SK1212002A3 - Isoquinoline derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance - Google Patents

Abstract

The invention refers to novel isoquinoline derivatives of formula (I), pharmaceutical compositions containing the same, and a process for the preparation of the active ingredient. The novel compounds have an influence on the central nervous system, and possess especially anxiolytic effect.

Description

Isoquinoline derivatives, pharmaceutical preparations containing them and method of preparation of the active substance

Technical field

The present invention. This invention relates to novel isoquinoline derivatives, to pharmaceutical compositions containing them, and to a process for the preparation of an active substance. The novel compounds of the invention affect the central nervous system and show in particular anxiolytic activity.

SUMMARY OF THE INVENTION

In particular, the present invention relates to novel isoquinoline derivatives of formula I

where

R 1, R 2 and R 1 independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C 1-4 alkoxy group, or

R ₂ forms with R methylenedioxy or ethylenedioxy,

R 4 represents a hydrogen atom, a C 1-4 alkoxy group or a trifluoromethyl group,

R 7 represents a hydrogen atom or a C 1-4 alkyl group,

R 8 represents a hydrogen atom or a C 1-4 alkyl group,

R 5, R fc, R g independently represent a hydrogen atom, or

R 5 forms a valence bond with R 6 and simultaneously

Rg forms a valence bond with Rg,

Rio and R | 1 independently represents a hydrogen atom, a halogen atom, a nitro group, a C 1-4 alkoxy group, a trifluoromethyl group or a cyano group,

X 1 and X 2 are independently hydrogen or X 1 forms a valence bond with X 2, furthermore their pharmaceutically acceptable acid addition salts and their quaternary derivatives of the general formula

R

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 'is C 1-4 alkyl, and

A is a residue of an inorganic acid or an organic acid of formula HA;

or in formula I

R and R ₂ are as defined above,

R 3, R 6 and R 7 are independently hydrogen,

Rs forms a valence bond with R9,

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 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 are independently hydrogen or X 1 forms a valence bond with X ₂ , furthermore their pharmaceutically acceptable acid addition salts;

or in formula I '

R and R ₂ are as defined above,

R 3, R 5, R 6 and R 7 are independently hydrogen,

Rg forms a valence bond with R9,

R4 represents a hydrogen atom or a C1-6 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 are independently hydrogen or

Xi forms a valence bond with X ₂ ,

R 1 represents a C 1-4 alkyl group and

A is a radical of an inorganic or organic acid of formula HA.

1-Styrylisoquinoline derivatives having anxiolytic activity are known from French patent application 2,719,586. In EP-A no. No. 787,493 discloses tetrahydroisoquinoline derivatives. These known compounds are useful against neurodegenerative diseases, schizophrenia, anxiety and depression.

Isoquinoline derivatives useful in the treatment of fungal infections are known from U.S. Pat. 3,4-Dihydro-6,7-dimethoxyisoquinolines having platelet function inhibiting properties are described in GB patent no. No. 1,181,959 and DE-OS no. 6,7-Dimethoxyisoquinoline derivatives having the same effect are known from DE-OS no. 1 902 402

1,2,3,4-Tetrahydroisoquinolines having analgesic, spasmolytic, antitussive and hypotensive effects are known from U.S. Pat. 410 007.

It is an object of the present invention to provide isoquinoline derivatives having better activity than the known compounds.

It has been found that this object is achieved by compounds of the formulas I and I 'which have a significant anxiolytic effect in the so-called light-dark transition test, and such an effect is not shown in the known 1-aryl-isoquinoline derivatives. Furthermore, the novel compounds do not induce or difficultly induce key enzymes of the liver metabolism that is part of the drug metabolism.

In the description and claims, in the definitions of substituents, the term halogen atom refers in particular to a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

A C _1-4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl group, preferably a methyl group.

Ci. _An alkyl group means, in addition to the groups listed above for the definition of a C 1-4 alkyl group, for example, n-pentyl or n-hexyl.

C 1-4 alkoxy is especially methoxy, ethoxy, n-propoxy or n-butoxy, preferably methoxy.

A pharmaceutically acceptable acid addition salt is an acid addition salt formed with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, or a pharmaceutically acceptable organic acid, such as formic acid, acetic acid, fumaric acid, maleic acid, lactic acid. , malic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, etc.

In definition A, the acid HA is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.

A sub-group of compounds of the invention are 1,2,3,4-tetrahydroisoquinoline derivatives of the general formula

R

la kde

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

R1 forms, with R.2, a methylenedioxy or ethylenedioxy group,

R4 represents a hydrogen atom or a C1-4 alkoxy group,

R 7 represents a hydrogen atom or a C 1-4 alkyl group,

R 8 represents a hydrogen atom or 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 hydrogen or X 1 forms a valence bond with X ₂ ,

Furthermore, their pharmaceutically acceptable acid addition salts and their quaternary derivative of the general formula

where R 1, R ₂ , R ₁ , R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, Xi and X ₂ are as defined above,

R 'g represents a C 1-4 alkyl group, and

A is a residue of an inorganic acid or an organic acid of formula HA.

Preferably the 1,2,3,4-tetrahydroisoquinoline derivatives of formula Ia are those wherein

R 1 and R ₂ independently represent methoxy or

R ₂ forms with R methylenedioxy or ethylenedioxy,

R ₃ represents a hydrogen atom,

R ₄ represents a hydrogen atom,

R ₇ represents a hydrogen atom,

R 5 represents a hydrogen atom or a methyl group,

R 10 represents a halogen atom, a trifluoromethyl group or a methoxy group,

R 11 represents a hydrogen atom or a methoxy group,

X 1 and X ₂ are independently hydrogen or X 1 form a valence bond with X ₂ , furthermore pharmaceutically acceptable acid addition salts thereof and a quaternary derivative of the formula Ia wherein R 1, R ₂ , R ₃ , R ₄ , R 5, R 6, R 7, R 8, R 9, R 10, R 11, Xi and X ₂ is as defined above,

R 'is methyl, and

A is a halogen ion.

Another group of compounds of the invention are the isoquinoline derivatives of the general formula

where

R 1, R ₂ and R ₃ independently represent a hydrogen atom, a halogen atom, a hydroxy group or C 1-6 alkyl; ₄ alkoxy, or

R ₂ forms with R methylenedioxy or ethylenedioxy,

R 4 represents a hydrogen atom, a C 1-4 alkoxy group or a trifluoromethyl group,

R 7 represents a hydrogen atom or 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, a trifluoromethyl group or a cyano group,

X 1 and X ₂ are independently hydrogen or

X, forms a valence bond with X ₂ , furthermore their pharmaceutically acceptable acid addition salts and their quaternary derivative of the general formula

R

1b wherein R 1, R ₂ , R 3, R 4, R 7, R 10, R 11, X 1 and X ₂ are as defined above,

R 1g represents a C 1-4 alkyl group, and

A is a residue of an inorganic acid or an organic acid of formula HA.

Preferred isoquinoline derivatives of formula Ib are those wherein

R 1, R ₂ and R ₃ independently represent a hydrogen atom or a methoxy group, or

R ₂ forms with R methylenedioxy or ethylenedioxy,

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, 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

X 1 forms a valence bond with X 2, furthermore pharmaceutically acceptable acid addition salts thereof and a quaternary derivative of the formula Ib wherein R 1, R 2, R 3, R 4, R 7, R 10, R 11, X 1 and X 2 are as defined above,

R'g represents a methyl group, and

A represents a halogen ion.

Another group of compounds of the invention are the 3,4-dihydroisoquinoline derivatives of the general formula

where

R 1 and R 2 independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C 1-4 alkoxy group, or

R1 forms a methylenedioxy group or an ethylenedioxy group with R2,

R 4 represents a hydrogen atom, a C 1-4 alkoxy group or a C 1-8 alkyl group,

R 5 represents a hydrogen atom or a trifluoromethyl group,

Rio and R | 1 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 are independently hydrogen or

X 1 forms a valence bond with X 2, and pharmaceutically acceptable acid addition salts thereof.

Preferred 3,4-dihydroisoquinoline derivatives of formula XIV are those wherein

R 1 and R 2 independently represent a hydrogen atom, a chlorine atom, a hydroxy or a methoxy group;

R1 forms a methylenedioxy group or an ethylenedioxy group with R2,

R4 represents a hydrogen atom or a C1-6 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 are independently hydrogen or

X 1 forms a valence bond with X 2, and pharmaceutically acceptable acid addition salts thereof.

Particularly preferred 3,4-dihydroisoquinoline derivatives of formula XIV are those wherein

R1 forms a methylenedioxy group with R2,

R4 represents a C1-6 alkyl group,

R 5 represents a hydrogen atom or a trifluoromethyl group,

R 10 and R 11 independently represent hydrogen, methoxy or trifluoromethyl,

X 1 forms a valence bond with X 2, and pharmaceutically acceptable acid addition salts thereof.

I

An even more preferred class of compounds of the invention are the 3,4-dihydroisoquinolinium derivatives of the general formula

where

R 1 and R ₂ are independently hydrogen, halogen, hydroxy or C 1-4 alkoxy, or

R1 forms a methylenedioxy group or an ethylenedioxy group with R2,

R 4 represents a hydrogen atom or a C 1-10 alkyl group,

R < e > _An 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 hydrogen or

Xi forms a valence bond with X ₂ ,

A is a radical of an inorganic or organic acid of formula HA.

Preferred 3,4-dihydroisoquinolinium derivatives of formula XI are those wherein

R 1 and R ₂ are independently hydroxy, chloro or methoxy, or

R ₂ forms with R methylenedioxy or ethylenedioxy,

R ₄ represents a hydrogen atom or a C 1-3 alkyl group,

R's is methyl,

R 10 and R 11 independently represent a hydrogen atom, a halogen atom or a trifluoromethyl group,

X 1 and X ₂ are independently hydrogen or

Xi forms a valence bond with X ₂ ,

A is an inorganic acid residue of formula HA.

Particularly preferred 3,4-dihydroisoquinolinium derivatives of formula XI are those wherein

R ₁ forms, with R _2, methylenedioxy or ethylenedioxy,

R ₄ is H or C 1 -3 alkyl,

R'e 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 are independently hydrogen or

Xi forms a valence bond with X ₂ ,

A represents a bromide ion or an iodide ion.

The compounds of the invention are prepared as follows:

a) the preparation of the isoquinoline derivatives of the formula Ib, wherein R, R _2, R 3, R 4, R 7, R and R are as defined in connection with the general formula I, Xj with X ₂ form a valence bond, condensation of 1-methyl-isoquinoline of the formula

wherein R 1, R ₂ , R 3, R 4 and R 7 are as defined above, with an aldehyde of general formula

R

ABOUT

wherein R 10 and R 11 are as defined in connection with general formula I;

or

b) the preparation of the isoquinoline derivatives of the formula Ib, wherein R, R _2, R 3, R 4, R 7, R, R 11, X and X ₂ are as defined in connection with the general formula I, is subjected to a 3,4-dihydroisoquinoline derivative of formula

R

IV wherein R 1, R ₂ , R 3, R ₄ , R _7, R ₁₀ , R 11, X 11; and X ₂ are as defined above, R 1 ₃ represents a hydrogen atom, catalytic dehydrogenation; or

c) for the preparation of 1,2,3,4-tetrahydroisoquinoline derivative of the formula Ia, wherein R, R _2, R _3, R _4, R _7, R _10, R, X | and X ₂ are as defined in connection with the general formula I, R is H, by hydrogenation 3,4dihydroizochinolínového derivative of formula IV wherein R _b R _2, R 3, R _4, R _7, R, R, X, and X ₂ are R13 is hydrogen; or

d) in the preparation of a 1,2,3,4-tetrahydroisoquinoline derivative of the general formula Ia, wherein R _b R ₂ , R ₃ , R ₄ , R ₇ , R ₇ , R ₇ , R ₇ , R ₇ , R ₇ , R ₇ and R ₇ ; _O , R _H , X 1 and X ₂ are as defined in connection with the general formula I, R 8 represents a C _1-4 alkyl group, by reaction of a 3,4-dihydroisoquinolinium derivative of the general formula

wherein R _t, R _2, R 3, R 4, R 7, R, R, X, and X ₂ are as defined above, R) ₂ represents C 1-4 alkyl, A is as defined for formula I ', with a reducing agent ; or

e) for the preparation of the isoquinoline derivatives of the formula Ib, wherein R, R 2, R 3, R 7, RJO, R, X, and X ₂ majú'význam as defined in connection with formula I, R 4 is trifluoromethyl, by reacting a derivative of formula 3,4dihydroizochinolínového IV wherein R 1, R ₂ , R 3, R 4, R ₇ , R 10, R 11, X 1 and X ₂ are as defined above, R 13 is Cl. ₄ alkoxy, with an alkali metal hydroxide; or

f) the preparation of the isoquinoline derivatives of the formula Ib, wherein R, R _2, R 3, R 7, R and R a are as defined for formula I, R ₄ is trifluoromethyl, X forms with X ₂ a valence bond, reaction of l -methyl-3,4-dihydroisoquinoline of formula

VI wherein R 1, R 2, R 3, R 4 and R ₇ are as defined above, R 13 represents a C 1-4 alkyl group, with an aldehyde of formula III, wherein R 10 and R 11 are as defined above, in the presence of a condensing agent; or

I

g) in the preparation of a 3,4-dihydroisoquinoline derivative of the general formula XIV wherein R 1, R 2, R 4, R 5, R 10, R 11, X 1 and X 2 and have the meaning given in connection with the general formula I

VIII wherein R 1, R 2, R 4, R 10, R 11, X 1 and X 2 are as defined above, R 3 is hydrogen and R 13 is hydrogen or trifluoromethyl; or

h) in the preparation of a 3,4-dihydroisoquinolinium derivative of the general formula XI wherein R 1, R 2, R 4, R 1e, R 10, R 11, X 1 and X 2 are as defined in connection with the compound of the general formula I HA, by reacting a 3,4-dihydroisoquinoline derivative of the general formula

wherein R 1, R-2, R ₄ , R 10, R 11, X 1 and X 2 are as defined above, with a reagent of the general formula R 1g-A, wherein R 1g and A are as defined above;

or

(i) in the preparation of a 3,4-dihydroisoquinolinium derivative of the general Formula XI wherein R 1, R ₂ , R 4, R 8, R 10, R 11, X 1 and X ₂ are as defined in connection with a compound of the Formula I of formula HA, by reacting a 1,2,3,4-tetrahydroisoquinolinium derivative of formula

where R 1, R ₂ , R ₄ , R ₈ , R _{8 O} , R 11, X 1 and X ₂ are as defined above, with an oxidizing agent;

and, if desired, converting a compound of formula I, wherein R 1, R ₂ , R 3, R 4, R 5, R 6, R ₇ , R 8, R 8, R 10, R 11, are as defined in connection with Formula I, X 1 forms a valence bond with X ₂ , by catalytic hydrogenation to the corresponding compound of formula I, wherein X | and X ₂ represents a hydrogen atom; or converting the obtained 1,2,3,4-tetrahydroquinoline derivative of formula (Ia) wherein R 1, R ₂ , R 3, R ₄ , R 7, R 10, R 11, X 1 and X ₂ are as defined in connection with formula I R 8 represents a hydrogen atom, by reaction with a C 1-4 alkyl halide to give a compound of formula Ia wherein R 8 represents a C 1-4 alkyl group; or converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt or liberating the base from its salt; or converting a compound of formula I obtained into a quaternary derivative of formula I ', 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 in in conjunction with Formula I, R 'is C 1-4 alkyl, A is an inorganic or organic acid radical of formula HA, by reaction with a compound of formula R'g-A, wherein R'g and A are as defined above; or converting the obtained quaternary isoquinoline derivative of the general formula Ib wherein R 1, R ₂ , R ₃ , R ₄ , R ₇ , R ₁₀ , Ru, X 1 and X ₂ have the meaning given in connection with the general formula I, R'g denotes Ci. ₄ alkyl group, A is the radical of an inorganic or organic acid HA, the compound of formula Ia, wherein R, R _2, R _3, R _4, R 7, R _0, R, X, and X ₂ are as defined above, R is C C _1-4 alkyl, by reaction with a reducing agent.

In process (a) according to the invention, the 1-methylisoquinoline of the formula II is condensed with the aldehyde of the formula III using the procedure known from the French patent application published under No. 2,719,586.

In process b) according to the invention, the 3,4-dihydroisoquinoline derivative of general formula IV is dehydrogenated in an analogous manner known from the literature [Heterocyclic Compounds, 38, 386-387, Ed. John Wiley & Sons, Inc., New York, (1994)].

In process c) of the invention, the 3,4-dihydroisoquinoline derivative is hydrogenated using a method known in the literature [Houben-Weyl: Met. Org. Chem., 4 (1c), 121, 271-281, 365, 401, Georg Tieme Verlag, Stuttgart, (1981)].

In process d) of the invention, the reduction of the 3,4-dihydroisoquinolinium derivative of general formula V is carried out using methods described in the literature and cited in connection with process c).

In process e) according to the invention, the alkoxy group at the 4-position is eliminated with an alkali metal hydroxide, preferably potassium hydroxide.

Process f) according to the invention can be carried out in a similar manner to process a). Carboxylic acid anhydride, preferably acetic anhydride, is preferably used as condensing agent.

In process g) of the invention, the amide of formula VIII is cyclized according to a method known from the literature [Heterocyclic compounds, ed. J. Wiley & Sons, Inc. 38, 3, 85-89 (1994); 38, 1, 173-175 (1994)].

In process h) according to the invention, a reagent of the formula R'g-A, preferably a C 1-4 alkyl halide, in particular methyl iodide or methyl bromide, is used and the reaction is carried out in the presence of an indifferent organic solvent at a temperature generally 10 to 160 ° C. The organic solvent may be non-polar, such as benzene, toluene, xylene, dichloromethane, etc. or a polar protic solvent such as methanol, ethanol, etc.

Process i) according to the invention is carried out in an analogous manner known from the literature [Houben-Weyl, Met. Org. Chem., Georg Tieme Verlag, Stuttgart, 4/1c, 517-518 (1981)].

The obtained isoquinoline derivative can be converted to another compound of formula I in a known manner.

For example, a styryl derivative wherein X 1 forming a valence bond with X 2 can be converted to a compound of formula I wherein X 1 and X 2 are hydrogen by catalytic hydrogenation [Houben-Weyl, Met. Org. Chem., 4, Id, 580-581, Georg Tieme Verlag, Stuttgart, (1981)].

The nitrogen atom of the 1,2,3,4-tetrahydroisoquinoline derivative of formula (Ia) wherein Rg is hydrogen may be alkylated in a known manner, for example using an alkyl halide.

A compound of formula I can be reacted with a compound of formula R'g-A, preferably a C 1-4 alkyl halide to give a quaternary compound of formula I '. The reaction is carried out in a non-polar organic solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, etc. or in a polar solvent such as an alkanol at a temperature of 10 to 160 ° C.

The quaternary isoquinoline derivative of the formula Ib can be reduced to give the corresponding 1,2,3,4-tetrahydroisoquinoline derivative of the formula Ia. The reduction is carried out using methods described in the literature cited in connection with process c).

1-Methylisoquinoline derivatives of the general formula II known compounds. Compounds of formula II wherein the trifluoromethyl group may be prepared by reaction of dihydroisoquinoline and potassium hydroxide.

are partially R ₄ is 1-methyl-1,21-methyl-1,2-dihydroisoquinoline by general cyclization of the acid amide of formula VI

wherein R 1, R ₂ and R 3 are as defined in connection with formula I, R 4 is trifluoromethyl, R 13 is C 1-4 alkoxy. The cyclization reaction is carried out in a manner known per se, as described in the literature [Heterocyclic Compounds, eds. J. Wiley & Sons, Inc., 38/3, 65-89 (1994); 38, 1, 173-175 (1994)].

The aldehydes of formula III are known compounds and are commercially available.

The 1,2-dihydroisoquinoline derivatives of formula (IV) are novel compounds prepared by cyclization of an acid amide of formula (VIII) wherein R 1, R ₂ , R 3, R 4, R 10, R 11, X 1 and X ₂ have the meaning in connection with formula I, R13 is C1-4 alkoxy. The cyclization reaction is carried out in an analogous manner to the cyclization of the acid amide of formula VII.

An acid amide of formula VIII can be prepared by reaction of an acid derivative of formula

wherein R 10, R 11, X 1 and X ₂ are defined in connection with formula I, with phenylethylamine of formula

X wherein R 1, R ₂ , R 3 and R 4 are as defined in connection with the general formula I, R 1 represents a C 1-4 alkoxy group analogously to the literature described [Houben-Weyl: Met. Org. Chem., E5 / 2, 993-1100, Georg Tieme Verlag, Stuttgart, (1981)].

The acid derivatives of the formula IX and the phenylethylamines of the formula X are commercially available.

Trifluoromethyl derivatives of formula X can be prepared from the corresponding cyanohydrin of formula

wherein R |, _R2, R 4 and R @ 5 are as defined above by reduction.

The cyanohydrin of the formula VI can be obtained by reaction of the corresponding acetophenone of the formula

XVI where R | and _R2 are as defined above, with an alkali metal cyanide.

1,2-dihydroisoquinolinium derivative of formula V can be prepared from the corresponding 1,2-dihydroisoquinoline by reaction with an alkylating agent of formula R ₂ N, wherein R | ₂ represents a C 1-4 alkyl group, A represents an inorganic or organic acid radical of formula HA.

The 3,4-dihydroisoquinoline derivative of formula XII is prepared by cyclizing the acid amide of formula VIII. The cyclization reaction is carried out as described for cyclization of the amide (VII).

The pharmacological activity of the compounds of the invention was determined by the following experiments.

1. Transition from light to dark

Male NMRI mice weighing 18-38 g were used for the experiment. Animals were maintained in reverse light-dark cycles for 2 weeks prior to experiment in polycarbonate cages. Behavior testing was performed in two compartments (light and dark) of automated test chambers, horizontal and vertical activities were recorded by interrupting the infrared rays. Test compounds were suspended in a 0.4% methylcellulose solution and administered intraperitoneally 30 minutes prior to testing. Therefore, exploring the new environment is limited. Anxiolytic compounds reduce the time spent in the dark area and / or increase the activity of the light compartment. Test compounds are considered to be effective when the time spent investigating changes substantially with respect to time with untreated controls in one or both compartments.

Minimum effective doses (i.e., the lowest dose producing statistically significant effects) were determined for each compound tested [Costall, B. et al.,

Pharm. Biochem. Behav., 32, 777-785 (1989); Young, R. and Johnson, D. N., Pharm. Biochem. Behav., 40, 739-743 (1991)].

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

Table I

Compound (Example No.) Minimum Effective Dose (mg / kg i.p.) 21 10 47 10 51 30 53 10 55 3 82 10 83 30 84 1 1- (4-Trifluoromethylstyryl) -6,7- methylenedioxy isoquinoline over 30

The data in Table I show that the test compounds of the invention show substantial activity in the light-dark transition assay, while the known reference compound is ineffective.

2. Measurement of spontaneous physical activity

Each group contained 30 animals (15 male and 15 female) weighing 20-25 g. Animals were treated with test compound or vehicle (control group). Test compounds were suspended in a 0.4% methylcellulose solution and administered orally to animals at 20 ml / kg 60 minutes prior to the test. The method provides general information on the effect of the test compound on the natural physical activity of the test animals, particularly on sedative effects. For anxyolithic compounds, the presence or absence of sedative capacity is critical for further development (absence is desirable). The measurement was performed in a 10-channel "Digital motility meter". Movement activity of three mice on the channel was determined by recording the number of interruptions of three infrared rays over 30 minutes. The ID 50 (dose causing 50% inhibition) was determined for each compound [Borsy, I. et al., Ar. Int. Pharmacodyn., 124,180-189 (1960); Stille, G. et al., II Farmaco Ed. Ex., 26, 603-625 (1971)].

The results are summarized in Table II. Diazepam [i.e. 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one].

Table II

Compound (Example #) ID 50 (mg / kg p.o.) 10 100 21 100 45 100 47 100 53 100 55 100 82 100 83 100 84 100 diazepam 18.4

The data in Table II clearly shows that the compounds of the invention do not affect spontaneous locomotor activity even at doses more than five times higher than the ID 50 value for diazepam.

3. Measurement of enzyme induction

Wistar rats weighing 140-160 g were used for the experiments. The test compounds were suspended in a 0.4% methylcellulose solution and administered at 100 mg / kg daily orally for 3 consecutive days. As a positive control, β-naphthoflavone per os at a dose of 25 mg / kg was used. A typical reaction for the CYP1A isoenzyme was followed by activity on ethoxyresorphinindeetylase (EROD) according to the method described by Pohl, R.J. and Fouts, J.R., Anal. Biochem., 107, 150-155 (1980). Control values obtained in untreated animals were considered 100% and activity on EROD was expressed as a percentage of untreated control. The results so obtained are summarized in Table III. 1- (4-Trifluoromethylstyl) -6,7-methylenedioxyisoquinoline was used as reference compound.

Table III

Compound (Example #) Relative activity of EROD (percent control) 10 99 21 87 45 103 47 102 51 133 53 74 55 111 82 114 83 97 84 75 1- (4-Trifluoromethylstyry) -6,7- metyléndioxyizochinolín 570 β-naftoflavón 550

The data in Table III clearly shows that treatment with the reference isoquinoline derivative resulted in a more than a 5-fold increase in enzyme activity (similar to β-naphthoflavone used as a positive control), while the results obtained with the compounds of the invention are approximately the same as the untreated control.

The experimental results summarized above show that the compounds of the invention exhibit significant central nervous system effects, in particular anxiolytic effects. Anxiolytic activity is significant in the light-dark transition assay, while the known 1-styrylisoquinoline derivatives were virtually ineffective in this assay. In addition, the novel compounds do not affect the motional dose at a dose that is more than five times higher than the ID 50 of the reference compound of diazepam.

In contrast to known anxiolytic 1-styrylisoquinoline derivatives, the compounds of the invention do not affect the key enzymes of hepatic drug metabolism. The low and insignificant enzyme induction potency of the novel compounds is very important with respect to drug safety.

Thus, the novel isoquinoline derivatives of the formula I can be used as active ingredients of pharmaceutical compositions.

The pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable acid addition salt thereof, or a quaternary derivative of a compound of Formula I, and one or more conventional carriers.

The pharmaceutical compositions of the invention are suitable for oral, parenteral or rectal administration or for topical treatment and may be solid or liquid.

Solid pharmaceutical compositions suitable for oral administration may be powders, capsules, tablets, film-coated tablets, microcapsules, and may contain binders such as gelatin, sorbitol, poly (vinylpyrrolidone), etc; fillers such as lactose, glucose, starch, calcium phosphate, etc .; tabletting aids such as magnesium stearate, talc, poly (ethylene glycol), silica, etc .; wetting agents such as sodium lauryl sulfate, etc., as a carrier.

Liquid pharmaceutical compositions suitable for oral administration may be solutions, suspensions or emulsions and may contain, for example, suspending agents such as gelatin, carboxymethylcellulose; emulsifiers such as sorbitan monooleate, etc .; solvents such as water, oils, glycerol, propylene glycol, ethanol, etc .; preservatives such as methyl p-hydroxybenzoate etc. as a carrier.

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

The dosage forms mentioned above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, USA (1990).

The pharmaceutical compositions according to the invention generally contain from 0.1 to 95.0% by weight. a compound of formula I or a pharmaceutically acceptable addition salt or quaternary derivative thereof. A typical adult patient dose is 0.1 to 1000 mg of a compound of Formula I per day. The above dose may be administered in one or more portions. The actual dose depends on a number of factors and is determined by the physician.

The pharmaceutical compositions of the invention are prepared by mixing a compound of formula I or a pharmaceutically acceptable acid addition salt or quaternary derivative of formula I 'with one or more carriers and converting the resulting mixture into a pharmaceutical composition in a conventional manner. Useful methods are known in the literature, for example Remington's Pharmaceutical Sciences mentioned above.

One subset of pharmaceutical compositions of the invention comprises

1,2,3,4-tetrahydroisoquinoline of the formula I or a pharmaceutically acceptable acid addition salt thereof or a quaternary derivative of the formula Ia.

Another subgroup of pharmaceutical compositions of the invention comprises an isoquinoline derivative of Formula Ib or a pharmaceutically acceptable acid addition salt thereof or a quaternary derivative thereof of Formula Ib.

Another subgroup of pharmaceutical compositions of the invention comprises a 3,4-dihydroisoquinoline derivative of the Formula XIV or a pharmaceutically acceptable acid addition salt thereof.

Yet another subgroup of pharmaceutical compositions of the invention comprises a 3,4-dihydroisoquinolinium derivative of Formula XI.

The invention further encompasses a method of treating a patient suffering, in particular, from a central nervous system disorder comprising treating a nontoxic dose of a 3,4-dihydroisoquinoline derivative of formula I or a pharmaceutically acceptable acid addition salt or quaternary derivative of formula Γ.

Further, the invention encompasses the use of an isoquinoline derivative of Formula I, or a pharmaceutically acceptable acid addition salt thereof, or a quaternary derivative thereof of Formula I ', for the preparation of a pharmaceutical composition having anxiolytic effect.

The invention is further illustrated by the following examples. These examples are given by way of illustration only and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of Acid Amides of Formula VII

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

To a solution of 12.46 g (50 mmol) of 3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine in 90 cm ³ of ethyl acetate was added dropwise at 0 DEG C. 4.91 cm ³ (5, 31 g (52 mmol) of acetic anhydride. The reaction mixture is stirred at room temperature for 2 hours and then poured into 90 cm @ ^{3 of} water. The two phases are separated. The aqueous phase is extracted twice using 60 cm ^{3 of} ethyl acetate each time. The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated. There was thus obtained 14.5 g (98%) of a colorless title compound.

Mp: 74-75 ° C (2-propanol-water).

For C 13 H 16 F 3 NO 3 (291.27) calculated: C 53.61%, H 5.54%, N 4.81%;

found: C 53.48%, H 5.50%, N, 4.75%.

IR (KBr, cm ^-1 ): 3330, 1613, 1119.

1 H-NMR (CDCl 3 250 MHz) δ 7.34 (1H, t, J = 8.3 Hz), 7.03 (2H, m), 6.93 (1H, s), 5.79 (1H, s), 4.13 (1H, ddd, H = 14.8 Hz, J = 5.4 Hz), 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 = 0.9 Hz), 1.99 (3H, s).

¹³ C-NMR (CDCl 3 62.9 MHz) δ: 170.1, 159.9, 135.0, 129.8, 124.9 (q, JCl = 288.8 Hz), 119.6, 114, 5, 113.9, 80.7 (q, ² JCF = 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

Following the procedure described for the preparation of the starting compound 1), the title compound is obtained. Yield: 98%.

Mp .: 119-120 ° C (2-propanol-water).

For C13H14F3NO4 (305.25) calculated: C 51.15%, H 4.62%, N 4.59%;

found: C 5 1.38%, H 4.67%, N 4.69%.

IR (KBr cm ^-1 ): 3340, 1679, 1171, 1111.

1 H-NMR (CDCl 3 200 MHz) δ: 6.97 (1H, s), 6.93 (1H, d J = 8.2 Hz), 6.83 (1H, d, J = 8.2 Hz) 6.00 (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), 3.89 (1H, ddq, J = 14.8 Hz, J = 5.3 Hz, J = 1.2 Hz), 3.33 (3H) , s), 1.99 (3H, s).

¹³ C-NMR (CDC13, 100.6 MHz) δ 170.0, 148.2, 126.8, 124.7 ^(q, J CF = 288.0 Hz), 121.1, 108.2, 107 Δ, 101.4, 80.3 (q, ² J _CF = 26.6 Hz), 52.2, 40.7, 23.1.

Preparation of 1-methyl-3,4-dihydroisoquinolines VI

3) 1-Methyl-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline, 2.91 g (10 mmol) of N-acetyl-1,3,3,3-trifluoro-2-methoxy-2- The (3-methoxyphenyl) propylamine is stirred in 4.46 cm ³ (7.67 g, 50 mmol) of phosphorus oxychloride at 85 ° C for 16 hours. The reaction mixture was cooled to room temperature and poured into 40 ice water. The pH is adjusted to 11 with concentrated aqueous ammonia and the solution is extracted three times using 30 cm of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and evaporated. The crude base was recrystallized from aceonitrile. There was thus obtained 2.22 g (81%) of a colorless title compound.

mp: 203-204 ° C (acetonitrile).

For C13H14F3NO2 (273.25) calculated: C 57.14%, H 5.16%, N 5.13%;

found: C 57.27%, H 5.26%, N 5.11%.

IR (KBr, cm ^-1 ): 1609, 1247, 1178.

1 H-NMR (CDCl 3 250 MHz) δ: 7.56 (1H, d, J = 8.7 Hz), 7.19 (1H, dd, J = 2.6 Hz, J = 0.8 Hz), 7.00 (1H, dd, J = 8.7Hz, J = 2.6Hz), 4.12 (1H, dq, J = 17.5Hz, J = 1.5Hz), 4.02 ( 1H, dq, J = 17.5Hz, J = 1.5Hz), 3.88 (3H, s), 3.27 (3H, s), 2.39 (3H, t, J = 1.7Hz) ).

¹³ C-NMR (CDCl 3 62.9 MHz) δ: 162.7, 161.5, 131.2, 127.8, 125.1 (q, J _CF -287.2 Hz), 123.2, 1 14.7, 11.4, 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-1-3,4-dihydroisoquinoline

Following the procedure described for the preparation of the starting compound 3), the title compound is obtained, which is recrystallized from acetonitrile. Yield: 75%.

1.1. 203-204 ° C (acetonitrile).

For C13H12F3NO3 (287.23) calculated: C 54.36%, H 4.21%, N 4.88%;

found: C 54.19%, H 4.27%, N 4.79%.

IR (KBr, cm ^-1 ): 1606, 1286, 1173.

1 H-NMR (CDCl 3 400 MHz) δ: 7.13 (1H, q, J = 0.9 Hz), 7.07 (1H, s), 6.06 (1H, d, J = 0.9 Hz) ), 6.06 (1H, d, J = 1.3 Hz), 4.01 (1H, ddd, J = 16.8 Hz, J = 3.0 Hz, J = 1.5 Hz), 4, Δ (1H, dd, J = 16.8 Hz, J = 1.5 Hz), 3.24 (3H, s), 2.37 (3H, t, J = 1.7 Hz).

¹³ C-NMR (CDCl 3 100.6 MHz) δ: 162.4, 149.8, 148.9, 125.2, (q, ¹ JCF = 287.3 Hz), 125.1, 107.3 (q ³ JCf = 1.9 Hz), 106.4, 102.0, 75.2 (q, ² J _CF = 27.6 Hz), 52.1,

49.1, 23.6.

Preparation of 1-methylisoquinolines of formula II:

5) 1-Methyl-6-methoxy-4-trifluoromethylisoquinoline

To a solution of 2.73 g (10 mmol) of 1-methyl-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline in 20 cm @ ^{3 of} 2-propanol was added 0.84 g (15 mmol) of powdered potassium hydroxide. The reaction mixture was stirred at 50 ° C for 2 hours and then evaporated. The residue is triturated with 10 cm ^{3 of} water and filtered. The crystals are washed with 5 cm ^{3 of} water. The crude product is recrystallized from petroleum ether (b.p. 80-100 ° C). Thus, 2.05 g (85%) of a colorless title compound are obtained.

Mp .: 95-96 ° C (petroleum ether).

Analysis: for C ₁₂ H ₁₀ F ₃ NO (241.21) calculated: C 59.75%, H 4.18%, N 5.81%;

found: C 59.57%, H 4.13%, N 5.76%.

IR (KBr, cm ^-1 ): 1624, 1256, 1165, 1 126.

1 H-NMR (CDCl _3, 250 MHz) δ: 8.64 (1H, 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, 140.8 (q, ³ JCF = 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

Following the procedure described in the preparation of the starting compound 5), the title compound is obtained as a colorless solid. Yield 90%.

1.1. 139-141 ° C (petroleum ether, b.p. 80-100 ° C).

Analysis: for C | ₂ HgF ₃ NO ₂ (255.196) calculated: C 56.48%, H 3.16%, N 5.49%;

found: 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 (1H, s), 7.44 (1H, s), 7.40 (1H, q, J = 1.8 Hz), 6.17 ( 2H, s), 2.91 (3H, s).

¹³ C-NMR (CDCl 3 100.6 MHz) δ: 161.1, 151.8, 148.6, 139.3 (q, ³ JCF = 6.5 Hz),

130.1, 124.7 (q, J _CF = 273.1 Hz), 124.6, 118.6 (q, ² J _CF = 30.5 Hz), 102.2, 100.6, 23.3.

Preparation of acid amides of formula VIII:

7) N-Cinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

To a suspension of 12.36 g (50 mmol) of 3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propionitrile, 30 cm ^{3 of} diethyl ether, 50.30 g (50 mmol) of sodium carbonate and 50 cm ^{3 of} water are added. a solution of 8.33 g (50 mmol) of cinnamoyl chloride in 50 ml of diethyl ether is added dropwise at 0 ° C and the reaction mixture is stirred for 2 hours. The precipitated crystals are filtered and washed with 20 cm ^{3 of} diethyl ether. Thus, 16.39 g (90%) of the title compound are obtained.

Mp .: 72-73 ° C (2-propanol, water).

For C20H20F3NO3 (379.38) calculated: C 63.32%, H 5.31%, N 3.69%;

found: C 63.12%, H 5.27%, N 3.76%.

IR (KBr, cm ^-1 ): 1662, 1630, 1179.

1 H-NMR (CDCl 3 250 MHz) δ: 7.63 (1H, 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 (1H, dd, J = 15.0 Hz, J = 5.4 Hz), 3.83 (3H, s), 3.39 (3H, q, J = 0.8 Hz).

¹³ C-NMR (CDCl 3 50.3 MHz) δ: 165.7, 159.8, 141.7, 135.0, 134.6, 129.8, 129.7, 128.8, 127.8, 124 9 (q, 1 JCF = 288.4 Hz), 120.1, 11.5, 11.5, 11.6, 80.6 (q, ² JCF = 26.3 Hz), 55, 3, 52.6, 40.9.

8) N- (4-Fluorcinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

Following the procedure described for the preparation of the starting compound 7), the title compound is obtained as a colorless solid. Yield: 75%.

Mp .: 100-101 ° C (2-propanol, water).

For C20H19F4NO3 (397.37) calculated: C 60.45%, H 4.82%, N 3.52%;

found: C 60.3 1%, H 4.80%, N 3.55%.

IR (KBr, cm ^-1 ): 3293, 1661, 1628, 1227, 1149. 1 H-NMR (CDCl 3 250 MHz) δ: 7.59 (1H, 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, Δ (1H, ddd, J = 14.9 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, J _CF = 249.2 Hz), 159.7, 140.4, 134.8,

130.7, 119.6 (d, ² J _CF = 8.8 Hz), 129.3 (q, * J _CF = 289.1 Hz), 122.4, 119.6, 119.4,

117.8, 115.8 (d, ² JCF = 22.6 Hz), 114.3, 113.5, 80.5 (q, ² JCF = 27.2 Hz), 55.2,

52.5, 40.9.

9) N- (4-Trifluoromethylcinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

Following the procedure described for the preparation of the starting compound 7), the title compound is obtained as a colorless solid. Yield: 72%.

Mp .: 85-86 ° C (2-propanol, water).

For C21H19F6NO3 (447.38) calculated: C 56.38%, H 4.28%, N 3.13%;

found: C 56.45%, H 4.32%, N 3.18%.

IR (KBr, cm ^-1 ): 3436, 1672, 1324, 1133.

1 H-NMR (CDCl ₃ 400 MHz) δ: 7.64 (1H, d, J = 15.6 Hz), 7.64-7.60 (4H, m), 7.35 (1H, t, J = 8.2 Hz), 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 = 14.9 Hz, J = 5.4 Hz), 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, 140.1, 138.1, 134.9, 131.4 (q, ² JCF = 32.8 Hz), 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, 'J _C F = 288.0 Hz), 122.5, 1 19.5, 1 14.5, 1 13.6, 80.7 (q, ² J _CF = 26.7 Hz ), 55.4, 52.7, 41.2.

O) N - (4-N-trocinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

Following the procedure described in the preparation of the starting compound 7), the title compound is obtained as a pale yellow solid. Yield: 64%.

mp: 80-81 ° C (2-propanol, water).

For C20H19F3N2O5 (424.38) calculated: C 56.61%, H 4.51%, N 6.60%;

found: C 56.36%, H 4.52%, N 6.60%.

IR (KBr, cm ^-1 ): 1659, 1515, 1345, 1168, 1120.

1 H-NMR (CDCl 3 200 MHz) δ: 8.23 (2H, d,> 8.8 Hz), 7.67 (1H, d, J = 15.6 Hz), 7.65 (2H, d, J = 8.8 Hz), 7.37 (1H, t,> 8.2 Hz), 7.15-7.03 (2H, m), 7.00-6.90 (1H, m), 6 55 (1H, d, > 15.6 Hz), 6.02 (1H, t, J = 5.2 Hz), 4.30 (1H, dd, > 15.0 Hz, > 5.5 Hz) 4.04 (1H, ddq, > 15.0 Hz, > 5.5 Hz, > 1.6 Hz), 3.84 (3H, s), 3.40 (3H, s).

¹³ C-NMR (CDCl 3 50.3 MHz) δ: 164.7, 159.9, 148.3, 140.9, 139.2, 134.8, 129.9,

128.5, 124.9 (q, 'J _C F = 288.8 Hz), 124.3, 124.2, 1 19.5, 1 14.5, 1 13.6, 80.7 (q, ² J ( _CF = 26.3 Hz), 55.3, 52.7, 41.3.

3Ί

11) Following the procedure described in the preparation of the starting compound 7), the title compound is obtained as a colorless solid. Yield: 85%.

Mp: 104-106 ° C (2-propanol, water).

and

For C21H17F6NO4 (461.36) calculated: C 54.67%, H 3.71%, N 3.04%;

found: C 54.46%, H 3.70%, N 3.05%.

IR (KBr, cm ^-1 ): 3310, 1665, 1630, 1326, 1170, 1125.

1 H-NMR (CDCl 3 200 MHz) δ: 7.66 (1H, d, J = 15.4 Hz), 7.61 (4H, m), 7.05-6.95 (2H, m), 6.85 (1H, d, J = 7.7Hz), 6.48 (1H, d, J = 15.4Hz), 6.01 (2H, s), 5.96 (1H, bs), 4.24 (1H, dd, J = 14.9 Hz, J = 5.1 Hz), 4.04 (1H, dd, 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, 148.2, 140.1, 138.0 (q, ⁴ JCF = 1.5 Hz), 131.3 (q, ² JCe = 32.4 Hz), 128.0, 126.8, 125.7 (q, ³ JCf = 3.8 Hz), 124.8 (q, J J = 288.0 Hz), 123.8 (q, ¹ J CF = 274.3 Hz), 122.5, 121.2, 108.3, 107.9, 101.48, 80.4 (q, ² J CF = 26.7 Hz), 52.4 , 41.0.

12) N- [2- (3,4-Methylenedioxyphenyl) ethyl] -4-trifluoromethylcinnamamide

A solution of 4.6 g (0.023 mol) of (3,4-methylenedioxyphenyl) ethylamine chlorohydrate in 50 cm @ ^{3 of} ether is added dropwise at 5-10 DEG C. and with stirring to a solution of 4.1 g (0.2 mol) of sodium hydroxide. in 30 cm ^{3 of} water. Then a solution of 4.2 g (0.02 mol) of 4-trifluoromethylcinnamoyl chloride in 20 cm ^{3 of} ether is added dropwise over 35 minutes and the mixture is stirred at 5 ° C for 0.5 hour. The precipitated carboxylic acid amide is filtered and dried. Thus, 4.3 g (63%) of the title compound are obtained.

Mp: 206-208 ° C.

13) N- [2- (3,4-Methylenedioxyphenyl) ethyl] -4-fluorocinnamamide

A mixture 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 of decalin is stirred at 180 ° C for 1 hour. Chloroform was added to the cooled mixture and the mixture was stirred at 5-10 ° C until the carboxylic acid amide crystallized. The precipitated crystals are filtered and recrystallized from ethanol. Thus, 4.9 g (53%) of the title compound are obtained.

Mp .: 160-162 ° C.

14) N- [3- (4-Trifluoromethylphenyl) propanol] -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

A suspension of 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-trifluoromethylphenyl) propionic acid is reacted at 150 ° C for 4 hours. . The crude product is recrystallized from aqueous ethanol. Thus, 1.55 g (69%) of the colorless title compound are obtained.

1.1 .: 58-59 ° C (ethanol-water)

For C21H21F6NO3 (449.40) calculated: C 56.13%, H 4.71%, N 3.12%;

found: C 56.16%, H 4.74%, N 3.09%.

IR (KBr, cm ^-1 ): 3309, 1650, 1338, 1279.

1 H-NMR (CDCl _3, 200 MHz) δ: 7.52 (2H, d, J = 8.1 Hz), 7.35-7.25 (3H, m), 7.046.88 (3H, m), 5.62 (1H, bs), 4.10 (1H, dd, J = 14.9 Hz, J = 5.3 Hz), 3.85 (1H, dd, J = 4.4 Hz), 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, 144.7, 134.7, 129.7, 128.7,

128.6 (q, ² J CF = 32.3 Hz), 125.4 (q, ³ J CF = 3.7 Hz), 124.7 (q, 'J _C F = 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

Following the procedure described for the preparation of the starting compound 14), the title compound is obtained as a colorless solid. Yield: 79%.

Mp .: 59-61 ° C (ethanol-water).

For C20H21F4NO3 (399.39) calculated: C 60.15%, H 5.30%, N 3.51%;

found: C 59.93%, H 5.28%, N 3.52%.

IR (KBr, cm ^-1 ): 3305, 1649, 151 1, 1280.

1 H-NMR (CDCl 3 200 MHz) δ: 7.38-7.25 (1H, m), 7.18-7.06 (2H, m), 7.05-6.87 (5H, m), 5.60 (1H, ds), 4.09 (1H, dd, J = 14.8 Hz, J = 5.1 Hz), 3.86 (1H, dd, J = 14.8 Hz, J = 4 0.08 Hz, 3.82 (3H, s), 3.26 (3H, s), 2.90 (2H, t, J = 7.5Hz), 2.46 (2H, t, J = 7) , 5 Hz).

¹³ C-NMR (CDCl 3 100.6 MHz) δ: 171.7, 161.5 (d, ¹ JCl = 244.2 Hz), 159.8, 136.2 (d, ⁴ JCl = 3.4 Hz) , 134.8, 129.7 (d, ³ JCf = 8.0 Hz), 129.7, 124.8 (q, ¹ JCF = 288.6 Hz), 119.4, 115.2 (d, ² JCf = 21.0 Hz), 114.4, 113.5 (q, ⁴ JCf = 1.1 Hz), 80.5 (q, ² Jcf = 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 the starting compound 14), the title compound is obtained as a colorless solid. Yield: 84%.

Mp: 75-76 ° C (ethanol-water).

For C21H19F6NO4 (463.38) calculated: C 54.43%, H 4.13%, N 3.02%;

found: C 54.52%, H 4.19%, N 3.05%.

IR (KBr, cm ^-1 ): 3317, 1620, 1334, 1247.

1 H-NMR (CDCl 3 200 MHz) δ: 7.53 (2H, d, J = 7.7 Hz), 7.30 (2H, d, J = 7.7 Hz), 7.00-6.80 (3H, m), 6.00 (2H, s), 4.06 (1H, dd, J = 14.9 Hz, J = 5.1 Hz), 3.84 (1H, dd, J = 14, 9 Hz, J = 5.1 Hz), 3.21 (3H, s), 3.01 (2H, t, J = 7.5 Hz), 2.51 (2H, t, J = 7.5 Hz) ).

¹³ C-NMR (CDCl 3 100.6 MHz) δ: 171.4, 148.3, 148.1, 144.7, 128.7 (q, ² JCF = 32.4 Hz), 128.7, 126, 8, 125.4 (q, ³ JCF = 3.7 Hz), 124.7 (q, ¹ J _CF = 288.4 Hz),

124.2 (q, * 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, 37.7, 31.1.

17) N- [3- (4-Fluorophenyl) propanoyl] -3,3,3-trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propylamine

Following the procedure described for the preparation of the starting compound 14), the title compound is obtained as a colorless solid. Yield: 83%

Mp .: 92-94 ° C (ethanol-water).

For C20H19F4NO4 (413.37) calculated: C 58.1 1%, H 4.63%, N 3.39%;

found: C 58.29%, H 4.67%, N 3.41%.

IR (KBr, cm ^-1 ): 3325, 1658, 1510, 1217.

1 H-NMR (CDCl _3, 200 MHz) δ: 7.18-7.10 (2H, m), 7.02-6.75 (5H, m), 6.00 (2H, s), 5.61 (1H, bs), 4.06 (1H, dd, J = 14.7Hz, J = 5.9Hz), 3.85 (1H, dd, J = 14.7Hz, J = 4.2Hz) 3.23 (3H, q, J = 0.7 Hz), 2.92 (2H, t, J = 7.5 Hz), 2.51 (2H, t, J = 7.5 Hz) .

^I3 C NMR (CDCl3 50.3 MHz) δ: 171.7, 161.6 (d, ² J _CF = 244.1 Hz), 148.3, 148.1,

136.2 (d, ⁴ J CF = 3.4 Hz), 129.7 (d, ⁴ J CF = 3.4 Hz), 129.7 (d, ³ J _CF = 7.6 Hz), 126.8 .

124.7 (q, 'J _C F = 288.4 Hz), 121.2, 115.2 (d, ² J _CF = 21.4 Hz), 108.2, 107.8, 101.5,

80.3 (q, ² J _CF = 26.5 Hz), 52.2, 40.6, 38.2, 30.5.

18) N- [2- (3,4-Methylenedioxyphenyl) ethyl] -4-trifluoromethylcinnamamide

A solution of 4.6 g (0.023 mol) of 3,4-methylenedioxyphenyl) ethylamine chlorohydrate in 50 cm @ ^{3 of} ether is added dropwise at 5-10 DEG C. with stirring to a solution of 4.1 g (0.2 mol) of sodium hydroxide. in 30 cm ^{3 of} water. A solution of 4.2 g (0.02 mol) of 4-trifluoromethylcinnamoyl chloride in 20 cm ^{3 of} ether is then added dropwise to the reaction mixture over 35 minutes and the reaction mixture is stirred at 5 ° C for 0.5 hour. The precipitated carboxylic acid amide is filtered and dried. Thus, 4.3 g (63%) of the title compound are obtained. 1.1. Mp 206-208 ° C.

19) N- [2- (3,4-Methylenedioxyphenyl) ethyl] cinnamamide

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 bicarbonate, and then a solution of 6.2 g (0.037 mol) of cinnamoyl chloride in 20 ml was added over 0.5 hours. cm ³ dichloromethane. The reaction mixture was stirred at 40 ° C for 2 hours, filtered and the dichloromethane was evaporated. There was thus obtained 10.6 g (96%) of the title compound as an oil.

20) N- [2- (3,4-Ethylenedioxyphenyl) ethyl] -3- (4-trifluoromethylphenyl) propionylamide

14.3 g (0.08 mol) of (3,4-ethylenedioxyphenyl) ethylamine and 18.4 g (0.08 mol) of 3 (4-trifluoromethylphenyl) propionic acid are heated in 20 cm ^{3 of} decalin at 160 to 170 ° C and the reaction mixture was stirred at room temperature for 4 hours. The resulting water is distilled off. The mixture is cooled to 60 ° C and 50 cm ^{3 of} ethanol are added with vigorous stirring. The suspension was cooled to 10 ° C, filtered and washed with cold ethanol. There was thus obtained 17.2 g (56%) of the title compound as a crude product.

mp: 161-163 ° C.

21) N- [2- (3,4-Methylenedioxyphenyl) ethyl] -4-fluorocinnamamide

A mixture 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} decalin is stirred at 180 ° C for 1 hour. Chloroform was added to the cold mixture and the mixture was stirred at 5-10 ° C until the carboxylic acid amide crystallized. The precipitated crystals are filtered and recrystallized from ethanol. Thus, 4.9 g (53%) of the title compound are obtained.

mp: 160-162 ° C.

22) N- [2- (4-Chloro-phenylethyl) -3- (4-trifluoromethyl-phenyl) -propionamide

7.8 g (0.05 mol) of (4-chlorophenyl) ethylamine and 10.5 g (0.05 mol) of 4-trifluoromethyl cinnamic acid are heated in 25 cm ^{3 of} decalin to 180 ° C and stirred at this temperature for 14 hours. To the mixture cooled to room temperature, diethyl ether (50 cm) was added portionwise. The crystalline carboxylic acid amide was filtered and washed with ether. This afforded 14 g (79%) of the title compound as a crude product.

mp: 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 are heated to 160 ° C and the melt obtained is stirred at this temperature for 4 hours. The resulting water is distilled off. The mixture was cooled to 0-5 ° C and the precipitated crystals were filtered. The crude product was purified by column chromatography. This afforded 10 g (47%) of the title compound as a yellow resin.

24) N- [2- (3,4-Methylenedioxyphenyl) ethyl] -3- (4-trifluoromethylphenyl) propionyl amide

A solution of 3.63 g of N- [2- (3,4-methylenedioxyphenyl) ethyl] -4-trifluoromethylcinnamamide in 100 cm @ ³ of acetic acid is hydrogenated in the presence of 1 g of palladium / carbon catalyst at atmospheric pressure until consumption of hydrogen. The catalyst was filtered off and the solution was evaporated to dryness. The crude product is recrystallized from acetone.

25) N- [2- (3,4-Ethylenedioxyphenyl) -2-propylethyl] -4- (trifluoromethyl) cinnamamide

12.3 g (55 mmol) of 2- (3,4-ethylenedioxyphenyl) -2-propylethylamine and 12.0 g (55 mmol) of 4-trifluoromethylcinnamic acid are heated in 100 cm ^{3 of} decalin at 160 to 165 ° C. The mixture was stirred at the above temperature for 2 hours and then cooled to room temperature. The solvent is removed by decantation, the residue of 50 cm ^{3 of} toluene is distilled off and the brownish crude product is purified by column chromatography. This afforded 12.1 g (52%) of the title compound as a thick oil which solidified on standing.

Preparation of the starting compounds of formula XII:

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 are dissolved in 80 cm ^{3 of} toluene. To the obtained solution is added dropwise 12 cm ^{3 of} phosphorus oxychloride and the reaction mixture is heated and stirred at this temperature for 2.5 hours. The precipitated crystalline dihydroquinoline is filtered and recrystallized from ethanol. The product obtained (12 g) is dissolved in 90 cm @ ^{3 of} methanol, basified to pH 9 with 20% aqueous sodium hydroxide solution, the precipitated substance is filtered off, washed with aqueous methanol (5: 1) and recrystallized from a mixture of ethanol and water. There was thus obtained 1.44 g (41%) of the title compound.

Mp: 85 ° C

For C20H18NO2 (361.37) calculated: C 66.48%, H 5.02%, N 3.88%;

found: C 66.34%, H 5.04%, N 3.90%.

1 H-NMR (CDCl 3 400 MHz) δ: 7.61 (2H, 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) 1.47 (2H, t, J = 7.1 Hz).

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

A solution of 10 g (0.033 mol) of N- [2- (3,4-methylenedioxyphenyl) ethyl] -3-phenylpropionylamide and 30 cm of phosphorus oxychloride in 70 cm of absolute benzene is boiled for 1.5 hours and then cooled to 50 ° C and precipitated. the crystals are filtered. The crude hydrochloride is dissolved in a mixture of 200 cm @ 3 of water and 200 cm @ 3 of methanol and the pH of the solution is adjusted to 13 by addition of 20% aqueous sodium hydroxide solution. The precipitated white crystalline base is filtered, washed with water, dried and recrystallized from a mixture of ethanol and water. Thus, 5.3 g (58%) of the title compound are obtained.

Mp .: 1112-115 ° C.

Preparation of the starting compounds of formula XVI:

28) α, α-Trifluoro-3-methoxyacetophenone

To a solution of ethyl trifluoroacetate (35.52 g, 0.25 mmol) in tetrahydrofuran (100 cm ³⁾ was slowly added dropwise at -70 ° C a solution of 3-methoxyphenylmagnesium bromide (prepared in the usual manner from 46.76 g (0.25 mol) of 3-bromoanisole, 6.32 g (0.26 mol) of magnesium and 200 cm ^{3 of} tetrahydrofuran). The reaction mixture was stirred at -70 ° C for 1 hour and then warmed to 0 ° C. 100 cm @ ^{3 of} 2N hydrochloric acid are then slowly added dropwise to the reaction mixture. The mixture was stirred for half an hour and the two phases were separated. The tetrahydrofuran phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The crude product was partitioned under reduced pressure. The fraction was collected at a pressure of 1600 Pa and a temperature of 83-85 ° C. Thus, 39.81 g (78%) of the title compound are obtained.

1 H-NMR (CDCl ₃ , 250 MHz) δ: 7.70-7.20 (4H, m), 3.88 (3H, s), literature data: 1 H-NMR δ: 7.72-7 16 (4H, m), 3.81 (3H, s).

29) α, α, α-Trifluoro-3,4-methylenedioxyacetophenone

Following the procedure described for the preparation of the starting compound 28), the title compound is obtained. The crude product was separated into fractions under reduced pressure. The fractions were separated at 373 Pa and at 84-85 ° C. Yield: 63%.

For C 9 H ₃ F ₃ O ₃ (218.134) calculated: C 49.56%, H 2.31%;

found: C 49.43%, H 2.20%.

IR (KBr, cm ^-1 ): 1702, 1614, 1364.

1 H-NMR (CDCl ₃ , 250 MHz) δ: 7.68 (1H, dd, J = 8.3Hz, J = 1.2Hz), 7.45 (1H, d, J = 1.2Hz) 6.90 (1H, d, J = 8.3Hz), 6.10 (2H, s).

Preparation of the starting compound of formula XV:

30) 3,3,3-Trifluoro-2-methoxy-2- (3-methoxyphenyl) propionitrile

A suspension of 61.25 g (0.3 mol) α, α, α-trifluoro-3-methoxyacetophenone, 150 cm ^{3 of} 1,2-dimethoxyethane and 32.65 g (0.50 mol) of potassium cyanide is stirred at room temperature 15. minutes. Dimethyl sulfide (50.45 g, 38.0 cm ³ , 0.40 mol) was added dropwise to the reaction mixture, and the mixture was stirred at 60 ° C for 5 minutes and then allowed to stand overnight. The mixture was filtered and the solvent was distilled off from the mother liquor. The crude product was separated into fractions under reduced pressure. The fractions were separated at 933 Pa and 80-82 ° C. There was thus obtained 60.0 g (82%) of the title compound.

For C11H10F3NO2 (245.20) calculated: C 53.88%, H 4.11%, N 5.71%;

found: C 53.50%, H 4.10%, N 5.51%.

IR (film, cm ^-1 ): 2850, 2250, 1190.

1 H-NMR (CDCl 3, 250 MHz) δ: 7.41 (1H, t, J = 8.0 Hz), 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-methylenedioxyacetophenone are dissolved in 330 cm 1,2-dimethoxyethane and the solution is stirred with 14.70 g (0.30 mol) of sodium cyanide 15 minutes. 20.73 g (0.15 mol) of potassium carbonate are added to the resulting suspension, and 42.7 cm ³ (56.76 g, 0.45 mol) of dimethyl sulfate are added dropwise to the reaction mixture and the mixture is stirred at room temperature for 3 hours. .

The mixture is then cooled to 0 ° C and 42 cm ^{3 of} aqueous ammonia are added dropwise. The mixture is diluted with 330 cm ^{3 of} water and extracted twice with 160 cm ^{3 of} ethyl acetate each time. The combined organic phases are washed twice with 160 cm ^{3 of} saturated aqueous sodium chloride solution each time and dried over anhydrous magnesium sulfate. The solvent was distilled off. Since the residue contains about 20% of the starting ketone, the above steps are repeated using identical amounts of substances to complete conversion. The crude product was purified by fractionation under reduced pressure using a Vigreux column. The fraction was collected at 40 Pa and a temperature between 78-88 ° C. Thus, 27.60 g (71%) of the title compound are obtained.

Analysis: for C ₁₁ H ₈ F ₃ NO ₃ (259.19) calculated: C 50.98%, H 3.11%, N 5.40%;

found: C 50.75%, H 3.17%, N 5.45%.

IR (film, cm ^-1 ): 2909, 2248, 1492, 1254, 1189.

1 H-NMR (CDCl 3, 200 MHz) δ: 7.17 (1H, 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 the starting compounds of formula X:

32) 3,3,3-Trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine

To a suspension of 24.52 g (0.10 mol) of 3,3,3-trifluoro-2- (3-methoxyphenyl) propionitrile, 23.78 g (0.10 mol) of cobalt chloride hexahydrate and 250 cm ^{3 of} methanol are added in several portions. and at 0 ° C, 3.78 g (0.10 mol) of sodium borohydride. The reaction mixture was stirred at room temperature and allowed to stand overnight. The solvent is distilled off and the residue is suspended in 500 cm @ ^{3 of} water. Unreacted sodium borohydride is hydrolyzed with 2N hydrochloric acid solution. The pH is then adjusted to 13 with 20% aqueous sodium hydroxide solution. The mixture is extracted three times using 300 cm @ ^{3 of} dichloromethane each time. The combined organic phases are dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was fractionated under reduced pressure. The fraction was collected at 533 Pa and a temperature of 103-104 ° C. There was thus obtained 15.20 g (61%) of the title compound.

For C11H14F3NO2 (249.23) calculated: C 53.01%, H 5.66%, N 5.62%;

found: C 52.65%, H 5.53%, N 5.78%.

IR (film, cm ^-1 ): 2800, 1174, 1119.

1 H-NMR (CDCl 3, 250 MHz) δ: 7.33 (1H, t, J = 8.2 Hz), 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 = 14.6Hz), 1.20 (2H, s).

¹³ C-NMR (CDCl 3, 62.9 MHz) δ: 159.7, 135.8, 129.4, 125.4 (q, ¹ JCF = 289.6 Hz), 119.2, 113.5, 82 2 (q, ² JCF = 24.8 Hz), 54.9, 52.5, 45.7.

Preparation of hydrochloride

12.46 g (50 mmol) of basic 3,3,3-trifluoro-2- (3-methoxyphenyl) propylamine are dissolved in 125 cm @ ^{3 of} diethyl ether and 8.63 cm @ 3 of 2-propanol containing (60 cm @ 3) are added dropwise. mmol, 25.3 g / 100 cm ³ ) hydrogen chloride. The precipitated crystals are filtered and washed with 30 cm ^{3 of} diethyl ether. There was thus obtained the hydrochloride of the title compound (12.28 g, 86%).

mp: 219-220 ° C (2-propanol, diethyl ether).

Analysis: for C ₁₁ H ₁₅ ClF ₃ NO ₂ (285.69) calculated: C 46.25%, H 5.29%, Cl 12.41%, N 4.90%;

found: C 45.92%, H 5.15%, Cl 12.72%, N 4.98%.

IR (film, cm ^-1 ): 2945, 1502, 1130.

1 H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.47 (3H, s), 7.44 (1H, t, J = 7.9 Hz), 7.10 (3H, m), 3 96 (1H, t, J = 14.8 Hz), 3.80 (3H, s), 3.61 (1H, t, J = 14.8 Hz), 3.30 (3H, s).

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

The title compound was prepared in a similar manner to the starting compound under 32). The crude product was separated into fractions under reduced pressure. The fraction was collected at a pressure of 14 mmHg and a temperature of 114-116 ° C. Yield 68%. The title compound is a colorless oil.

For C11H12F3NO3 (263.22) calculated: C 50.19%, H 4.60%, N 5.32%;

found: C 49.96%, H 4.58%, N 5.34%.

IR (film, cm ^-1 ): 2951, 1492, 1167.

1 H-NMR (CDCl 3, 200 MHz) δ: 6.97 (1H, m), 6.93 (1H, ddd, J = 8.2 Hz, J = 1.8 Hz, J = 0.4 Hz) 6.83 (1H, dd, J = 8.2Hz, J = 0.4Hz), 5.97 (2H, s), 3.39 (3H, q, J = 1.2Hz), 3 36 (1H, d, J = 14.6 Hz), 3.12 (1H, dq, J = 14.6 Hz, J = 1.6 Hz), 1.28 (2H, bs).

¹³ C-NMR (CDCl 3, 100.6 MHz) δ: 147.9, 147.7, 127.8, 125.3 (q, * JCF = 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 JCF = 24.8 Hz), 52.3 (q, J = 289.6 Hz), 45.3 (q, ³ J _CF = 1.1 Hz).

Preparation of hydrochloride

Proceed as described for the preparation of the hydrochloride mentioned under (32). Yield: 81%.

Mp: 248-249 ° C.

Analysis for C ,, H, ₃ C1 F ₃ NO 3 (299.68) calculated: C 44.09%, H 4.37%, Cl 11.83%, N 4.67%;

found: C 44.31%, H 4.40%, Cl 11.81%, N 4.65%.

IR (film, cm ^-1 ): 2925, 1449, 1112, 1076.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.55 (3H, bs), 7.1 (1H, s), 7.05-7.02 (2H, m), 6.10 (2H , s), 3.90 (1H, d, J = 14.9 Hz), 3.57 (1H, d, J = 14.9 Hz), 3.29 (3H, s) ·

Example 1

6-Methoxy-1-styryl-4-trifluoromethylisoquinoline

Method A)

To a solution of 1.19 g (3 mmol) of 4,6-dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydroisoquinolinium chloride in 10 cm ^{3 of} methanol is added 0.42 g (7.5 mmol) at 0 ° C. powdered potassium hydroxide and the reaction mixture was stirred at room temperature for 2 hours. The mixture is evaporated and the residue is triturated with 10 cm ^{3 of} water and filtered. The crystals are washed with 5 cm @ ^{3 of} water and then twice with 3 cm @ ^{3 of} ethanol each time. There was thus obtained 0.94 g (95%) of the title compound as a pale yellow solid.

Mp .: 202-203 ° C (chloroform).

Method B)

A suspension of 2.73 g (10 mmol) of 1-methyl-4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline, 1.17 g (11 mmol) of benzaldehyde and 1.33 g (13 mmol) of acetic anhydride is allowed to stand. React at 100 ° C for 16 hours. The precipitated crystals are filtered and washed at 0 ° C twice with 5 cm ^{3 of} ethanol each time. Thus, 2.14 g (65%) of the title compound are obtained.

Mp .: 202-203 ° C (chloroform).

Method C)

A suspension of 1.41 g (10 mmol) of 1-methyl-6-methoxy-4-trifluoromethylisoquinoline, 1.17 g (11 mmol) of benzaldehyde and 1.33 g (13 mmol) of acetic anhydride is reacted at 100 ° C. 16 hours. The precipitated crystals were collected

They are filtered and washed at 0 DEG C. twice with 5 cm @ ^{3 of} ethanol. Thus, 1.98 g (60%) of the title compound are obtained.

mp: 202-203 ° C (chloroform).

For C19H14F3NO (329.32) calculated: C 69.20%, H 4.28%, N 4.25%;

found: C 69.02%, H 4.25%, N 4.20%.

IR (KBr, cm ^-1 ): 1619, 141 1, 1318, 1221, 1100.

1 H-NMR (CDCl 3, 200 MHz) δ: 8.79 (1H, s), 8.36 (1H, d, J = 9.5 Hz), 8.07 (1H, d, J = 15.8) Hz), 7.92 (1H, d, J = 15.8 Hz), 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, 141.1 (q, ³ J CF = 6.5 Hz), 138.7, 136.3, 135.0, 129 , 3, 128.9, 127.7, 127.1, 124.8 (q, JCf = 273.1 Hz), 121.8, 120.5, 117.8 (q, ² JCf = 30.1 Hz), 102.1, 55.6.

MS (m / z,%): 329 (37), 328 (100), 314 (7), 310 (3), 298 (8), 286 (10), 285 (37), 252 (7).

6-Methoxy-1-styryl-4-trifluoromethylisoquinolinium chloride

0.99 g (3 mmol) of the above base is reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride. This afforded 0.74 g (67%) of the title compound as a pale yellow solid.

mp: 189-190 ° C (ethanol, diisopropyl ether, decomposition).

Analysis for C 9 H, C1 F ₃ NO ₅ (365.78) calculated: C 62.39%, H 4.13%, Cl 9.69%, N 3.83%;

found: C 62.21%, H 4.17%, Cl 9.60%, N 3.86%.

IR (film, cm ^-1 ): 1618, 1240.

1 H-NMR (DMSO-d 6, 250 MHz) δ: 8.92 (1H, d, J = 9.4 Hz), 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), 7.32 (1H, s), 4.00 (3H, s).

Example 2

- (4-Fluorostyryl) -6-methoxy-4-trifluóŕmetylizochinolín

Method A)

1.14 g (3 mmol) of 1- (4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline are dissolved in a mixture of 20 cm ^{3 of} toluene and 10 cm ^{3 of} methanol. To the resulting solution was added 0.25 g (4.5 mmol) of powdered potassium hydroxide at 0 ° C, the reaction mixture was stirred at room temperature and then evaporated. The residue is triturated with 10 cm ^{3 of} water and filtered. The crystals are washed with 5 cm @ ^{3 of} water and then at 0 DEG C. twice with 3 cm @ ^{3 of} ethanol each time. This afforded 0.92 g (93%) of the title compound as a pale yellow solid.

Mp: 187-188 ° C (chloroform).

Method B)

The procedure described in Example 1, Method B) was followed.

Yield: 64%.

Mp: 188-189 ° C (chloroform).

Method C)

The procedure described in Example 1, Method C) was followed.

Yield: 63%.

Mp: 188-189 ° C (chloroform).

For C19H13F4NO (347.32) calculated: C 65.71%, H 3.77%, N 4.03%;

found: C 65.84%, H 3.79%, N 4.08%.

IR (KBr, cm ^-1 ): 1618, 1510, 1321, 1275, 1130.

1 H-NMR (CDCl 3, 250 MHz) δ: 8.77 (1H, s), 8.31 (1H, d, J = 9.1 Hz), 8.01 (1H, d, J = 15.5) Hz), 7.81 (1H, d, J = 15.5 Hz), 7.70-7.63 (2H, m), 7.35-7.29 (2H, m),

7.11 (2H, t, J = 8.7 Hz), 3.98 (3H, s).

¹³ C-NMR (CDCl 3 62.9 MHz) δ: 165.2, 161.5, 159.5 (d, ¹ JCF = 221.5 Hz), 141.3 (q, ³ Jci-6.6 Hz) ), 136.9, 134.8, 132.6, 129.3, 129.2, 126.8, 124.8 (q, ¹ JCF = 273.6 Hz), 121.8, 120.3, 117 7 (q, ² JCF = 29.3 Hz), 115.8 (d, ² JCF = 21.0 Hz), 102.1, 55.4.

MS (m / z,%): 347 (34); 346 (100); 332 (10); 328 (4); 316 (9); 304 (10); 303 (34); 252 (8);

- (4-Fluorostyryl) -6-methoxy-4-trifluoromethylisoquinolinium chloride

1.04 g (3 mmol) of the above base is reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride. There was thus obtained 0.63 g (72%) of the hydrochloride of the title compound.

Mp: 189-190 ° C (ethanol, dec.).

For C19H14ClF4NO (383.77) calculated: C 59.46%, H 3.68%, Cl 9.24%, N 3.65%;

found: C 59.19%, H 3.72%, Cl 9.10%, N 3.58%.

IR (film, cm ^-1 ): 3437, 1615, 1228, 1162.

1 H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.95 (1H, d, J = 9.5 Hz), 8.77 (1H, s), 8.29 (1H, d, J = 15.6 Hz), 8.18 (1H, d, J = 15.6 Hz), 8.04 (1H, d, J = 5.6 Hz), 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)

Following the procedure described in Example 1, Method A), the title compound was obtained as a pale yellow solid. Yield: 90%.

mp: 160-161 ° C (chloroform).

Method B)

Following the procedure described in Example 1, Method B), the title compound was obtained. Yield: 62%

mp: 160-161 ° C (chloroform).

Method C)

Following the procedure described in Example 1, Method C), the title compound was obtained. Yield: 70%.

mp: 160-161 ° C (chloroform).

For C20H13F6NO (397.32) calculated: C 60.46%, H 3.30%, N 3.53%;

found: C 60.70%, H 3.27%, N 3.63%.

IR (KBr, cm ^-1 ): 1620, 1409, 1324, 1121.

1 H-NMR (CDCl ₃ , 250 MHz) δ: 8.80 (1H, s), 8.34 (1H, d, J = 9.7 Hz), 8.08 (1H, d, J = 15, 6 Hz), 7.98 (1H, d, J = 15.6 Hz), 7.78 (2H, d, J = 8.3 Hz), 7.68 (2H, d, J = 8.3 Hz) 7.37 (1H, s), 7.35 (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, 141.4 (q, ³ J CF = 6.5 Hz), 139.8, 136.5, 135.0, 130, 1 (q, ² JCF = 32.5 Hz), 127.8, 126.8, 125.8 (q, ³ JCF = 4.6 Hz),

124.8 (q, "J _CF = 271.8 Hz), 124.5, 124.2 ^(q, J CF = 271.0 Hz), 122.6, 120.8, 1 18.5 (q, ² JCF = 27.8 Hz), 102.1, 55.6.

MS (m / z,%): 397 (57), 396 (100), 382 (11), 378 (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 is reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride. This afforded 0.72 g (66%) of the hydrochloride of the title compound as a yellow solid.

Mp: 189-190 ° C (ethanol, dec.).

Analysis: for C ₂₀ H ₁₄ ClF ₆ NO (433.78) calculated: C 55.38%, H 3.25%, Cl 8.17%, N 3.23%;

found: C 55.62%, H 3.37%, Cl 8.29%, N 3.19%.

IR (film, cm ^-1 ): 3433, 1613, 1319, 1132.

1 H-NMR (DMSO-d ₆ , 250 MHz) δ: 8.92 (1H, d, J = 9.5 Hz), 8.83 (1H, s), 8.47 (1H, d, J = 15.5 Hz), 8.20-8.13 (3H, s), 7.81 (2H, d, J = 8.2 Hz), 7.54 (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) isoquinolinium iodide

A mixture of 1.00 g (2.5 mmol) of the above base and 10 cm ^{3 of} methyl iodide is heated to boiling for 40 hours. The precipitated crystals are filtered and the crude product is recrystallized from ethanol. This afforded 0.78 g (58%) of the title quaternary salt as an orange-yellow solid.

mp: 213-215 ° C (ethanol).

Analysis: for C ₂ H | ₆ F ₆ INO (539.26) calculated: C 46.77%, H 2.99%, N 2.60%;

found: 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 (1H, s), 8.69 (1H, d, J = 9.5 Hz), 8.12 (2H, d, J = 8.2 Hz), 7.94 (1H, d, J = 16.4 Hz), 7.92 (2H, d, J = 8.2 Hz), 7.78 (1H, dd, J = 9, 5 Hz, J = 2.9 Hz), 7.47 (1H, d, J = 16.4 Hz), 7.46 (1H, s), 4.36 (3H, s), 4.14 (3H) , with).

¹³ C-NMR (DMSO d6 100.6 MHz) δ: 166.5, 160.0, 144.7, 138.5 (q), 137.5 (q, ³ JCF = 6.9 Hz), 135 , 3, 134.5, 130.4 (q, ² JCF = 31.9 Hz), 129.3, 126.0 (q, ³ JCF = 3.8 Hz), 124.1 (q, * JCF = 272.1 Hz), 123.5, 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); 378 (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)

Following the procedure described in Example 1, Method A), the title compound was obtained as a lemon-yellow solid. Yield: 92%.

mp: 223-224 ° C (chloroform).

Method B)

Following the procedure described in Example 1, Method B), the title compound was obtained. Yield 74%.

mp: 222-223 ° C (chloroform).

Method C

Following the procedure described in Example 1, Method C), the title compound was obtained. Yield: 73%.

mp: 222-223 ° C (chloroform)

For C19H13F3N2O3 (374.32) calculated: C 60.97%, H 3.50%, N 7.48%;

found: C 60.78%, H 3.46%, N 7.46%.

IR (KBr, cm ^-1 ): 1619, 1327, 1,106.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.92 (1 (, d,> 9.3 Hz), 8.87 (1H, s), 8.56 (1Η, d, J = 15, 3 Hz), 8.29 (2H, d, J = 8.7 Hz), 8.21 (2H, d,> 8.7 Hz), 8.18 (1H, d,> 15.3 Hz), 7.55 (1H, d,> 9.3 Hz), 7.30 (1H, s), 4.00 (1H, s).

¹³ C-NMR (CDCl 3, 50.3 MHz) δ: 161.9, 157.4, 147.5, 142.8, 135.7, 134.2, 129.3, 128.7, 127.0, 126 2 (q, 'J _C F = 274.3 Hz), 124.1, 121.8, 120.7, 1 16.4 (q, ² J _CF = 32.7 Hz), 101.7, 55 , the ninth

MS (m / z,%): 374 (100); 373 (99); 359 (12); 355 (7); 344 (12); 343 (28); 328 (27); 327 (68); 326 (15); 313 (15); 285 (29); 284 (23); 283 (16); 252 (26); 216 (12); 215 (19).

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

1.12 g (3 mmol) of the above base is reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride. There was thus obtained 0.86 g (70%) of the hydrochloride of the title compound as a light yellow solid.

1.1: above 250 ° C (ethanol).

For C19H14ClF3N2O3 (410.78) calculated: C 55.56%, H 3.44%, Cl 8.63%, N 6.82%;

found: C 55.87%, H 3.29%, Cl 8.56%, N 6.84%.

IR (film, cm ^-1 ): 2440, 1646, 1345, 1262.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.96 (1H, d, J = 9.5 Hz), 8.86 (1H, s), 8.57 (1H, d, J = 15.4 Hz), 8.36-8.14 (5H, m), 7.57 (1H, dd, J = 9.5 Hz, J = 2.2 Hz), 7.30 (1H, s) 3.85 (3H, s).

Example 5

6,7-Methylenedioxy-4-trifluoromethyl-1- (4-trifluoromethylstyl) isoquinoline

Method A)

Following the procedure described in Example 1, Method A), the title compound was obtained as a pale yellow solid. Yield: 92%.

Mp .: 180-182 ° C (chloroform).

Method B)

Following the procedure described in Example 1, Method B), the title compound was obtained. Yield: 64%.

Mp .: 180-182 ° C (chloroform).

Method C)

Following the procedure described in Example 1, Method C), the title compound was obtained. Yield 68%.

Mp .: 180-182 ° C (chloroform).

For C ₂₀ H ₁₁ F ₆ NO 2 (41 1.30) calculated: C 58.40%, H 2.70%, N 3.41%;

found: C 58.22%, H 2.73%, N 3.35%.

IR (KBr, cm ^-1 ) ··· 1615, 1478, 1324, 1110.

H-NMR (CDC1 _3, 200 MHz) δ: 8.72 (1H, s), _8: 04 (1H, d, J = 15.4 Hz), 7.84 (1H, d, J = 1 5 4 Hz), 7.76 (2H, s), 7.69 (2H, s), 7.66 (1H, s), 7.43 (1H, q, J = 1.8 Hz), 6, 20 (2 H, s).

¹³ C-NMR (CDCl 3 100.6 MHz) δ: 155.8, 152.0, 149.0, 139.8 (q, ⁴ JCf = 1.5 Hz), 136.7, 136.2, 131, 5, 130.6 (q, ² J CC = 32.8 Hz), 127.7, 125.8 (q, ³ J CC = 3.8 Hz), 124.6 (q, ¹ J CC = 273.1 Hz) , 124.0 (q, ¹ J CF = 272.0 Hz), 124.0, 102.4, 101.1, 100.5 (q, ³ J _CF = 2.7 Hz).

MS (m / z,%): 41 (37), 410 (100), 392 (10), 382 (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-trifluoromethylstyryl) isoquinolinium chloride

1.23 g (3 mmol) of the above base is reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / 100 cm ³ ) of hydrogen chloride. There was thus obtained 1.03 g (77%) of the hydrochloride as a light yellow solid.

mp: 259-260 ° C (methanol, diisopropyl ether, decomposition).

For C ₂₀ H ₁₂ ClF ₆ NO 2 (447.77) calculated: C 53.65%, H 2.70%, Cl 7.92%, N 3.13%;

found: C 53.82%, H 2.63%, Cl 7.87%, N 3.16%.

IR (film, cm ^-1 ): 1630, 1482, 1320, 1180, 1134.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.73 (1H, s), 8.41 (1H, s), 8.38 (1H, d, J = 14.4 Hz), δ 16 (2H, d, J = 8.2Hz), 8.1 (1H, d, J = 15.4Hz), 7.80 (2H, d, J = 8.2Hz), 34 (1H, q, J = 1.4Hz), 6.36 (2H, s).

Example 6

- [2- (4-trifluoromethylphenyl) ethyl] -6,7-etyléndioxychinolín

5.5 g (0.015 mol) of 1- (4-trifluoromethylstyryl) -6,7-ethylenedioxyisoquinoline are dissolved in 100 cm @ ^{3 of} methanol. The solution obtained is hydrogenated in the presence of 1 g of palladium on carbon catalyst at a pressure of 1.515 MPa. The catalyst is filtered off and concentrated aqueous ammonia is added to the residue until the pH reaches 9. The precipitated crystalline material is filtered and crystallized from ethanol. Thus, 2.4 g (44%) of the title compound are obtained.

mp: 110-111 ° C.

For C20H16F3NO2 (359.35) calculated: C 66.85%, H 4.49%, N 3.90%;

found: C 66.34%, H 4.42%, N 4.03%.

IR (KBr, cm ^-1 ): 1509, 1292, 1168, 1096, 1065.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 8.27 (1H, d, J = 8 Hz), 7.53 (2H, d, J = 8.1 Hz), 7.47 (1H , s), 7.36 (3H, m), 7.21 (1H, s), 4.37 (4H, m), 3.46 (2H, d, J = 7.6 Hz, J ₂ = 8.6 Hz), 3.25 (2H, dd, J = 7.6 Hz, J = 8.6 Hz).

Example 7 1- [2- (4-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-dihydroisoquinolinium iodide are dissolved in 150 cm @ ^{3 of} methanol and 1 g is added under stirring. sodium borohydride. The reaction mixture was stirred at room temperature for 2 hours and then evaporated. 100 cm ^{3 of} water are added to the residue, the aqueous phase is extracted with dichloromethane, dried over anhydrous sodium sulphate and evaporated. The residual oily substance was dissolved and an equimolar amount of fumaric acid dissolved in ethanol was added to the solution. The precipitated crystals were filtered and recrystallized from aqueous acetone to give 1.33 g (67%) of the title compound.

Mp: 192-194 ° C

For C25H26F3NO2 (493.48) calculated: C 60.85%, H 5.31%, N 2.84%;

found: C 60.12%, H 5.28%, N 2.82%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.60 (2H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.1 Hz), 6.64 (1H, s), 6.61 (2H, s), 6.56 (1H, s), 4.18 (4H, bs), 3.40 (1H, t, J = 5.2 Hz), 3 06 (1H, m), 2.80-2.50 (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

Dissolve 5.0 g (12 mmol) of 1- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinolinium iodide in 370 cm ^{3 of} methanol. To this solution is added 1 g (24 mmol) of sodium borohydride under ice-cooling, and then the reaction mixture is stirred at room temperature for 3 hours, evaporated to half its original volume and 200 cm ^{3 of} water are added. The remaining methanol is distilled off and the aqueous phase is extracted with dichloromethane. The organic solution was dried and evaporated under reduced pressure. The residue was dissolved in diethyl ether, the pH was adjusted to 1 by addition of 2-propanol containing hydrogen chloride. The precipitated hydrochloride is filtered off and recrystallized from 2-propanol. Thus, 3.6 g (82%) of the title compound are obtained.

Mp: 175-177 ° C

For C20H23ClFNO2 (363.86) calculated: C 66.02%, H 6.37%, N 3.85%;

found: C 65.45%, H 6.35%, N 3.95%.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 11.36 (1H, bs), 7.29 (2H, dd, J 1 = 5.9 Hz, J ₂ = 8.2 Hz), 7.10 (2H, t, J = 8.8 Hz), 6.76 (1H, s), 6.74 (1H, s), 4.30 (1H, 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 are dissolved in 50 cm ^{3 of} acetone. To the resulting solution was added 14.1 g of methyl iodide and the reaction mixture was allowed to stand at room temperature for 24 hours. The precipitated quaternary isoquinolinium salt is filtered off, dissolved in 150 cm @ ^{3 of} methanol, and 3.5 g of sodium borohydride are 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 are added to the residue and the solution is extracted with dichloromethane. The organic solution was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from ethanol. There was thus obtained 3.7 g (52%) of the title compound.

mp: 208-211 ° C.

Analysis: for C ₁₉ H ₂₁ ClFNO ₂ (349.83) calculated: C 65.23%, H 6.05%, N 4.00%;

found: C 64.80%, H 6.00%, N 4.07%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 11.53 (1H, bs), 7.31 (2H, dd, J = 6.0 Hz, J ₂ = 8.1 Hz), 7 1 (2H, t, J = 8.8Hz), 6.83 (2H, s), 6.2 (2H, s), 4.43 (2H, t, J = 5.6Hz), 3 49 (1H, m), 3.24 (1H, m), 2.7-3.1 (3H, m), 2.78 (3H, s), 2.45 (1H, m),

2.8 (1 H, m).

Example 10

- [2- (4-Trifluoromethylphenyl) ethyl] -2-methyl-4-propyl-6,7-ethylenedioxyisoquinolinium iodide

Dissolve 4.0 g (0.1 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-4-propyl-6,7-ethylenedioxyisoquinoline in 100 cm ^{3 of} nitromethane. To the resulting solution was added 14.1 g of methyl iodide and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and the crystalline isoquinolinium salt was filtered. The crude product was recrystallized from acetonitrile / ether. Thus, 2.7 g (49%) of the title compound are obtained.

mp: 214-216 ° C.

Analysis: for C ₂₄ H ₂ 5F3lNO ₂ (543.37) calculated: C 53.05%, H 4.64%, N 2.58%;

found: C 52.83%, H 4.69%, N 2.60%.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.29 (1H, 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 (2H, m), 1.7 (3H, t, J = 7.4 Hz).

Example 11

- (4-Trifluórmetylstyryl) -4-propyl-6,7-etyléndioxyizochinolíniumchlorid

6.2 g (0.015 mol) of N- [2- (3,4-ethylenedioxyphenyl) ethyl] -4-trifluoromethylcinnamamide are dissolved in 90 cm @ 3 of absolute benzene. 25 cm @ ^{3 of} phosphorus oxychloride are added to the solution obtained and the reaction mixture is heated at reflux for 4 hours. 100 cm @ ^{3 of} methanol are added to the still hot solution and the solution is evaporated to dryness. More methanol is added and the evaporation is repeated three times using 50 cm ^{3 of} methanol each. The methanolic isoquinoline hydrochloride solution was passed through an Amberlist 46 anion exchanger and the product was precipitated with diisopropyl ether. There was thus obtained 1.3 g (31%) of the title compound.

Mp: 188-190 ° C.

For C23H21ClF3NO2 (435.87) calculated: C 63.38%, H 4.86%, N 3.21%;

found: C 63.39%, H 4.85%, N 3.19%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.48 (1H, s), 8.22 (1H, d, J = 16.2 Hz), 8.16 (4H, m), 7 Δ 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 = 7.6 Hz), 1.7 (2H, hx, J = 7.4 Hz), 0.99 (3H, t, J = 7.3 Hz).

Example 12

- [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 are dissolved in 80 cm ^{3 of} methanol and added in portions 2.1 g of sodium borohydride. The solution was stirred at room temperature for 3 hours and then evaporated to dryness. 150 cm ^{3 of} water are added to the residue and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, evaporated under reduced pressure and the residual white solid is recrystallized from ethanol. Thus, 2.8 g (77%) of the title compound are obtained.

Mp: 51-52 ° C.

For C20H20F3NO2 (363.3) calculated: C 66.11%, H 5.55%, N 3.85%;

found: C 66.08%, H 5.53%, N 3.86%.

1 H-NMR (CDCl 3, 400 MHz) δ: 7.5 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 6.54 (1H, s), 6.53 (1H, s), 5.88 (2H, s), 3.38 (1H, t, J = 5.4 Hz), 3.1 (1H, m), 2.55- 2.84 (5H, m), 2.45 (3H, s), 2.3 (2H, m).

Example 13

- (4-Trifluórmetylstyryl) -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

3.4 g (0.01 mol) of 1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline are dissolved in 150 cm @ ^{3 of} methanol. 1.4 g of sodium borohydride were added portionwise with stirring, and the solution was stirred at room temperature for 3 hours. The mixture is evaporated to one quarter of its original volume and 200 cm ^{3 of} water are added to the residue, the methanol present is distilled off, the solid is filtered off and washed with water until neutral. The product is recrystallized from ethanol. Thus, 2.6 g (74%) of the title compound are obtained. Mp: 124-125 ° C.

For C19H16F3NO2 (347.34) calculated: C 65.70%, H 4.64%, N 4.03%;

found: C 65.90%, H 4.67%, N 4.06%.

1 H-NMR (CDCl _3, 200 MHz) δ: 7.56 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 6.61 (1H, d, J = 15.8 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 = 7.7Hz), 3.3-3.0 (2H, m), 2.9-2.6 (2H, m).

Example 14

- [2- (4-trifluoromethylphenyl) ethyl] -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4tetrahydroizochinolíniumjodid

5.1 g (0.01 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline are dissolved in 60 cm ^{3 of} acetone. 8 cm @ ^{3 of} methyl iodide are added to the obtained solution, and the reaction mixture is stirred at room temperature for 24 hours. The precipitated substance is filtered and recrystallized from ethanol. Thus, 4.2 g (83%) of the title compound are obtained.

Mp: 229-231 ° C.

For C21H23F3INO2 (505.32) calculated: C 49.92%, H 4.59%, N 2.77%;

found: C 49.01%, H 4.61%, N 2.73%.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 7.66 (2H, d, J = 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz), 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), 2.682.68 (1H, m, m).

6Ί

Example 15

- (4-Trifluoromethylstyryl) -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolinium iodide

The procedure described in Example 14 was followed to give the title compound. Yield: 59%.

mp: 256-258 ° C.

For C21H21FINO2 (503.30) calculated: C 50.31%, H 4.21%, N 2.78%;

found: C 49.88%, H 4.25%, N 2.87%.

Example 1 6

- [2- (4-fluorophenyl) ethyl] -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroizochinolíniumjodid

2.93 g (6.5 mmol) of 1- [2- (4-trifluorophenyl) ethyl] -2,2-dimethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2.8 cm < ^{3 > of} methyl iodide are added. Heat to boiling in 40 cm ^{3 of} nitromethane with stirring for 3 hours. The mixture was cooled to room temperature and then allowed to stand in the freezer. The crystalline material is filtered, washed with cold acetone and recrystallized from ethanol. Thus it is obtained

1.3 g (43%) of the title compound.

mp: 213-215 ° C.

For C20H23FINO2 (455.31) calculated: C 52.76%, H 5.09%, N 3.08%;

found: C 53.11%, H 5.21%, N 3.15%.

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 0.02 (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 (2H, m), 2.52-2.0 (2H, m).

Example 17

- [2- (4-Fluorophenyl) ethyl] -2-methyl-6,7-methylenedioxyisoquinolinium iodide

A solution of 5.9 g (0.02 mol) of 1- [2- (4-trifluorophenyl) ethyl] -2-methyl-6,7-methylene-3 * 3 dioxyisoquinoline and 6.1 cm @ 3 of methyl iodide in 250 cm @ 3 of acetone is treated with ethyl acetate. Allow to stand at room temperature for 20 hours. The resulting suspension was cooled to 0 ° C, washed with acetone, and the product was recrystallized from methanol. Thus, 4.7 g (54%) of the title compound are obtained.

Mp .: 224-227 ° C.

Analysis: for C ₁₉ H ₇ FINO2 (437.25) Calculated: C 52.19%, H 3.92%, N 3.20%;

found: C 52.24%, H 3.99%, N 3.29%.

IR (KBr, cm ^-1 ): 1031, 932.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.58 (1H, d, J = 6.8 Hz), 8.19 (1H, d, J = 6.8 Hz), 8.05 (1 H, s), 7.71 (1H, s), 7.41 (2H, d, J = 8.5 Hz, J ₂ = 5.7 Hz), 7.14 (2H, t, J = 8.5 Hz), 6.46 (2H, s), 4.38 (3H, s), 3.78 (2H, t, J = 8.1 Hz), 3.04 (2H, t, J = 8.1 Hz).

Example 18 1- [2- (4-Fluorophenyl) ethyl] -2,3-dimethyl-6,7-methylenedioxyisoquinolinium iodide

3.0 g (0.0097 mol) of 1- [2- (4-fluorophenyl) ethyl] -2,3-dimethyl-6,7-methylenedioxyisoquinoline and 3.2 cm ^{3 of} methyl iodide are dissolved in 25 cm ^{3 of} nitromethane.

The reaction mixture is heated to boiling for 1.5 hours, 1.6 cm ^{3 of} methyl iodide are added and the reaction mixture is heated to boiling for an additional hour. The mixture is cooled to room temperature, 50 cm ^{3 of} diethyl ether are added, the mixture is stirred for 2 hours and filtered.

The product is recrystallized from dimethylformamide. There was thus obtained 2.19 g (50%) of the title compound.

mp: 271-273 ° C.

For C20H19FINO2 (451.28) calculated: C 53.23%, H 4.24%, N 3.10%;

found: C 53.28%, H 4.12%, N 3.14%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.09 (1H, s), 7.92 (1H, s), 7.53 (1H, s), 7.40 (2H, m) 7.13 (2H, m), 6.40 (2H, s), 4.22 (3H, s), 3.83 (2H, t,> 8.0 Hz), 3.00 (2H, t J = 8.0 Hz) 2.80 (3H, s).

Example 19

- (4-Fluorostyryl) -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

To a solution of 4.4 g (0.015 mmol) of 1- (4-fluorostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline in 200 cm ^{3 of} methanol is added in three portions with stirring

1.6 g of sodium borohydride. The reaction mixture is stirred at 25-30 ° C for 2 hours (TLC benzene: methanol 8: 2, R f = 0.46 UV), then evaporated to dryness under reduced pressure. 150 cm @ ^{3 of} water are added to the residue and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate, evaporated and the residue is crystallized from diethyl ether. The product was filtered and recrystallized from ethanol. Thus, 2.7 g (82%) of the title compound are obtained.

mp Mp 112-113 ° C.

Analysis: for C 18 H 16 FNO ₂ (217.33) calculated: C 72.71%, H 5.42%, N 4.71%;

found: C 72.37%, H 5.41%, N 4.51%.

1 H-NMR (CDCl ₃ , 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 = 15.8 Hz), 6.18 (1H, dd, J = 15.8 Hz, J ₂ = 8.0

Hz), 5.8 (2H, s), 4.51-4.48 (1H, m), 3.24-3.17 (1H, m), 3.02-2.99 (1H, m) .

2.99-2.68 (2 H, m).

Example 20

- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-6,7-metyléndioxyizochinolíniumjodid

5.1 g (0.015 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-6,7-methylenedioxyisoquinoline and 5 cm ^{3 of} methyl iodide are heated to boiling in 25 cm ^{3 of} nitromethane for 30 minutes and then the mixture is heated. Cool to room temperature, pour into 250 cm ^{3 of} acetone and stir. The precipitated crystalline solid was filtered, washed with cold acetone, and the crude isoquinoline salt was recrystallized from 4: 1 hexane / ethanol. Thus, 5.4 g (75%) of the title compound are obtained.

Mp: 258-260 ° C.

For C20H17F3INO2 (487.26) calculated: C 49.30%, H 3.52%, N 2.87%;

found: C 48.62%, H 3.44%, N 2.93%.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.61 (2H, 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 = 8.0) Hz), 3.14 (2H, t, J = 8.0 Hz).

Example 21

- (4-Trifluoromethylstyryl) -2-methyl-6,7-methylenedioxy isoquinolinium iodide

6.8 g (0.02 mol) of 1- (4-trifluoromethylstyryl) -2-methyl-6,7-methylenedioxyisoquinoline are dissolved in 40 cm @ ^{3 of} dichloromethane and 9.95 g (0.065 mol) of methyl iodide are added. The reaction mixture is heated to boiling 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. Thus, 5.9 g (61%) of the title compound are obtained.

Mp: 233-235 ° C.

For C20H15F3INO2 (485.25) calculated: C 49.51%, H 3.12%, N 2.89%;

found: C 49.05%, H 3.1 8%, N 2.82%.

1 H-NMR (CDCl 3, 400 MHz) δ: 8.77 (1H, d, J = 11Hz), 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 are dissolved in 110 cm @ ^{3 of} methanol and 0.8 g of sodium borohydride are added in two portions. The solution was stirred for 1 hour and then evaporated under reduced pressure. 110 cm @ ^{3 of} water are added to the residue and the mixture is extracted three times using 50 cm @ ^{3 of} dichloromethane each time. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue was recrystallized from ethanol. Thus, 2.5 g (57%) of the title compound are obtained.

Mp: 85-88 ° C.

For C20H18F3NO2 (361.37) calculated: C 66.48%, H 5.02%, N 3.88%;

found: C 66.60%, H 5.13%, N 3.91%.

IR (KBr, cm ^-1 ): 2844, 1166, 1121, 957.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.69 (4H, m), 6.78 (1H, d, J = 8.7 Hz), 6.69 (1H, s), 6 56 (1H, s), 6.34 (1H, d, J = 8.7Hz), 5.93 (2H, m), 3.86 (1H, m), 3.29 (3H, s) 3.1-2.9 (4H, m).

Example 23

- (4-Fluorostyryl) -2-methyl-6,7-metyléndioxyizochinolíniumjodid

38.1 g (0.13 mol) of 1- (4-fluorostyryl) -2-methyl-6,7-methylenedioxyisoquinoline are dissolved in 200 cm @ ^{3 of} nitromethane. To this solution was added 98.4 g of methyl iodide. The reaction mixture was stirred at 120 ° C for 1.5 hours. The precipitated solid crystals are filtered to give 12 g of crude product which is recrystallized from 70 ml of methanol. Thus, 7.4 g (62%) of the title compound are obtained.

Mp: 228-230 ° C.

For C19H15FINO2 (435.25) calculated: C 52.43%, H 3.47%, N 3.22%;

found: C 52.05%, H 3.38%, N 3.25%.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.62 (1H, 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), 7.387.32 (3H, m), 6 44 (2H, s); 4.34 (3H, s).

Example 24

- (4-Fluorostyryl) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolinium chloride g (0.07 mol) 1- (4-fluorostyryl) -2-methyl-6,7-methylenedioxy 1,2,3,4-Tetrahydroisoquinolinium iodide is dissolved in 1200 cm ^{3 of} methanol and 4.7 g of sodium borohydride are added in portions at 20 ° C. The solution was stirred at room temperature for 1 hour and then evaporated under reduced pressure. 500 cm ^{3 of} water are added to the residue. The aqueous solution is extracted with 440 cm ^{3 of} dichloromethane. The organic phase is dried over anhydrous sodium sulfate. After addition of 20 cm @ ^{3 of} hydrogen chloride-containing ethanol, the solution is evaporated to dryness, the residue is crystallized from benzene to give 18.7 g of a crude product which is recrystallized from 110 cm @ ^{3 of} 2-propanol. Thus, 16.3 g (76%) of the title compound are obtained.

Mp: 210-213 ° C.

Analysis for C ₉ H ₁₉ C1FNO ₂ (347.33) calculated: C 65.61%, H 5.51%, N 4.03%;

found: C 65.68%, H 5.59%, N 3.98%.

1 H-NMR (CDCl 3, 200 MHz) δ: 12.1 (1H, bs), 7.36 (2H, m), 6.98 (2H, m), 6.596.52 (3H, m), 6, O 2 (1H, m), 5.85 (2x 1H, 2xs), 3.78-3.75 (1H, m), 3.01-2.4 (4H, m), 3.45 (3H, s) .

Example 25

- (4-Trifluórmetylstyryl) -2-ethyl-6,7-metyléndioxyizochinolíniumjodid

Dissolve 2.0 g (5.8 mmol) of 1- (4-trifluoromethylstyryl) -2-ethyl-6,7-methylenedioxyisoquinoline in 15 cm ^{3 of} nitromethane and add to the solution.

4.7 cm ^{3 of} ethyl iodide. The solution was stirred at 120 ° C for 4 hours and then evaporated under reduced pressure. The residue was crystallized from diethyl ether and the crude product was recrystallized from acetone. Thus, 1.9 g (65%) of the title compound are obtained.

Mp: 234-236 ° C.

For C21H17F3INO2 (499.27) calculated: C 50.52%, H 3.43%, N 2.81%;

found: C 50.34%, H 3.40%, N 2.81%.

IR (KBr, cm ^-1 ): 1439, 1462, 1328.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.68 (1H, d, J = 6.9 Hz), 8.28 (1H, d, J = 6.9 Hz), 8.06 (2H, d, J = 8.2Hz), 7.89 (2H, d, J = 8.2Hz), 7.86 (1H, d, J = 16.7Hz),

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

- (4-Cyanostyryl) -2-methyl-6,7,8-trimetoxyizochinolíniumjodid

1.8 g (55 mmol) of 1- (4-cyanostyryl) -2-methyl-6,7,8-trimethoxyisoquinoline are dissolved in 15 cm @ ^{3 of} nitromethane. Methyl iodide (3.7 g) was added and the reaction mixture was stirred at 120 ° C for 4 hours. The mixture was evaporated and the residue was recrystallized 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. There was thus obtained 1 g (40%) of the title compound.

Mp .: 130-133 ° C.

For C23H23IN2O3 (502.35) calculated: N 5.58%;

found: N 5.38%.

IR (KBr, cm ^-1 ): 3438, 2225, 1406.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.15 (1H, s), 8.02 (1H, d, J = 16.9 Hz), 7.91 (4H, m), 7 45 (1H, s), 6.95 (1H, d, J = 16.8 Hz), 4.14 (3H, s), 4.06 (3H, s), 3.85 (3H, s) 3.68 (3H, s); 2.80 (3H, s).

Example 27

- [2- (3,4-Dimethoxyphenyl) ethyl] -2-methyl-6,7-dimetoxyizochinolíniumjodid

7.2 g (0.02 mol) of 1- (2- (3,4-dimethoxyphenyl) ethyl) -6,7-dimethoxyisoquinoline are dissolved in 60 cm @ ^{3 of} nitromethane and 14.2 g of methyl iodide are added thereto and the reaction The mixture is stirred at 120 DEG C. for 4 hours, then the mixture is cooled and 100 cm @ ^{3 of} diethyl ether are added to precipitate the product into crystalline form, the crystals are filtered to give 8.7 g of crude product. water / ethanol to give 4.8 g (71%) of the title compound.

Mp: 188-190 ° C.

For C22H28INO5 (513.37) calculated: N 2.73%;

found: N 2.63%.

Example 28

- [2- (3,4-Dimethoxyphenyl) ethyl] -6,7-dimethoxyisoquinoline

3.51 g (0.01 mol) of 1- (3,4-dimethoxystyryl) -6,7-dimethoxyisoquinoline are dissolved in 100 cm @ ³ of acetic acid. 0.5 g of Pd / C catalyst is added to the resulting solution and the mixture is hydrogenated at room temperature and. pressure of 1.01 MPa until hydrogen is consumed. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue is dissolved in 50 cm ^{3 of} methanol and the base is prepared by adding 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. There was thus obtained 1.5 g (43%) of the title compound.

Mp: 146-147 ° C.

For C21H23NO4 (353.422) calculated: C 71.37%, H 6.56%, N 3.96%;

found: C 71.04%, H 6.54%, N 3.89%.

IR (KBr, cm ^-1 ): 1516, 1234, 1158.

1 H-NMR (CDCl 3, 400 MHz) δ: 8.35 (1H, d, J = 5.5Hz), 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 = 7.8 Hz), 3.15 (2H, t, J = 7.8 Hz).

Example 29

- [2- (3,4-Dimethoxyphenyl) ethyl] -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline fumarate

To a solution of 3.0 g (0.006 mol) of 1- [2- (3,4-dimethoxyphenyl) ethyl] -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinium iodide in 200 cm ^{3 of} methanol is added at at room temperature and with stirring 0.45 g of sodium borohydride. The reaction mixture was stirred for 2 hours and then evaporated under reduced pressure. 200 cm @ ^{3 of} water are added to the residue and the aqueous solution is extracted three times with 60 cm @ ^{3 of} dichloromethane each. The combined organic phases are dried over anhydrous sodium sulphate and evaporated under reduced pressure to give 2 g of crude product, which is dissolved in 20 cm of ethanol. To this solution is added a solution of 0.62 g of fumaric acid in 40 cm ^{3 of} ethanol. The precipitated crystalline fumarate salt is filtered and washed with cold ethanol. Thus, 1.1 g (34%) of the title compound are obtained.

Mp: 84-85 ° C.

IR (KBr, cm ^-1 ): 3430, 2540, 1713, 1518, 1257.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 6.83 (1H, d, J = 8.2 Hz), 6.76 (1H, d, J = 1.5 Hz), 6.69 (1H 1H, dd, J = l, 6 Hz, _J2 = 8 Hz), 6.67 (1H, s), 6.65 (1 H, s), 6.60 (2H, 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) 1.60 (2H, m), 2.45 (3H, s), 2.44 (1H, m), 2.00 (2H, m).

Example 30

- [2- (4-trifluoromethylphenyl) ethyl] -4-propyl-6,7-etyléndioxyizochinolín

4.8 g (0.012 mol) of 1- (4-trifluoromethylstyryl) -4-propyl-6,7-ethylenedioxyisoquinoline are dissolved in 200 cm @ ³ of acetic acid and the solution is hydrogenated in the presence of 1 g of Pd / C catalyst at room temperature and pressure. 1.01 MPa until hydrogen is consumed. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was dissolved in aqueous methanol and concentrated aqueous ammonia was added to prepare the free base. Thus it is obtained

3.9 g (81%) of the title compound.

mp: 89-90 ° C.

Analysis for C 3 H _{22 2} F3NO ₂ (401.432) calculated: C 68.82%, H 5.52%, N 3.49%;

found: C 68.19%, H 5.51%, N 3.46%.

IR (KBr, cm ^-1 ): 1512, 1331, 1109, 1069.

1 H-NMR (CDCl _3, 200 MHz) δ: 8.11 (1H, 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 = 7.3Hz).

Example 3 1

- (4-Trifluórmetylstyryl) -4-propyl-6,7-etyléndioxyizochinoIíniumchlorid

0.9 g (3.7 mmol) of 1-methyl-6,7-etyléndioxyizochinolínu, 0.7 g (4.1 mmol) of 4-trifluoromethylbenzaldehyde and 3 cm ³ of acetic anhydride was stirred at 150 to 160 ° C for 3 hours and the mixture was evaporated under reduced pressure. 1.3 g of crude product are obtained, which is dissolved in 25 cm @ ^{3 of} acetone. To the resulting solution was added 2-propanol containing hydrogen chloride and the precipitated hydrochloride salt was filtered and washed with cold acetone. Thus, 0.6 g (37%) of the title compound are obtained.

mp: 203-210 ° C.

For C23H21ClF3NO2 (435.87) calculated: C 63.38%, H 4.86%, N 3.21%;

found: C 63.39%, H 4.85%, N 3.19%.

IR (KBr, cm -1): 3420, 2526, 1326, 1067.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.48 (1H, s), 8.32 (1H, d, J = 16.2 Hz), 8.16 (4H, m), 7 Δ 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 = 7.6 Hz), 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 is stirred in 4 cm ^{3 of} acetic anhydride at 160 ° C for 3 hours. The reaction mixture was evaporated under reduced pressure and the residual oil was purified by column chromatography. The crude product obtained is recrystallized twice from 2-propanol. Thus, 5.1 g (50%) of the title compound are obtained.

mp: 141-143 ° C.

For C21H19NO4 (349.39) calculated: C 72.19%, H 5.48%, N 4.01%;

found: C 71.56%, H 5.60%, N 3.98%.

IR (KBr, cm ^-1 ): 3420, 1505, 1271, 1137.

1 H-NMR (CDCl 3, 200 MHz) δ: 8.35 (1H, d, J = 5.39 Hz), 7.94 (1H, d, J = 15.8 Hz), 7.79 (1H, s), 7.67 (1H, d, J = 15.8 Hz), 7.37 (1H, d, J = 5.5 Hz), 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 (3H, s).

Example 33

- (4-Trifluoromethylstyryl) -4-propyl-6,7-methylenedioxy isoquinoline

3.5 g (15 mmol) of 1-methyl-4-propyl-6,7-methylenedioxyisoquinoline and 4.0 g (22.6 mmol) of 4-trifluoromethylbenzaldehyde are stirred in 35 cm @ ^{3 of} acetic anhydride at 160 DEG C. for 1 hour. 4 hours. The reaction mixture was evaporated under reduced pressure and the residue was recrystallized from diethyl ether. The crude product obtained (2.17 g) is recrystallized from absolute ethanol. Thus, 1.6 g (28%) of the title compound are obtained.

mp: 156-158 ° C.

For C22H18F3NO2 (385.389) calculated: C 68.57%, H 4.71%, N 3.63%;

found: C 68.43%, H 4.76%, N 3.55%.

IR (KBr, cm ^-1 ): 1470, 1328, 1234, 1120.

1 H-NMR (CDCl 3, 400 MHz) δ: 8.28 (1H, s), 7.93 (1H, d, J = 15.6 Hz), 7.83 (1H, d, J = 15.6 Hz), 7.74 (2H, d, J = 8.2 Hz), 7.63 (2H, d, J = 8.1 Hz), 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

- (4-Fluorostyryl) -6,7-methylenedioxy-3,4-dihydroizochinolíniumchlorid

12.5 g (0.04 mol) of N- [2- (3,4-methylenedioxyphenyl) ethyl] -4-fluorocinamide are dissolved in 100 cm and 25 ml of phosphorus oxychloride are added. The mixture was heated to boiling for 1.5 hours and then cooled to 10 ° C and stirred at this temperature for 1 hour. The crystalline product is filtered off, washed with a small amount of benzene at 10 DEG C. and recrystallized from 400 cm @ ^{3 of} 2-propanol. Thus, 7.1 g (53.7%) of the title compound are obtained.

Mp: 219-221 ° C.

Example 35

- (4-Trifluoromethylstyryl) -6,7-methylenedioxy-3,4-dihydroisoquinolinium iodide g (0.055 mol) of 2- (3,4-methylenedioxyphenyl) -N-4-trifluoromethylcinnamamide is heated to boiling in 70 cm ^{3 of} benzene in the presence of 20 cm ^{3 of} phosphorus oxychloride for 3.5 hours. The reaction mixture is cooled to 20 ° C, n

the precipitated salt is washed with hexane and recrystallized from 110 cm @ 3 of ethanol. There was thus obtained 7.2 g (72%) of the title compound.

Mp: 208-212 ° C.

Analysis: for C ₁₉ H ₅ ClF ₃ NO 2 (381.70) calculated: C 59.78%, H 3.96%, Cl 9.29%, N 3.67%;

found: 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-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine are stirred in 4.46 cm ³ (7.67 g, 50 mmol) of phosphorus oxychloride at at 85 ° C for 16 hours. The reaction mixture is cooled to room temperature and poured into 40 cm ^{3 of} ice water. The pH of the mixture is adjusted to 11 with concentrated ammonia. The solution is extracted three times with 30 cm ^{3 of} ethyl acetate each, the combined organic phases are dried over anhydrous magnesium sulphate and evaporated. The crude base is dissolved in 10 cm ^{3 of} methanol and 1.16 g (10 mmol) of maleic acid in 10 cm ^{3 of} methanol are added thereto, followed by dropwise addition of 40 cm ^{3 of} diisopropyl ether. The precipitated crystals are filtered and washed with 10 cm ^{3 of} diisopropyl ether. Thus, 2.54 g (53%) of the title compound are obtained.

Mp .: 149-151 ° C (ethanol-diisopropyl ether).

For C24H12F3NO6 (477.44) calculated: C 60.3 8%, H 4.64%, N 2.93%;

found: C 60.50%, H 4.56%, N 3.03%.

IR (film, cm ^-1 ): 1600, 1493, 1252, 1177.

¹ H-NMR (DMSO-d 6, 400 MHz) δ: 8.14 (1H, d, J = 8.8 Hz), 7.86 (2H, dd, J = 8.7 Hz, J = 5.7 Hz), 7.57 (1H, d, J = 15.8 Hz), 7.50-7.40 (3H, m), 7.13 (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 the crude base are dissolved in 40 cm @ ^{3 of} diisopropyl ether and to the solution is added dropwise 1.73 cm @ ^{3 of} 2-propanol containing

-J

12. Hydrogen chloride (25.3 g / 100 cm). The precipitated crystals are filtered and washed with 10 cm ^{3 of} diisopropyl ether. Thus, 2.11 g (53%) of the title compound are obtained.

Mp .: 188 ° C (ethanol).

For C20H19ClF3NO2 (397.82) calculated: C 60.38%, H 4.81%, Cl 8.91%, N 3.54%;

found: C 60.24%, H 4.84%, 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 (1H, d, J = 8.9 Hz), 8.22 (1H, m), 7.88 (2H, dd, J) = 7.6 Hz, J = 1.8 Hz), 7.73 (1H, d, J = 16.1 Hz), 7.53 (3H, m), 7.35 (1H, dd, J = 8 9 Hz, J = 2.6 Hz), 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) δ: 166.9, 166.6, 149.6, 135.7, 134.2, 133.7, 132.3, 129.8, 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

- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroizochinolíniumbromid

2.33 g (0.0075 mol) of 1- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-ethylenedioxy-1,2,3,4-tetrahydroisoquinoline are dissolved in 100 cm @ ^{3 of} dichloromethane. The solution is cooled to 0-5 ° C and N-bromosuccinimide (1.6 g, 0.009 mol) is added in several portions over 15 minutes. The mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. The precipitated crystals are filtered, the filtrate is evaporated and the resulting solid is recrystallized from acetone. There was thus obtained 1.76 g (58%) of the title compound.

Mp .: 177-180 ° C.

For C 20 H 21 BrFNO 2 (406.30) calculated: H 5.21%, N 3.45%;

found: H 5.43%, N 3.29%.

@ 1 H (KBr, cm @ -1): 1735, 1301, 1219.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.61 (s, 1H), 7.31 (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

- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroizochinolíniumjodid

2.8 g (0.0075 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinoline are dissolved in 120 cm ^{3 of} acetone. 5 cm @ ^{3 of} methyl iodide are added to the solution obtained. The mixture is heated to boiling for 1 hour and then cooled with ice water to 0-5 ° C and stirred at this temperature for 2-3 hours. After crystallization, the crystals are filtered, washed with cold acetone and recrystallized from acetone. Thus, 2.2 g (58%) of the title compound are obtained.

Mp .: 205-207 ° C.

For C21H21F3INO2 (503.30) calculated: C 50.12%, H 4.21%, N 2.78%;

found: C 49.10%, H 4.1%, N 2.71%.

1 H-NMR (CDCl 3, 400 MHz) δ: 7.56 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz), 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 (2H, m) 3H, s), 3.53 (2H, t, J = 7.6Hz), 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 are dissolved in 80 cm ^{3 of} toluene. To the solution obtained, 12 cm ^{3 of} phosphorus oxychloride are added dropwise and the reaction mixture is heated at 80 ° C for 2.5 hours. The precipitated crystalline dihydroisoquinoline is filtered and recrystallized from ethanol. The product obtained (12 g) is dissolved in 90 cm ^{3 of} methanol, basified to pH 9 by addition of 20% aqueous sodium hydroxide solution, the precipitate is filtered, washed with aqueous methanol (5: 1) and recrystallized from a mixture of ethanol and water. There was thus obtained 1.44 g (41%) of the title compound.

mp: 85 ° C

For C20H18NO2 (361.37) calculated: C 66.48%, H 5.02%, N 3.88%;

found: C 66.34%, H 5.04%, N 3.90%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.61 (2H, d, J = 8.0 Hz), 7.47 (2H, d,> 8.0 Hz), 7.10 ( 1H, s), 6.74 (1H, s), 4.24 (4H, m), 3.48 (2H, t,> 7.4 Hz), 2.96 (4H, m), 2.47 (2H, t, > 7.1 Hz).

Example 40

7-Chloro-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroisoquinoline hydrochloride

Dissolve 10.0 g (0.028 mol) of N- [2- (4-chlorophenyl) ethyl] -3- (4-trifluoromethylphenyl) propionylamide in 80 cm ^{3 of} xylene. To the stirred mixture was added 12 g of phosphorus pentoxide and the reaction mixture was stirred at 110-120 ° C for 5 hours. The mixture was cooled to room temperature and the xylene was removed from the precipitated solids by decantation. 100 cm ^{3 of} methanol are added, the crystals are filtered off, 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 x 50 cm ³ ). The combined organic phases were dried on anhydrous sodium sulfate and evaporated to dryness ^1. 10.6 g of an oily base are obtained, which is purified by column chromatography using a 8: 2 mixture of toluene and methanol. 1.4 g of the base obtained are converted into 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. Filter the salt and wash with a small amount of cold ether. There was thus obtained 1.3 g (87%) of the title compound.

Mp: 173-175 ° C.

For C18H16Cl2F3N (374.23) calculated: C 57.77%, H 4.31%, N 3.74%, Cl 18.95%;

found: C 57.30%, H 4.30%, N 3.69%, Cl 18.80%.

1 H-NMR (CDCl _3, 400 MHz) δ: 15.81 (1H, 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 (1H, d, J = 8.3 Hz), 3.94 (2H t, J = 7.6 Hz), 3.68 (2H, t, J = 7.6 Hz), 3.26 (2H, t, J = 8.0 Hz), 3.01 (2H, t , J = 8.0 Hz).

Example 41

- (4-Fluorostyryl) -4-methyl-6,7-methylenedioxy-3,4-dihydroizochinolínhydrochlorid

To a solution of 3.27 g (0.01 mol) of N- [2-methyl (3,4-methylenedioxyphenyl) ethyl] -4-fluorocinamide in 50 cm ^{3 of} absolute toluene is added with stirring 4.66 g (0.05 mol) of oxychloride The reaction mixture was stirred at 120 ° C under argon until reaction was complete. 50 cm @ ^{3 of} methanol are then added dropwise to a hot solution and the mixture is evaporated. The residue was dissolved in methanol and evaporated again. This process is repeated 5 to 6 times and then the methanolic product solution is poured into an Amberlist 46 ion exchange resin. The solution is evaporated and diethyl ether is added. The precipitated crystals are filtered. Thus, 2.38 g (69%) of the title compound are obtained.

1.1 .: decomposition 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 = 16.1 Hz), 7.15 (2H, m), 6.97 (1H, s), 6.20 (2H, s), 3.89 (1H, ddd, J = 14.5 Hz, J ₂ = 5.5 Hz, ₃ J = 3.50 Hz), 3.71 (1H, ddd, J = 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).

Example 42

1- (4-Fluorostyryl) -6,7-methylenedioxy-4-propyl-3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield 74%.

Mp .: 184-185 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 14.24 (1H, bs), 8.42 (1H, d, J = 16.0 Hz), 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 (1 H, ddd, J = l4,8 Hz, J ₂ = 5.5 Hz, J = ₃ Hz), 3.78 (1H, ddd, J = l4,8 Hz, J ₂ = 3.6 Hz, J ₃ = 2.6 Hz), 2.94 (1H, m), 1.25-1.60 (4H, m), 0.93 (3H, t, J = 7.6 Hz).

Example 43

4-Butyl-1- (4-fluorostyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield 67%.

Mp: 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 = 15.8 Hz), 7.15 (2H, m), 6.91 (1H, s), 6.20 (2H , s), 4.00 (1H, dd, J = 14.8 Hz, J ₂ = 5.3 Hz), 3.79 (1H, dd, J = 14.8 Hz, J ₂ = 3.3 Hz), 2.95 (1H, m), 1.25-1.60 (6H, m), 0.90 (3H, t, J = 7.6 Hz).

Example 44

4-Ethyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield: 60%.

Mp .: 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 (1 H, s), 6.20 (2H, s), 4.05 (1H, br dd, J = 14.9 Hz, J ₂ = 5.5 Hz), 3.83 (1H, d, J = 14.9 Hz, J ₂ = 3.50 Hz), 2.93 (1H, m), 1.63 (2H, m), 1.01 (3H, t, J = 7.6 Hz) .

Example 45

4-Butyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield 71%.

Mp: 191-193 ° C.

1 H-NMR (DMSO-d 6 + CDCl 3, 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), 6.20 (2H, s), 4.04 (1 H, ddd, J = 15.0 Hz, J ₂ = 5.5 .

J ₃ = above 1 Hz), 3.82 (1H, ddd, J 1 = 15.0 Hz, J ₂ = 3.5 Hz, J ₃ = 3.4 Hz), 2.97 (1H, m),

1.2 + 1.60 (6H, m), 0.9 (3H, J = 7.6 Hz).

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. Yield 63%.

Mp .: 200-202 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 14.02 (1H, bs), 8.47 (1H, d, J = 16.0 Hz), 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, Δ (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 = 14.8 Hz, J ₂ = 3.6 Hz, J ₃ = 4.9 Hz), 2.91 (1H, m), 1.25 + 1.60 (4H, m), 0.92 (3H, t, 7.6 Hz).

Example 47

6,7-Methylenedioxy-4-propyl-1- (4-trifluoromethylstyl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield 70%.

Mp: 201-204 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 14.53 (1H, bs), 8.45 (1H, d, J = 16.1 Hz), 7.88 (2H, d, J = 8.0) Hz), 7.69 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 16.1 Hz), 7.32 (1H,

s), 6.88 (1 H, s), 6.18 (2H, s), 4.05 (1H, dd, J = 15.0 Hz, J ₂ = 3.6 Hz), 3.81 ( 1H, dd, J = 15.0 Hz, J _3, 4 = 5.6 Hz), 2.96 (1H, m), 1.25 to 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 was obtained. Yield 66%.

mp: 227-230 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 14.08 (1H, bs), 8.47 (1H, d, J = 16.0 Hz), 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 = 14.6 Hz, J ₂ = 7.6 Hz, J ₃ = 4.0 Hz), 3.87 (3H, s), 3.68 (1H, dd, J J = 14.6 Hz, J ₂ = 5.5 Hz, J ₃ = 3.6 Hz), 3.12 (1H, m), 1.30 (3H, d, J = 7.0 Hz).

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 was obtained. Yield 58%.

mp: 206-208 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 13.98 (1H, bs), 8.40 (1H, d, J = 16.0 Hz), 7.39 (1H, dd, J) = 8 3 Hz, J ₂ = 2.0 Hz), 7.36 (1H, s), 7.33 (1H, d, J = 16.0 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 (1H, dd, J, = 15 0 Hz, J ₂ = 5.4 Hz, J ₃ = 2.4 Hz), 3.98 (3H, s), 3.95 (3H, s), 3.75 (1H,

J 1 = 15.0 Hz, J ₂ = 3.9 Hz, J ₃ = 4.6 Hz), 2.88 (1H, 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 was obtained. Yield: 79%.

mp: 186-188 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 13.72 (1H, bs), 8.40 (1H, d, J = 16.0 Hz), 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 (1 H, dd, J = 14.8 Hz, J ₂ = 5.54 Hz), 3.80 (1H, dd, J = 14.8 Hz, J ₂ = 3.3 Hz), 2 92 (1H, m), 1.62 (2H, m), 1.00 (3H, t, J = 7.6Hz).

Example 5 1

4-Ethyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield: 61%.

mp: 182-185 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 13.89 (1H, bs), 7.33 (1H, s), 8.44 (1H, d, J = 15.8 Hz), 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, Δ (1H, m), 3.87 (3H, s), 3.76 (1H, m), 2.82 (1H, m), 1.63 (2H), 1.00 (3H, t, J = 7.6 Hz).

Example 52

1- (4-Fluorostyryl) -4-hexyl-6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained.

Yield: 71%

mp: 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 = 7.6 Hz).

Example 53

4-Hexyl-6,7-methylenedioxy-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield: 80%.

mp: 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), 6.20 (2H, s), 4.04 (1H, brdd, J 1 = 14.9 Hz, J ₂ = 3.8 Hz), 3.82 (1H, brdd, J ₃ ) = 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 was obtained. Yield: 74%.

Mp: 129-131 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 14.02 (1H, bs), 8.47 (1H, d, J = 15.7 Hz), 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, m), 3.75 (1H, m), 2.88 (1H, m), 1, 20 + 1.60 (10H, m), 0.88 (3H, t, J = 7.6Hz).

Example 55

4-Butyl-6,7-methylenedioxy-1- (4-methoxystyryl) -3,4-dihydroisoquinoline hydrochloride

Following the procedure described in Example 41, the title compound was obtained. Yield: 67%.

Mp: 140-142 ° C.

1 H-NMR (CDCl 3, 400 MHz) δ: 13.95 (1H, bs), 8.45 (1H, d, J = 15.8 Hz), 7.74 (2H, d, J = 8.0) Hz), 7.32 (1 H, s), 7.25 (1 H, d, J = 15.8 Hz), 6.95 (2 H, d, J = 8.0 Hz), 6.85 (1 H, s), 6.16 (2H, s), 3.87 (3H, s), 4.00 (1H, br dd, J = 14.8 Hz, J ₂ = 3.8 Hz), 3.76 ( 1H, br dd, J = 14.8 Hz, 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 was obtained. Yield: 81%.

Mp: 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 = 2.0 Hz), 7.43 (1H, d, J = 15.8 Hz), 7.41 (1H, dd, J = 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 = 14.9 Hz, J ₂ = 3.3 Hz), 3.76 (1H, dd, J 1 = 14.9 Hz, J ₂ = 3.3 Hz), 3.76 (1H, 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 was obtained. Yield: 70%.

Mp: 212-215 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 12.86 (1H, s), 8.25 (1H, d, J = 15.8 Hz), 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 = 16 Hz, J ₂ = 6.0 Hz) 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, br dd, J = 14.8 Hz, J ₂ = 5.3 Hz), 3.77 (1H, br dd, J = 14 8 Hz, J ₂ = 2.8 Hz), 3.06 (1H, m), 1.25 + 1.55 (4H, m), 0.9 (3H, t, J = 7.6 Hz) .

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 was obtained. Yield: 77%.

mp: 209-211 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 13.87 (1H, bs), 8.37 (1H, d, J = 15.9 Hz), 7.39 (1H, dd, J, = 8) 3 Hz, J ₂ = 2.0 Hz), 7.38 (1H, s), 7.33 (1H, d, J = 15.9 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, Jj = 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 , 6 Hz).

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 was obtained. Yield: 63%.

mp: 201-203 ° C.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 13.91 (1H, bs), 8.37 (1H, d, J = 15.8 Hz), 7.39 (1H, dd, J = 8, 4 Hz, J-2.0 Hz), 7.38 (1H, s), 7.32 (1H, d, J = 15.8 Hz), 7.30 (1H, d, J = 2.0 Hz) 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 _t = 14.8 Hz, J ₂ = 7.5 Hz, J ₃ = 2.5 Hz), 3.67 (1H, ddd, J = 14, 8 Hz, J ₂ = 5.2 Hz, J ₃ = 1.8 Hz, 3.12 (1H, m), 1.30 (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 was 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 = 14.6 Hz, J ₂ = 5.7 Hz), 3.74 (1H, dd, J = 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 of N- [2- (3,4-methylenedioxyphenyl) ethyl] fluorocinamide are dissolved in

-j n

100 cm @ 3 of benzene and 25 cm @ 3 of phosphorus oxychloride are added to the obtained solution. The reaction mixture is heated to boiling for 1.5 hours, then cooled to 10 ° C and stirred at this temperature for 1 hour. The crystalline product is filtered off, washed with a small amount of benzene, cooled to 10 DEG C. and recrystallized from 400 cm @ ^{3 of} 2-propanol. Thus, 7.1 g (53.7%) of the title compound are obtained.

Mp: 219-221 ° C.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 12.55 (1H, bs), 8.3 (1H, d, J = 16.1 Hz), 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).

Example 62

1- (4-Trifluoromethylstyryl) -6,7-methylenedioxy-3,4-dihydroisoquinoline hydrochloride g (0.055 mol) of 2- (3,4-methylenedioxyphenyl) ethyl N- (4-trifluoromethyl) cinnamamide was heated to boiling in 70 ° C. cm ^{3 of} benzene in the presence of 20 cm ^{3 of} phosphorus oxychloride for 3.5 hours. The reaction mixture is cooled to 20 DEG C., the precipitated salt is washed with hexane and recrystallized from 110 cm @ ^{3 of} ethanol. There was thus obtained 7.2 g (72%) of the title compound.

1.1 .: 208-212 C. C.

For C19H15ClF3NO2 (381.70) calculated: C 59.78%, H 3.96%, Cl 9.29%, N 3.67%;

found: C 59.74%, H 3.94%, Cl 9.22%, N 3.61%.

1 H-NMR (DMSO-d 6, 200 MHz) δ: 12.56 (1H, bs), 8.23 (1H, d, J = 16.1 Hz), 8.09 (2H, d, J = 8) 1 Hz), 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 = 8.1 Hz), 3.09 (2H, d, J = 8.1 Hz).

Example 63

6,7-ethylenedioxy-1- [2- (4-trifluoromethylphenyl) ethyl] -4-propyl-3,4-dihydroisoquinoline oxalate

To a solution of 7.5 g (0.017 mol) of N- (2- (3,4-ethylenedioxyphenyl) ethyl] -3- (4-trifluoromethylphenyl) propionylamide in 100 cm ^{3 of} absolute benzene is added 6 cm ^{3 of} phosphorus oxychloride. The residue is distilled off (3 x 75 cm ^{3 of} methanol and 75 cm ^{3 of} benzene) and the crude product is dissolved in 200 cm ^{3 of} dichloromethane and crushed ice and sodium hydroxide are added to the obtained solution with stirring. The aqueous phase is extracted twice with 80 cm ^{3 of} dichloromethane each, the combined organic phases are dried over anhydrous sodium sulphate and evaporated to dryness, and the remaining crude product is purified by column chromatography. to give 4.8 g of base which is converted to the oxalate salt in absolute diethers to give 5.7 g (69%) of the title compound.

Mp: 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 = 3.1 Hz) J ₂ = 15.4 Hz), 3.58 (1H, dd, J 1 = 5.3 Hz, J ₂ = 14.9 Hz), 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) , 6 Hz).

IR (KBr, cm ^-1 ): 3420, 2700, 1750, 1648, 1328.

Example 64

6,7-ethylenedioxy-1 - [(4-trifluoromethyl) styryl] -4-propyl-3,4-dihydroisoquinoline oxalate

To a solution of 6.8 g (0.016 mol) of N- [2-propyl-2- (3,4-ethylenedioxyphenyl) ethyl] 4-trifluorocinamide in 70 cm ^{3 of} absolute benzene is added 6 cm ^{3 of} phosphorus oxychloride. The reaction mixture was heated to boiling for 2 hours and then evaporated. 3 x 60 cm ^{3 of} methanol are distilled off from the residue, ether (100 cm ³ ) is added, the mixture is heated to boiling for 15 minutes, then the ether is removed by decantation and this procedure is repeated twice. The crude product is dissolved in dichloromethane and crushed ice and sodium hydroxide are added under stirring to pH 10-11. The separated aqueous phase is extracted twice using 50 cm ^{3 of} dichloromethane each. The combined organic phases were dried over anhydrous sodium sulfate, and evaporated to give 2.9 g (45%) of an oily product. The crude product was dissolved in absolute ethers and an equimolar amount of oxalic acid was added to the solution. The crystalline salt is filtered. Thus, 3.22 g (41%) of the title compound are obtained.

Mp: 140-143 ° C.

Example 65

7-hydroxy-l- [2- (4-trifluoromethyl-phenyl) -ethyl] -6-methoxy-3,4-dihydroisoquinoline

A solution of 30 g (0.082 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline in 250 cm ^{3 of} concentrated hydrochloric acid is stirred under a stream of nitrogen in a 120 ° C oil bath for 50 hours. The solution is cooled in ice water, the crystalline substance is filtered off and dissolved in 300 cm @ ^{3 of} methanol. Addition of 100 cm ^{3 of} concentrated ammonia liberates the base. The solvent is removed from the precipitated gum. The residue was recrystallized from acetonitrile. There was thus obtained 11.7 g (33%) of the title compound.

Mp: 129-132 ° C.

Example 66

- (2-phenylethyl) -6,7-methylenedioxy-3,4-dihydro-isoquinoline

A solution of 10 g (0.033 mol) of N- [2- (3,4-methylenedioxyphenyl) ethyl] -3-phenylpropionylamide and 30 cm ^{3 of} phosphorus oxychloride in 70 cm ^{3 of} absolute benzene is heated to boiling for 1.5 hours and then cooled to 50 ° C and the precipitated crystals are filtered off. The crude hydrochloride is dissolved in a mixture of 200 cm of water and 200 cm of methanol and the pH of the solution is adjusted to 13 by addition of 20% aqueous sodium hydroxide solution. The precipitated white crystalline base is filtered, washed with cold water, dried and recrystallized from ethanol and water. Thus, 5.3 g (58%) of the title compound are obtained. Mp: 112-115 ° C.

Example 67

a) 4,6-Dimethoxy-1-styryl-4-trifluoromethyl-3,4-dihydroisoquinolinium maleate

A mixture of 3.79 (10 mmol) of N-cinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine and 4.46 cm ³ (7.67 g, 50 mmol) of phosphorus oxychloride is stirred at 85 ° C 16 hours. The reaction mixture is cooled to room temperature and poured into 40 cm ^{3 of} water. The pH is then adjusted to 11 by addition of concentrated aqueous ammonia. The mixture is extracted three times using 30 cm ^{3 of} ethyl acetate each time. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated. The crude base is dissolved in 10 cm @ ^{3 of} methanol and 1.6 g (10 mmol) of maleic acid in 10 cm @ ^{3 of} methanol and then 40 cm @ ^{3 of} diisopropyl ether are added dropwise. The precipitated crystals are filtered and washed with 10 cm ^{3 of} diisopropyl ether. Thus, 2.54 g (53%) of the title compound are obtained.

Mp .: 149-151 ° C (ethanol-diisopropyl ether).

For C24H12F3NO6 (477.4) calculated: C 60.3 8%, H 4.64%, N 2.93%;

found: C 60.50%, H 4.56%, N 3.03%.

IR (film, cm ^-1 ): 1600, 1493, 1252, 1177.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.14 (1H, d, J = 8.8 Hz), 7.86 (2H, dd, J = 8.7 Hz, J = 5.7 Hz), 7.57 (1H, d, J = 15.8 Hz), 7.50-7.40 (3H, m), 7.13 (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 of the crude base are dissolved in 40 cm ^{3 of} diisopropyl ether and then 1.73 cm ^{3 of} isopropanol containing 25.3 g / 100 cm ^{3 of} hydrogen chloride (12 mmol) are added dropwise. The precipitated crystals are filtered and washed with 10 cm ^{3 of} diisopropyl ether. Thus, 2.11 g (53%) of the title compound are obtained.

Mp .: 188 ° C (ethanol).

Analysis for C ₂ oH 19CIF3NO2 (397.82) calculated: C 60.38%, H 4.81%, Cl 8.91%, N 3.54%;

100 found: C 60.24%, H 4.84%, 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 (1H, d, J = 8.9 Hz), 8.22 (1H, m), 7.88 (2H, dd, J = 7.6 Hz, J = 1.8 Hz), 7.73 (1H, d, J = 16.1 Hz), 7.53 (3H, m), 7.35 (1H, dd, J = 8.9 Hz, J = 2.6 Hz), 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) δ: 166.9, 166.6, 149.6, 135.7, 134.2, 133.7, 132.3, 129.8, 129.3, 124.4 (q, ¹ J CF = 287.5 Hz), 119.0, 115.9, 115.8, 114.7, 75.0 (q, ² J _CF = 28.5 Hz) , 55.8, 53.3, 42.2.

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-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine were treated with 4.46 cm ³ (7.67 g, 50 mmol) of the title compound. mmol) of phosphorus oxychloride as described in Example 67, Section A). The crude base obtained is recrystallized from hexane. There was obtained 2.54 g (67%) of a gray-brown colored 1- (4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline.

Mp .: 92-93 ° C (hexane).

For C20H17F4NO2 (379.35) calculated: C 63.32%, H 4.52%, N 3.69%;

found: C 63.05%, H 4.48%, N 3.61%.

IR (KBr, cm ^-1 ): 2959, 1646, 1510, 1180.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 7.70 (1H, d, J = 8.6 Hz), 7.53 (2H, m), 7.42 (1H, d, J = 15.9 Hz), 7.24 (1H, d, J = 2.6 Hz), 7.14 (1H, d, J = 15.9 Hz), 7.10-7.02

101 (3Η, m), 4.26 (1H, d, J = 17.2Hz), 4.17 (1H, d, J = 17.2Hz), 3.90 (3H, s), 3, 32 (3 H, s).

¹³ C-NMR (CDCl 3, 100.6 MHz) δ: 163.1 (d, JCl = 249.1 Hz), 161.8, 161.6, 135.5, 132.6, 132.4, 129 0 (d, ³ JCF = 8.4 Hz), 128.1, 125.2 (q, J _CF = 286.1 Hz),

123.6 (d, ⁴ J CF = 2.3 Hz), 123.0, 115.8 (d, ² J CF = 22.1 Hz), 114.8, 112.8, 75.1 (q, ² J) _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 solution obtained was added dropwise a solution of 0.58 g (5 mmol) of maleic acid in 7 cm of methanol and then 20 cm of diisopropyl ether. The precipitated crystals are filtered and washed with 7 cm ^{3 of} diisopropyl ether. This afforded 1.66 g (67%) of the title compound as a yellow solid.

Mp .: 139-140 ° C (ethanol-diisopropyl ether).

For C24H21F4NO6 (495.43) calculated: C 58.19%, H 4.27%, N 2.83%;

found: 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 (1H, 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-3,3-dihydroisoquinolinium chloride

1.14 g (3 mmol) of 1- (4-fluorostyryl) -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroisoquinoline are reacted with 0.5 cm ^{3 of} 2-propanol containing 3.6 mmol (25.3 g / ml). 100 cm @ 3 of hydrogen chloride as described in Example 67, section B). This afforded 0.94 g (75%) of the title compound as a pale yellow solid.

Mp: 213-214 ° C.

102

For C20H18ClF4NO2 (415.81) calculated: C 57.77%, H 4.36%, Cl 8.53%, N 3.37%;

found: C 57.54%, H 4.31%, Cl 8.57%, N 3.40%.

IR (film, cm ^-1 ): 2541, 1599, 1241.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.51 (1H, d, J = 8.8 Hz), 8.16 (1H, d, J = 15.8 Hz), 8.05 -7.96 (2H, m), 7.77 (1H, d, J = 15.8 Hz), 7.50-7.30 (3H, m), 7.25 (1H, s), 4, 49 (1H, d, J = 16.1 Hz), 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 maleate

Following the procedure described in Example 67, Section A, starting from 4.47 g (10 mmol) of N- (trifluoromethylcinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine. This was recrystallized from hexane to give 3.09 g (72%) of a gray-brown 4,6-dimethoxy-4- (trifluoromethyl) -1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline.

Mp: 87-88 ° C.

Found: C2iHj7F ₆ NO 2 (429.36) calculated: C 58.75%, H 3.99%, N 3.26%;

found: C 58.58%, H 3.95%, N 3.30%.

IR (KBr, cm ^-1 ): 1608, 1325, 1166.

1 H-NMR (CDCl 3, 400 MHz) δ: 7.69 (1H, d, J = 8.7 Hz), 7.67-7.61 (4H, m), 7.48 (1H, d, J = 15.9 Hz), 7.30 (1H, d, J = 15.9 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.04 (1H, dd, J = 8 7 Hz, J = 2.4 Hz), 4.28 (1H, d, J = 17.5 Hz), 4.18 (1H, d, J = 17.5 Hz), 3.91 (3H, s), 3.33 (3H, s).

103 ¹³ C-NMR (CDCl 3, 100.6 MHz) δ: 161.9, 161.4, 139.7, 135.1, 132.8, 130.5 (q, ² JCF = 32.4 Hz), 128.0, 127.5, 126.3, 125.4 (q, J _C = 293.8 Hz), 125.8 (q, ³ J CF = 3.8 Hz), 124.0 (q, (JCf = 272.0 Hz), 122.8, 11.9, 11.12, 75.1 (q, ² JCf = 27.8 Hz), 55.6, 52.6, 49.6.

I ‘

2.15 g (5 mmol) of the obtained base was converted to the maleate salt as described in Example 68. This afforded 1.96 g (72%) of the title compound as a yellow solid.

Mp .: 139-140 ° C (ethanol-diisopropyl ether).

For C ₂₅ H ₂ F ₆ NO 6 (545.44) calculated: C 55.05%, H 3.88%, N 2.57%;

found: C 55.18%, H 3.80%, N 2.69%.

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 = 8.4Hz), 7.60 (1H, d, J = 16.1Hz), 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

1.29 g (3 mmol) of the base obtained as described in section A) is reacted with 0.5 cm ^{3 of} 2-propanol containing 25.3 g / 100 cm ³ (3.6 mmol) of hydrogen chloride as described in Example 67 , 5e or B). This afforded 0.86 g (72%) of the light yellow title compound.

Mp .: 234-235 ° C (ethanol, dec.).

Found: C ₂ | H | ₂ 8C1F6NO: C 54.15%, H 3.89%, Cl 7.61%, N 3.01%;

104 found: C 53.94%, H 3.86%, Cl 7.57%, N 2.99%.

IR (film, cm ^-1 ): 1599, 1423, 1252.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 8.56 (1H, d, J = 8.9 Hz), 8.31 (1H, d, J = 16.1 Hz), 8.13 (2H, d, J = 8.2Hz), 7.94 (1H, d, J = 16.1Hz), 7.90 (2H, d, J = 8.2Hz), 7.43 (1H δ d, J = 8.9 Hz, J = 2.4 Hz), 7.26 (1H, bs), 4.54 (1H, d, J = 16.5 Hz), 4.27 (1H, d) J = 16.5 Hz), 4.03 (3H, s), 3.4 (3H, s).

Example 70

A) 4,6-Dimethoxy-1- (4-nitrostyryl) -4-trifluoromethyl-3,4-dihydroisoquinolinium maleate

The procedure described in Example 67, Section A) was followed, starting from 4.24 g (10 mmol) of N-4-nitrocinnamoyl-3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine. The crude base was recrystallized from hexane. Thus, 2.58 g (63%) of a gray-brown 4,6-dimethoxy-1- (4-nitrostyryl) -4-trifluoromethyl-3,4-dihydroisoquinoline are obtained.

mp: 146-147 ° C (hexane).

For C20H12F3N2O4 (406.36) calculated: C 59.11%, H 4.22%, N 6.89%;

found: C 58.87%, H 4.24%, N 6.83%.

IR (KBr, cm ^-1 ): 1612, 1514, 1313, 1178.

1 H-NMR (CDCl 3, 200 MHz) δ: 8.24 (2H, dd, J = 8.8 Hz, J = 1.9 Hz), 7.75-7.65 (3H, m), 7, 53 (1H, d, J = 15.9Hz), 7.37 (1H, d, J = 15.9Hz), 7.25 (1H, d, J = 2.6Hz), 7.06 ( 1H, dd, J = 8.3Hz, J = 2.6Hz), 4.32 (1H, d, J = 17.6Hz), 4.18 (1H, d, J = 17.7Hz) 3.92 (3H, s), 3.34 (3H, s).

105

2.03 g (5 mmol) of the obtained base was converted to the maleate salt as described in Example 68. This afforded 1.65 g (63%) of the title compound as a yellow solid.

Mp .: 168-170 ° C (ethanol-diisopropyl ether).

For C24H21F3N2O8 (522.44) calculated: C 55.18%, H 4.05%, N 5.36%;

found: C 55.32%, H 4.07%, N 5.26%.

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 = 8.8 Hz), 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), 6.37 (2H, s), 4.33 (2H, d, J = 7.4 Hz), 4.03 (3H, s), 3.45 (3 H, s).

B) 4,6-Dimethoxy-1- (4-nitrostyryl) -4-trifluoromethyl-3,4-dihydroisoquinolinium chloride

1.22 g (3 mmol) of the base obtained as described in section A) is reacted with 0.5 cm ^{3 of} 2-propanol containing 25.3 g / 100 cm ³ (3.6 mmol) of hydrogen chloride as described above. in Example 67, section B). This afforded 0.90 g (68%) of the light yellow title compound.

Mp: 245-246 ° C (ethanol, dec.).

For C20H18ClF3N2O4 (442.82) calculated: C 54.25%, H 4.10%, Cl 8.01%, N 6.33%;

found: C 54.14%, H 4.08%, 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 (1H, d, J = 8.8 Hz), 8.36 (1H, d, J = 8.8 Hz), 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

106

Hz), 7.25 (1H, s), 4.51 (1H, d, J = 16.5Hz), 4.02 (1H, d, J = 16.5Hz), 4.02 (3H, s), 3.38 (3H, s).

Example 71

6,7-Methylenedioxy-4-methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinolinium chloride

Follow the procedure described in Example 67, section A), starting from 4.61 g (10 mmol) of N- (4-trifluoromethylcinnamoyl) -3,3,3-trifluoro-2-methoxy-2- (3,4-methylenedioxyphenyl) propylamine. The crude base was recrystallized from hexane. There was thus obtained 2.44 g (55%) of a gray-brown colored 6,7-methylenedioxy-4-methoxy-4-trifluoromethyl-1- (4-trifluoromethylstyryl) -3,4-dihydroisoquinoline.

Mp .: 87-88 ° C (hexane).

Analysis: for C ₂₁ H ₁₅ F ₆ NO ₃ (443.35) calculated: C 56.89%, H 3.41%, N 3.16%;

found: C 56.71%, H 3.39%, N 3.22%.

IR (KBr, cm ^-1 ): 1579, 1389, 1167.

1 H-NMR (CDCl ₃ , 400 MHz) δ: 7.70-7.60 (4H, 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 = 1.3Hz), 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, 148.9, 139.5, 135.4, 130.6 (q, ² J CF = 32.4 Hz), 127 , 5, 126.1, 125.7 (q, ³ J _CF = 5.4 Hz), 125.6, 125.3 (q, 1 J CF-287.3 Hz), 124.5, 124.0 ( q, J ₍ f = 272.0 Hz), 107.6, 106.4, 102.1, 75.2 (q, ² J CF ⁼ 27.5 Hz), 52.4, 49.6.

107

The 1.33 g (3 mmol) of the base obtained above is treated with 0.5 cm ^{3 of} 2-propanol containing 25.3 g / 100 cm ³ (3.6 mmol) of hydrogen chloride. There was thus obtained 1.05 g (73%) of a light yellow title compound.

mp: 248-250 ° C (acetone, diisopropyl ether, decomposition).

For C21H16ClF8NO3 (479.81) calculated: C 52.5? %, H 3.36%, Cl 7.39%, N 2.92%;

found: C 52.61%, H 3.38%, Cl 7.38%, N 2.94%.

IR (film, cm ^-1 ): 1623, 1514, 1394, 1325, 1171, 1 126.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.15-8.05 (4H, m), 7.90-7.80 (3H, m), 7.32 (1H, m), 6.37 (1H, d, J = 0.9 Hz), 6.34 (1H, d,> 0.9 Hz), 4.45 (1H, d,> 17.0 Hz), 4.24 (1H 1H, d,> 17.0 Hz), 3.60 (1H, bs), 3.35 (3H, s).

Example 72

4,6-Dimethoxy-4-trifluoromethyl-1- [2- (4-trifluoromethylphenyl) ethyl] -3,4-dihydroxyisoquinolinium chloride

The procedure described in Example 67, ye / xia A) was followed, starting from 1.12 g (2.5 mmol) of N- [3- (4-trifluoromethylphenyl) propanoyl] -3,3,3-trifluoro-2-methoxy- 2- (3-methoxyphenyl) prop.ylamine and 2.0 cm ³ (3.36 g, 22 mmol) of phosphorus oxychloride. The crude base is dissolved in 10 cm ^{3 of} diisopropyl ether and 0.4 cm ^{3 of} 2-propanol containing 25.3 g / 100 cm ³ (3 mmol) of hydrogen chloride are added dropwise. There was thus obtained 0.96 g (82%) of a colorless title compound.

mp: 185-187 ° C (dec., ethanol).

For C ₂₁ H ₂₀ ClF ₆ NO 2 (467.84) calculated: C 53.91%, H 4.31%, Cl 7.58%, N 2.99%;

108 found: C 53.72%, H 4.30%, Cl 7.56%, N 2.97%.

IR (film, cm ^-1 ): 2494, 1666, 1328, 1252.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.38 (1H, d, J = 8.8 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 (2 H, m).

¹³ C-NMR (DMSO-d 6, 50.3 MHz) δ: 175.0, 166.0, 144.1, 134.8, 132.8, 129.6, 127.5 (q, ² JCf = 31) , 7 Hz), 125.3 (q, ³ J CF = 3.8 Hz), 124.5 (q, J * _C F = 270.2 Hz).

124.3 (q, 'J _C F = 287.4 Hz), 118.6, 116.0, 114.2, 74.8 (q, ² J _CF = 28.2 Hz), 56.7, 52.9 , 42.4, 33.4.33.0.

Example 73

- [2- (4-fluorophenyl) ethyl] -4,6-dimethoxy-4-trifluoromethyl-3,4-dihydroizochinolíniumchlorid

Follow the procedure described in Example 67, section A), starting from 1.00 g (2.5 mmol) of N- [3- (4-trifluorophenyl) propanoyl] -3,3,3-trifluoro-2-methoxy-2- (3-methoxyphenyl) propylamine and 2.0 cm ^{3 of} phosphorus oxychloride. The crude base is dissolved in 10 cm ^{3 of} diisopropyl ether and 0.4 cm ^{3 of} 2-propanol containing

25.3 g / 100 cm ³ (3 mmol) of hydrogen chloride. There was thus obtained 0.86 g (82%) of a colorless title compound.

mp: 190-191 ° C (dec., ethanol).

For C20H20ClF4NO2 (417.84) calculated: C 57.49%, H 4.82%, Cl 8.48%, N 3.35%;

found: C 57.44%, H 4.83%, Cl 8.58%, N 3.42%.

ID (film, cm ''): 1602, 1512, 1254, 1,177.

109 1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.37 (1H, d, J = 8.6 Hz), 7.40-7.35 (3H, m), 7.20 (1H δ d, J = 2.3 Hz), 7.14 (2H, t, J = 8.8 Hz), 4.41 (1H, d, J = 16.7 Hz), 4.20 (1H, d J = 16.7 Hz), 4.00 (3H, s), 3.70-3.30 (2H, m), 3.31 (3H, s), 3.00-2.85 (2H, m).

¹³ C-NMR (DMSO-d6, 50.3 MHz) δ: 175.6, 166.2, 161.2 (d, J CF = 241.9 Hz), 135.3, 135.0, 132.8 130.6 (d, ³ J CF = 8.0 Hz), 124.3 (q, J _CF = 287.6 Hz), 118.5,

116.1, 115.3 (d, ² JCF = 21.4 Hz), 114.3, 74.8 (q, ² JCF = 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 was obtained as a white solid. Yield: 75%

Mp: 196-197 ° C (ethanol, dec.).

Analysis: for C ₂₁ H ₁₈ ClF ₆ NO 3 (48 1.83) calculated: C 52.35%, H 3.77%, Cl 7.36%, N 2.91%;

found: C 52.16%, H 3.79%, Cl 7.33%, N 2.90%.

IR (film, cm ^-1 ): 2494, 1666, 1328, 1252.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 7.95 (1H, s,), 7.67 (2H, d, J = 8.2Hz), 7.58 (2H, d, J = 8.2 Hz), 7.28 (1H, s), 6.34 (2H, d, J = 14.9 Hz), 4.36 (1H, 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).

110

Example 75

- [2- (4-fluorophenyl) ethyl] -6,7-methylenedioxy-4-methoxy-4-trifluoromethyl-3,4dihydroizichinolíniumchlorid

Following the procedure described in Example 67, Section A), the title compound was obtained as a white solid. Yield: 80%.

mp: 195-196 ° C (ethanol, dec.).

For C20H18ClF4NO3 (431.82) calculated: C 55.63%, H 4.20%, Cl 8.21%, N 3.24%;

found: C 55.36%, H 4.24%, Cl 8.20%, N 3.27%.

IR (film, cm ^-1 ): 1671, 1608, 1512, 1300, 1179.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 8.07 (1H, s), 7.45-7.35 (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 JCF = 242.2 Hz), 155.0,

150.1, 135.2 (d, ⁴ JCF = 3.1 Hz), 130.7 (d, ³ JCF = 8.0 Hz), 130.6, 127.6, 124.2 (q, ¹ JCF) = 287.6 Hz), 115.2 (d, ² JCF = 21.0 Hz), 10.8, 104.2, 75.1 (q, ² J _CF = 28.6 Hz), 52.8 , 41.8, 33.8, 33.0.

Example 76

- [2- (4-Trifluoromethylphenyl) ethyl] -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium bromide g (0.0125 mol) 1- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl The 6,7-methylenedioxy-3,4-dihydroisoquinoline is reacted with N-bromosuccinimide at 0 ° C in dichloromethane. The reaction mixture was stirred at room temperature for 1 hour and then allowed to stand for 24 hours and evaporated. The

Diethyl ether was added to the residue, the precipitated crystals were filtered off and recrystallized from a mixture of hexane and acetonitrile. There was thus obtained 1.5 g (30%) of the title compound.

mp: 244-245 ° C

For C ₂₀ H 19 BrF ₃ NO ₂ (392.27) calculated: C 54.31%, H 4.33%, Br 18.70%, N 3.17%;

found: C 53.65%, H 4.35%, Br 18.21%, N 3.28%.

1 H-NMR (DMSO-d ₆ , 200 MHz) δ: 7.67 (1H, s), 7.64 (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 = 8 Hz) 2.96 (4H, m).

Example 77 1- (2-Phenylethyl) -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium iodide

Dissolve 3.2 g (0.011 mol) of 1- (2-phenylethynyl) -6,7-methylenedioxy-3,4-dihydroisoquinoline in 30 cm ^{3 of} acetone. 4 cm @ ^{3 of} methyl iodide are added to the obtained solution, and the reaction mixture is left to stand at room temperature overnight. The precipitated crystalline material is filtered off, washed with cold acetone and recrystallized from acetone. Thus, 3.5 g (76%) of the title compound are obtained.

mp: 180 ° C.

For C19H20INO2 (431.28) calculated: N 3.32%;

found: N, 3.25%.

112 1 H-NMR (DMSO-d ₅ , 200 MHz) δ: 7.69 (1H, s), 7.28 (5H, m), 7.11 (1H, s), 6.23 (2H, s) ), 3.92 (2H, t, J = 7.6Hz), 3.61 (3H, s), 3.47 (2H, t, J = 7.6Hz), 2.94 (4H, m) ).

Example 78

1- (4-Trifluoromethylstyryl) -2-methyl-4-propyl-6,7-methylenedioxy-3,4-dihydroisoquinolinium iodide dihydrate

7.2 g (0.019 mol) of 1- (4-trifluoromethylstyryl) -4-propyl-6,7-methylenedioxy-3,4-dihydroisoquinoline are dissolved in 150 cm ^{3 of} acetone. To the solution is added 10 cm @ ^{3 of} methyl iodide and the reaction mixture is left to stand at room temperature overnight. Then the mixture is evaporated to dryness and the oily product is crystallized from a mixture of diisopropyl ether and diethyl ether. The crystalline crude product is dissolved in 90 cm ^{3 of} acetone, precipitated by the addition of 300 cm ^{3 of} diisopropyl ether and filtered. Thus, 1.7 g (16%) of the title compound are obtained.

mp: 203-205 ° C.

For C23H23F3INO2 (565.38) calculated: C 48.86%, H 4.81%, N 2.48%;

found: C 49.08%, H 4.73%, N 2.63%.

1 H-NMR (DMSO-d 6, 200 MHz) δ: 7.94 (2H, d, J = 8.1 Hz), 7.84 (1H, d, J = 16.5 Hz), 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 (1H, s) 2H, s), 4.40 (1H, dd, J = 4.8 Hz, J ₂ = 14.7 Hz), 4.02 (3H, s), 3.90 (1H, dd, J = 4.0 Hz, J ₂ = 14.7 Hz), 3.10 (1H, m), 1.58 (2H, m), 1.44 (2H, m), 0.98 (3H, t, J = 7.0 Hz).

113

Example 79

- [2- (4-Trifluoromethylphenyl) ethyl 1-2-methyl-7-chloro-3,4-dihydroisoquinolinium iodide

1.7 g (0.005 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl-7-chloro-3,4-dihydroisoquinoline are dissolved in 30 cm ^{3 of} acetone. 3 cm @ ^{3 of} methyl iodide are added to the obtained solution and the reaction mixture is left to stand at room temperature for 24 hours. The mixture was cooled to 0 ° C, filtered and washed with acetone. There was thus obtained 1.5 g (62%) of the title compound.

Mp .: 224-227 ° C.

For C ₁₉ H 18 ClF ₃ IN (479.71) calculated: C 47.57%, H 3.78%, Cl 7.93%, N 2.92%;

found: C 47.26%, H 3.75%, Cl 7.11%, N 2.93%.

1 H-NMR (DMSO-d 6, 400 MHz) δ: 8.02 (1H, d, J = 2.2 Hz), 7.75 (1H, dd, J ₁ = 2.2 Hz, J ₂ = 8, 1 Hz), 7.60 (2H, d, J = 8.2 Hz), 7.52 (2H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.1 Hz) 4.06 (2H, t, J = 7.6Hz), 3.81 (3H, s), 3.65 (2H, t, J = 7.8Hz), 3.11 (2H, t J = 7.6 Hz), 3.06 (2H, t, J = 7.8 Hz).

Example 80

- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroizochinolíniumbromid

8.85 g (27 mmol) of 1- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-ethylenedioxy-3,4-dihydroisoquinoline are dissolved in 200 cm @ ^{3 of} dichloromethane. To this solution was added 5.34 g (30 mmol) of N-bromosuccinimide at 0 ° C. The reaction mixture was stirred at room temperature for 3 hours, then concentrated to half its original volume under reduced pressure. The crude product is precipitated from the residue by addition of cyclohexane and the product is recrystallized from 20 cm @ ^{3 of} isopropanol. Thus, 4.23 g (38%) of the title compound are obtained.

114

Mp .: 177-180 ° C.

For C ₂₀ H ₂₁ BrFNO ₂ (406.30) calculated: N 3.45%;

found: N, 3.29%.

1 H-NMR (DMSO-d 6, 200 MHz) δ: 7.61 (1H, s), 7.31 (2H, m), 7.11 (2H, m), 6.99 (1H, s), 4.35 (4H, m), 3.95 (2H, t, J = 7.4 Hz), 3.66 (3H, s), 3.47 (2H, t, J = 7.6 Hz), 2.94 (4 H, m).

Example 81

- [2- (4-trifluoromethylphenyl) ethyl] -2-methyl 6-methoxy-7-hydroxy-3,4dihydroízochinolíniumjodid

2.0 g (6 mmol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -6-methoxy-7-hydroxy-3,4-dihydroisoquinoline are dissolved in 30 cm ^{3 of} acetone and 5 cm ^{3 of} methyl iodide are added. The precipitated crystals are filtered, washed with cold ether, dissolved in 350 cm ^{3 of} acetone and precipitated by addition of ether. Thus, 1.87 g (63%) of the title compound are obtained.

Mp: 210-213 ° C.

Analysis: for C ₂₀ H ₂₁ F ₃ INO ₂ (491.29) calculated: C 48.90%, H 4.31%, N 2.85%;

found: C 48.56%, H 4.42%, N 2.96%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 9.55 (1H, 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), 3.97 (2H, t, J = 7.6 Hz), 3.92 (3H, s), 3 69 (3H, s), 3.41 (2H, t, J = 8.0 Hz), 3.02 (4H, t, J = 8.0 Hz).

115

Example 82

- [2- (4-Trifluoromethylphenyl) ethyl] -2-methyl-4-propyl-6,7-ethylendioxy-3,4-dihydroisoquinolinium iodide

Dissolve 4.0 g (0.01 mol) of 1- [2- (4-trifluoromethylphenyl) ethyl] -4-propyl-6,7-ethylenedioxy-3,4-dihydroisoquinoline in 80 cm ^{3 of} acetone. 9 g of methyl iodide are then added and the reaction mixture is allowed to stand at room temperature for 24 hours. The precipitated quaternary salt is filtered and recrystallized from acetone. Thus, 3.1 g (56%) of the title compound are obtained.

mp: 177-180 ° C.

For C24H27F3INO2 (545.38) calculated: C 52.86%, H 4.99%, N 2.57%;

found: C 52.73%, H 5.04%, N 2.62%.

‘H-NMR (CDCl 3, 400 MHz) δ: 7.55 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz),

7.29 (1 H, s), 6.77 (1H, s), 4.38 (2H, m), 4.34 (1H, dd, J = 5.4 Hz, J ₂ = 14 Hz);

4.29 (2H, m), 3.83 (3H, s), 3.74 (1H, dd, J = 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) 1 Hz).

Example 83

- [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 are dissolved in 120 cm ^{3 of} acetone. 5 cm @ ^{3 of} methyl iodide are added to the solution obtained. The reaction mixture was refluxed for 1 hour and then cooled to 0-5 ° C with ice water and stirred at this temperature for 2-3 hours. After crystallization, the crystals are filtered off, washed with cold

116 with acetone and recrystallized from acetone. Thus, 2.2 g (58%) of the title compound are obtained.

Mp .: 205-207 ° C.

For C21H21F3INO2 (503.30) calculated: C 50.12%, H 4.21%, N 2.78%;

found: C 49.61%, H 4.25%, N 2.82%.

1 H-NMR (DMSO-d 6, 200 MHz) δ: 7.64 (2H, d, J = 8.3 Hz), 7.58 (1H, s), 7.52 (2H, d, J = 8) 3 Hz), 6.96 (1H, s), 4.33 (2H, m), 3.95 (2H, t, J = 7.5 Hz), 3.69 (3H, s), 3, 49 (2H, t, J = 7.7Hz), 2.99 (4H, m).

Example 84

- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-methylenedioxy-3,4-dihydroizochinolíniumbromid

2.9 g (9 mmol) of 1- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinoline are dissolved in 70 cm ^{3 of} dichloroethane and 1.7 g are added. (0.01 mol) of N-bromosuccinimide with stirring. The reaction mixture was stirred at 0 ° C for 3 hours and then evaporated under reduced pressure. Ether was added to the oily residue, the mixture was stirred at 0 ° C and the precipitated crystals were filtered off. This afforded 1.9 g (53%) of the title compound.

Mp: 191-193 ° C.

Analysis: for C 18 H 18 BrFNCH (392.27) calculated: C 58.18%, H 4.88%, Br 20.37%, N 3.57%;

found: C 57.94%, H 5.13%, Br 20.59%, N 3.69%.

117 1 H-NMR. (DMSO-d ₆ , 400 MHz) δ: 7.68 (1H, s), 7.31 (2H, m), 7.11 (2H, m),

7.11 (1H, s), 6.22 (2H, s), 3.93 (2H, t, J = 7.7Hz), 3.64 (3H, s), 3.46 (2H, t) .

J = 7.7 Hz), 2.98 (2H, t, J = 7.7 Hz), 2.91 (2H, t, J = 7.7 Hz).

Example 85

- (4-Fluorostyryl) -2-methyl-6,7-methylenedioxy-3,4-dihydroizochinolíniumbromid

To a solution of 1.39 g (0.0125 mol) of 1- (4-fluorostyryl) -2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline in 100 cm @ 3 of dichloromethane is added at 0 DEG C. 4.6. g (0.025 mol) of N-bromosuccinimide and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness under reduced pressure and acetonitrile was added to the residue. The crystalline material is filtered and recrystallized from acetonitrile. There was thus obtained 3.1 g (63%) of the title compound.

Mp: 215-218 ° C.

Analysis calculated for: C 18 H 11 BrFNO 3 (390.27): C 58.48%, H 4.39%, Br 20.48%, N 4.39%;

found: 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 = 16.3 Hz), 7.18 (1H, d, J = 16.3 Hz), 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 = 7.5 Hz).

Example 86

- (4-Trifluórmetylstyryl) -2-methyl-6,7-methylenedioxy-3,4-dihydroÍzochinolíniumbromid

4.8 g (0.0135 mol) of 2- (4-trifluoromethylstyryl) -2-methyl-6,7-methylenedioxy-3,4-dihydroisoquinoline are dissolved in 100 cm @ ^{3 of} dichloromethane. To the solution cooled to 100 ° C was added with stirring 2.5 g (0.0141 mol) of N118 bromosuccinimide. The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for a further 2 hours. The precipitated crystals were filtered and washed with dichloromethane. The crude product was recrystallized from a 1: 1 mixture of ether and ethanol. Thus, 2.4 g (41%) of the title compound are obtained.

mp: 213 ° C.

For C 20 H 17 BrF 3 NO 3 (440.26) calculated: C 54.56%, H 3.39%, Br 17.76%, N 3.18%;

found: C 54.20%, H 4.00%, 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 Hz), 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

- [2- (4-fluorophenyl) ethyl] -2-methyl-6,7-methylenedioxy-3,4-dihydroizochinolíniumjodid

3.12 g (0.01 mol) of 1- [2- (4-fluorophenyl) ethyl] -6,7-methylenedioxy-3,4-dihydroisoquinoline are dissolved in 30 cm @ ^{3 of} nitromethane. To this solution is added 7.76 g of methyl iodide and the reaction mixture is stirred at 120 ° C for 4 hours and then cooled to room temperature and 50 cm ^{3 of} ether are added to precipitate the product. The crystals are filtered off, washed with ether and recrystallized from acetone. Thus, 3.6 g (82%) of the title compound are obtained.

mp: 197-198 ° C.

For C19H19FINO2 (439.272) calculated: C 51.95%, H 4.36%, N 3.19%;

119 found: C 51.66%, H 4.32%, N 3.09%.

1 H-NMR (DMSO-d ₆ , 400 MHz) δ: 7.68 (1H, s), 7.32 (2H, m), 7.12 (2H, m), 7.11 (1H, s) 6.23 (2H, 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).

120

Claims (12)

PATENT CLAIMS A 3,4-dihydroisoquinoline derivative of the Formula I wherein R ₂ forms with R methylenedioxy, R4 represents a C1-6 alkyl group, R 5 represents a hydrogen atom or a trifluoromethyl group, R 3, R 6 and R ₇ are independently hydrogen, Rs forms a valence bond with Rg, Xi forms a valence bond with X ₂ , R 10 and R 11 independently represent a hydrogen atom, a methoxy group, a trifluoromethyl group, or a pharmaceutically acceptable acid addition salt thereof and a quaternary derivative of the general formula I ' 121 where R 1 and R 2 independently represent a hydrogen atom, a halogen atom, a hydroxy group or a C 1-4 alkoxy group, or R1 forms, with R-2, methylenedioxy or ethylenedioxy, R4 represents a hydrogen atom or a C1-6 alkyl group, R 3, R 5, R 6 and R 7 are independently hydrogen, Rs forms a valence bond with R9, R 1g 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 hydrogen or Xi forms a valence bond with X ₂ , A is a radical of an inorganic or organic acid of formula HA. 122 The 3,4-dihydroisoquinoline derivative of the Formula XIV according to claim 1, wherein R1 forms a methylenedioxy group with R2, R ₄ represents a C 1-6 alkyl group, R 5 represents a hydrogen atom or a trifluoromethyl group, R 10 and R 13 independently represent hydrogen, methoxy, trifluoromethyl, X, forms with X? a pharmaceutically acceptable acid addition salt thereof. or 123 The 3,4-dihydroisoquinolinium derivative of the general Formula XI according to claim 1, wherein R 1 and R -2 are independently hydrogen, halogen, hydroxy, or C 1-4 alkoxy, or R1 forms a methylenedioxy group or an ethylenedioxy group with R2, R ₄ is H or Cj.6 alkyl, R 'is C 1. _An alkyl group, R 10 and R 11 independently represent a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a hydrogen atom. ₄ alkoxy or trifluoromethyl, X 1 and X 2 are independently hydrogen or Xi forms a valence bond with X2, A is a radical of an inorganic or organic acid of formula HA. 124 A 3,4-dihydroisoquinolinium derivative of the general formula XI according to claim 4 3, where R 1 and R ₂ are independently hydroxy, chloro or methoxy, or R ₂ forms with R methylenedioxy or ethylenedioxy, R 4 represents a hydrogen atom or a C 1-3 alkyl group, R'g represents a methyl group, R 10 and R 15 independently represent a hydrogen atom, a halogen atom or a trifluoromethyl group. X 1, X ₂ and A are as defined in claim 3. A 3,4-dihydroisoquinolinium derivative of the general formula XI according to claim 5 4, where R ₂ forms with R methylenedioxy or ethylenedioxy, R 10 and R 11 independently represent a hydrogen atom, a fluorine atom or a trifluoromethyl group, R 4, R'g, X, X ₂ and A are as defined in Claim fourth A pharmaceutical composition comprising, as an active ingredient, a 3,4-dihydroisoquinoline derivative of the Formula I wherein R 1, R ₂ , R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, Xi and X ₂ is as defined in claim 1, or a pharmaceutically acceptable acid addition salt or quaternary derivative thereof, 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 and A are as defined in claim 1, and one or more conventional carriers. 125 Pharmaceutical composition according to claim 6, characterized in that it contains, as active ingredient, a 3,4-dihydroisoquinoline derivative of the general formula XIV, wherein R 1, R 1, R 4, R 5, R 10, R 11, Xi and X ₂ are as defined in claim 2 , or a pharmaceutically acceptable acid addition salt thereof. Pharmaceutical composition according to claim 6, characterized in that it contains as active ingredient a 3,4-dihydroisoquinolinium derivative of the general formula XI, wherein R 1, R 2, R 4, R 1e, R 1, R 1, X 1, X 2 and A are as defined in claim 3. Pharmaceutical composition according to claim 8, characterized in that it contains, as active ingredient, a 3,4-dihydroisoquinolinium derivative of the general formula XI, wherein R 1, R ₂ , R 4, R ₈ , R 8, R 11, Xi, X ₂ and A are as defined in claim 4. Pharmaceutical composition according to claim 9, characterized in that it contains, as active ingredient, a 3,4-dihydroisoquinolinium derivative of the general formula XI, wherein R 1, R ₂ , R 4, R 8, R 10, R 11, X 1, X 2 and A are as defined in Claim 5. 11. A method of treatment, wherein the patient is suffering from anxiety is treated with a non-toxic dose of 3,4-dihydroisoquinoline derivative of the formula I, wherein R, R _2, R 3, R 4, R 5, R d, R 7, R, R 9, R 10, R 11, X 1 and X ₂ are as defined in claim 1, or a pharmaceutically acceptable acid addition salt or 3,4-dihydroisoquinolinium derivative thereof, 126 of formula I ', wherein R _b R ₂ , R 3, R 4, R 5, R 6, R 7, R 7, R 9, R 10, R 11, X 1 and X ₂ are as defined above, R 8 and A are as defined in claim 1. Use of a 3,4-dihydroisoquinoline derivative of the Formula I 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 in of claim 1, or a pharmaceutically acceptable acid addition salt thereof, or a 3,4-dihydroisoquinolinium derivative of the formula I ', 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, Rg and A are as defined in claim 1 for the preparation of a pharmaceutical composition having anxiolytic effect.