 146-
147 ° C. _{Analysis: C 21 H 23 NO 4 (} 353.422) calculated for: C71.37%, H6.56%, N3.96 %: Result: C71.04%, H6.54%, N3.89 %. IR (KBr, cm ^-1 ): 1516, 1234, 1158. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.35 (1 H, d, J = 5.5)
Hz), 7.39 (1H, d, J = 5.5Hz), 7.22 (1H, s), 7.
05 (1H, s), 6.81 (2H, s), 6.74 (1H, s), 4.01 (
3H, s), 3.96 (3H, s). 3.85 (3H, s), 3.80 (3H,
s), 3.48 (2H, t, J = 7.8Hz), 3.15 (2H, t, J = 7.
8 Hz).

[0306]   Example 29   1- / 2- (3,4-dimethoxyphenyl) ethyl / -2-methyl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline fumarate   200 cm³In methanol of 3.0 g (0.006 mol) of 1- / 2- (3,4-
Dimethoxyphenyl) ethyl / -2-methyl-6,7-dimethoxy-1,2,3,4-teto
To a solution of lahydroisoquinolinium iodide, 0.45 g of tetrahydroboric acid
Sodium is added under stirring at room temperature. The reaction mixture was stirred for 2 hours and then reduced.
Evaporate under pressure. 200 cm to the residue³Water is added and the aqueous solution is added 60 cm each time.³The di
Extract 3 times with chloromethane. Combined organic phase over anhydrous sodium sulfate
Dry and evaporate under reduced pressure to give 2 g of crude product, which is 20 cm³Eta
Dissolves in knoll. 40 cm in the formed solution³0.62 in ethanol
Pour a solution of g fumaric acid. The crystalline fumarate that precipitates is filtered and a small amount of cooling air is added.
Wash with Tanol. In this way 1.1 g (34%) of the title compound was obtained.
To be M. p. : 84-85 ° C. IR (KBr, cm^-1): 3430, 2540, 1713, 1518, 1257
.¹ H-NMR (DMSO-d₆, 400 MHz) δ: 6.83 (1H, d, J = 8.
2Hz), 6.76 (1H, d, J = 1.5Hz), 6.69 (1H, dd, J) ₁ = 1.6Hz, J₂= 8.1 Hz), 6.67 (1H, s), 6.65 (1H,
s), 3.72 (3H, s), 3.70 (3H, s), 3.70 (3H, s),
3.49 (1H, m), 3.15 (1H, m), 2.70 (2H, m), 2.6
0 (2H, m), 2.45 (3H, s), 2.44 (1H, m), 2.00 (2
H, m).

Example 30 1- / 2- (4-Trifluoromethylphenyl) ethyl / -4-propyl-6,7-ethylenedioxyisoquinoline 4.8 g (0.012 mol) of 1- (4-tri Fluoromethylstyryl) -4-propyl-6,7-ethylenedioxyisoquinoline was dissolved in 200 cm ³ of acetic acid and the solution was allowed to stand at room temperature and a pressure of 10 bar in the presence of 1 g of Pd / C catalyst. , Add hydrogen until the end of consumption of hydrogen gas. The free base is prepared by filtering off the catalyst, evaporating the filtrate to dryness, dissolving the residue in aqueous methanol and adding concentrated aqueous ammonia. In this way 3.9 g (81%) of the title compound are obtained. M. p. : 89-90 ° C. _{Analysis: C 23 H 22 F 3 NO} 2 (401.432) calculated for: C68.82%, H5.52%, N3.49 %: Result: C68.19%, H5.51%, N3.46 %. IR (KBr, cm ^-1 ): 1512, 1331, 1109, 1069. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 8.11 (1 H, s), 7.54
(2H, d, J = 8.4 Hz), 7.50 (1H, s), 7.41 (1H, s)
, 7.39 (2H, d, J = 6.0 Hz), 4.40 (4H, m), 3.50 (
2H, m), 3.25 (2H, m), 2.88 (2H, t, J = 7.7Hz),
1.75 (2H, hx, J = 7.6Hz), 1.02 (3H, t, J = 7.3H)
z).

Example 31 1- (4-Trifluoromethylstyryl) -4-propyl-6,7-ethylenedioxyisoquinolinium chloride 0.9 g (3.7 mmol) 1-methyl-6, 7-ethylenedioxyisoquinoline, 0.7 g (4.1 mmol) 4-trifluoromethylbenzaldehyde,
And 3 cm ³ of acetic anhydride are stirred at 150-160 ° C. for 3 hours, then the mixture is evaporated under reduced pressure. The 1.3 g of crude product obtained are dissolved in 25 cm ³ of acetone. To the solution formed, 2-propanol containing hydrogen chloride is added, the precipitated hydrochloride salt is filtered and washed with a little cold acetone. In this way 0.6 g (37%) of the title compound is obtained. M. p. : 203-210
° C. _{Analysis: C 23 H 21 ClF 3 NO} 2 (435.87) calculated for: C63.38%, H4.86%, N3.21 %: Result: C63.39%, H4.85%, N3.19 %. IR (KBr, cm ^-1 ): 3420, 2526, 1326, 1067. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.48 (1 H, s), 8.3
2 (1H, d, J = 16.2 Hz), 8.16 (4H, m), 7.86 (2H,
d, J = 8.3 Hz), 7.71 (1H, s), 4.56 (2H, m), 4.5
2 (2H, m), 3.05 (2H, d, t, J = 7.6Hz), 1.70 (2H
, Hx, J = 7.4 Hz), 0.99 (3H, t, J = 7.3 Hz).

Example 32 1- (3,4-Dimethoxystyryl) -6,7-ethylenedioxyisoquinoline 5.9 g (29 mmol) of 1-methyl-6,7-ethylenedioxyisoquinoline, and 5.2 g (31 mmol) 3,4-dimethoxybenzaldehyde was added to 4
Stir in cm ³ acetic anhydride at 160 ° C. for 3 hours. The reaction mixture is evaporated under reduced pressure and the residual oil is purified by column chromatography. The crude product obtained is recrystallized twice from 2-propanol. In this way, 5.1 g (
50%) of the title compound is obtained. M. p. 141-143 ° C. _{Analysis: C 21 H 19 NO 4 (} 349.39) calculated for: C72.19%, H5.48%, N4.01 %: Result: C71.56%, H5.60%, N3.98 %. IR (KBr, cm ^-1 ): 3420, 1505, 1271, 1137. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 8.35 (1 H, d, J = 5.3)
9 Hz), 7.94 (1H, d, J = 15.8 Hz), 7.79 (1H, s),
7.67 (1H, d, J = 15.8Hz), 7.37 (1H, d, J = 5.5H)
z), 7.28 (1H, m), 7.23 (2H, m), 6.91 (1H, d, J
= 8.1 Hz), 4.40 (4H, s), 3.98 (3H, s), 3.93 (3)
H, s).

Example 33 1- (4-Trifluoromethylstyryl) -4-propyl-6,7-methylenedioxyisoquinoline 3.5 g (15 mmol) 1-methyl-4-propyl-6,7-ethylene Dioxyisoquinoline, and 4.0 g (22.6 mmol) of 4-trifluoromethyl-
Benzaldehyde is stirred for 4 hours at 160 ° C. in 35 cm ³ of acetic anhydride. The reaction mixture is evaporated under reduced pressure and the residue is crystallized from diethyl ether. 2.17 g of the crude product obtained are recrystallized from 40 cm ³ of absolute ethanol. In this way 1.6 (28%) of the title compound is obtained. M. p
． 156-158 ° C. _{Analysis: C 22 H 18 F 3 NO} 2 (385.389) calculated for: C68.57%, H4.71%, N3.63 %: Result: C68.43%, H4.76%, N3.55 %. IR (KBr, cm ^-1 ): 1470, 1328, 1234, 1120. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.28 (1 H, s), 7.93
(1H, d, J = 15.6 Hz), 7.83 (1H, d, J = 15.6 Hz),
7.74 (2H, d, J = 8.2Hz), 7.63 (1H, d, J = 8.1Hz)
), 7.60 (1H, s), 7.26 (1H, s), 6.13 (2H, s), 2
． 90 (2H, t, J = 7.6Hz), 1.75 (2H, hx, J = 7.5Hz)
), 1.03 (3H, t, J = 7.4Hz).

Example 34 1- (4-Fluorostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinolinium chloride 12.5 g (0.04 mol) of N- / 2- (3, 4-methylenedioxyphenyl)-
Ethyl / -4-fluorocinnamic amide is dissolved in 100 cm ³ of benzene and 25 ml of phosphorus (V) trichloride oxide are poured into the solution formed. The mixture is boiled for 1.5 hours, then cooled to 10 ° C. and stirred at the latter temperature for 1 hour. The crystalline crude product is filtered, washed with low amount of benzene at 10 ° C. and 400 cm ³ of 2-
Recrystallize from propanol. In this way 7.1 g (53.7%) of compound are obtained. M. p. : 219-221 ° C.

Example 35 1- (4-Trifluoromethylstyryl) -6,7-methylenedioxy-3,4-dihydroisoquinolinium chloride 20 g (0.055 mol) 2- (3,4) -Methylenedioxyphenyl) ethyl-
The N-4-trifluoromethylcinnamic amide is boiled in 70 cm ³ of benzene in the presence of 20 cm ³ of phosphorus (V) trichloride for 3.5 hours. Reaction mixture at 20 ° C.
After cooling to room temperature, the precipitated salt is washed with some hexane and recrystallized from 110 cm ³ of ethanol. In this way 7.2 g (72%) of the title compound are obtained. M. p. : 208-212 ° C. Analysis: Calculated for C ₁₉ H ₁₅ ClF ₃ NO ₂ (381.70): C 59.78%, H 3.96%, Cl 9.29%, N 3.67%: Results: C 59.78%, H 3.94%, Cl 9.32%, N 3.61%.

Example 36 A) 4,6-Dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydroisoquinolinium maleate 3.79 g (10 mmol) of N-cinnamoyl-3,3 3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine was added to 4.46 cm ³ (7.6
7 g, 50 mmol) of phosphorus (V) trichloride oxide at 16 ° C. for 16 hours. The reaction mixture cooled to room temperature is poured onto 40 cm ³ of ice water. The pH is adjusted to 11 by addition of concentrated aqueous ammonia. The solution is extracted 3 times with 30 cm ³ of ethyl acetate each time, the combined organic phases are dried over anhydrous magnesium sulphate and evaporated. The crude base is dissolved in 10 cm ³ of methanol, and to the solution formed is added dropwise 1.16 g (10 mmol) of a solution of maleic acid in 10 cm ³ of methanol, then 40 cm ³ of diisopropyl ether. . The precipitated crystals are filtered and washed with 10 cm ³ of diisopropyl ether. In this way 2.54 g (53%) of the title compound is obtained. M. p. : 149-1
51 ° C (ethanol-diisopropyl ether). _{Analysis: C 24 H 12 F 3 NO} 6 (477.44) calculated for: C60.38%, H4.64%, N2.93 %: Result: C60.50%, H4.56%, N3.03 %. IR (film, cm ⁻¹ ): 1600, 1493, 1252, 1177. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.14 (1 H, d, J = 8.
8 Hz), 7.86 (2H, dd, J = 8.7 Hz, J = 5.7 Hz), 7.5
7 (1H, d, J = 15.8Hz), 7.50-7.40 (3H, m), 7.1
3 (1H, d, J = 3.0 Hz), 6.21 (2H, s), 4.24 (2H, s)
), 3.92 (3H, s), 3.30 (3H, s). B) 4,6-Dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydroisoquinolinium chloride 3.61 g (10 mmol) of crude base was dissolved in 40 cm ³ of diisopropyl ether. , And 12 mol (25.3 g / 100 cm ³ ) in the solution formed.
Of 2-propanol 1.73Cm ³ containing hydrogen chloride are added dropwise. The precipitated crystals are filtered and washed with 10 cm ³ of diisopropyl ether. In this way 2.11 g (53%) of the title compound is obtained. M. p. 188 ° C (ethanol). _{Analysis: C 20 H 19 ClF 3 NO} 2 (397.82) calculated for: C60.38%, H4.81%, Cl8.91 %, N3.54%: Result: C60.24%, H4.84%, Cl 8.92%, N 3.49%. IR (film, cm ^-1 ): 3435, 1508, 1477. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 8.49 (1 H,
d, J = 8.9 Hz), 8.22 (1H, m), 7.88 (2H, dd, J = 7)
． 6 Hz, J = 1.8 Hz), 7.73 (1 H, d, J = 16.1 Hz), 7.
53 (3H, m), 7.35 (1H, dd, J = 8.9Hz, J = 2.6Hz)
, 7.29 (1H, d, J = 2.6 Hz), 6.60 (1H, bs), 4.42
(1H, d, J = 16.0 Hz), 4.26 (1H, d, J = 16.0 Hz),
4.04 (3H, s), 3.42 (3H, s). ¹³ C-NMR (DMSO-d ₆ + CDCl ₃ , 100.6 MHz) 166.9, 16
6.6, 149.6, 135.7, 134.2, 133.7, 132.3, 12
9.8, 129.3, 124.4 (q, ¹ J _CF = 287.5 Hz), 119.0
, 115.9, 115.8, 114.7, 75.0 ( ² J _CF = 28.5 Hz),
55.8, 53.3, 42.2.

Example 37 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-ethylenedioxy
-3,4-Dihydroisoquinolinium bromide 2.33 g (0.0075 mol) of 1- / 2- (4-fluorophenyl) ethyl /-
2-Methyl-6,7-ethylenedioxy-1,2,3,4-tetrahydroisoquinoline is dissolved in 100 cm ³ of dichloromethane. The solution was cooled to 0-5 ° C. and 1.6 g (0.009 mol) of N-bromosuccinimide was added in several portions of 1
Add during 5 minutes. The mixture is stirred at the latter temperature for 1 hour and then at room temperature for 2 hours. The crystals which precipitate are filtered off, the filtrate is evaporated and the residual solid is recrystallised from acetone. In this way 1.76 g (58%) of the title compound is obtained. M. p. 177-180 ° C. Analysis: C ₂₀ H ₂₁ BrFNO calculated for _{2 (406.30): H5.21%,} N3.45%: Result: H5.43%, N3.29%. IR (KBr, cm ^-1 ): 1735, 1301, 1219. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.61 (s, 1H), 7.3
1 (m, 2H), 7.11 (m, 2H), 6.99 (s, 1H), 4.35 (m
4H), 3.95 (m, 2H), 3.66 (s, 3H), 3.47 (m, 2H).
), 2.94 (m, 4H).

Example 38 1- / 2- (4-trifluoromethylphenyl) ethyl / -2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolinium iodide 2.8 g (0 .0075 mol) of 1- / 2- (4-trifluoromethylphenyl)
Ethyl-2-methyl-6,7-ethylene-dioxy-3,4-dihydroisoquinoline is dissolved in 120 cm ³ of acetone. The solution formed, adding methyl iodide 5 cm ^3. The mixture is boiled for 1 hour, then cooled to 0-5 ° C with ice water and stirred at this temperature for 2-3 hours. After crystallization, the crystals are filtered, washed with cold acetone and recrystallized from acetone. In this way, 2.2 g (58%)
The compound of the title is obtained. M. p. : 205-207 ° C. Analysis: C ₂₁ H ₂₁ F ₃ INO calculated for _{2 (503.30): C50.12%,} H4.21%, N2.78%: Result: C49.10%, H4.11%, N2.71 %. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.56 (2H, d, J = 8.2)
Hz), 7.37 (2H, d, J = 8.2Hz), 7.18 (1H, s), 6.
78 (1H, s), 4.36 (2H, m), 4.27 (2H, m), 4.12 (
2H, t, J = 7.6 Hz), 3.90 (3H, s), 3.53 (2H, t, J)
= 7.6 Hz), 3.18 (4H, m).

Example 39 6,7-Ethylenedioxy-1- / 2- (4-trifluoromethylphenyl) ethyl /
-3,4-Dihydroisoquinoline 14.2 g (0.037 mol) of 2- (3,4-ethylenedioxyphenyl) -ethyl-N-3- (4-trifluoromethylphenyl) propionylamide was added to 80c.
Dissolves in m ³ of toluene. To the resulting solution, 12 cm ³ of phosphorus (V) trichloride oxide are added dropwise, the reaction mixture is heated to 80 ° C. and stirred at this temperature for 2.5 hours. The crystalline dihydroquinoline that precipitates is filtered and recrystallized from ethanol. The product obtained (12 g) is dissolved in 90 cm ³ of methanol, made alkaline to pH 9 by the addition of 20% aqueous sodium hydroxide solution, the substance which precipitates is filtered off and washed with aqueous methanol (5: 1). , And recrystallize from a mixture of ethanol and water. In this way 1.44 g (41%) of the title compound are obtained. M. p. : 85 ° C. _{Analysis: C 20 H 18 NO 2 (} 361.37) calculated for: C66.48%, H5.02%, N3.88 %: Result: C66.34%, H5.04%, N3.90 %. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.61 (2 H, d, J = 8.
0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.10 (1H, s), 6
． 74 (1H, s), 4.24 (4H, m), 3.48 (2H, t, J = 7.4)
Hz), 2.96 (4H, m), 2.47 (2H, t, J = 7.1Hz).

Example 40 7-Chloro-1-/-2- (4-trifluoromethylphenyl) ethyl / -3,4-dihydroisoquinoline hydrochloride 10.0 g (0.028 mol) of N- / 2- ( 4-chlorophenyl) ethyl / 3- (
4-Trifluoromethylphenyl) propionylamide is dissolved in 80 cm ³ of xylene. To the stirred mixture is added 12 g of phosphorus (V) oxide and the reaction mixture is stirred at 110-120 ° C for 5 hours. The mixture is cooled to room temperature and xylene is decanted from the precipitated solid. 100 cm ³
Of methanol are added, the crystals are filtered, the pH is adjusted to 8 by addition of concentrated ammonium hydroxide, then 150 cm ³ of water are added and the methanol is distilled off. The aqueous phase is extracted with dichloromethane ⁽³ × 50cm 3). The combined organic phases are dried over anhydrous sodium sulphate and evaporated to dryness. 10.6
g of oily base is obtained, which is purified by column chromatography using a mixture of toluene and methanol in the ratio 8: 2. 1. of the bases obtained
A 4 g portion is converted to an acid addition salt in a mixture of 10 cm ³ of ethyl acetate and 5 cm ³ of ether using isopropanol containing hydrogen chloride. The salts are filtered and washed with low amount of cold ether. In this way, 1.35 g (87
%) Of the title compound is obtained. M. p. 173-175 ° C. _{Analysis: C 18 H 16 Cl 2 F} 3 calculated for N (374.23): C57.77%, H4.31%, N3.74%, Cl18.95%: Result: C57.30%, H4.30% , N 3.69%, Cl 18.80% :. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 15.81 (1 H, bs), 7.
67 (1H, d, J = 7.6 Hz), 7.65 (1H, s), 7.53 (2H,
d, J = 8.1 Hz), 7.43 (2H, d, J = 8.1 Hz), 7.37 (1
H, d, J = 8.3 Hz), 3.94 (2H, t, J = 7.6 Hz), 3.68
(2H, t, J = 7.6Hz), 3.26 (2H, t, J = 8.0Hz), 3.
01 (2H, t, J = 8.0 Hz).

Example 41 1- (4-Fluorostyryl) -4-methyl-6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride 3.27 g (0.01 mol) in 50 cm ³ of anhydrous toluene. ) N- / 2-methyl-
To a solution of 2- (3,4-methylenedioxyphenyl) ethyl / -4-fluorocinnamic amide was added 4.66 g (0.05 mol) of phosphorus (V) trichloride oxide with stirring,
The reaction mixture is then heated to 120 ° C. under argon pressure until the end of the reaction until the end of the reaction. Then 50 cm ³ of methanol was added drop by drop to the warmed solution,
Then the mixture is evaporated. The residue is dissolved in methanol and then evaporated again.
This procedure is repeated 5-6 times and then a solution of the product in methanol is poured onto the ion exchange Amberlite 46 resin. The solution is evaporated and diethyl ether is added. The precipitated crystals are filtered. In this way 2.38 g (69%) of the title compound are obtained. M. p. : Decomposes above 200 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 14.02 (1H
, Bs), 8.44 (1H, d, J = 16.1 Hz), 7.85 (2H, m),
7.51 (1H, s), 7.43 (1H, d, J = 16.1Hz), 7.15 (
2H, m), 6.97 (1H, s), 6.20 (2H, s), 3.89 (1H,
ddd, J ₁ = 14.5 Hz, J ₂ = 5.5 Hz, J ₃ = 3.50 Hz), 3.7
1 (1H, ddd, J ₁ = 14.5 Hz, J ₂ = 7.2 Hz, J ₃ = 4.1 Hz)
3.19 (1H, hx, J = 8.9 Hz), 1.32 (3H, d, J = 7.1)
Hz).

[0319]   Example 42   1- (4-fluorostyryl) -6,7-methylenedioxy-4-propyl-3,4-di
Hydroisoquinoline hydrochloride   Following the procedure described in Example 41, the title compound is obtained. yield
74%. M. p. : 184-185 ° C¹ H-NMR (CDCl₃, 400 MHz) δ: 14.24 (1H, bs), 8.
42 (1H, d, J = 16.1Hz), 7.79 (2H, m), 7.35 (1H
, D, J = 16.0 Hz), 7.32 (1H, s), 7.14 (2H, m), 6
． 87 (1H, s), 6.17 (2H, s), 4.04 (1H, ddd, J₁=
14.8Hz, J₂= 5.5 Hz, J₃= 1 Hz), 3.78 (1H, ddd, J ₁ = 14.8 Hz, J₂= 3.6 Hz, J₃= 2.6 Hz), 2.94 (1H, m
), 1.25-1.60 (4H, m), 0.93 (3H, t, J = 7.6Hz)
.

Example 43 4-Butyl-1- (4-fluorostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride The title compound was obtained according to the procedure described in Example 41. To be Yield 67%. M. p. : 163-166 ° C ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 13.98 (1H
, Bs), 7.50 (1H, s), 8.45 (1H, d, J = 15.8 Hz),
7.85 (2H, m), 7.42 (1H, d, J = 15.8Hz), 7.15 (
2H, m), 6.91 (1H, s), 6.20 (2H, s), 4.00 (1H,
dd, J ₁ = 14.8 Hz, J ₂ = 5.3 Hz), 3.79 ( ₁ H, dd, J ₁ =
14.8 Hz, J ₂ = 3.3 Hz), 2.95 (1 H, m), 1.25-1.60
(6H, m), 0.90 (3H, t, J = 7.6Hz).

Example 44 4-Ethyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl)-
3,4-Dihydroisoquinoline Hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 60%. M. p. : 162-165 ° C ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 14.10 (1H
, Bs), 8.47 (1H, d, J = 16.1 Hz), 7.98 (2H, d, J)
= 14.7 Hz), 7.70 (2H, d, J = 14.7 Hz), 7.62 (1H)
, D, J = 16.1 Hz), 7.58 (1H, s), 6.94 (1H, s), 6
． 20 (2H, s), 4.05 (1H, brdd, J ₁ = 14.9 Hz, J ₂ = 5
． 5 Hz), 3.83 ( ₁ H, d, J ₁ = 14.9 Hz, J ₂ = 3.50 Hz),
2.93 (1H, m), 1.63 (2H, m), 1.01 (3H, t, J = 7.
6 Hz).

[0322]   Example 45   4-Butyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl)-
3,4-dihydroisoquinoline hydrochloride   Following the procedure described in Example 41, the title compound is obtained. yield
71%. M. p. : 191-193 ° C¹ H-NMR (DMSO-d₆+ CDCl₃, 400 MHz) δ: 14.10 (1H
, Bs), 8.50 (1H, d, J = 16.2 Hz), 7.95 (2H, d, J
= 8.1 Hz), 7.70 (2H, d, J = 8.1 Hz), 7.59 (1H, d
, J = 16.2 Hz), 7.50 (1H, s), 6.91 (1H, s), 6.2
0 (2H, s), 4.04 (1H, ddd, J₁= 15.0Hz, J₂= 5.5H
z, J₃=> 1 Hz) 3.82 (1H, ddd, J₁= 15.0Hz, J ₂ = 3.5Hz, J₂= 3.4 Hz), 2.97 (1H, m), 1.2 + 1.60
(6H, m), 0.9 (3H, t, J = 7.6Hz).

Example 46 6,7-Methylenedioxy-1- (4-methoxystyryl) -4-propyl-3,4-dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound was obtained. To be Yield 63%. M. p. : 200-202 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 14.02 (1 H, bs), 8.
47 (1H, d, J = 16.0Hz), 7.74 (2H, m), 7.32 (1H
, S), 7.25 (1H, d, J = 16.0 Hz), 6.95 (2H, m), 6
． 84 (1H, s), 6.16 (2H, s), 4.01 (1H, ddd, J ₁ =
14.8 Hz, J ₂ = 5.3 Hz, J ₃ = 2.6 Hz), 3.87 (3H, s),
_{3.75 (1H, ddd, J 1} = 14.8Hz, J 2 = 3.6Hz, J 2 = 4.9
Hz), 2.91 (1H, m), 1.25 + 1.60 (4H, m), 0.92 (
3H, t, J = 7.6 Hz).

Example 47 6,7-Methylenedioxy-4-propyl-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline hydrochloride The title compound was prepared according to the procedure described in Example 41. Is obtained. Yield 70%. M. p. : 201-204 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 14.53 (1 H, bs), 8.
45 (1H, d, J = 16.1Hz), 7.88 (2H, d, J = 8.0Hz)
, 7.69 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 16.1)
． Hz), 7.32 (1H, s), 6.88 (1H, s), 6.18 (2H, s)
), 4.05 (1H, dd, J ₁ = 15.0 Hz, J ₂ = 3.6 Hz), 3.81
(1H, dd, J = 15.0Hz , J 3,4 = 5.6Hz), 2.96 (1H, m
), 1.25 + 1.60 (4H, m), 0.93 (3H, t, J = 7.6Hz)
.

Example 48 4-Methyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. To be Yield 66%. M. p. : 227-230 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 14.08 (1 H, bs), 8.
47 (1H, d, J = 16.0Hz), 7.74 (2H, m), 7.33 (1H
, S), 7.25 (1H, d, J = 16.0 Hz), 6.95 (2H, m), 6
． 90 (1H, s), 6.16 (2H, s), 3.88 (1H, dd, J ₁ = 1)
4.6 Hz, J ₂ = 7.6 Hz, J ₃ = 4.0 Hz), 3.87 (3H, s), 3
． 68 (1H, dd, J = 14.6Hz, J 2 = 5.5Hz, J 3 = 3.6Hz)
3.12 (1H, m), 1.30 (3H, t, J = 7.0Hz).

Example 49 4-Butyl-1- (3,4-dimethoxystyryl) -6,7-methylenedioxy-3,4
-Dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 58%. M. p. : 206-208 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.98 (1 H, bs), 8.
40 (1H, d, J = 16.0 Hz), 7.39 (1H, dd, J ₁ = 8.3H)
z, J ₂ = 2.0 Hz), 7.36 (1H, s), 7.33 (1H, d, J = 1)
6.0 Hz), 7.30 (1H, d, J = 2.0 Hz), 6.91 (1H, d, J
= 8.3 Hz), 6.85 (1H, s), 6.17 (2H, s), 3.99 (1)
H, dd, J ₁ = 15.0 Hz, J ₂ = 5.4 Hz, J ₃ = 2.4 Hz), 3.9
8 (3H, s), 3.95 (3H, s), 3.75 (1H, J ₁ = 15.0Hz
, J ₂ = 3.9 Hz, J ₃ = 4.6 Hz), 2.88 (1 H, m), 1.20 + 1
． 60 (6H, m), 0.89 (3H, t, J = 7.6Hz).

Example 50 4-Ethyl-1- (4-fluorostyryl-6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride) Following the procedure described in Example 41, the title compound is obtained. Yield 79% Mp: 186-188 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.72 (1H, bs), 8.
40 (1H, d, J = 16.0Hz), 7.88 (2H, m), 7.60 (1H
, S), 7.46 (1H, d, J = 16.0 Hz), 7.17 (2H, m), 6
． 95 (1H, s), 6.21 (2H, s), 4.01 (1H, dd, J ₁ = 1
4.8 Hz, J ₂ = 5.54 Hz, 3.80 ( ₁ H, dd, J ₁ = 14.8 Hz)
, J ₂ = 3.3 Hz), 2.92 (1 H, m), 1.62 (2 H, m), 1.00
(3H, t, J = 7.6Hz).

Example 51 4-Ethyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride The title compound was obtained according to the procedure described in Example 41. To be Yield 61%. M. p. 182-185 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.89 (1 H, bs), 7.
33 (1H, s), 8.44 (1H, d, J = 15.8Hz), 7.75 (2H
, M), 7.25 (1H, d, J = 15.8 Hz), 6.95 (2H, m), 6
． 87 (1H, s), 6.16 (2H, s), 4.03 (1H, m), 3.87
(3H, s), 3.76 (1H, m), 2.82 (1H, m), 1.63 (2H
), 1.00 (3H, t, J = 7.6Hz).

Example 52 1- (4-Fluorostyryl) -4-hexyl-6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. To be Yield 71%. M. p. 158-160 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 14.18 (1H
, Bs), 8.43 (1H, d, J = 16.2 Hz), 7.82 (2H, m),
7.40 (1H, s), 7.38 (1H, d, J = 16.2 Hz), 7.14 (
2H, m), 6.88 (1H, s), 6.19 (2H, s), 4.00 (1H,
brdd, J ₁ = 1.8 Hz, J ₂ = 5.5 Hz), 3.79 (1H, brdd,
J ₁ = 14.8 Hz, J ₂ = 3.5 Hz), 2.94 (1H, m), 1.20 + 1
． 60 (10H, m), 0.87 (3H, t, J = 7.6Hz).

Example 53 4-Hexyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline hydrochloride The title compound was prepared according to the procedure described in Example 41. Is obtained. Yield 80%. M. p. 171-173 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 14.46 (1H
, Bs), 8.48 (1H, d, J = 16.2 Hz), 7.92 (2H, d, J
= 8.0 Hz), 7.70 (2H, d, J = 8.0 Hz), 7.55 (1H, d
, J = 16.2 Hz), 7.40 (1H, s), 6.89 (1H, s), 6.2
0 (2H, s), 4.04 (1H, brdd, J ₁ = 14.9 Hz, J ₂ = 3.8)
Hz), 3.82 (1H, brdd, J ₁ = 14.9 Hz, J ₂ = 5.5 Hz),
2.95 (1H, m), 1.20 + 1.66 (10H, m), 0.88 (3H,
t, J = 7.6 Hz).

Example 54 4-Hexyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. To be Yield 74%. M. p. 129-131 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 14.02 (1 H, bs), 8.
47 (1H, d, J = 15.7Hz), 7.32 (1H, s), 7.75 (2H)
, D, J = 8.0 Hz), 7.25 (1H, d, J = 15.7 Hz), 6.95
(2H, d, J = 8.0 Hz), 6.84 (1H, s), 6.16 (2H, s)
3.87 (3H, s), 3.99 (1H, s), 3.75 (1H, m), 2.
88 (1H, m), 1.20 + 1.60 (10H, m), 0.88 (3H, t,
J = 7.6 Hz).

Example 55 4-Butyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. To be Yield 67%. M. p. : 140-142 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.95 (1 H, bs), 8.
45 (1H, d, J = 15.8Hz), 7.74 (2H, d, J = 8.0Hz)
, 7.32 (1H, s), 7.25 (1H, d, J = 15.8 Hz), 6.95
(2H, d, J = 8.0 Hz), 6.85 (1H, s), 6.16 (2H, s)
3.87 (3H, s), 4.00 (1H, brdd, J ₁ = 14.8Hz, J ₂ = 3.8Hz), 3.76 (1H, brdd, J ₁ = 14.8Hz, J ₂ = 5.2
Hz), 2.89 (1H, m), 1.20 + 1.60 (6H, m), 0.89 (
3H, t, J = 7.6 Hz).

Example 56 1- (3,4-dimethoxystyryl) -4-hexyl-6,7-methylenedioxy-3,
4-Dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 81%. M. p. 183-185 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 13.25 (1H
, Bs), 8.37 (1H, d, J = 15.8 Hz), 7.71 (1H, s),
7.45 (1H, d, J = 2.0Hz), 7.43 (1H, d, J = 15.8H)
z), 7.41 (1H, dd, J ₁ = 8.2 Hz, J ₂ = 2.0 Hz), 6.96
(1H, d, J = 8.2 Hz), 6.93 (1H, s), 6.22 (1H, d,
J = 1.0 Hz), 6.21 (1H, d, J = 1.0 Hz), 3.96 (3H,
s), 3.94 (3H, s), 3.94 (1H, dd, J ₁ = 14.9Hz, J ₂ = 3.3Hz), 3.76 (1H, dd, J ₁ = 14.9Hz, J ₂ = 3.3Hz
), 3.76 ( ₁ H, dd, J ₁ = 14.9 Hz, J ₂ = 5.5 Hz), 2.98
(1H, m), 1.20-1.60 (10H, m), 0.87 (3H, t, J =
7.6 Hz).

Example 57 1- (3,4-dimethoxystyryl) -6,7-methylenedioxy-4-propyl-3,
4-Dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 70%. M. p. : 212-215 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 12.86 (1 H, s), 8.2
5 (1H, d, J = 15.8Hz), 7.89 (1H, s), 7.56 (1H,
d, J = 2.0 Hz), 7.52 (1H, d, J = 15.8 Hz), 7.38 (
_{1H, dd, J 1 = 16Hz} , J 2 = 6.0Hz), 7.08 (1H, s), 7.
04 (1H, d, J = 8.2 Hz), 6.25 (1H, s), 6.24 (1H,
s), 3.92 (3H, s), 3.89 (3H, s), 3.86 (1H, brd)
d, J ₁ = 14.8 Hz, J ₂ = 5.3 Hz), 3.77 (1H, brdd, J ₁
= 14.8 Hz, J ₂ = 2.8 Hz), 3.06 (1H, m), 1.25 + 1.5
5 (4H, m), 0.9 (3H, t, J = 7.6Hz).

Example 58 1- (3,4-Dimethoxystyryl) -4-ethyl-6,7-methylenedioxy-3,4
-Dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 77%. M. p. : 209-211 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.87 (1 H, bs), 8.
37 (1H, d, J = 15.9Hz), 7.39 (1H, dd, J ₁ = 8.3H)
z, J ₂ = 2.0 Hz), 7.38 (1H, s), 7.33 (1H, d, J = 1)
5.9 Hz), 7.30 (1H, d, J = 2.0 Hz), 6.91 (1H, d,
J = 8.3 Hz), 6.86 (1H, s), 6.17 (2H, s), 4.02 (
1H, ddd, J ₁ = 15.0 Hz, J ₂ = 5.4 Hz), J ₃ = 2.3 Hz),
3.98 (3H, s), 3.95 (3H, s), 3.75 (1H, ddd, J ₁
= 15.0 Hz, J ₂ = 4.2 Hz, J ₃ = 4.2 Hz), 2.82 (1H, m)
, 1.61 (2H, m), 1.00 (3H, t, J = 7.6Hz).

Example 59 1- (3,4-dimethoxystyryl) -4-methyl-6,7-methylenedioxy-3,4
-Dihydroisoquinoline hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 63%. M. p. : 201-203 ° C. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 13.91 (1 H, bs), 8.
37 (1H, d, J = 15.8Hz), 7.39 (1H, dd, J = 8.4Hz)
, J = 2.0 Hz), 7.38 (1H, s), 7.32 (1H, d, J = 15.
8Hz), 7.30 (1H, d, J = 2.0Hz), 6.91 (1H, d, J =
8.4 Hz), 6.91 (1H, s), 6.16 (2H, s), 3.98 (3H)
, S), 3.95 (3H, s), 3.87 (1H, ddd, J ₁ = 14.8 Hz
, J ₂ = 7.5 Hz, J ₃ = 2.5 Hz), 3.67 (1H, ddd, J ₁ = 14.
8 Hz, J ₂ = 5.2 Hz, J ₃ = 1.8 Hz), 3.12 (1 H, m), 1.3
0 (3H, d, J = 7.0 Hz).

Example 60 4-Methyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl)-
3,4-Dihydroisoquinoline Hydrochloride Following the procedure described in Example 41, the title compound is obtained. Yield 61%. M. p. : 216-218 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 14.18 (1H
, Bs), 8.48 (1H, d, J = 16.0 Hz), 7.98 (2H, s),
7.70 (2H, s), 7.63 (1H, d, J = 16.0 Hz), 7.59 (
1H, s), 6.99 (1H, s), 6.21 (2H, s), 3.93 (1H,
dd, J ₁ = 14.6 Hz, J ₂ = 5.7 Hz), 3.74 (1H, dd, J ₁ =
14.6 Hz, J ₂ = 5.2 Hz), 3.22 (1H, m), 1.34 (3H,
d, J = 7.0 Hz).

Example 61 1- (4-Fluorostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride 12.5 g N- / 2- (3,4-methylenedioxyphenyl) Ethyl / -4-fluorocinnamic amide was dissolved in 100 cm ³ of benzene and to the resulting solution,
Pour 25 cm ³ of phosphorus (V) trichloride oxide. The reaction mixture is boiled for 1.5 hours, then cooled to 10 ° C. and stirred at this temperature for 1 hour. The crystalline crude product is filtered, washed with a little benzene cooled to 10 ° C. and recrystallized from 400 cm ³ of 2-propanol. In this way 7.1 g (53.7%) of compound are obtained. M. p. : 219-221 ° C. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 12.55 (1 H, bs), 8
． 3 (1H, d, J = 16.1Hz), 7.96 (2H, m), 7.87 (1H
, S), 7.60 (1H, d, J = 16.1 Hz), 7.37 (2H, t, J =
9 Hz), 7.17 (1H, s), 6.25 (2H, s), 3.79 (2H, t)
, J = 8.0 Hz), 3.04 (2H, t, J = 8.0 Hz).

[0339]   Example 62   1- (4-trifluoromethylstyryl) -6,7-methylenedioxy-3,4-dihi
Droisoquinoline hydrochloride   20 g (0.055 mol) of 2- (3,4-methylenedioxyphenyl) ethyl-
20 cm of N- (4-trifluoromethyl) cinnamic amide³Phosphorus (V) trichloride oxidation
3.5 hours in the presence of objects, 70 cm³Boil in benzene. 2 reaction mixtures
Cool to 0 ° C., wash the precipitated salt with some hexane and 100 cm ³ Recrystallize from ethanol. Thus, 7.2 g (72%) of the title
The compound of M. p. : 208-212 ° C. Analysis: C₁₉H₁₅ClF₃NO₂About (381.70) Calculation: C59.78%, H3.96%, Cl9.29%, N3.67%: Results: C 59.74%, H 3.94%, Cl 9.22%, N 3.61%.¹ H-NMR (DMSO-d₆, 200 MHz) δ: 12.56 (1H, bs), 8
． 23 (1H, d, J = 16.1Hz), 8.09 (2H, d, J = 8.1Hz)
), 7.89 (1H, s), 7.88 (2H, d, J = 8.1 Hz), 7.78
(1H, d, J = 16.1 Hz), 7.2 (1H, s), 6.26 (2H, s)
3.82 (2H, t, J = 8.1Hz), 3.09 (2H, d, J = 8.1H)
z).

Example 63 6,7-Ethylenedioxy-1- / 2- (4-trifluoromethylphenyl) ethyl /
-4-Propyl-3,4-dihydroisoquinoline oxalate 7.5 g (0.017 mol) of N- / 2- (3, in 100 cm ³ of anhydrous benzene.
To a solution of 4-methylenedioxyphenyl) ethyl / 3- (4-trifluoromethylphenyl) propionylamide is added 6 cm ³ of phosphorus (V) trichloride oxide.
The reaction mixture is boiled for 3 hours and then evaporated under reduced pressure. 3 × 75 cm ³ from the residue
Of methanol and 75 cm ³ of benzene are distilled off. 20 crude product
Dissolve in 0 cm ³ of dichloromethane and add crushed ice and 20% aqueous sodium hydroxide solution to the resulting solution under thorough stirring until the pH value of the aqueous phase remains at 10-11. After stirring for 30 minutes, the phases are separated. The aqueous phase is extracted twice with 80 cm ³ of dichloromethane each time. The combined organic phases are dried over anhydrous sodium sulphate and evaporated to dryness. The residual crude product is purified by column chromatography to give 4.8 g of base, which is converted to the oxalate salt in anhydrous diethyl ether. In this way 5.7 g (69%) of the title compound is obtained. M. p. : 122-125 ° C. ¹ H-NMR (DMSO-d ₆ + CDCl ₃ , 400 MHz) δ: 7.63 (2H,
d, J = 8.1 Hz), 7.54 (1H, s), 7.45 (2H, d, J = 8.
1 Hz), 6.88 (1H, s), 4.37 (2H, m), 4.30 (2H, m)
) 3.69 (1H, dd, J ₁ = 3.1 Hz, J ₂ = 15.4 Hz), 3.58
(1H, dd, J ₁ = 5.3Hz, J ₂ = 14.9Hz), 3.43 (1H, m)
3.14 (2H, m), 3.01 (1H, m), 2.75 (1H, m), 1.
23 (1H, m), 1.11 (3H, m), 0.79 (3H, t, J = 6.6H
z). IR (KBr, cm ^-1 ): 3420, 2700, 1750, 1648, 1328
.

Example 64 6,7-Ethylenedioxy-1-/ (4-trifluoromethyl) styryl / -4-propyl-2-3,4-dihydroisoquinoline oxalate 6.6 in 70 cm ³ of anhydrous benzene. 8 g (0.016 mol) of N- / 2-propyl
- a (3,4-ethylenedioxyphenyl) solution of ethyl / -4-trifluoromethyl cinnamic amide is added in 6 cm ³ phosphorus (V) trichloride oxide. The reaction mixture is boiled for 2 hours and then evaporated. 3 × 60 cm ³ of methanol are distilled off from the residue, 100 cm ³ of ether are added, the mixture is stirred and boiled for 15 minutes, then the ether is decanted off and the procedure is repeated twice. The crude product obtained is dissolved in dichloromethane and the pH is adjusted to 11 by addition of 20% aqueous sodium hydroxide solution under stirring. The separated aqueous phase is extracted twice with dichloromethane using 50 cm ³ of dichloromethane each time. The combined organic phase was dried over anhydrous sodium sulfate and evaporated to 2.9 g (45
%) Oily product. The crude product is dissolved in anhydrous ether and an equimolar amount of oxaloacetic anhydride is added to the solution. The crystalline salt is filtered. In this way, 3
． 22 g (41%) of the title compound are obtained. M. p. : 140-143 ° C.

Example 65 7-Hydroxy-1- / 2- (4-trifluoromethylphenyl) ethyl / -6-methoxy-3,4-dihydroisoquinoline 30 g (0.082 mol) in 250 cm ³ of concentrated hydrochloric acid. A solution of 1- / 2- (4-trifluoromethylphenyl) ethyl / -6,7-dimethoxy-3,4-dihydroisoquinoline in 50 ° C. on an oil bath at 120 ° C. under a stream of nitrogen for 50 h. . The solution is cooled in ice water, the crystalline material is filtered off and then dissolved in 300 cm ³ of methanol.
The base is liberated by the addition of 100 cm ³ of concentrated aqueous ammonia. The solvent is decanted from the sticky substance that is precipitated. The residue is recrystallized from acetonitrile. In this way 11.7 g (33%) of the title compound is obtained. M. p. 129-132 ° C.

Example 66 1- (2-Phenylethyl) -6,7-methylenedioxy-3,4-dihydroisoquinoline 10 g (0.0033 mol) N- / 2- (in 70 cm ³ of anhydrous benzene. 3,4-
Methylenedioxyphenyl) ethyl / -3-phenylpropylamide and 30c
A solution of phosphorus (V) trichloride oxide in m ³ is boiled for 1.5 hours, then cooled to 50 ° C. and the precipitated crystals are filtered. 200 ml of water and 200 cm ³ of crude hydrochloride
Dissolve m ³ in a mixture with methanol and adjust the pH value of the solution to 13 by adding 20% aqueous sodium hydroxide solution. The white crystalline salt which precipitates is filtered, washed with cold water, dried and recrystallized from a mixture of ethanol and water. In this way 5.3 g (58%) of the title compound is obtained. M. p. : 112
-115 ° C.

[0344]   Example 67   A) 4,6-dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydro
Isoquinolinium maleic acid   3.79 g (10 mmol) of N-cinnamoyl-3,3,3-trifluoro-2-
Methoxy-2- (3-methoxyphenyl) propylamine and 4.46 cm³(7
． 67 g, 50 mmol) of phosphorus (V) trichloride oxide at 85 ° C.
Stir for hours. 40 cm of the reaction mixture cooled to room temperature³Pouring on ice water. Concentrated
The pH is adjusted to 11 by the addition of aqueous ammonia. Mix each 30 cm³
Extract 3 times with ethyl acetate. Combined organic phase over anhydrous magnesium sulfate
Dry and evaporate. 10 cm of crude base³Dissolved in methanol, and
10 cm in the resulting solution³1.16 g (10 mol) of Murray in methanol
Acid solution, then 40 cm³Add diisopropyl ether drop by drop
. The precipitated crystals are filtered, 10 cm³Wash with diisopropyl ether.
In this way 2.54 g (53%) of the title compound is obtained. M. p. :
149-151 ° C (ethanol-diisopropyl ether). Analysis: C_{twenty four}H₁₂F₃NO₆About (477.44) Calculation: C60.38%, H4.64%, N2.93%: Results: C60.50%, H4.56%, N3.03%. IR (film, cm^-1): 1600, 1493, 1252, 1177.¹ H-NMR (DMSO-d₆, 400 MHz) δ: 8.14 (1H, d, J = 8.
8 Hz), 7.86 (2H, dd, J = 8.7 Hz, J = 5.7 Hz), 7.5
7 (1H, d, J = 15.8Hz), 7.50-7.40 (3H, m), 7.1
3 (1H, d, J = 3.0 Hz), 6.21 (2H, s), 4.24 (2H, s)
), 3.92 (3H, s), 3.30 (3H, s).   B) 4,6-dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydro
Isoquinolinium chloride   3.61 g of crude base, 40 cm³Dissolved in diisopropyl ether of
Come on, 25.3g / 100cm³1.73 cm containing hydrogen chloride (12 mol) ³ Isopropanol is added drop by drop. The precipitated crystals are filtered, 10 cm³ Wash with diisopropyl ether. In this way, 2.11 g (53%)
The compound of the title is obtained. M. p. 188 ° C (ethanol). Analysis: C₂₀H₁₉ClF₃NO₂About (397.82) Calculation: C60.38%, H4.81%, Cl8.91%, N3.54%: Results: C60.24%, H4.84%, Cl8.92%, N3.49%. IR (film, cm^-1): 3435, 1508, 1477.¹ H-NMR (DMSO-d₆+ CDCl₃, 400 MHz) δ: 8.49 (1H,
d, J = 8.9 Hz), 8.22 (1H, m), 7.88 (2H, dd, J = 7)
． 6 Hz, J = 1.8 Hz), 7.73 (1 H, d, J = 16.1 Hz), 7.
53 (3H, m), 7.35 (1H, dd, J = 8.9Hz, J = 2.6Hz)
, 7.29 (1H, d, J = 2.6 Hz), 6.60 (1H, bs), 4.42
(1H, d, J = 16.0 Hz), 4.26 (1H, d, J = 16.0 Hz),
4.04 (3H, s), 3.42 (3H, s).¹³ C-NMR (DMSO-d₆+ CDCl₃100.6 MHz) δ: 166.9,
166.6, 149.6, 135.7, 134.2, 133.7, 132.3,
129.8, 129.3, 124.4 (q,¹J_CF= 287.5 Hz), 119
． 0, 115.9, 115.8, 114.7, 75.0 (q,²J_CF= 28.5
Hz), 55.8, 53.3, 42.2.

[0345]   Example 68   A) 1- (4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-
3,4-dihydroisoquinolinium maleate   3.97 g (10 mmol) of N- (4-fluorocinnamoyl) -3,3,3-to
3. Fluoro-2-methoxy-2- (3-methoxyphenyl) propylamine
46 cm³(7.67 g, 50 mmol) phosphorus (V) trichloride oxide and Example 6
React in the manner described in Section 7, Section A. The resulting crude base is hexa
Recrystallize from Thus, 2.54 g (67%) of dark brown 1- (
4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-3,4-dihi
A droisoquinoline compound is obtained. M. p. : 92-93 ° C (hexane). Analysis: C₂₀H₁₇F_FourNO₂About (379.35) Calculation: C63.32%, H4.52%, N3.69%: Results: C63.05%, H4.48%, N3.61%. IR (KBr, cm^-1): 2959, 1646, 1510, 1180.¹ H-NMR (DMSO-d₆, 400 MHz) δ: 7.70 (1H, d, J = 8.
6Hz), 7.53 (2H, m), 7.42 (1H, d, J = 15.9Hz),
7.24 (1H, d, J = 2.6Hz), 7.14 (1H, d, J = 15.9H)
z), 7.10-7.02 (3H, m), 4.26 (1H, d, J = 17.2H)
z), 4.17 (1H, d, J = 17.2 Hz), 3.90 (3H, s), 3.
32 (3H, s).¹³ C-NMR (CDCl₃100.6 MHz) δ: 163.1 (q,¹J_CF= 2
49.1 Hz), 161.8, 161.6, 135.5, 132.6, 132.
4, 129.0 (q,³J_CF= 8.4 Hz), 128.1, 125.2 (q,¹J _CF = 286.1 Hz), 123.6 (d,^FourJ_CF= 2.3 Hz), 123.0,
115.8 (q,²J_CF= 22.1 Hz), 114.8, 112.8, 75.1
(Q,²J_CF= 27.5 Hz), 55.6, 52.6, 49.4.

1.90 g (5 mmol) of the base obtained are dissolved in 7 cm ³ of methanol. To the resulting solution, a solution of 0.58 g (5 mmol) of maleic acid in 7 cm ³ of methanol is added dropwise, followed by 20 cm ³ of diisopropyl ether. The crystals which precipitate are filtered off and washed with 7 cm ³ of diisopropyl ether. Thus, 1.66 g (67%) of the title compound is obtained in the form of a yellow solid. M. p. 139-140 ° C (ethanol-diisopropyl ether). Analysis: Calculated for C ₂₄ H ₂₁ F ₄ NO ₆ (495.43): C 58.19%, H 4.27%, N 2.83%: Result: C 57.91%, H 4.28%, N 2.87%. IR (KBr, cm ^-1 ): 1600, 1350, 1253, 1179. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.16 (1 H, d, J = 8.
8 Hz), 7.90-7.80 (2H, m), 7.58 (2H, s), 7.40-
7.20 (3H, m), 7.20-7.10 (1H, m), 6.21 (2H, s)
), 4.25 (2H, s), 3.93 (3H, s), 3.31 (3H, s).

B) 1- (4-Fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-
3,4-Dihydroisoquinolinium chloride 1.14 g (3 mmol) of 1- (4-fluorostyryl) -4,6-dimethoxy-
4-Trifluoromethyl-3,4-dihydroisoquinoline was added to 0.5 cm ³ of 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride in the method described in Example 67, section B. Reacts with 2-propanol. In this way
0.94 g (75%) of the title compound is obtained in the form of a pale yellow solid. M. p. : 213-214 ° C (ethanol, decomposition). _{Analysis: C 20 H 18 ClF 4 NO} 2 (415.81) calculated for: C57.77%, H4.36%, Cl8.53 %, N3.37%: Result: C57.54%, H4.31%, Cl 8.57%, N 3.40%. IR (film, cm ⁻¹ ): 2541, 1599, 1241. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.51 (1 H, d, J = 8.
8 Hz), 8.16 (1 H, d, J = 15.8 Hz), 8.05-7.96 (2
H, m), 7.77 (1H, d, J = 15.8 Hz), 7.50-7.30 (3
H, m), 7.25 (1H, s), 4.49 (1H, d, J = 16.1Hz),
4.25 (1H, d, J = 16.1 Hz), 4.02 (3H, s), 3.39 (
3H, s).

Example 69 A) 4,6-Dimethoxy-4- (trifluoromethyl) -1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinolinium maleic acid 4.47 g (10 mmol) ) N- (4-trifluoromethyl-cinnamoyl)-
Follow the procedure described in Example 67, section A, starting from 3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) -propylamine. The crude base is recrystallized from hexane. In this way 3.09 g (72%) of dark brown 4,6-dimethoxy-4- (trifluoromethyl) -1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline are obtained. . M. p. : 87-88 ° C (hexane). _{Analysis: C 21 H 17 F 6 NO} 2 (429.36) calculated for: C58.75%, H3.99%, N3.26 %: Result: C58.58%, H3.95%, N3.30 %. IR (KBr, cm ^-1 ): 1608, 1325, 1166. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.69 (1 H, d, J = 8.7)
Hz), 7.67-61 (4H, m), 7.48 (1H, d, J = 15.9Hz)
), 7.30 (1H, d, J = 15.9 Hz), 7.25 (1H, d, J = 2.
4 Hz), 7.04 (1 H, dd, J = 8.7 Hz, J = 2.4 Hz), 4.2
8 (1H, d, J = 17.5Hz), 4.18 (1H, d, J = 17.5Hz)
3.91 (3H, s), 3.33 (3H, s). ¹³ C-NMR (CDCl ₃ , 100.6 MHz) δ: 161.9, 161.4, 1
39.7, 135.1, 132.8, 130.5 (q, ² J _CF = 32.4 Hz)
, 128.0, 127.5, 126.3, 125.4 (d, ¹ J _CF = 293.8.
Hz), 125.8 (q, ³ J _CF = 3.8 Hz), 124.0 (q, ¹ J _CF = 27)
2.0 Hz), 122.8, 114.9, 112.9, 75.1 (q, ² J _CF =
27.8 Hz), 55.6, 52.6, 49.6.

2.15 g (5 mmol) of the obtained base are converted to the maleate salt in the method described in Example 68. In this way, 1.96 g (72%)
The title compound in yellow is obtained. M. p. 139-140 ° C (ethanol-diisopropyl ether). Analysis: Calculated for C ₂₅ H ₂₁ F ₆ NO ₆ (545.44): C55.05%, H3.88%, N2.57%: Results: C55.18%, H3.80%, N2.69%. IR (KBr, cm ^-1 ): 1605, 1335, 1252, 1168. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 8.14 (1H, d, J = 8.8)
Hz), 8.04 (1H, s), 8.00 (1H, s), 7.81 (1H, s)
, 7.74 (2H, d, J = 8.4 Hz), 7.60 (1H, d, J = 16.1)
Hz), 7.35-7.20 (1H, m), 7.14 (1H, s), 6.25 (
2H, s), 4.26 (2H, s), 3.92 (3H, s), 3.30 (3H,
s).

B) 4,6-Dimethoxy-4- (trifluoromethyl) -1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinolinium chloride A) As described in section A. 1.29 g (3 mmol) of the base thus obtained were added in an amount of 25.3 g / 10 in the method described in Example 67, section B).
Reacts with 0.5 cm ³ of 2-propanol containing 0 cm ³ (3.6 mmol) of hydrogen chloride. In this way 0.86 g (72%) of the pale yellow title compound is obtained. M. p. : 234-235 ° C (ethanol, decomposition). _{Analysis: C 21 H 18 ClF 6 NO} 2 calculated for: C54.15%, H3.89%, Cl7.61 %, N3.01%: Result: C53.94%, H3.86%, Cl7.57 %, N 2.99%. IR (film, cm ⁻¹ ): 1599, 1423, 1252. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.56 (1 H, d, J = 8.
9Hz), 8.31 (1H, d, J = 16.1Hz), 8.13 (2H, d, J
= 8.2 Hz), 7.94 (1H, d, J = 16.1 Hz), 7.90 (2H,
d, J = 8.2 Hz), 7.43 (1H, dd, J = 8.9 Hz, J = 2.4H
z), 7.26 (1H, bs), 4.54 (1H, d, J = 16.5Hz), 4
． 27 (1H, d, J = 16.5Hz), 4.03 (3H, s), 3.4 (3H)
, S).

Example 70 A) 4,6-Dimethoxy-1- (4-nitrostyryl) -4-trifluoromethyl-3
4,4-Dihydroisoquinolinium maleate From 4.24 g (10 mmol) of N-4-nitrocinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine Start
Follow the procedure described in Example 67, section A). The crude base is recrystallized from hexane. Thus, 2.58 g (63%) of dark brown 4,6-dimethoxy
-1-4-Nitrostyryl) -4-trifluoromethyl-3,4-dihydroisoquinoline is obtained. M. p. 146-147 ° C (hexane). _{Analysis: C 20 H 12 F 3 N} 2 O 4 (406.36) calculated for: C59.11%, H4.22%, N6.89 %: Result: C58.87%, H4.24%, N6.83 %. IR (KBr, cm ^-1 ): 1612, 1514, 1313, 1178. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 8.24 (2H, dd, J = 8.
8Hz, J = 1.9Hz), 7.75-7.65 (3H, m), 7.53 (1H
, D, J = 15.9 Hz), 7.37 (1H, d, J = 15.9 Hz), 7.2
5 (1H, d, J = 2.6Hz), 7.06 (1H, dd, J = 8.3Hz, J
= 2.6 Hz), 4.32 (1H, d, J = 17.6 Hz), 4.18 (1H,
d, J = 17.7 Hz), 3.92 (3H, s), 3.34 (3H, s).

2.03 g (5 mmol) of the obtained base is converted to the maleate salt in the method described in Example 68. In this way, 1.65 g (63%)
The title compound in yellow is obtained. M. p. 168-170 ° C (ethanol-diisopropyl ether). _{Analysis: C 24 H 21 F 3 N} 2 O 8 (522.44) calculated for: C55.18%, H4.05%, N5.36 %: Result: C55.32%, H4.07%, N5.26 %. IR (KBr, cm ^-1 ): 1599, 1251, 1176. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 8.32 (2H, d, J = 8.8)
Hz, 7.97 (1H, d, J = 8.8Hz), 7.86 (1H, s), 7.
82 (1H, s), 7.58 (1H, d, J = 16.0 Hz), 7.40-7.
37 (1H, m), 7.27 (1H, m), 7.25-7.15 (1H, m),
63.7 (2H, s), 4.33 (2H, d, J = 7.4Hz), 4.03 (3
H, s), 3.45 (3H, s).

B) 4,6-Dimethoxy-1- (4-nitrostyryl) -4-trifluoromethyl-3
1,4-Dihydroisoquinolinium chloride, 1.22 g (3 mmol) of the base obtained as described under section A) was added to the process described in Example 67, section B), 25.3g / 100
Reacts with 0.5 cm ³ of 2-propanol containing cm ³ (3.6 mmol) of hydrogen chloride. In this way 0.90 g (68%) of the pale yellow title compound is obtained. M. p. : 245-246 ° C (ethanol, decomposition). _{Analysis: C 20 H 18 ClF 3 N} 2 O 4 (442.82) calculated for: C54.25%, H4.10%, Cl8.01 %, N6.33%: Result: C54.14%, H4.08 %, Cl 8.07%, N 6.23%. IR (film, cm ^-1 ): 1599, 1345, 1250, 1181. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.48 (1 H, d, J = 8.
8Hz), 8.36 (1H, d, J = 8.8Hz), 8.24-8.06 (4H
, M), 7.97 (1H, d, J = 16.1 Hz), 7.40 (1H, dd, J
= 8.8 Hz, J = 2.2 Hz), 7.25 (1H, s), 4.51 (1H, d)
, J = 16.5 Hz), 4.02 (1H, d, J = 16.5 Hz), 4.02 (
3H, s), 3.38 (3H, s).

Example 71 6,7-Methylenedioxy-4-methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinolinium chloride 4.61 g ( 10 mmol) of N- (4-trifluoromethylcinnamoyl)-
3,3,3-Trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl)
Starting from propylamine, follow the procedure described in Example 67, section A). The crude base is recrystallized from hexane. In this way, 2.44 g (55%
) Dark brown 6,7-methylenedioxy-4-methoxy-4-trifluoromethyl-1-
(4-Trifluoromethylstyryl) -3,4-dihydroisoquinoline is obtained.
M. p. : 87-88 ° C (hexane). _{Analysis: C 21 H 15 F 6 NO} 3 (443.35) calculated for: C56.89%, H3.41%, N3.16 %: Result: C56.71%, H3.39%, N3.22 %. IR (KBr, cm ^-1 ): 1579, 1389, 1167. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.70-7.60 (4 H, m),
7.46 (1H, d, J = 15.9 Hz), 7.24 (1H, d, J = 15.9)
Hz), 7.19 (1H, s), 7.18 (1H, s) 6.15 (1H, d, J
= 1.3 Hz), 6.09 (1H, d, J = 1.3 Hz), 4.26 (1H, d
, J = 17.7 Hz), 4.16 (1H, d, J = 17.7 Hz), 3.30 (
3H, s). ¹³ C-NMR (CDCl ₃ , 100.6 MHz) δ: 161.0, 150.1, 1
48.9, 139.5, 135.4, 130.6 (q, ² J _CF = 32.4 Hz)
127.5, 126.1, 125.7 (d, ³ J _CF = 5.4 Hz), 125.
6, 125.3 (q, ¹ J _CF = 287.3 Hz), 124.5, 124.0 (q
, ¹ J _CF = 272.0 Hz), 107.6, 106.4, 102.1, 75.2.
(Q, ² J _CF = 27.5 Hz), 52.4, 49.6.

1.33 g (3 mmol) of the base obtained above is reacted with 0.5 cm ³ of 2-propanol containing 25.3 g / 100 cm ³ (3.6 mmol) of hydrogen chloride. In this way 1.05 g (73%) of the pale yellow title compound is obtained. M. p. : 248-250 ° C (acetone, diisopropyl ether, decomposition)
. Analysis: Calculated for C ₂₁ H ₁₆ ClF ₈ NO ₃ (479.81): C52.57%, H3.36%, Cl7.39%, N2.92%: Results: C52.61%, H3.38%, Cl 7.38%, N 2.94%. IR (film, cm ^-1 ): 1623, 1514, 1394, 1325, 117
1, 1126. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.15-8.05 (4 H, m
), 7.90-7.80 (3H, m), 7.32 (1H, m), 6.37 (1H
, D, J = 0.9 Hz), 6.34 (1H, d, J = 0.9 Hz), 4.45 (
1H, d, J = 17.0 Hz), 4.24 (1H, d, J = 17.0 Hz), 3
． 60 (1H, bs), 3.35 (3H, s).

[0356]   Example 72   4,6-dimethoxy-4-trifluoromethyl-1- (2- (4-trifluoromethyl
Phenyl) -ethyl / -3,4-dihydroisoquinolinium chloride   1.12 g (2.5 mmol) of N- / 3- (4- (trifluoromethylphenyl)
) Propanoyl / -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl)
Le) propylamine and 2.0 cm³(3.36 g, 22 mmol) phosphorus (V
) Starting with oxide trichloride, following the procedure described in Example 67, section A).
U 10 cm of crude base³Dissolved in diisopropyl ether and formed
25.3g / 100cm in the solution³0.4 containing (3 mmol) hydrogen chloride
cm³2-propanol is added drop by drop. In this way, 0.96 g (8
2%) of the colorless title compound is obtained. M. p. 185-187 ° C (decomposition, ethanol). Analysis: C_{twenty one}H₂₀ClF₆NO₂About (467.84) Calculation: C53.91%, H4.31%, Cl7.58%, N2.99%: Results: C53.72%, H4.30%, Cl7.56%, N2.97%. IR (film, cm^-1): 2494, 1666, 1328, 1252.¹ H-NMR (DMSO-d₆, 400 MHz) δ: 8.38 (1H, d, J = 18)
． 8 Hz), 7.66 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J
= 8.5 Hz), 7.36 (1H, dd, J = 8.8 Hz, J = 2.4 Hz),
, 7.20 (1H, s), 4.42 (1H, d, J = 16.3 Hz), 4.19
(1H, d, J = 16.3 Hz), 3.99 (3H, s), 3.75-3.40
(2H, m), 3.31 (3H, s), 3.20-3.00 (2H, m).¹³ C-NMR (DMSO-d₆, 50.3 MHz) δ: 175.0, 166.0,
144.1, 134.8, 132.8, 129.6, 127.5 (q,²J_CF=
31.7 Hz), 125.3 (q,³J_CF= 3.8 Hz), 124.5 (q,¹J _CF = 270.2 Hz), 124.3 (q,¹J_CF= 287.4 Hz), 118.
6, 116.0, 114.2, 74.8 (q,²J_CF= 28.2 Hz), 56.
7, 52.9, 42.4, 33.4, 33.0.

Example 73 1- / 2- (4-Fluorophenyl) ethyl / -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinolinium chloride 1.00 g (2.5 Mmol) N- / 3- (4-fluorophenyl) -propanoyl / -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) -propylamine and 2.0 cm ³ of phosphorus ( V) Example 6 starting with trichloride oxide
Follow the procedure described in Section 7, A). The crude base was dissolved in 10 cm ³ of diisopropyl ether and the solution formed was 25.3 g / 100 cm ³ (3
0.4 cm ³ of 2-propanol containing (mmol) hydrogen chloride is added dropwise. In this way 0.86 g (82%) of the colorless title compound is obtained. M. p. : 190-191 ° C (ethanol, decomposition). _{Analysis: C 20 H 20 ClF 4 NO} 2 (417.84) calculated for: C57.49%, H4.82%, Cl8.48 %, N3.35%: Result: C57.44%, H4.83%, Cl 8.58%, N 3.42%. IR (film, cm ^-1 ): 1602, 1512, 1254, 1177. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.37 (1 H, d, J = 8.
6 Hz), 7.40-7.35 (3H, m), 7.20 (1H, d, J = 2.3)
Hz), 7.14 (2H, t, J = 8.8Hz), 4.41 (1H, d, J = 1)
6.7 Hz), 4.20 (1H, d, J = 16.7 Hz), 4.00 (3H, s)
) 3.70-3.30 (2H, m), 3.31 (3H, s), 3.00-2.8
5 (2H, m). ¹³ C-NMR (DMSO-d ₆ , 50.3 MHz) δ: 175.0, 166.2,
161.2 (d, ¹ J _CF = 241.9 Hz), 135.3, 135.0, 132
． 8, 130.6 (d, ³ J _CF = 8.0 Hz), 124.3 (d, ¹ J _CF = 287)
． 6 Hz), 118.5, 116.1, 115.3 (d, ² J _CF = 21.4 Hz
), 114.3, 74.8 (q, ² J _CF = 28.0 Hz), 56.8, 53.0
42.1, 33.5, 33.2.

Example 74 6,7-Methylenedioxy-4-methoxy-4-trifluoromethyl-1- / 2- (4-
Trifluoromethylphenyl) ethyl / -3,4-dihydroisoquinolinium chloride Following the procedure described in Example 67, section A), the title compound is obtained as a colorless solid. Yield 75%. M. p. 196-197 ° C (ethanol, decomposition). Analysis: Calculated for C ₂₁ H ₁₈ ClF ₆ NO ₃ (481.83): C52.35%, H3.77%, Cl7.36%, N2.91%: Results: C52.16%, H3.79%, Cl7.33%, N2.90%. IR (film, cm ^-1 ): 2494, 1666, 1328, 1252. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.95 (1 H, s), 7.6
7 (2H, d, J = 8.2Hz), 7.58 (2H, d, J = 8.2Hz), 7
． 28 (1H, s), 6.34 (2H, d, J = 14.9Hz), 4.36 (1
H, d, J = 16.8 Hz), 4.16 (1H, d, J = 16.8 Hz), 3.
80-3.35 (2H, m), 3.27 (3H, s), 3.15-2.90 (2H
, M).

Example 75 1- / 2- (4-Fluorophenyl) ethyl / -6.7-methylenedioxy-4-methoxy-4-trifluoromethyl-3,4-dihydroisoquinolinium chloride Example Following the procedure described in Example 67, section A), the title compound is obtained as a colorless solid. Yield 80%. M. p. 195-196 ° C (ethanol, decomposition). _{Analysis: C 20 H 18 ClF 4 NO} 3 (431.82) calculated for: C55.63%, H4.20%, Cl8.21 %, N3.24%: Result: C55.36%, H4.24%, Cl 8.20%, N 3.27%. IR (film, cm ^-1 ): 1671, 1608, 1512, 1300, 117
9. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.07 (1 H, s), 7.4
5-7.35 (2H, m), 7.32 (1H, s), 7.14 (2H, t, J =
8.8 Hz), 6.37 (2H, d, J = 3.7 Hz), 4.44 (1H, d,
J = 17.1 Hz), 4.15 (1H, d, J = 17.1 Hz), 3.70-3
． 30 (2H, m), 3.30 (3H, s), 3.05-2.95 (2H, m)
. ¹³ C-NMR (DMSO-d ₆ , 100.6 MHz) δ: 175.8, 161.2
(D, ¹ J _CF = 242.2 Hz), 155.0, 150.1, 135.2 (d, ⁴ J _CF = 3.1 Hz), 130.7 (d, ³ J _CF = 8.0 Hz), 130.6, 1
27.6, 124.2 (q, ¹ J _CF = 287.6 Hz), 115.2 (d, ² J _CF = 21.0 Hz), 110.8, 104.2, 75.1 (q, ² J) _CF = 28.6
Hz), 52.8, 41.8, 33.8, 33.0.

Example 76 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium bromide 6 g (0.0125 mol) 1- / 2- (4-trifluoromethylphenyl) ethyl / 2-methyl-6,7-methylene-dioxy-3,4-dihydroisoquinoline of
Reacts with N-bromosuccinimide in dichloromethane at ° C. The reaction mixture is stirred at room temperature for 1 hour, then left for 24 hours and evaporated. Diethyl ether is added to the residue, the precipitated crystals are filtered and recrystallized from a mixture of hexane and acetonitrile. In this way 1.5 g (30%) of the title compound is obtained. M. p. : 244-245 ° C. _{Analysis: C 20 H 19 BrF 3 NO} 2 (392.27) calculated for: C54.31%, H4.33%, Brl8.70 %, N3.17%: Result: C53.65%, H4.35%, Brl 8.21%, N 3.28%. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.67 (1 H, s), 7.6
4 (2H, d, J = 8Hz), 7.54 (2H, d, J = 8Hz), 7.11 (
11H, s), 6.21 (2H, s), 3.95 (2H, t, J = 8Hz), 3
． 69 (3H, s), 3.49 (2H, t, J = 8Hz), 2.96 (4H, m)
).

Example 77 1- (2-Phenylethyl) -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium iodide 3.2 g (0.011 mol) of 1- (2-Phenylethyl) -6,7-methylenedioxy-3,4-dihydroisoquinoline is dissolved in 30 cm ³ of acetone. To the formed solution was added 4 cm ³ of methyl iodide and the reaction mixture was added overnight.
Leave at room temperature. The yellow crystalline material which precipitates is filtered off, washed with some cold acetone and then recrystallised from acetone. In this way, 3.5 g (76
%) Of the title compound is obtained. M. p. : 180 ° C. Analysis: C ₁₉ H ₂₀ INO calculated for ₂ (431.28): N3.32%: Result: N3.25%. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.69 (1 H, s), 7.2
8 (5H, m), 7.11 (1H, s), 6.23 (2H, s), 3.92 (2
H, t, J = 7.6 Hz), 3.61 (3H, s), 3.47 (2H, t, J =
7.6 Hz), 2.94 (4H, m).

[0362]   Example 78   1- (4-trifluoromethylstyryl) -2-methyl-4-propyl-6,7-methyl
Dioxy-3,4-dihydroisoquinolinium iodide dihydrate   7.2 g (0.019 mol) of 1- (4-trifluoromethylstyryl) -4-p
Ropyr-6,7-methylene-dioxy-3,4-dihydroisoquinoline, 150 cm ³ Dissolved in acetone. 10 cm for the formed solution³Pour methyl iodide
, And the reaction mixture is left overnight at room temperature. The mixture was then evaporated to dryness and
The oily product as a mixture of diisopropanol ether and diethyl ether.
To crystallize. 90 cm of crude crystal product³Dissolved in acetone, 300 cm³of
Precipitate by addition of diisopropanol ether and filter. like this
This gives 1.7 g (16%) of the title compound. M. p. : 203-2
05 ° C. Analysis: C_{twenty three}H_{twenty three}F₃INO₂About (565.38) Calculation: C 48.86%, H 4.81%, N 2.48%: Results: C 49.08%, H 4.73%, N 2.63%.¹ H-NMR (DMSO-d₆, 200 MHz) δ: 7.94 (2H, d, J = 8.
1Hz), 7.84 (1H, d, J = 16.5Hz), 7.72 (2H, d, J
= 8.1 Hz), 7.25 (1H, d, J = 16.5 Hz), 7.18 (1H,
s), 6.85 (1H, s), 6.15 (2H, s), 4.40 (1H, dd,
J₁= 4.8Hz, J₂= 14.7 Hz), 4.02 (3H, s), 3.90 (1
H, dd, J₁= 4.0Hz, J₂= 14.7 Hz), 3.10 (1H, m), 1
． 58 (2H, m), 1.44 (2H, m), 0.98 (3H, t, J = 7.0)
Hz).

Example 79 1- / 2- (4-trifluoromethylphenyl) ethyl-2-methyl-7-chloro-3,
4-dihydroisoquinolinium iodide 1.7 g (0.005 mol) of 1- / 2- (4-trifluoromethylphenyl) ethyl-7-chloro-3,4-dihydroisoquinoline was added to 30 cm ³ of acetone. Dissolves in. To the solution formed is added 3 cm ³ of methyl iodide and the reaction mixture is left at room temperature for 24 hours. The reaction mixture is cooled to 0 ° C., filtered and washed with cold acetone. In this way 1.5 g (62%) of the title compound is obtained. M. p. : 224-227 ° C. Analysis: Calculated for C ₁₉ H ₁₈ Cl ₃ IN (479.71): C47.57%, H3.78%, Cl7.93%, N2.92%: Results: C47.26%, H3.75%, Cl7. .11%, N2.93%. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.02 (1 H, d, J = 2.
2 Hz), 7.75 ( ₁ H, dd, J ₁ = 2.2 Hz, J ₂ = 8.1 Hz), 7.
60 (2H, d, J = 8.2Hz), 7.52 (2H, d, J = 8.2Hz),
7.48 (1H, d, J = 8.1Hz), 4.06 (2H, t, J = 7.6Hz)
), 3.81 (3H, s), 3.65 (2H, t, J = 7.8Hz), 3.11
(2H, t, J = 7.6Hz), 3.06 (2H, t, J = 7.8Hz).

Example 80 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-ethylenedioxy
-3,4-Dihydroisoquinolinium bromide 8.85 g (27 mmol) of 1- / 2- (4-trifluorophenyl) ethyl /
2-Methyl-6,7-ethylenedioxy-3,4-dihydroisoquinoline was added to 200c
Dissolve in m ³ of dichloromethane. To the solution formed, 5.34 g (30 mmol) of N-bromosuccinimide is added at 0 ° C. Reaction mixture at room temperature for 3
Stir for hours and then concentrate under reduced pressure to half the original volume. From the residue, the crude product is precipitated by addition of cyclohexane and recrystallized from 20 cm ³ of isopropanol. In this way 4.23 g (38%) of the title compound is obtained. M. p. 177-180 ° C. Analysis: C ₂₀ H ₂₁ BrFNO calculated for ₂ (406.30): N3.45%: Result: N3.29%. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.61 (1 H, s), 7.3
1 (2H, m), 7.11 (2H, m), 6.99 (1H, s), 4.35 (4
H, m), 3.95 (2H, t, J = 7.4Hz), 3.66 (3H, s), 3
． 47 (2H, t, J = 7.6Hz), 2.94 (4H, m).

Example 81 1- / 2- (4-trifluoromethylphenyl) ethyl / -2-methyl-6-methoxy-
7-Hydroxy-3,4-dihydroisoquinolinium iodide 2.0 g (6 mmol) of 1- / 2- (4-trifluoromethylphenyl) ethyl
/ -6-Methoxy-7-hydroxy-3,4-dihydroisoquinoline is dissolved in 30 cm ³ of acetone and 5 cm ³ of methyl iodide is added to the solution formed. The crystals which precipitate are filtered off, washed with cold ether, dissolved in 350 cm ³ of acetone and precipitated by addition of ether. In this way, 1.87 g (
63) The title compound is obtained. M. p. : 210-213 ° C. Analysis: C ₂₀ H ₂₁ F ₃ INO calculated for _{2 (491.29): C48.90%,} H4.31%, N2.85%: Result: C48.56%, H4.42%, N2.96 %. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.55 (1 H, bs), 7.
67 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8.0 Hz),
7.40 (1H, s), 7.09 (1H, s), 7.09 (1H, s), 3.9
7 (2H, t, J = 7.6Hz), 3.92 (3H, s), 3.69 (3H, s)
), 3.41 (2H, t, J = 8.0Hz), 3.02 (4H, t, J = 8.0)
Hz).

Example 82 1- / 2- (4-trifluoromethylphenyl) ethyl / -2-methyl-4-propyl-
6,7-Ethylenedioxy-3,4-dihydroisoquinolinium iodide 4.0 g (0.01 mol) of 1- / 2- (4-trifluoromethylphenyl) ethyl / -4-propyl-6 8,7-ethylenedioxy-3,4-dihydroisoquinoline,
Dissolve in 0 cm ³ of acetone. After the addition of 9 g of methyl iodide, the reaction mixture is left at room temperature for 24 hours. The quaternary salt that precipitates is filtered and recrystallized from acetone. In this way 3.1 g (56%) of the title compound is obtained.
M. p. 177-180 ° C. Analysis: C ₂₄ H ₂₇ F ₃ INO calculated for _{2 (545.38): C52.86%,} H4.99%, N2.57%: Result: C52.73%, H5.04%, N2.62 %. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.55 (2H, d, J = 8.1)
Hz), 7.34 (2H, d, J = 8.1Hz), 7.29 (1H, s), 6.
77 (1H, s), 4.38 (2H, m), 4.34 (1H, dd, J ₁ = 5.
4 Hz, J ₂ = 14.1 Hz), 4.29 (2H, m), 3.83 (3H, s)
3.74 ( ₁ H, dd, J ₁ = 4.8 Hz, J ₂ = 14.4 Hz), 3.64 (
2H, m), 3.22 (1H, m), 3.13 (1H, m), 3.01 (1H,
m), 1.5-1.2 (4H, m), 0.95 (3H, t, J = 7.1Hz).

Example 83 1-2- (4-trifluoromethylphenyl) ethyl / -2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolinium iodide 2.8 g (0 .0075 mol) of 1- / 2- (4-trifluoromethylphenyl)
Ethyl / -6,7-ethylenedioxy-3,4-dihydroisoquinoline is dissolved in 120 cm ³ of acetone. The solution formed, adding methyl iodide 5 cm ^3. The reaction mixture is heated under reflux for 1 hour, then cooled to 0-5 ° C. with ice water and stirred at this temperature for 2-3 hours. After crystallization, the crystals are filtered, washed with cold acetone and recrystallized from acetone. In this way, 2.2 g (58
%) Of the title compound is obtained. M. p. : 205-207 ° C. Analysis: C ₂₁ H ₂₁ F ₃ INO calculated for _{2 (503.30): C50.12%,} H4.21%, N2.78%: Result: C49.61%, H4.25%, N2.82 %. ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.64 (2 H, d, J = 8.
3Hz), 7.52 (2H, d, J = 8.3Hz), 6.96 (1H, s), 4
． 33 (2H, m), 3.95 (2H, t, J = 7.5Hz), 3.69 (3H
, S), 3.49 (2H, t, J = 7.7Hz), 2.99 (4H, m).

Example 84 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-methylenedioxy
-3,4-Dihydroisoquinolinium bromide 2.9 g (9 mmol) of 1- / 2- (4-fluorophenyl) ethyl / 2-methyl-6,7-methylenedioxy-3,4-dihydro Isoquinoline is dissolved in 70 cm ³ of dichloroethane and to the solution formed 1.7 g (0.01 mol) of N-bromosuccinimide are added under stirring. The reaction mixture is stirred at 0 ° C. for 3 hours and then evaporated under reduced pressure. Ether was added to the oily residue and the mixture was adjusted to 0.
Stir at 0 ° C. and filter the precipitated crystals. In this way, 1.9 g (5
3%) of the title compound is obtained. M. p. : 191-193 ° C. Analysis: Calculation for C ₁₉ H ₁₉ BrFNO ₂ (392.27): C 58.18%, H 4.88%, Br 20.37%, N 3.57%: Result: C 57.94%, H 5.13%, Br 20. 59%, N 3.69%. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.68 (1 H, s), 7.3
1 (2H, m), 7.11 (2H, m), 7.11 (1H, s), 6.22 (2
H, s), 3.93 (2H, t, J = 7.7Hz), 3.64 (3H, s), 3
． 46 (2H, t, J = 7.7Hz), 2.98 (2H, t, J = 7.7Hz)
2.91 (2H, t, J = 7.7Hz).

Example 85 1- (4-Fluorostyryl) -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium bromide 4.39 g (0.0125) in 100 cm ³ of dichloroethane. Mol) 1- (4
To a solution of -fluorostyryl) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline was added 4.6 g (0.025 mol) of N-bromosuccinimide at 0 ° C. Add and stir the reaction mixture at room temperature for 3 hours. The reaction mixture is then evaporated to dryness under reduced pressure and acetonitrile is added to the residue. The crystalline material is filtered and recrystallized from acetonitrile. In this way 3.1 g (63%) of the title compound is obtained. M. p. : 215-218
° C. Analysis: For C ₁₉ H ₁₇ BrFNO ₂ (390.27) Calculated: C 58.48%, H 4.39%, Br 20.48%, N 4.39%: Results: C 57.70%, H 4.36%, Br 20. 12%, N 4.60%. ¹ H-NMR (CDCl ₃ , 250 MHz) δ: 7.8-7.9 (2H, m), 7.
65 (1H, d, J = 16.3Hz), 7.18 (1H, d, J = 16.3Hz)
), 7.08-7.15 (3H, m), 6.88 (1H, s), 6.13 (2H)
, S), 4.14 (2H, t, J = 7.5 Hz), 4.07 (3H, s), 3.
25 (2H, t, J = 7.5Hz).

Example 86 1- (4-trifluoromethylstyryl) -2-methyl-6,7-methylenedioxy-
3,4-Dihydroisoquinolinium bromide 4.8 g (0.0135 mol) of 1- (4-trifluoromethylstyryl) -2-
Methyl-6,7-methylenedioxy-3,4-dihydroisoquinoline was added to 100 cm ³
Dissolved in dichloroethane. To a solution cooled to 0 ° C, 2.5 g (0.014
1 mol) N-bromosuccinimide is added under stirring. The reaction mixture is 0
Stir at 1 ° C for 1 hour and at room temperature for a further 2 hours. The precipitated crystals are filtered and washed with some dichloromethane. The crude product is recrystallized from a mixture of ether and ethanol (1: 1). In this way, 2.4 g (41
%) Of the title compound is obtained. M. p. : 213 ° C. _{Analysis: C 20 H 17 BrF 3 NO} 3 (440.26) calculated for: C54.56%, H3.39%, Br17.76 %, N3.18%: Result: C54.20%, H4.00%, Br 17.70%, N 3.11%. ¹ H-NMR (CDCl ₃ , 250 MHz) δ: 7.95 (2H, d, J = 8.2)
Hz), 7.83 (1H, d, J = 16.4 Hz), 7.69 (2H, d, J =
8.2 Hz), 7.23 (1H, d, J = 16.4), 7.11 (1H, s),
6.87 (1H, s), 6.13 (2H, s), 4.22 (2H, t, J = 7.
5Hz), 4.08 (3H, s), 3.27 (2H, t, J = 7.5Hz).

Example 87 1- / 2- (4-Fluorophenyl) ethyl / 2-methyl-6,7-methylenedioxy
-3,4-Dihydroisoquinolinium iodide 3.12 g (0.01 mol) of 1- / 2- (4-fluorophenyl) ethyl / -6,
7-Methylenedioxy-3,4-dihydroisoquinoline is dissolved in 30 cm ³ of nitroethane. To the solution formed, 7.76 g of methyl iodide are added and the reaction mixture is stirred at 120 ° C. for 4 hours, then cooled to room temperature and 50 c
The product is precipitated by addition of m ³ of ether. The crystals are filtered, washed with ether and recrystallized from acetone. In this way 3.6 g (82%) of the title compound is obtained. M. p. : 197-198 ° C. Analysis: For C ₁₉ H ₁₉ FlNO ₂ (439.272) Calculated: C 51.95%, H 4.36%, N 3.19%: Results: C 51.66%, H 4.32%, N 3.09%. ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.68 (1 H, s), 7.3
1 (2H, m), 7.12 (2H, m), 7.11 (1H, s), 6.23 (2
H, s), 3.94 (2H, t, J = 7.7Hz), 3.64 (3H, s), 3
． 46 (2H, t, J = 7.8Hz), 3.00 (2H, t, J = 7.8Hz)
2.91 (2H, t, J = 7.8Hz).

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] October 22, 2001 (2001.10.22)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Chemical 1] (In the formula, R ₁ forms a methylenedioxy group together with R ₂ ; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₃ , R ₆ And R ₇ is
Independently represent a hydrogen atom; R ₈ forms a valence bond with R ₉ ; X ₁ forms a valence bond with X ₂ ; R ₁₀ and R ₁₁ independently represent A hydrogen atom, a methoxy group or a trifluoromethyl group), a 3,4-dihydroisoquinoline derivative represented by the formula, a pharmaceutically suitable acid addition salt thereof, and the general formula (I ′)

[Chemical 2] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or an ethylenedioxy group. An oxy group is formed; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R ₃ ,
R ₅ , R ₆ and R ₇ independently represent a hydrogen atom; R ₈ forms a valence bond with R ₉ ; R ′ ₈ represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ independently represents a hydrogen atom, a halogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ is X. A quaternary derivative represented by the formula ( ₂₎ , which forms a valence bond with ₂ ; A represents a residue of an inorganic acid or an organic acid represented by the formula HA).

[Chemical 3] (Wherein R ₁ together with R ₂ forms a methylenedioxy group; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ Each independently represent a hydrogen atom, a methoxy group or a trifluoromethyl group; X ₁ forms a valence bond together with X _2. ) 3,4-dihydroisoquinoline derivative Furthermore, a pharmaceutically suitable acid addition salt thereof.

[Chemical 4] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or an ethylenedioxy group. form an oxy group; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R _'8 represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ are independently a hydrogen atom, a halogen atom , C _1-4 alkoxy group or trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ forms a valence bond with X ₂ ; Formula HA
Which represents a residue of an inorganic acid or an organic acid represented by
Dihydroisoquinolinium derivative.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Contents of correction]

A 1-styrylisoquinoline derivative having an anxiolytic effect is disclosed in French Patent Publication No. 2,71.
Known by issue No. 9,586. European Patent 787,493 discloses tetrahydroisoquinoline derivatives. These known compounds are effective against neurodegenerative diseases, schizophrenia, anxiety and depression. Isoquinoline derivatives suitable for the treatment of fungal infections are known from US Pat. No. 4,963,562. British Patent 1,181,959 and German Patent Publication 1,902,559 disclose 3,4-dihydro-6,7-dimethoxyisoquinoline having platelet function inhibiting properties. German Patent 1,902,402 discloses 6,7-dimethoxyisoquinoline derivatives having the same action. 1,2,3,4-Tetrahydroisoquinolines having analgesic, antispasmodic, antitussive and antihypertensive effects are known from Swiss Patent No. 410,007.

[Procedure amendment]

[Submission date] June 20, 2002 (2002.6.20)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Chemical 1] (In the formula, R ₁ forms a methylenedioxy group together with R ₂ ; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₃ , R ₆ And R ₇ is
Independently represent a hydrogen atom; R ₈ forms a valence bond with R ₉ ; X ₁ forms a valence bond with X ₂ ; R ₁₀ and R ₁₁ independently represent A hydrogen atom, a methoxy group or a trifluoromethyl group), a 3,4-dihydroisoquinoline derivative represented by the formula, a pharmaceutically suitable acid addition salt thereof, and the general formula (I ′)

[Chemical 2] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or an ethylenedioxy group. An oxy group is formed; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R ₃ ,
R ₅ , R ₆ and R ₇ independently represent a hydrogen atom; R ₈ forms a valence bond with R ₉ ; R ′ ₈ represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ independently represents a hydrogen atom, a halogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ is X. A quaternary derivative represented by the formula ( ₂₎ , which forms a valence bond with ₂ ; A represents a residue of an inorganic acid or an organic acid represented by the formula HA).

[Chemical 3] (Wherein R ₁ together with R ₂ forms a methylenedioxy group; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ Each independently represent a hydrogen atom, a methoxy group or a trifluoromethyl group; X ₁ forms a valence bond together with X _2. ) 3,4-dihydroisoquinoline derivative Furthermore, a pharmaceutically suitable acid addition salt thereof.

[Chemical 4] (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or an ethylenedioxy group. form an oxy group; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R _'8 represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ are independently a hydrogen atom, a halogen atom , C _1-4 alkoxy group or trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ forms a valence bond with X ₂ ; Formula HA
Which represents a residue of an inorganic acid or an organic acid represented by
Dihydroisoquinolinium derivative.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 217/18 C07D 217/18 217/20 217/20 217/24 217/24 491/056 491/056 ( 31) Priority claim number P 9902592 (32) Priority date July 29, 1999 (July 29, 1999) (33) Priority claim country Hungary (HU) (81) Designated country EP (AT, BE, CH) , CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN , GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, M , RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK , DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ , TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Jura Simig Hungary, Hung -1126 Budapest Holoshii Simon Uzza 25 (72) Inventor Ratslaw Poshzavar Hungary, Herb-1181 Pest Sontvaaly Uzza 44 (72) Inventor Chabazaanthai Hung, Hung-1113 Budapest Somborjai Uzza 8 (72) Inventor Maria Inze Hungary, Her-1025 Budapest Trkwetz Utza 74 Be (72) Inventor, Garboldnyi Hungary Her- 1122 Budapest Kristina Kurt 2-4 (72) Inventor Ratslow Baratz Har-1080 Hungary Haro-1088 Budapest-Barosch-Uzza 38 (72) Inventor Zortan Greff Hung-Har-1028 Budapest Zhongziwilag Uzza 8 (72) Inventor Peter Cotai Nazi Hungary Har-2600 Vak Nazy-Mezo Uzza 73 (72) Inventor Zortan Ratkai Hung-Har-1101 Budapest Monoli Uzza 19 (72) Inventor Peter Seresh Hungari -Har -1531 Budapest Lada Barnen Uzza 25 (72) Inventor Andrash Birkei Gorzo Hungary -Har -2022 Budapest Ort Uzza 70 (72) Inventor Istvan Gachary Hungary -1021 Budapest Tarlogato Utza 64 Beh (72) invention Jordi Levi Hungary Har-2092 Budakesiga Gabor Aaron Uzza 10 (72) Inventor Carrolli Chihani Hungary Har-1171 Budapest Posta Mestel-Uzza 37 (72) Inventor Bartogel Hungary Har-1151 Budapest Benkozyt 72 (72) ) Inventor Andras Edjed Hungary, Hungary-1145 Budapest Uvidek Uzza 58 F-term (reference) 4C034 AB03 AK02 AK03 AK08 AK15 AM20 4C050 AA01 AA08 BB07 CC17 EE0 1 FF02 FF05 GG01 HH01 4C086 AA02 AA03 AA04 BC30 CB22 MA02 MA05 NA14 ZA02 ZA03

Claims (19)

[Claims] 1. The general formula (I) [Chemical 1] (In the formula, R₁, R₂And R₃Are independently hydrogen atom, halogen atom, hydroxy
Group or C_1-4Represents an alkoxy group or R₁Is R₂With methylenedioxy
Form a group or an ethylenedioxy group; R_FourIs a hydrogen atom, C_1-4An alkoxy group or
Represents a trifluoromethyl group; R₇Is a hydrogen atom or C_1-4Represents an alkyl group; R ₈ Is a hydrogen atom or C_1-4An alkyl group; R_Five, R₆And R₉Independently, water
Represents an elementary atom or R_FiveIs R₆Forms a valence bond with R, and at the same time, R₈Is
R₉Forms a valence bond with R;_TenAnd R₁₁Are independently hydrogen atom, halo
Gen atom, nitro group, C_1-4Alkoxy group, trifluoromethyl group or cyano group
Represents; X₁And X₂Each independently represents a hydrogen atom or X₁Is X₂along with
Forming an valence bond), and an isoquinoline derivative represented by
A sharp acid addition salt, and general formula (I ') [Chemical 2] (In the formula, R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R₈, R₉, R_Ten, R₁₁, X₁as well as
X₂Is as defined above; R '₈Is C_1-4Represents an alkyl group; and A is
Represents a residue of an inorganic acid or an organic acid represented by the formula HA), and a quaternary derivative represented by
Alternatively, in the general formula (I), R₁And R₂Is as described above; R₃, R₆ And R₇Each independently represent a hydrogen atom; R₈Is R₉Form a valence bond with
; R_FourIs a hydrogen atom, C_1-4Alkoxy group or C_1-6Represents an alkyl group; R_FiveBut water
Represents an elementary atom or a trifluoromethyl group; R_TenAnd R₁₁But independently, a hydrogen atom
, Halogen atom, nitro group, C_1-4Represents an alkoxy group or trifluoromethyl group
Yes; X₁And X₂Each independently represents a hydrogen atom, or X₁Is X₂Atom with
An isoquinoline derivative forming a valence bond, and a pharmaceutically suitable acid addition salt thereof, or
In the general formula (I ′) is R₁And R₂Is as described above; R₃, R_Five, R₆Over
And R₇Each independently represent a hydrogen atom; R₈Is R₉Forms a valence bond with;
R_FourIs a hydrogen atom or C_1-6Represents an alkyl group; R_TenAnd R₁₁But independently, hydrogen
Atom, halogen atom, C_1-4Represents an alkoxy group or a trifluoromethyl group; X₁ And X₂Each independently represents a hydrogen atom, or X₁Is X₂Valence bond with
To form R '₈But C_1-4Represents an alkyl group; and A is a compound represented by the formula HA
A quaternary derivative representing a residue of organic acid or organic acid. 2. A compound represented by the general formula (Ia): (In the formula, R ₁ , R ₂ and R ₃ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is methylenedioxy. Form a group or an ethylenedioxy group; R ₄ represents a hydrogen atom or a C _1-4 alkoxy group; R ₇ represents a hydrogen atom or a C _1-4 alkyl group; R ₈ represents a hydrogen atom or C It is a _1-4 alkyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ are independently A 1,2,3,4-tetrahydroisoquinoline derivative according to claim 1, which represents a hydrogen atom or X ₁ forms a valence bond together with X _2. Acid addition salts, and general formula (I'a) (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above. ; R _'8 represents a C _1-4 alkyl group; and, a is
A quaternary derivative represented by the formula HA, which represents a residue of an inorganic acid or an organic acid. 3. In the general formula (Ia), R₁And R₂But independently, methoxy
Represents a group or R₁Is R₂Together with methylenedioxy group or ethylenedioxy
Form a group; R₃Represents hydrogen; R_FourRepresents a hydrogen atom; R₇Is a hydrogen atom;
R₈Represents a hydrogen atom or a methyl group; R_TenIs a halogen atom, trifluoromethy
Represents a group or a methoxy group; R₁₁Represents a hydrogen atom or a methoxy group; X₁as well as
X₂Each independently represents a hydrogen atom, or X₁Is X₂Form a valence bond with
The 1,2,3,4-tetrahydroisoquinoline derivative according to claim 2, which further comprises
, A pharmaceutically suitable acid addition salt thereof, and R in the general formula (I′a)₁, R₂, R₃, R _Four , R_Five, R₆, R₇, R₈, R₉, R_Ten, R₁₁, X₁And X₂Is as defined above
Yes; R '₈Represents a methyl group; and quaternary derivative in which A represents a halide ion
body. 4. The general formula (Ib) [Chemical 5] (In the formula, R₁, R₂And R₃Are independently hydrogen atom, halogen atom, hydroxy
Group or C_1-4Represents an alkoxy group or R₁Is R₂With methylenedioxy
Form a group or an ethylenedioxy group; R_FourIs a hydrogen atom, C_1-4An alkoxy group or
Represents a trifluoromethyl group; R₇Is a hydrogen atom or C_1-4Represents an alkyl group; R _Ten And R₁₁Are independently hydrogen atom, halogen atom, nitro group, C_1-4Arcoki
Represents a Si group, a trifluoromethyl group or a cyano group; X₁And X₂Independently, water
Represents an elementary atom or X₁Is X₂Form a valence bond with)
The isoquinoline derivative according to claim 1, a pharmaceutically suitable acid addition salt thereof, and
General formula (I'b) [Chemical 6] (In the formula, R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂Is as defined above
It's a cage; R '₈Is C_1-4Represents an alkyl group; and A represents a group represented by the formula HA
(Representing a residue of organic acid or organic acid). 5. In the general formula (Ib), R ₁ , R ₂ and R ₃ independently represent a hydrogen atom or a methoxy group, or R ₁ together with R ₂ is a methylenedioxy group or Forms an ethylenedioxy group; R ₄ represents a hydrogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; R ₇ represents a hydrogen atom or a methyl group; R ₁₀ represents a hydrogen atom or a halogen atom , A nitro group, a methoxy group, a trifluoromethyl group or a cyano group; R ₁₁ represents a hydrogen atom or a methoxy group; X ₁ and X ₂ are independently
A hydrogen atom or X ₁ forms a valence bond together with X ₂ ), the isoquinoline derivative according to claim 4, further a pharmaceutically suitable acid addition salt thereof, and a general formula ( In I′b), R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined above; R ′ ₈ represents a methyl group; And a quaternary derivative in which A represents a halide ion. 6. A compound represented by the general formula (XIV): (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or ethylene. Forms a dioxy group; R ₄ is a hydrogen atom, a C _1-4 alkoxy group or C _1-6
Represents an alkyl group; R ₅ represents a hydrogen atom or a trifluoromethyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, a nitro group, a C _1-4 alkoxy group or a trifluoromethyl group. X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ forms a valence bond together with X ₂ ).
, 4-Dihydroisoquinoline derivatives, and pharmaceutically suitable acid addition salts thereof. 7. In formula (XIV), R ₁ and R ₂ independently represent a hydrogen atom, a chlorine atom, a hydroxy group or a methoxy group, or R ₁ together with R ₂ is methylenedi. form an oxy group or an ethylenedioxy group; R ₄ represents hydrogen atom or a C _{1 -6} alkyl group; R ₅ represents hydrogen atom; R ₁₀ and R ₁₁ are independently hydrogen atom, 7. A fluorine atom, a methoxy group or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ together with X ₂ forms a valence bond. 3,4-dihydroisoquinoline derivative, and a pharmaceutically suitable acid addition salt thereof. 8. In the general formula (XIV), R ₁ forms a methylenedioxy group together with R ₂ ; R ₄ represents a C _1-6 alkyl group; R ₅ represents a hydrogen atom or trifluoro A methyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a methoxy group or a trifluoromethyl group; X ₁ together with X ₂ forms a valence bond. 4-Dihydroisoquinoline derivatives, as well as their pharmaceutically suitable acid addition salts. 9. A compound represented by the general formula (XI): (In the formula, R ₁ and R ₂ independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C _1-4 alkoxy group, or R ₁ together with R ₂ is a methylenedioxy group or ethylene. A dioxy group is formed; R ₄ represents a hydrogen atom or a C _1-6 alkyl group; R 4
' ₈ represents a C _1-4 alkyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom, a C _1-4 alkoxy group or a trifluoromethyl group; X ₁ and X ₂ are ,
Independently, represent a hydrogen atom, or X ₁ forms a valence bond with X ₂ ; A
Represents a residue of an inorganic acid or an organic acid represented by the formula HA), and the 3,4-dihydroisoquinolinium derivative according to claim 1. 10. In formula (XI), R ₁ and R ₂ independently represent a hydroxy group, a chlorine atom or a methoxy group, or R ₁ together with R ₂ is a methylenedioxy group or Forming an ethylenedioxy group; R ₄ represents a hydrogen atom or a C _1-3 alkyl group; R ′ ₈ represents a methyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a halogen atom Or represents a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, or X ₁ forms a valence bond with X ₂ ; A is represented by the formula HA The 3,4-dihydroisoquinolinium derivative according to claim 9, which represents a residue of an inorganic acid. 11. In the general formula (XI), R ₁ together with R ₂ forms a methylenedioxy group or an ethylenedioxy group; R ₄ represents a hydrogen atom or a C _1-3 alkyl group; ' ₈ represents a methyl group; R ₁₀ and R ₁₁ independently represent a hydrogen atom, a fluorine atom or a trifluoromethyl group; X ₁ and X ₂ independently represent a hydrogen atom, Alternatively, X ₁ , together with X ₂ , forms a valence bond; A is a 3,4-dihydroisoquinolinium derivative according to claim 10, which represents a bromide ion or an iodide ion. 12. A compound represented by the general formula (I) (wherein R is₁, R₂, R₃, R_Four, R_Five, R₆, R ₇ , R₈, R₉, R_Ten, R₁₁, X₁And X₂Is as defined in claim 1
Or a pharmaceutically suitable acid addition salt thereof or a general formula
(I ') (wherein R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R₈, R₉, R_Ten, R₁₁,
X₁And X₂Is as described above; R '₈And A are defined in claim 1.
In the method for producing the quaternary derivative represented by   a) In the general formula (Ib), R₁, R₂, R₃, R_Four, R₇, R_TenAnd R₁₁But one
As defined in relation to general formula (I); X₁Is X₂Form a valence bond with
To prepare an isoquinoline derivative of formula (II) [Chemical 9] (In the formula, R₁, R₂, R₃, R_FourAnd R₇Is as described above) 1-
Methyl isoquinoline is represented by the general formula (III) [Chemical 10] (In the formula, R_TenAnd R₁₁Is as defined in relation to general formula (I))
Condensed with an aldehyde   b) In the general formula (Ib), R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁as well as
X₂Is an isoquinoline derivative as defined in relation to general formula (I).
General formula (IV) for manufacturing [Chemical 11] (In the formula, R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂As above
And R₁₃Represents a hydrogen atom) 3,4-dihydroisoquinoline derivative represented by
Subjecting the body to catalytic dehydrogenation; or   c) In the general formula (Ia), R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁as well as
X₂Is as defined in relation to general formula (I); R₈Is a hydrogen atom 1
In order to prepare a 1,2,3,4-tetrahydroisoquinoline derivative, the compound of general formula (IV)
By the way, R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂But as above
And R₁₃Hydrogenates a 3,4-dihydroisoquinoline derivative in which is a hydrogen atom
; Or   d) In the general formula (Ia), R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁as well as
X₂Is as defined in relation to general formula (I); R₈Is C_1-4Alkyl group
To prepare a 1,2,3,4-tetrahydroisoquinoline derivative of formula
(V) [Chemical 12] (In the formula, R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂As above
And R₁₂Is C_1-4Represents an alkyl group; A is defined in relation to general formula (I ′)
A 3,4-dihydroisoquinolinium derivative represented by
React with an agent; or   e) In the general formula (Ib), R₁, R₂, R₃, R₇, R_Ten, R₁₁, X₁And X₂But
, As defined in relation to general formula (I); R_FourBut trifluoromethyl
In order to prepare an isoquinoline derivative representing a group, in the general formula (IV), R₁, R₂ , R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂, As described above; R₁₃Is C_1-4 A 3,4-dihydroisoquinoline derivative representing an alkoxy group is treated with an alkali metal hydroxide.
React with a compound; or   f) In the general formula (Ib), R₁, R₂, R₃, R₇, R_TenAnd R₁₁However, the general formula (
As defined in relation to I); R_FourRepresents a trifluoromethyl group; X₁ Is X₂To prepare isoquinoline derivatives that form valence bonds with
Formula (VI) in the presence of the agent [Chemical 13] (In the formula, R₁, R₂, R₃, R_FourAnd R₇Is as described above; R₁₃Is C_1-4Al
1-methyl-3,4-dihydroisoquinoline represented by
In formula (III), R_TenAnd R₁₁Is reacted with an aldehyde as described above
; Or   g) In the general formula (XIV), R₁, R₂, R_Four, R_Five, R_Ten, R₁₁, X₁And X₂
Is 3,4-dihydroisoquinoline as defined in relation to general formula (I)
To prepare a derivative of the general formula (VIII) [Chemical 14] (In the formula, R₁, R₂, R_Four, R_Ten, R₁₁, X₁And X₂Is as described above; R₃ Represents a hydrogen atom; and R₁₃Represents a hydrogen atom or a trifluoromethyl group)
Cyclizing the acid amide represented by: or   h) In the general formula (XI), R₁, R₂, R_Four, R '₈, R_Ten, R₁₁, X₁And X₂
Is as defined in relation to general formula (I); A is a compound of formula HA
In order to prepare a 3,4-dihydroisoquinoline derivative representing a residue of organic acid,
(XII) [Chemical 15] (In the formula, R₁, R₂, R_Four, R_Ten, R₁₁, X₁And X₂Is as defined above.
A 3,4-dihydroisoquinoline derivative represented by the general formula     R '₈-A (In the formula, R '₈And A is as described above); or   i) In the general formula (XI), R₁, R₂, R_Four, R '₈, R_Ten, R₁₁, X₁And X₂
Is as defined in relation to general formula (I); A is a compound of formula HA
In order to prepare a 3,4-dihydroisoquinolinium derivative which is a residue of organic acid,
General formula (XIII) [Chemical 16] (In the formula, R₁, R₂, R_Four, R '₈, R_Ten, R₁₁, X₁And X₂Is as described above
A 1,2,3,4-tetrahydroisoquinolinium derivative represented by
And, if desired,   In the general formula (I), R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R₈, R₉, R_{1 0} And R₁₁Is as defined in relation to general formula (I); X₁Is X₂With
The compound obtained by forming a valence bond with the compound of formula (I)
At X₁And X₂Is converted to the corresponding compound in which is a hydrogen atom; or   In the general formula (Ia), R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂
Is as defined in relation to general formula (I); R₈Is a hydrogen atom
The 1,2,3,4-tetrahydroisoquinoline derivative_1-4Alkyl halogen
In the general formula (Ia), R₈Is C_1-4Is an alkyl group
Convert to compound; or   The obtained compound represented by the general formula (I) is converted into a pharmaceutically suitable acid adduct.
Or free the base from the salt; or   The obtained compound represented by the general formula (I) is represented by the general formula     R '₈-A (In the formula, R '₈And A are as described below).
And in the general formula (I ′), R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R₈, R₉,
R_Ten, R₁₁, X₁And X₂Is as defined in relation to general formula (I); R
'₈Is C_1-4Represents an alkyl group; A is a residue of an inorganic acid or organic acid represented by the formula HA
Is converted to a quaternary derivative;   In the general formula (I'b), R₁, R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂ Is as defined in relation to general formula (I); R '₈Is C_1-4Alkyl group
The obtained quaternary a represents a residue of an inorganic acid or an organic acid represented by the formula HA.
By reacting a soquinoline derivative with a reducing agent, in the general formula (Ia), R₁,
R₂, R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂Is as described above; R₈But
C_1-4Isoquinoline derivative characterized by conversion into a compound representing an alkyl group
, A method for producing a pharmaceutically suitable acid addition salt or quaternary derivative thereof. 13. General formula (I) (in the formula, R₁, R₂, R₃, R_Four, R_Five, R₆, R ₇ , R₈, R₉, R_Ten, R₁₁, X₁And X₂Is as defined in claim 1
Is present), an isoquinoline derivative represented by the formula, a pharmaceutically suitable acid addition salt thereof, or a general formula
(I ') (wherein R₁, R₂, R₃, R_Four, R_Five, R₆, R₇, R₈, R₉, R_Ten, R₁₁,
X₁And X₂Is as described above; R '₈And A are defined in claim 1.
And a quaternary derivative represented by
A pharmaceutical composition, characterized in that it contains the abovementioned common carriers. 14. General formula (Ia) (in the formula, R₁, R₂, R₃, R_Four, R₇, R₈, R _Ten , R₁₁, X₁And X₂Is as defined in claim 2)
1,2,3,4-tetrahydroisoquinoline derivative, a pharmaceutically suitable acid addition salt thereof,
Or general formula (I'a) (wherein R₁, R₂, R₃, R_Four, R₇, R₈, R_Ten, R₁₁, X₁Over
And X₂Is as described above; R '₈And A are defined in claim 2.
A quaternary derivative represented by the formula (1) is contained as an active ingredient.
The pharmaceutical composition according to claim 13, wherein 15. General formula (Ib) (in the formula, R₁, R₂, R₃, R_Four, R₇, R_Ten,
R₁₁, X₁And X₂Is as defined in claim 4)
Norrin derivatives, pharmaceutically suitable acid addition salts thereof, or general formula (I'b) (wherein R is₁, R ₂ , R₃, R_Four, R₇, R_Ten, R₁₁, X₁And X₂Is as described above; R '₈as well as
A is as defined in claim 4), a quaternary derivative represented by
14. The pharmaceutical composition according to claim 13, which is contained as an active ingredient. 16. A compound represented by the general formula (XIV) (wherein R ₁ , R ₂ , R ₄ , R ₅ , R ₁₀ and R _{11 are:}
, X ₁ and X ₂ are as defined in claim 6, and 3,4-
14. The pharmaceutical composition according to claim 13, comprising a dihydroisoquinoline derivative or a pharmaceutically suitable acid addition salt thereof as an active ingredient. 17. A compound represented by the general formula (XI) (wherein R ₁ , R ₂ , R ₄ , R ′ ₈ , R ₁₀ and R _{11 are:}
, X ₁ , X ₂ and A are as defined in claim 9) 3
The pharmaceutical composition according to claim 13, which comprises a 4,4-dihydroisoquinolinium derivative as an active ingredient. 18. A non-toxic dose of the general formula (I), wherein R₁, R_Two, R_Four, R '
₈, R₁₀, R₁₁, X₁And X_TwoIs as defined in claim 1.
) Or a pharmaceutically suitable acid addition salt thereof, or general formula (I ′) (wherein R₁, R_Two, R
_Three, R_Four, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, X₁And X_TwoIs
As defined above, R₈And A are as defined in claim 1.)
The 3,4-dihydroisoquinolinium derivative represented by
How to treat an affected patient. 19. In a method for producing a pharmaceutical composition having an anxiolytic effect, in particular, a compound represented by the general formula (I) (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R _{7 are used).} , R ₈ , R ₉ ,
R ₁₀ , R ₁₁ , X ₁ and X ₂ are as defined in claim 1), an isoquinoline derivative represented by the formula, a pharmaceutically suitable acid addition salt thereof, or a general formula (I ′) (in the formula,
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , X ₁ and X ₂ are
As above; R ′ ₈ and A are as defined in claim 1)
A method for producing a pharmaceutical composition, which comprises converting the quaternary derivative represented by: into a pharmaceutical composition using one or more common carriers.