HRP20000750A2 - Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient - Google Patents

Description

Field of invention

The invention is from the field of pharmaceutical chemistry and organic chemical synthesis.

Solution of problems with examples of execution

This invention relates to new benzofuran derivatives, pharmaceutical composites containing them as an active ingredient, and to the process of preparing the active ingredient. The new compounds act on the circulatory system and the heart, and also have a certain effect on the central nervous system.

More specifically, this invention relates to a new benzofuran derivative of the following formula:

[image] I

where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group,

X denotes an oxygen atom or a sulfur atom,

Z denotes a hydrogen atom or a hydroxyl group,

Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where

R3 denotes hydrogen or a C1-4 alkyl group,

R4 is a C1-4 alkyl group, or

R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms as the following heteroatoms ,

A denotes a group of formula CH, COH, C-CN, C-COOR3 or COR4, where R3 and R4 are as previously defined,

B denotes a methylene group, or

A gives, together with B, a group of the formula -C=C-,

Ar denotes a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl-4 alkyl) group, a biphenyl group, a naphthyl group, where the last mentioned species can be arbitrarily substituted with a C1-4 alkoxy group or

C2-4 alkenyl group, partially saturated, 5- or 6-membered heterocyclic group which is condensed with a phenyl group and contains one or more oxygen atoms, and said heterocyclic group is optionally substituted with one to three C1-4 alkyl groups; A 5- or 6-membered, saturated or unsaturated heterocyclic group contains a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group which is arbitrarily substituted with C1- 4 by an alkoxy group or a halogen atom; a C2-4 alkenyl group, a C2-4 alkenyloxy group, a C1-4 alkoxy group which is optionally substituted with a di(C1-4 alkyl)amino group or with a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom; wherein said heterocyclic group is optionally substituted with a C1-4 alkyl group, or

A denotes a group of the formula N-(CH2)n-Ar', where

Ar' denotes a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, where the last group is optionally substituted with a C1-4 alkoxy group or a C2-4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group which is fused with a phenyl group and contains one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C1-4 alkyl groups; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 are as previously defined,

n has the value 0 or 1,

or pharmaceutically acceptable acid addition salts thereof.

According to the literature, certain furancarboxylic amides have antidepressant properties / Yakugaku Zasshi, 97 (5), 540 (1977); C.A., 87, 152125d (1997)/, while benzofuran derivatives having amino, amidino, thiocarboxamidino or dialkylaminoalkyl substituents on the furan ring are H2 receptor antagonists and, therefore, show antiulcer activity /published PCT application No. WO 86 02550; CA, 105, 226586u (1986)/.

Tetrahydronaphthoxy derivatives that show hypotensive action are known from DE-OS no. 22 35 597. The chemical structure of such compounds resembles that of piperazinylalkylbenzofuran derivatives of formula I.

The aim of this invention is to prepare new benzofuran derivatives - some of them act on the circulatory system and the heart, while others act on the central nervous system.

It was found that the above objectives are achieved by new benzofuran derivatives of formula I.

In the descriptions and patent claims, in the definition of substituents, the halogen atom is primarily a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

The C 1-4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl. Preferably, the C 1-4 alkyl group is a methyl group.

The C2-4 alkenyl group is vinyl, allyl, methallyl or crotyl, preferably an allyl or methallyl group.

The C1-4 alkoxy group is primarily a methoxy, ethoxy, n-propoxy, isopropoxy or butoxy group, preferably a methoxy or isopropoxy group.

A C2-4 alkenyloxy group is preferably an allyloxy or metalyloxy group.

C1-4 alkoxy group substituted with di(C1-4 alkyl)amino group is, in the first place, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy or 4-dimethylaminobutoxy group, preferably 2- dimethylaminoethoxy group.

A partially saturated, 5- or 6-membered heterocyclic group fused to a phenyl group containing one or two oxygen atoms is a dihydrobenzofuran, benzodioxolane, dihydrobenzpyran or benzodioxane group.

A 5- or 6-membered, saturated or unsaturated heterocyclic group containing a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom is preferably a heterocyclic group where the heteroatom consists of a nitrogen atom or an oxygen atom or a sulfur atom, and the heterocyclic ring does not contain double bond or one or more double bonds. Such a heterocyclic group is, for example, pyrrolyl, pyrrolidinyl, piperidinyl, pyridyl, morpholinyl, furyl or thienyl. The above heterocyclic group is preferably a thienyl group.

A 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom is preferably pyrrolidinyl, piperidinyl, piperazinyl or morpholine, wherein their nitrogen atom is connected to the carbon atom of the C1-4 alkoxy group.

A saturated or unsaturated heterocyclic group having 5 to 10 members is, for example, pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl, piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolyl, pyrazolidinyl, thienyl, hexamethyleneimin-1-yl, heptamethyleneimine. -1-yl etc.

A pharmaceutically suitable acid addition salt is an acid addition salt formed with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or with an organic acid such as acetic acid, maleic acid, lactic acid, malic acid, tartaric acid, etc.

The invention includes all possible isomers of compounds of formula I and their mixtures.

A preferred subgroup of the benzofuran derivatives of this invention consists of compounds of formula I wherein

R1 denotes a hydrogen atom or a Cl-4 alkyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydrogen atom or a hydroxyl group,

Z denotes a hydrogen atom, a halogen atom or a nitro group,

A denotes a group of formula CH, COH or C-CN,

B denotes a methylene group, or

A forms with B a group of the formula -C=C-,

Ar denotes a hydrogen atom, a benzyl group, a phenyl group substituted with the substituents R5, R6 and R7, a biphenyl group, a naphthyl group substituted with a C1-4 alkoxy group; or a thienyl group, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group, a C2-4 alkenyloxy group, a phenoxy group or a methylenedioxy group,

and their pharmaceutically acceptable acid addition salts.

Within the above subgroup, suitable benzofuran derivatives consist of compounds of formula I wherein

R1 denotes a methyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

A is a group of formula CH, COH or C-CN,

B denotes a methylene group, or

A forms with B a group of the formula -C=C-,

Ar denotes a phenyl group which is optionally substituted with a halogen atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group,

and their pharmaceutically acceptable acid addition salts.

Particularly preferred benzofuran derivatives of formula I are the following:

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy)-2-hydroxypropyl/-4-hydroxy-4-(3-methoxyphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-phenylpiperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine or

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine,

and their pharmaceutically acceptable acid addition salts.

Further suitable subgroups of the benzofuran derivatives of this invention consist of piperazinylalkylbenzofuran derivatives of the following formula:

[image] Ia

where

R1 denotes a C1-4 alkyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

Ar' denotes a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and which is condensed with a phenyl group, or a phenyl group which is substituted by R5, R6 and R7, where

R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group or a methylenedioxy group,

n has the value 0 or 1,

and their pharmaceutically acceptable acid addition salts.

Within the subgroup of formula Ia, suitable piperazinylalkylbenzofuran derivatives of the present invention comprise derivative compounds of formula Ia wherein

R1 denotes a methyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

Ar' denotes a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group which is optionally substituted with one or two halogen atoms, one or two methyl groups, a methylenedioxy group, a trifluoromethyl group or a methoxy group,

n has the value 0 or 1,

and their pharmaceutically acceptable acid addition salts.

Particularly preferred benzofuran derivatives of formula Ia are the following:

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoro-methylphenyl)piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-benzylpiperazine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)-piperazine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)-piperazine,

1-(3-[2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl]-4-(2-pyridyl)piperazine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)-piperazine or

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-methoxyphenyl)-piperazine,

and their pharmaceutically acceptable acid addition salts.

The following compounds of this invention were prepared:

a) halide of the following formula

[image] II

where R1, R2, X, Y and Z are as defined in relation to formula I, Hal denotes a halogen atom, reacts with a secondary amine of the following formula

[image] IV

where A, B and Ar are as defined in formula I; or

b) for the preparation of benzofuran derivatives of formula I, where Y denotes a hydroxyl group, R1, R2, X, Z, A, B and Ar are defined in connection with formula I, an epoxide of the following formula

[image] III

wherein R 1 , R 2 , Z and X are as above, reacted with a secondary amine of formula IV, where A, B and Ar are as above; or

c) a compound of the following formula

[image] V

wherein R 1 , X and Z are as defined in relation to formula I, reacts with a halogen compound of the following formula

[image] XI

wherein R 2 , Y, A, B and Ar are as defined in relation to formula I, Hal denotes a halogen atom;

d) to prepare a benzofuran derivative of formula I, where R1, R2, X, Z, A, B and Ar are as defined in relation to formula I, a compound of formula V, where R1, X and Z are as mentioned above, is reacted with epoxy of the following formula

[image] XII

where R 2 , A, B and Ar are as previously stated; or

e) for the preparation of benzofuran derivatives of formula I, where A gives with B a group of formula -C=C-, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, benzofuran of formula I, where A denotes a group of the formula COH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as previously stated, is dehydrated; or

f) for the preparation of benzofuran derivatives of formula I, where A denotes a COH group, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in relation to formula I, however Ar is not a hydrogen atom, a ketone formulas

[image] XV

where R1, R2, X, Y and Z are as previously defined, reacts with an arylmagnesium halide of the formula

Hal-Mg-Ar XVI

where Ar is previously defined, Hal denotes a halogen atom, and the resulting adduct decomposes with water; or

g) for the preparation of benzofuran derivatives of formula I, where A denotes a COH group, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in relation to formula I, however Ar is not a hydrogen atom, a ketone of formula XV, where R1, R2, X, Y and Z are as previously defined, reacts with an aryllithium compound of the following formula

Li-Ar XVII

where Ar is previously defined, and the resulting adduct decomposes with water; or

h) for the preparation of a benzofuran derivative of formula I, where A denotes a group of formula CH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, a compound of formula I, where A gives with B a group of the formula -C=C-, R1, R2, X, Y, Z and Ar are as previously defined, is hydrogenated; or

i) for the preparation of benzofuran derivatives of formula I, where A denotes a group of formula CH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, an epoxide of formula III, where R1, R2, Z and X as previously defined, react with a secondary amine of formula IV, where A denotes the CHOH group, B and Ar are as defined above, under dehydrating reaction conditions, and is a compound of formula I, where A gives with B group of the formula -C=C-, R1, R2, X, Y, Z and Ar are, as previously defined, hydrogenated in the reaction mixture in which it was prepared; and

if desired, the resulting base of formula I is reacted with an inorganic or organic acid to give its pharmaceutically acceptable acid addition salt, or to be liberated from the acid addition salt by means of a base.

In process a) of this invention, the reaction of the halide of formula II with the secondary amine of formula IV is preferably carried out in an excess of the corresponding secondary amine of formula IV. However, the reaction can also be carried out in an inert solvent in the presence of a suitable base, possibly in a two-phase system.

In the reaction, the solvent can be, for example, alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, halogenated solvents, preferably dichloromethane, 1,2-dichloroethane or chlorobenzene.

In the reaction, the base can be an inorganic base such as alkali metal hydroxide or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, or an organic base, preferably trialkylamine or tetraalkylammonium hydroxide. A particularly preferred base is triethylamine. The base is used in 0.8-1.1 molar equivalent, preferably 0.9-1.0 molar equivalent, calculated according to the compound of formula II.

The resulting product of formula I is separated from the reaction mixture using a method known per se. For example, if the product crystallizes from the solvent used in the reaction mixture or can be precipitated by another solvent that is miscible with the original solvent, then the product is filtered and purified by recrystallization or chromatography.

If the product does not crystallize from the reaction mixture, then the solvent is evaporated, and the residues are recrystallized from a suitable solvent.

In some cases, it is convenient to partition the evaporated residue between water and a water-immiscible organic solvent, then basify the mixture, separate the phases, evaporate the organic phase, and purify the remaining base by recrystallization.

In process b) of this invention, the reaction of epoxide of formula III with secondary amine of formula IV is carried out in an inert solvent or in an excess of secondary amine.

The reaction solvent can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methylethyl ketone, dimethylformamide, water or a mixture thereof, preferably ethanol, isopropanol or 5-20% by mass, preferably 10% by mass of their solution in water.

Each mole of epoxide of formula III reacts with 0.8-2.0, preferably 0.85-1.2 moles of secondary amine of formula IV. If used as a base, the secondary amine of formula IV is added directly to the reaction mixture. If a secondary amine salt of formula IV is used, the base can be liberated in the reaction mixture in situ by adding a molar equivalent amount of inorganic or organic base calculated according to the amount of secondary amine salt.

As an inorganic base, an alkali metal or alkaline earth metal hydroxide solution is used, preferably sodium or potassium hydroxide, primarily 5-40% by mass, preferably 10-25% by mass.

As an organic base, trialkylamine or tetraalkylammonium hydroxide, specifically triethylamine, is preferably used.

Generally, the reaction is carried out at the boiling point of the solvent used or at a lower temperature.

The product is separated from the reaction mixture as described for the above procedure a).

In process c) of this invention, the reaction of the compound of formula V with the halogen compound of formula XI is carried out in an inert solvent in the presence of an inorganic or organic base and a phase transition catalyst.

The inorganic base is primarily hydroxide or carbonate of an alkali metal or alkaline earth metal, preferably sodium or potassium hydroxide or potassium carbonate. The organic base is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is taken in 1-2, preferably 1.2 molar equivalent amounts, calculated according to the compound of formula V.

The halogen compound of formula XI is used in 1-3, preferably 1.8-2 molar equivalent amount, calculated according to the compound of formula V.

The reaction solvent can be, for example, methanol, ethanol, propanol, butanol, acetone, methylethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methylethyl ketone.

The phase transition catalyst can be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylgenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.

The reaction can be carried out at a temperature of 40 to 100°C, preferably 60 to 80°C.

The product is separated from the reaction mixture in a manner known per se. For example, after the completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residues are separated between water and an organic solvent that does not mix with water, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residues are purified by recrystallization from a suitable solvent or by vacuum distillation.

In process d) of this invention, a compound of formula V is reacted with an epoxide of formula XII in an inert solvent.

The solvent can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methylethyl ketone, dimethylformamide, water or their mixture, preferably ethanol, isopropanol or 5-20% by mass, preferably 10% by mass of their mixture in water .

The compound of formula V is used in 0.8-2.0, preferably 0.85-1.2 molar equivalent amount, which is calculated according to the epoxide of formula XII.

In general, the reaction is carried out at the boiling point of the solvent used, or at a lower temperature.

The product can be separated from the reaction mixture as previously described in connection with process c).

In process e) of this invention, the dehydration of the compound of formula I, where A denotes a group of the formula COH, B denotes a methylene group, is carried out using a strong mineral acid, preferably hydrochloric acid, in an inert solvent, preferably alcohol, especially preferably in ethanol with heating, preferably fermentation. It is preferable that the starting compound is used in a concentration of 5-40%, preferably 15-25%. If the product is separated from the solution after cooling, it is filtered. Otherwise, a solution that does not dissolve the product, which is mixed with the solvent used in the reaction (preferably ether) is added to the reaction mixture, and the settled crystals are filtered.

In processes f) and g) of the present invention, the ketone of formula XV is reacted with an arylamgensium halide of formula XVI or an aryllithium compound of formula XVII in an inert aprotic organic solvent, preferably ether, tetrahydrofuran or dioxane at a temperature between -10°C and the boiling point of the solvent, preferably 10 to 30°C. The product can be obtained from the reaction mixture - after the decomposition of the complex that was formed in the reaction with acid and evaporation of the solvent - by recrystallization or salt formation. If the product or its salt does not crystallize, the reaction mixture that was decomposed with acid is made alkaline, and the product is dissolved in an organic solvent that does not mix with water, the organic phase is dried, evaporated, and the resulting base is purified by crystallization or chromatography.

In process h) and i) of this invention, the compound of formula I, where A and B give a group of the formula -C=C-, is conveniently reduced by catalytic hydrogenation using a noble metal catalyst on a carbon support, preferably palladium on carbon, especially preferably palladium 10% on carbon catalyst in alcohol, preferably methanol. After removal of the catalyst by filtration, the product is separated by evaporation of the solvent and crystallization of the residue. Alternatively, the residue can be converted into a salt by evaporation.

If the product or its salt does not crystallize, the reaction mixture is partitioned between water and an organic solvent that is immiscible with water, the organic phase is dried, evaporated, and the remaining base is purified by recrystallization or chromatography.

The reduction can also be carried out in the reaction mixture in which the starting compound was prepared.

Halides of formula II are new compounds, so the invention also covers these compounds.

Halides of formula II can be prepared by reacting a compound of formula V with a dihaloalkane of the following formula:

[image] VI

where Y, R2 and Hal are as previously defined.

Alternatively, a halide of formula II can be prepared by reacting a compound of formula V with a haloalkanol derivative of the following formula:

[image] VII

where Y, R2 and Hal are as previously defined, and by translating the hydroxyl group of the resulting hydroxyalkyl derivative of the following formula

[image] VIII

where R 1 , R 2 , X, Y and Z are as defined above, to a halogen atom.

The compound of formula V reacts with the dihaloalkane of formula VI in an inert solvent in the presence of an inorganic or organic base and a phase transition catalyst.

The inorganic base is primarily hydroxide or carbonate of an alkali metal or alkaline earth metal, preferably sodium or potassium hydroxide or potassium carbonate. The inorganic base is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is used in a 1 to 1.5 molar amount, calculated according to the compound of formula V. The dihaloalkane of formula VI is taken in a 1-3, preferably 1.8-2 molar equivalent amount, calculated according to the compound of formula V.

In the reaction, the solvent can be, for example, methanol, ethanol, propanol, butanol, acetone, methylethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methylethyl ketone.

The phase transition catalyst can be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylgenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.

The reaction can be carried out at a temperature of 40 to 100°C, preferably 60 to 80°C.

The product is separated from the reaction mixture in a manner known per se. For example, after the completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residues are separated between water and an organic solvent that does not mix with water, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residues are purified by recrystallization from a suitable solvent or by vacuum distillation.

The reaction of the compound of formula V with the haloalkanol derivative of formula VII is carried out in an analogous manner as described in connection with the reaction of the compound of formula V with the dihaloalkane of formula VI.

The resulting hydroxyalkyl derivatives of formula VIII are converted into the desired halides of formula II using halogenating agents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus pentabromide, phosphorus pentaiodide, phosphorus tribromide, preferably thionyl chloride.

The halogenating agent is used in an excess of 1-4 mol, preferably 1.2-2.2 mol for each mol of the starting hydroxyalkyl derivative of formula VIII.

The reaction is carried out in an inert solvent, preferably with halogenated alkanes, especially chloroform, dichloromethane or 1,2-dichloroethane, or an excess of the halogenating agent is used as a solvent.

After evaporation of the solvent, the product is separated in the same manner as described in connection with the reaction of the compound of formula V and the dihaloalkane of formula VI.

Some epoxides of formula III are known in the literature / Japanese patent application published under number J6 0258-174-A; CA, 104, 207136k (1986)/. They are prepared from compounds of formula V by reaction with epichlorohydrin in an alkaline medium. Alternatively, they can be prepared by reacting a compound of formula V with a halide of the following formula:

[image] IX

where R2 and Hal are previously defined, and by oxidation of the resulting allyl derivative of the following formula:

[image] X

where R 1 , R 2 , X and Z are as previously stated.

The compound of formula V reacts with 1-3 molar equivalents of epichlorohydrin in the presence of an alkali metal or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide used in an amount of 1-3 molar equivalents.

The reaction is carried out in methanol, ethanol, propanol, acetone, methylethyl ketone, acetonitrile, dimethylformamide, water or their mixture, preferably an aqueous solution of methanol or an aqueous solution of ethanol, preferably at the boiling point of the solvent or at a lower temperature.

The epoxide of formula III resulting from the reaction can be separated in a manner known per se. For example, after the completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residues undergo partitioning between water and an organic solvent that does not mix with water, the separated organic phase is dried and evaporated to dryness under reduced pressure. In general, the residues are pure enough for further reactions. If necessary, the product can be purified by chromatography or crystallization.

One allylic derivative of the formula X, where X denotes an oxygen atom, R1 denotes a methyl group, R2 denotes a hydrogen atom and Z is a hydrogen atom, is known from the literature /Aust. J. Chem., 36 (6), 1263 (1983)/. It is prepared from a compound of formula V which reacts with a halide of formula IX in an alkaline medium in the presence of a phase transition catalyst.

In this reaction, an alkaline medium is achieved using hydroxide or carbonate of an alkali metal or an alkaline earth metal, preferably sodium or potassium hydroxide or potassium carbonate. The mentioned bases are used in 12 molar equivalent amounts.

In this reaction, the solvent is, for example, methanol, ethanol, propanol, butanol, acetone, methylethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water or their mixture, preferably ethanol, acetone or methylethyl ketone.

The phase transition catalyst can be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylgenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.

The reaction is carried out at a temperature of 40 to 100°C, preferably 60 to 80°C.

The product is separated from the reaction mixture in a manner known per se. For example, after the completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residues are separated between water and an organic solvent that does not mix with water, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residues are purified by recrystallization from a suitable solvent or by vacuum distillation.

An allylic derivative of formula X is oxidized to the corresponding epoxide of formula III with an organic oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, perphthalic acid, 2,3-dichloro-5,5-dicyano-1,4-benzoquinone (DDQ), preferably m-chloroperbenzoic acid at a temperature of 0 to 40°C, preferably 20 to 30°C.

The solvent in the reaction is 1,2-dichloroethane, chloroform, 1,1,2-trichloroethylene, chlorobenzene, preferably dichloromethane or 1,2-dichloroethane.

The product separates in a manner known per se. For example, after the end of the reaction, water is added to the reaction mixture, the solution is made alkaline by the addition of sodium carbonate, the phases are separated, the organic phase is dried, and evaporated to dryness under reduced pressure. Residues are purified by recrystallization from a suitable solvent or by chromatography.

Some halogen compounds of formula XI are known /Peltz, K., Protiva, M., Coll. Czech. Chem. Commun., 32 (8), 2840 (1967), US-P No. 4,110,536; Chem. Abstr., 90, P 121596r)/. They are prepared by reacting the corresponding secondary amine of formula IV with the corresponding dihaloalkane of formula VI. Other halogen compounds of formula XI are also simply prepared according to the above procedure.

Some epoxides of formula XII are also known. They are prepared from the corresponding compound of formula IV which reacts with epichlorohydrin in an alkaline medium /CH-P No. 474,511; Chem. Abstr., 72, 55506m (1970)/. Some compounds of formula XII can also be prepared by reacting the corresponding secondary amine of formula IV with the corresponding halide of formula IX, and by converting the double bond of the resulting compound of the following formula

[image] XIV

where R 2 , A, B and Ar are as previously defined, to the epoxy group under the conditions described in connection with the oxidation of compounds of formula X. Other epoxides of formula XII can also be easily prepared according to the procedures previously described.

Ketones of formula XV are novel compounds, so this invention also encompasses them. They are prepared by reacting the halide of the formula II or the epoxide of the formula III with the piperidone of the following formula

[image] XIII

The reaction conditions are identical to those used in procedures a) and b) of this invention.

A ketone of formula XV is reacted with an arylmagnesium halide of formula XVI as described in the literature /J-P No. 14,632 ('67); Chem. Abstr., 68, 114618s (1968)/.

The reaction of aryllithium derivatives of formula XVII with ketone of formula XV can also be carried out in a manner known in the literature / Elpern, B., Wetteran, W., Carabates, Ph., Grunbach, L., J. Am. Chem. Soc., 80, 4916 (1958)/.

Arylmagnesium halides of formula XVI and aryllithium derivatives of formula XVII are commercially available.

Secondary amines of formula IV are generally commercially available or can be easily prepared by known procedures.

The biological activity of the compounds of this invention was tested by the following tests:

1. Measurement of the protective effect on the heart in ischemic rats (Langendorff)

Compounds with a cardioprotective effect protect the myocardium from any damage during ischemia and/or reperfusion. Of the numerous methods used to determine the protective effect on the heart, one of the best known and frequently used tests consists in the isolated perfused rat heart subjected to global ischemia /Longman, S.D. and Hamilton, T.C., Medicinal Research Reviews, 12/. During global ischemia, heart muscle contractions occur due to an increase in calcium concentration in the heart muscle. The time elapsed from the onset of global ischemia to the onset of contraction (ie, time to contraction = TTC) is prolonged by several cardioprotective compounds. In this way, the effectiveness of compounds can be tested by measuring TTC.

Male Sprague-Dawley rats weighing 300 to 350 g were injected with 2500 IU (0.5 ml) of heparin i.p. and 10 minutes later the animals were anesthetized with sodium pentobarbital /5-ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione sodium salt/ at a dose of 60 mg/kg i.p. The heart was quickly removed and the aorta was connected to a cannula attached to a Langendorff device. The heart was perfused at constant pressure (8000 Pa) with a modified, carbogenized Krebs-Henseleit solution. The composition of the solution was as follows (in mM):

NaCl 118, KC1 4.7, MgSO4 1.6, CaCl2 2.5, NaHCO3 24.88, KH2PO4 1.18, EDTA 0.5, glucose 11. The partial pressure of CO2 and pH of the solution were maintained within physiological limits (pCO2 4000 -4650 Pa, pH = 7.3-7.45).

An opening was made in the wall of the left atrium, and a plastic balloon filled with water was attached to a metal cannula that was placed in the left ventricle. Left ventricular end-diastolic pressure was set to a value between 666-1333 Pa during the equilibration time by changing the fluid volume in the balloon, but this was not changed afterwards.

After 20 minutes for equilibration, the hearts were perfused for 10 minutes with vehicle (0.04% dimethyl sulfoxide), in the case of the control group, or with a solution of the test substance at a concentration of 10-6 or 10-5 M, in the case of the tested groups. The activity of the test compound was not tested after, after a period of 10 minutes, the systolic pressure of the left ventricle was reduced by more than 20%, compared to the control value determined before the treatment.

Global ischemia was initiated by complete cessation of perfusing flow and carbogenization for 25 min. The time from the onset of ischemia to the onset of myocardial contraction, i.e. to an increase of 666 Pa in the end diastolic pressure in the left ventricle (TTC), was measured.

3 parallel experiments were performed with the tested compounds for each concentration and the parameters were measured for three hearts with the carrier (0.04 dimethyl sulfoxide) together with the tested substance.

The average values of individual TTC values were calculated, and the effect of the tested substances was expressed as a percentage of change compared to the group treated with the vehicle. Compounds that prolong TTC compared to the control group are cardioprotective compounds. As a reference substance, lemakalim was used, i.e. (3S)-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-2H-1-benzpyran- 6-carbonitrile. The obtained results are presented in Table I.

Table I

Effect of TTC prolongation in the isolated rat heart (Langendorff)

[image]

Several representatives of benzofuran derivatives that were tested cause a significantly higher TTC prolongation at a concentration of 10-6 than the reference substance lemakalim.

Compounds of the present invention induced significantly greater TTC prolongation in the isolated perfused ischemic rat heart during ischemia. This fact is proof of a protective effect on the heart.

The compound of example 9 significantly exceeds the effect of lemakalim at a concentration of 10-6 M. Thus, we find that the protective effect on the heart can be used for human therapy. The above-mentioned protective effect on the heart offers the possibility of preventing the undesirable effects of serious coronary arrhythmias, which often occur with prolonged use of active substances. In particular, it seems that the treatment of fluctuating patients with angina is suitable because this disease is considered a condition that precedes myocardial infarction. Further application of the compounds can be therapy for the protection of the heart before surgery, for example in the case of transiently stopped blood vessel circulation (coronary balloon dilatation) or stopped heart due to operative reasons. A faster and more complete regulation of the heart's work can be achieved by treatment to protect the heart that is being prepared for transplantation. In this case, the compound of the present invention is added to the heart feeding solution.

2. Determination of influence on serotonin nerve transmission

Analysis of 5-HT1A receptor binding

Analysis of 5-HT1A receptor binding was performed according to the method of Peroutka /Peroutka, S.J., J. Neurochem., 47, 529 (1986)/. Binding was determined in membrane fragments prepared from rat frontal cortex using tritium-labeled 8-hydroxy-N,N-dipropyl-2-aminotetralin as a specific ligand. Non-specific binding was determined at a concentration of 10 μM 5-HT /5-hydroxytryptamine/. The final incubation volume was 250 microliters. Samples for analysis were incubated at 25°C for 30 minutes. The reaction was stopped by the addition of 9 ml of an ice-cold solution of tris(hydroxymethyl)aminomethane hydrochloride with a pH value of 7.7, after which rapid filtration was performed under reduced pressure. Filtration was performed using Whatman GFIB glass fiber filter paper soaked in 0.05% polyethyleneimine solution for 2 to 3 hours prior to use. The radioactivity remaining on the filter was determined by a liquid scintillation counter.

The obtained results are summarized in Table II. Buspirone, i.e. 8-{4-[ 4-(2-pyrimidinyl)-1-piperazinyl]butyl}-8-azaspiro/4,5/decane-7,9-dione, was used as a reference compound.

Table II

Effect of compounds on 5-HT1A receptor binding

[image]

From the data in Table II, it can be seen that the compounds of this invention have an appropriate affinity for serotonin 5-HT1A receptors. Most of the tested compounds are superior to buspirone, which was used as a reference substance.

Rat elevated maze test

The test was carried out in accordance with the modified procedure of Pelow and associates /J. Neuroscientists. Methods, 14, 149 (1985)/. The elevated plus-labyrinth consists of two open and two closed branches (40 cm) that are the same size (50×15 cm), placed in the shape of a cross. Branches of identical type are placed opposite each other. The connection between the four branches is a central square field (15×15 cm). The device is made of wooden material, raised to a height of 50 cm and illuminated by a weak light above. Male Sprague-Dawley rats weighing 220 to 260 g were used for the experiment.

The rats were treated with the test substance 60 minutes before the test. Animals were placed in the central square field and tested for 5 min. The following 4 parameters were determined:

- time spent in open branches;

- time spent in closed branches;

- number of entries into open branches;

- number of entries into closed branches.

A compound is considered effective when a significant increase is found in either the time spent in the open branches (in seconds) or the number of entries into the open branches compared to control animals (in percent). The minimum effective dose (MED) was determined based on the time spent in open branches for each tested compound. The obtained results are presented in Table III. Buspirone was used as a reference substance.

Table III

[image]

It can be seen from Table III that the compound of Example 25 is superior by one order of magnitude to buspirone in the test characterizing the anxiolytic effect. It should be emphasized that buspirone, which strongly binds to 5-HT1A, is widely used in clinical practice.

Based on the results obtained in research related to the influence on serotonin nerve transmission, the compounds of this invention can be used in various diseases that are associated with disorders of the central nervous system.

Many clinical and preclinical studies indicate that 5-HT1A receptors have a certain role in various pathophysiological processes. Buspirone, which was used as a reference substance in our study and which acts through the 5-HT1a receptor stops aggressive behavior in rhesus monkeys /Tomkins, E.C., Clemento, A.J., Taylor, D.P., Perlach, J., Res. Commun. Physiol. Psychiatrist. Behav., 5, 337 (1980)/ and indicates an anxiolytic effect in clinical research /Goldberg, H.L. and Finnerty, R.J., Am. J. Psychiatry, 136, 1184 (1979)/. In our studies, several compounds of this invention surpassed the anxiolytic activity of buspirone.

5-HT1A receptors have also been suggested to have some role in clinical conditions of depression, as 5-HT1A ligands have been shown to exhibit antidepressant potential in animal test models /Porsolt, R.D., Roux, S. and Wettstein, J.G., Pharmacol. Res., 31, 169 (1995)/. The next therapeutic possibility consists in the therapy of cognitive deficiencies in the case of drugs that act on the 5-HT1A receptor. Administration of 8-hydroxy-N,N-dipropyl-2-aminotetralin to rats improves memory and learning ability /Carli, M. and Samanin, R., Br. J. Pharmacol., 105, 720 (1992)/. In addition to the clinical conditions mentioned above, if the active substance acts through the 5-HT1A receptor, it can be used in the case of eating disorders.

This assumption is based on the fact that 8-hydroxy-N,N-dipropyl-2-aminotetralin, which acts through the 5-HT1A receptor, under certain circumstances increases food intake, while under other conditions it decreases food intake /Dourish, C.T., Hutson, P.H. and Curzon, G., Psychopharmacology, 86, 197 (1985); Dourish, C.T., Hutson, P.H. and Curzon, G., Brain Res. Bull., 15, 377 (1985)/. Thus, it has been found that the compounds of this invention can be effective for some clinical conditions that are related to the central nervous system, the symptoms of which can be anxiety, depression, cognitive deficiency or eating disorder.

The above assumption is also confirmed by the following test.

3. Determination of the anxiolytic effect based on Vogel's conflict test

The anxiolytic effect was tested by the method of Vodel and associates /Vogel, J.R., Beer, B., Clody, D.E., Psychopharmacologia (Berl.), 21, 1 (1971)/. Male Wistar rats weighed 180 to 200 g and were kept thirsty for 48 hours and fasted for 24 hours before testing.

The substances to be tested and the carriers are administered to the animals half an hour before the test. In the test area, the rats were allowed to drink from a drinking tube that entered the area. After every 20th lick, the device emits an electric shock of 0.7 mA through the drinking tube. During the test duration of 5 minutes, the number of these electric shocks received by the animal during thirst quenching was registered. The compound effect is expressed as an increase in the acceptable number of electric shocks in percent. A minimum effective dose (MED) was determined for each compound.

Meprobamate /2-methyl-2-propyltrimethylenecarbamate/ was used as a reference substance. The obtained results are summarized in Table IV.

Table IV

[image]

It is clear from Table IV that the tested benzofuran derivative exceeds the activity of meprobamate as a reference substance, which is used as a reference for Vogel's conflict test, by a factor greater than 2.

In summary, the above tests clearly indicate that the compounds of this invention have a significant effect on the heart. At the same time, due to their mechanism of action, the compounds of this invention may be suitable for treating diseases of the central nervous system such as depression, anxiety, cerebral ischemia, schizophrenia, etc.

Thus, it was obtained that new benzofuran derivatives can be used as active ingredients in pharmaceutical composites.

The pharmaceutical compositions of the present invention contain a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and one or more suitable carriers.

The pharmaceutical compositions of this invention are suitable for peroral, parenteral or rectal administration or for local action, and may be solid or liquid.

Solid pharmaceutical composites suitable for oral administration can be powders, capsules, tablets, coated tablets, microcapsules, etc., and can contain binders such as gelatin, sorbitol, poly(vinyl-pyrrolidone), etc.; fillers such as lactose, glucose, starch, calcium phosphate, etc.; excipients for tableting such as magnesium stearate, talc, poly(ethylene glycol), silica gel, etc.; humectants such as sodium lauryl sulfate etc. as a carrier.

Liquid pharmaceutical compositions for oral administration can be solutions, suspensions or emulsions and can contain, eg. suspending agents such as gelatin, carboxymethylcellulose, etc.; 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 composites suitable for parenteral administration generally consist of sterile solutions of the active substance.

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

The pharmaceutical compositions of the present invention contain, in general, 0.1 to 95.0 percent (by weight) of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. A typical dose for adult patients is 0.1 to 1000 mg of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, per day. The above dose can be administered in one or more meals. The actual dose depends on many factors and is determined by the doctor.

The pharmaceutical composites of this invention are prepared by mixing the compound of formula I or its pharmaceutically suitable acid addition salt with one or more carriers, and by converting the resulting mixture into a pharmaceutical composite in a manner known per se. Useful methods are known from the literature, eg Remington's Pharmaceutical Sciences.

A preferred subgroup of the pharmaceutical composites of this invention comprises a benzofuran derivative of formula I, where

R1 denotes a hydrogen atom or a C1-4 alkyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydrogen atom or a hydroxyl group,

Z denotes a hydrogen atom, a halogen atom or a nitro group,

A denotes a group of formula CH, COH or C-CN,

B denotes a methylene group, or

A forms with B a group of the formula -C=C-,

Ar denotes a hydrogen atom, a benzyl group, a phenyl group which is substituted by the substituents R5, R6 and R7, a biphenyl group, a naphthyl group which is arbitrarily substituted with a C1-4 alkoxy group; or a thienyl group, where

R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl

group, C1-4 alkoxy group, C2-4 alkenyloxy group, phenoxy group or methylenedioxy group,

or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

Conveniently, within the above subgroup, the pharmaceutical compositions of the present invention comprise a benzofuran derivative of formula I, wherein

R1 denotes a hydrogen atom or a C1-4 alkyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

A is a group of formula CH, COH or C-CN,

B denotes a methylene group, or

A gives with B a group of the formula -C=C-,

Ar denotes a phenyl group which is optionally substituted with a halogen atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group,

or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

Further preferred subgroups of the pharmaceutical composites of this invention contain a piperazinylalkylbenzofuran derivative of formula Ia, where

R1 denotes a C1-4 alkyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

Ar' denotes a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and which is condensed with a phenyl group, or a phenyl group which is substituted by the substituents R5, R6 and R7, where

R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a Cl-4 alkyl group, a Cl-4 alkoxy group or a methylenedioxy group,

n has the value 0 or 1,

or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

Conveniently, within the above subgroup, the pharmaceutical compositions of the present invention contain a piperazinylalkylbenzofuran derivative of formula Ia, where

R1 denotes a methyl group,

R2 denotes a hydrogen atom,

X denotes an oxygen atom,

Y is a hydroxyl group,

Z denotes a hydrogen atom,

Ar' denotes a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group which is arbitrarily substituted with one or two halogen atoms, one or two methylene groups, a methylenedioxy group, a trifluoromethyl group or a methoxy group,

n has the value 0 or 1,

or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

Particularly preferred pharmaceutical composites of this invention include as active ingredient the following benzofuran derivatives or its pharmaceutically acceptable acid addition salts:

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-methoxyphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-phenylpiperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy)-2-hydroxypropyl/-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl-4-(diphenylmethyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy)-2-hydroxypropyl/-4-benzylpiperazine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)-piperazine,

1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)-piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-pyridyl)piperazine,

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)-piperazine or

1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl)-4-(3-methoxyphenyl)-piperazine.

Also, the invention defines a method of treating a disease, which includes the application of a therapeutically effective, non-toxic amount of a benzofuran derivative of formula I or its pharmaceutically suitable acid addition salt to a patient who particularly suffers from heart disease or central nervous system disease.

The invention is further illustrated by the following examples.

Preparation of halides of formula II

1) 7-(3-bromopropyloxy)-2,2-dimethyl-2,3-dihydrobenzofuran

80.8 g (0.4 mol) of 1,3-dibromopropane and 83 .0 g (0.6 mol) of anhydrous potassium carbonate, and the reaction mixture was boiled with stirring for 24 hours. After cooling, the inorganic salt was filtered, and the filtrate was evaporated to dryness under reduced pressure. The final product was recrystallized from methanol, filtered and dried at room temperature.

Thus, 34.7 g (61 %) of the title compound were obtained. T.p.: 54-56°C.

Preparation of epoxy formula III

2) 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

a) 7-acetoxy-2,2-dimethyl-2,3-dihydro-benzofuran

12.2 g (0.12 mol) of acetic anhydride was added to a solution of 16.4 g (0.1 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 40 ml of glacial acetic acid, the reaction mixture was boiled for 30 minutes, and steamed to dryness under reduced pressure. The remaining oil was mixed with 60 ml of ice water, the white crystalline product was filtered, washed with ice water and dried under reduced pressure.

Thus, 20.4 g (99 %) of the title compound were obtained. After recrystallization from methanol, mp: 49-50°C.

b) 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran

A solution of 16.0 g (0.1 mol) of bromine in 40 ml of glacial acetic acid was added dropwise to a solution of 20.6 g (0.1 mol) of 7-acetoxy-2,2-dimethyl-2,3- of dihydrobenzofuran in 150 ml of chloroform with stirring and cooling at a temperature of 15-20°C for 30 minutes. The resulting solution was stirred for 15 minutes, then evaporated to dryness under reduced pressure. The last product in the form of honey was mixed with 150 ml of ice water, the settled crystals were filtered, and washed with ice water until neutral. The crystals thus obtained were suspended in 80 ml of methanol at 0°C, filtered again and dried under reduced pressure.

Thus, 22.0 g (77%) of the title compound were obtained. T.p.: 76°C.

c) 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol

24.2 g (0.085 mol) of 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran was mixed in a mixture of 70 ml of methanol and 68 ml of 10% aqueous sodium hydroxide solution at 20-25°C during 3 hours. The reaction mixture was acidified with concentrated hydrochloric acid to pH 2, methanol was predistilled under reduced pressure, and the ratios were extracted 3 times using 50 ml of dichloromethane each time. The combined organic layers were washed twice using 20 ml of water each time to remove traces of acid, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with n-hexane to give a crystalline substance which was filtered and dried under reduced pressure.

Thus, 19.9 g (96.4%) of the title compound were obtained. T.p.: 70°C.

d) 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

To a solution of 19.9 g (0.082 mol) of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 60 ml of 10% aqueous sodium hydroxide solution, 13.65 g (0.147 mol) of epichlorohydrin was added. and the reaction mixture was stirred at 45-50°C for 3 hours. After cooling, the separated oil was dissolved in 100 ml of dichloromethane, the aqueous phase was extracted with 30 ml of dichloromethane, the combined organic phase was extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure.

Thus, 23.5 g (98 %) of the title compound were obtained in the form of honey, which was used directly for the preparation of compounds of formula I. After a long standing, the product crystallizes. T.p.: 46-48°C.

3) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

To a solution of 15.0 g (0.09 mol) of 2,2-dimethyl2,3-dihydrobenzofuran-7-ol in 100 ml of a 10% aqueous solution of sodium hydroxide, 20.0 g (0.216 mol) of epichlorohydrin was added, and the reaction mixture stirred at 48 to 50°C for 2.5 hours. After cooling, the separated oil was dissolved in 100 ml of dichloromethane, the aqueous phase was extracted with 50 ml of dichloromethane, the combined organic phases were extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure . The title compound was obtained as a honey-like solid which was triturated with 60 ml of n-hexane to give white crystals. The precipitated crystals were filtered and dried under reduced pressure.

Thus, 19.5 g (97%) of the title compound were obtained. T.p.: 51-52°C.

4) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran

0.35 g of 82% m-chloroperbenzoic acid was added to a solution of 0.204 g (0.001 mol) of 2,2-dimethyl-7-(2-propenyloxy)-2,3-dihydrobenzofuran in 5 ml of dichloromethane, and the reaction mixture was stirred for 10 hours. 5 ml of 10% aqueous solution of sodium bicarbonate was added to the reaction mixture, the phases were separated, the organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The remaining oily product was purified by column chromatography (the column was filled with silica gel and eluted with a mixture of 24 parts by volume of dichloromethane and 1 part by volume of acetone).

Thus, 0.068 g (31%) of the title compound was obtained. T.p.: 49-51°C.

5) 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran

a) 7-Acetoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 16.5 g (0.08 mol) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran in 60 ml of chloroform, 6 ml of (0.06 mol) of acetic anhydride. 4 ml (5.53 g, 0.06 mol) of concentrated nitric acid (density: 1.42; 65%) was added to the resulting solution drop by drop over 30 to 40 minutes, making sure that the temperature of the mixture was between 25 and 28°C. The reaction mixture was stirred for a further 10 minutes, 100 ml of ice water was added, the phases were separated, the organic phase was washed with ice water until neutral, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crystalline product was suspended in 40 ml of methanol at 0°C, filtered and dried under reduced pressure.

Thus, 14.8 g (74%) of the title compound were obtained. M.p.: 142-143°C.

b) 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-ol

13.3 g (0.053 mol) of 7-acetoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran was mixed in a mixture of 40 ml of methanol and 42.5 ml of 10% aqueous sodium hydroxide solution at 20 to 25° C for 30 minutes. The resulting purple solution was acidified to pH 1 with concentrated hydrochloric acid, methanol was predistilled under reduced pressure, and the residues were extracted with 50 ml of dichloromethane. The phases were separated, the aqueous phase was extracted twice, each time with 25 ml of dichloromethane. The combined organic phases were extracted twice, each time with 20 ml of water, to remove the acid, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with n-hexane to give a crystalline substance which was filtered and dried under reduced pressure.

Thus, 10.8 g (97.8%) of the title compound were obtained. T.p.: 96-97°C.

c) 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran

14.5 g (0.156 mol) of epichlorohydrin was added to a solution of 10.8 g (0.052 mol) of 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-ol in 62 ml of 10% aqueous sodium hydroxide solution, and the reaction mixture was stirred at 48 to 52°C for 2.5 hours. After cooling, the separated oil was dissolved in 60 ml of dichloromethane, the aqueous phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were triturated with n-hexane, then filtered and dried under reduced pressure.

Thus, 13.3 g (96.7 %) of the title compound were obtained. M.p.: 108°C (after recrystallization from methanol).

6) 2,2-dimethyl-7-(2-allyloxy)-2,2-dihydrobenzofuran

To a solution of 8.20 g (0.05 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of acetone, 12.1 g (0.12 mol) of allyl bromide and 20.75 g (0.15 mol) of anhydrous potassium carbonate, and the reaction mixture was boiled with stirring for 12 hours. After cooling, the inorganic salts were filtered off and the filtrate was evaporated under reduced pressure to remove the solvent. The last oily product was purified by vacuum distillation.

Thus, 9.20 g (90%) of the title compound were obtained. T.v.. 77°C/53.3 Pa.

7) 2,2-dimethyl-7-(2-allyloxy)-2,3-dihydrobenzofuran

To a solution of 8.20 g (0.05 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of acetone, 7.63 g (0.10 mol) of allyl bromide and 20.7 g of (0.15 mol) of anhydrous potassium carbonate, and the reaction mixture was boiled with stirring for 12 hours. After cooling, the inorganic salts were filtered off and the filtrate was evaporated under reduced pressure to remove the solvent. The last oily product was purified by vacuum distillation.

Thus, 8.90 g (87 %) of the title compound were obtained.

T.v.: 77°C/53.3 Pa.

Preparation of compounds of formula X

8) 2,2-dimethyl-7-(2-methyl-2-propenyloxy)-2,3-dihydrobenzofuran

To a solution of 24.6 g (0.15 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 350 ml of acetone, 27.1 g (0.3 mol) of methallyl chloride and 62.25 g were added. (0.45 mol) of anhydrous potassium carbonate, and the reaction mixture was boiled with stirring for 22 hours. After cooling, the inorganic salts were filtered off and the filtrate was evaporated under reduced pressure to remove the solvent. The last oily product was purified by vacuum distillation.

Thus, 25.0 g (76.5 %) of the title compound were obtained. T.v.: 80-83°C/27-40 Pa.

Preparation of benzofuran derivatives of formula I

Example 1

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

2.28 g (0.012 mol) of 4-( 4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 12 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 12 hours, and then the two phases were separated. The organic phase was extracted twice, each time with 50 ml of water, dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to remove the solvent. The residues were dissolved in 30 ml of ethanol containing 5% hydrogen chloride, then evaporated to dryness on a water bath under reduced pressure. The last product was triturated with 40 ml of ethyl acetate, and the crystalline product was settled and filtered.

Thus, 3.75 g (72.8 %) of the title compound were obtained. M.p.: 165°C.

Example 2

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

Mixture 2.15 g (0.005 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl)-4-(4-methoxyphenyl)-1,2,3,6- tetrahydropyridine hydrochloride, 20 ml of dichloromethane and 3 ml of 10% aqueous sodium hydroxide solution were mixed for 10 minutes. The two phases were separated, the organic phase was extracted twice, each time with 5 ml of water, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The evaporated residue was recrystallized from a small amount of ethanol.

Thus, 1.54 g (78.5%) of the titled base was obtained. T.p.: 96-97°C.

Example 3

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 3.0 g (0.0105 mol) of 7-(3-bromopropyloxy)-2,2-dimethyl-2,3-dihydrobenzofuran in 50 ml of dichloromethane, 2.07 g (0.01 mol) of 4-hydroxy -4-(4-methoxyphenyl)piperidine and 5 ml of 10% aqueous sodium hydroxide solution, and the reaction mixture was stirred at room temperature for 14 hours. The phases were separated, the organic phase was extracted twice, each time with 20 ml of water, and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues (4.15 g) were dissolved in 30 ml of ethanol containing 5% hydrogen chloride at 40°C, and the obtained solutions were maintained at that temperature for 5 minutes, and then evaporated again under reduced pressure. The residues were triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

Thus, 2.79 g (85 %) of the title compound were obtained. M.p.: 165°C.

Example 4

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

0.82 g (0.002 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-propyl)-4-(4-methoxyphenyl)-1,2,3,6- of tetrahydropyridine was mixed in 10 ml of ethanol containing 5% hydrogen chloride at 40°C for 5 minutes, and the solution was evaporated under reduced pressure. The residues were triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

Thus, 0.75 g (87 0) of the title compound was obtained. M.p.: 165°C.

Example 5

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-hydroxy-4-(4-methoxyphenyl)-piperidine

0.41 g (0.002 mol) of 4-hydroxy-4-( 4-methoxyphenyl)piperidine and 1 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 14 hours, and the phases were separated. The organic phase was extracted twice, each time with 5 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were recrystallized from 3 ml of ethanol.

Thus, 0.35 g (43%) of the title compound was obtained. T.p.: 116-117°C.

Example 6

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

2.63 g (0.01 mol) of 4-( 3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 10 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 24 hours, and the phases were separated. The organic phase was extracted twice, each time with 10 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues (4.68 g) were dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated again to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.86 g (82.5 %) of the title compound were obtained. M.p.: 186-187°C.

Example 7

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)propyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride

To a solution of 3.00 g (0.0105 mol) of 7-(3-bromo-propyloxy)-2,2-dimethyl-2,3-dihydrobenzofuran in 50 ml of dichloromethane, 2.45 g (0.01 mol) of 4 -hydroxy-4-(3-trifluoromethylphenyl)piperidine and 5 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 24 hours, and the phases were separated. The organic phase was extracted twice, each time with 10 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues (4.91 g) were dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated again to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.30 g (67.9 %) of the title compound were obtained. T.p.: 154-155°C.

Example 8

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 1.20 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol, 1.30 g (0.005 mol) of 4-(3-trifluoromethylphenyl)-1 ,2,3,6-tetrahydropyridine hydrochloride and 1.1 ml of a 20% aqueous solution of sodium hydroxide. The reaction mixture was boiled for 5 hours and evaporated under reduced pressure. The residue was partitioned between 15 ml of dichloromethane and 10 ml of water, the organic layer was extracted twice, each time with 10 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues (2.42 g) were dissolved in 15 ml of ethanol containing 5% hydrogen chloride, and the resulting solution was again evaporated to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 2.02 g (83.5 %) of the title compound were obtained. M.p.: 160-162°C (after recrystallization from isopropanol).

Example 9

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride

4.90 g (0.02 mol) of 4-hydroxy-4-( 3-trifluoromethylphenyl)piperidine. The reaction mixture was boiled for 6 hours and evaporated to dryness under reduced pressure. The oily residues were dissolved in 15 ml of methanol, and a mixture of 3 ml of concentrated hydrochloric acid and 3 ml of water at a temperature of 15 to 20°C was added to the cold solution. The settled crystals were filtered, washed with cold methanol, and dried under reduced pressure.

Thus, 8.06 g (86 %) of the title compound were obtained. M.p.: 156-158°C (recrystallized from isopropanol).

Example 10

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.30 g (0.01 mol) of 4-(4-chlorophenyl)-1 ,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of a 20% aqueous solution of sodium hydroxide. The reaction mixture was boiled for 6 hours and then evaporated under reduced pressure. The residue was partitioned between 20 ml of chloroform and 20 ml of water, and the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues (4.3 g) were dissolved in 15 ml of ethanol containing 10% hydrogen chloride, and the resulting solution was again evaporated to dryness. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.48 g (77.3 %) of the title compound were obtained. M.p.: 164-166°C (after recrystallization from isopropanol).

Example 11

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-thienyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.04 g (0.01 mol) of 4-(2-thienyl)-1 ,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide solution. The reaction mixture was boiled for 6 hours and then evaporated under reduced pressure. The residue was partitioned between 20 ml of chloroform and 20 ml of water, the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 15 ml of ethanol containing 10 g of hydrogen chloride, and the resulting solution was evaporated to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.50 g (82 %) of the title compound were obtained. M.p.: 180°C.

Example 12

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 2.80 g (0.013 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.13 g (0.01 mol) of 4-(4-fluorophenyl)-1 ,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide solution. The reaction mixture was boiled for 6 hours and then evaporated under reduced pressure. The residues were partitioned between 20 ml of chloroform and 20 ml of water, the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 15 ml of ethanol containing 10 g of hydrogen chloride, and the resulting solution was evaporated to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.2 g (73.8 %) of the title compound were obtained. T.p.: 153-155°C.

Example 13

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-benzylpiperidine hydrochloride

To a solution of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 2.62 g (0.015 mol) of 4-benzylpiperidine was added. The reaction mixture was boiled for 6 hours and then evaporated under reduced pressure. The residues were partitioned between 20 ml of chloroform and 20 ml of water, the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 15 ml of ethanol containing 10 g of hydrogen chloride, and the resulting solution was evaporated to dryness under reduced pressure.

The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 2.67 g (62 %) of the title compound were obtained. T.p.: 130-132°C.

Example 14

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine

To a solution of 3.40 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-benzofuran in 30 ml of isopropanol, 3.15 g (0.015 mol) of 4-hydroxy-4-(4-chlorophenyl) was added. - piperidine. The reaction mixture was boiled for 6 hours, cooled, the settled crystals were filtered, washed with isopropanol, and dried under reduced pressure.

Thus, 5.40 g (83.4 %) of the title compound were obtained. M.p.: 148-150°C (recrystallized from acetone).

Example 15

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine hydrochloride

0.86 g (0.002 mol) of 1-[3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl]-4-hydroxy-4-(4-chlorophenyl)piperidine was dissolved in 10 ml of methanol, and 2 ml of methanol containing 5% hydrogen chloride was added to the obtained solution, while cooling with ice. The solution was evaporated to dryness under reduced pressure, the crystalline residue was triturated with ether, filtered and then dried under reduced pressure.

Thus, 0.87 g (93%) of the title compound was obtained. M.p.: 172-174°C.

Example 16

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine

To a solution of 3.4 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 2.53 g (0.013 mol) of 4-hydroxy-4-(4-fluorophenyl) was added. piperidine, and the reaction mixture was boiled for 4 hours. Isopropanol was predistilled under reduced pressure, the residues were triturated with 120 ml of petroleum ether (b.p. 60°C), the settled crystals were filtered, washed with a mixture of 1 volume part of acetone and 4 volume parts of petroleum ether, and dried under reduced pressure.

Thus, 4.55 g (84 %) of the title compound were obtained. M.p.: 147-148°C (after recrystallization from ethanol).

Example 17

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine hydrochloride

0.83 g (0.002 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)-piperidine dissolved is in 10 ml of methanol, and 2 ml of methanol containing 5% hydrogen chloride was added to the resulting solution, while cooling with ice. The solution was evaporated to dryness under reduced pressure, the crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 0.79 g (87.5 %) of the title compound was obtained. M.p.: 173-175°C.

Example 18

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 1.40 g (0.0063 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol, 0.98 g (0.005 mol) of 4-(4-phenyl)-1 ,2,3,6-tetrahydropyridine hydrochloride and 1.1 ml of a 20% aqueous solution of sodium hydroxide. The reaction mixture was boiled for 5 hours and then evaporated under reduced pressure. The residues were partitioned between 10 ml of chloroform and 10 ml of water, and the organic phase was extracted twice, each time with 10 ml of water, then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 15 ml of ethanol containing 5% hydrogen chloride, and the resulting solution was also evaporated under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 1.93 g (92.8 %) of the title compound were obtained. M.p.: 166-167°C.

Example 19

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/piperidine

To a solution of 2.30 g (0.0105 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol, 0.85 g (0.01 mol) of piperidine was added. The resulting solution was boiled for 3 hours, cooled, then 20 ml of isopropanol containing 5% hydrogen chloride was added, with cooling to 15 to 20°C. The reaction mixture was evaporated to dryness under reduced pressure, the residues were recrystallized from a mixture of ethanol and ether, the crystals were separated and filtered, washed with ether, and dried under reduced pressure.

Thus, 2.60 g (76 %) of the title compound were obtained.

T.p.: 128-130°C.

Example 20

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride

To a solution of 3.3 g (0.015 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.5 g (0.014 mol) of 4-hydroxy-4-phenylpiperidine was added. The obtained solution was boiled for 3 hours, then it was cooled to 15°C, and after cooling to 15 to 20°C, 10 ml of ethanol containing 10% hydrogen chloride was added. The reaction mixture was evaporated to dryness under reduced pressure, the residues were triturated with ether, the settled crystals were filtered and dried under reduced pressure.

Thus, 3.62 g (60%) of the title compound were obtained. M.p.: 176-177°C.

Example 21

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine

1.4 g (0.003 mol) of 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride) was dissolved in 50 ml of warm of water, and 5 ml of a 10% aqueous solution of sodium hydroxide was added to the resulting solution. The precipitated crystals were filtered, washed with water, and recrystallized from methanol.

Thus, 1.00 g (78%) of the titled base was obtained. M.p.: 127-129°C.

Example 22

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperidine hydrochloride

3.10 g (0.015 mol) of 4-hydroxy-4-(2- methoxyphenyl) piperidine. The reaction mixture was boiled for 5 hours, cooled to 15°C, and after cooling to 15 to 20°C, 4 ml of ethanol containing 15% hydrogen chloride was added. The resulting solution was evaporated to dryness under reduced pressure, and the residues were recrystallized from a mixture of ethanol and ether. The precipitated crystals were filtered and dried under reduced pressure.

Thus, 4.73 g (68 %) of the title compound were obtained. T.p.: 102-104°C.

Example 23

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(6-methoxynaphth-2-yl)piperidine hydrochloride

2.6 g (0.01 mol) of 4-hydroxy-4-(6- methoxynaphth-2-yl) piperidine. The reaction mixture was boiled for 6 hours, cooled to 15°C, and after cooling to 15 to 20°C, 3 ml of ethanol containing 15% hydrogen chloride was added. The reaction mixture was evaporated to dryness under reduced pressure, and the residues were triturated with ter. The settled crystals were filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.

Thus, 4.6 g (89.5 %) of the title compound were obtained. T.p.: 125-127°C.

Example 24

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)-piperidine hydrochloride

2.12 g (0.01 mol) of 4-hydroxy-4-(3- chlorophenyl) piperidine. The reaction mixture was boiled for 6 hours, cooled to 15°C, and after cooling to 15 to 20°C, 3 ml of ethanol containing 15% hydrogen chloride was added. The reaction mixture was evaporated to dryness under reduced pressure, and the residues were triturated with ether. The settled crystals were filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.

Thus, 3.64 g (77.8 %) of the title compound were obtained. T.p.: 138-140°C.

Example 25

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-methoxyphenyl)-piperidine hydrochloride

3.10 g (0.015 mol) of 4-hydroxy-4-(3- methoxyphenyl) piperidine. The resulting solution was boiled for 4 hours and evaporated to dryness under reduced pressure. The residues were dissolved in 40 ml of ethyl acetate, cooled to 15°C, and after cooling to 15 to 20°C, 6 ml of ethanol containing 15% hydrogen chloride was added. The reaction mixture was evaporated to dryness under reduced pressure, and the residues were triturated with ether. The settled crystals were filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.

Thus, 5.90 g (84.8 %) of the title compound were obtained. T.p.: 128-130°C.

Example 26

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)-piperidine

To a solution of 3.80 g (0.0173 mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 3.10 g (0.015 mol) 4-hydroxy-4-(4- methoxyphenyl) piperidine. The resulting solution was boiled for 4 hours and evaporated to dryness under reduced pressure. The residues were treated with 40 ml of ethyl acetate, the settled crystals were filtered and dried under reduced pressure.

Thus, 4.70 g (73.4 %) of the title compound were obtained. T.p.: 144-146°C.

Example 27

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(5-fluoro-2-methoxyphenyl)piperidine hydrochloride

3.37 g (0.015 mol) of 4-hydroxy-4-(5- fluoro-2-methoxyphenyl)piperidine. The resulting solution was boiled for 6 hours, cooled to 15°C, and after cooling to 15 to 20°C, 4 ml of ethanol containing 15% hydrogen chloride was added. The reaction mixture was evaporated to dryness under reduced pressure, and the residues were triturated with ether. The precipitated crystals were filtered and recrystallized from 40 ml of ethyl acetate.

Thus, 5.60 g (77.5 %) of the title compound were obtained. T.p.: 156-158°C.

Example 28

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride

3.34 g (0.015 mol) of 4-(3-trifluoromethylphenyl)piperidine hydrochloride and 2 ml of 40% aqueous solution of sodium hydroxide. The reaction mixture was boiled for 6 hours and evaporated to dryness under reduced pressure. The residues were partitioned between 30 ml of water and 50 ml of dichloromethane, the phases were separated and the organic phase was extracted twice, each time with 20 ml of water, then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were dissolved in 25 ml of ethanol containing 5% hydrogen chloride, and the solution was evaporated to dryness under reduced pressure. The crystalline residues were triturated with ether, the separated crystals were filtered and dried under reduced pressure.

Thus, 5.15 g (77.1 %) of the title compound were obtained. M.p.: 172-174°C.

Example 29

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine

2.86 g (0.015 mol) of 4-hydroxy-4-(4 -methylphenyl)piperidine. The resulting solution was boiled for 5 hours. After cooling, the solution was further cooled to 5°C in an ice bath, the settled crystals were filtered and dried under reduced pressure.

Thus, 5.17 g (83.8 %) of the title compound were obtained. T.p.: 138-139°C.

Example 30

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine hydrochloride

4.11 g (0.01 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine was dissolved in 15 ml of methanol, and 12 ml of methanol containing 5% hydrogen chloride was added to the ice-cooled solution. The solution was evaporated to dryness under reduced pressure, the crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 4.17 g (93 %) of the title compound were obtained. T.p.: 164-166°C.

Example 31

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

To a solution of 3.52 g (0.016 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 25 ml of ethanol, 3.37 g (0.015 mol) of 4-(4-methoxyphenyl)-1,2 ,3,6-tetrahydropyridine hydrochloride and 2 ml of 40% aqueous sodium hydroxide solution. The reaction mixture was boiled for 6 hours, then evaporated to dryness under reduced pressure, and the residues were diluted with 50 ml of water, the settled crystals were filtered and dried under reduced pressure.

Thus, 6.1 g (92.8 %) of the title compound were obtained. T.p.: 104-105°C (after recrystallization from petroleum ether with a boiling point of 120°C).

Example 32

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

4.09 g (0.01 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl)-4-(4-methoxyphenyl)-1,2, 3,6-tetrahydropyridine was dissolved in 15 ml of methanol, and 12 ml of methanol containing 5% hydrogen chloride was added to the ice-cooled solution. The solution is evaporated to dryness under reduced pressure, the crystalline residues are triturated with ether, filtered and dried under reduced pressure.

Thus, 4.05 g (91 %) of the title compound were obtained. M.p.: 162-164°C.

Example 33

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

1.10 g (0.0025 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl)-4-(4-methoxyphenyl)-1,2, 3,6-tetrahydropyridine was dissolved in 5 ml of ethanol containing 20% hydrogen chloride, and the solution was boiled for 10 minutes. After cooling, the solution was diluted with 50 ml of ether, the settled crystals were filtered, washed with ether and dried under reduced vacuum.

Thus, 0.98 g (93%) of the title compound was obtained. M.p.: 161-163°C.

Example 34

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3,5-dimethyl-4-methoxyphenyl)piperidine hydrochloride

3.45 g (0.015 mol) of 4-hydroxy-4-(3 ,5-dimethyl-4-methoxyphenyl)piperidine. The reaction mixture was reacted at 55 to 60°C for 2 hours, then cooled to 0°C, and 5 ml of ethanol containing 10% hydrogen chloride was added while cooling. The reaction mixture was evaporated to dryness under reduced pressure, and the residues were triturated with ether. The precipitated crystals were filtered and dried under reduced pressure.

Thus, 6.42 g (87 %) of the title compound were obtained. T.p.: 92-96°C.

Example 35

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3,5-dimethyl-4-methoxyphenyl)piperidine hydrochloride

To 1.26 g (0.0057 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.18 g (0.005 mol) of 4-hydroxy-4-(3,5-dimethyl- 4-methoxyphenyl)piperidine, and the reaction mixture was reacted at 60°C for 1 hour. The melt was cooled, then dissolved in ether, and 1 ml of ethanol containing 20% hydrogen chloride was added to the obtained solution. The settled crystals were filtered, washed with ether, and dried under reduced pressure.

Thus, 2.04 g (83 %) of the title compound were obtained. T.p.: 94-96°C.

Example 36

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidine

2.57 g (0.01 mol) of 4-hydroxy-4-(3, 4-methylenedioxyphenyl)piperidine hydrochloride and 4.2 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was boiled for 5 hours and evaporated to dryness under reduced pressure. The residues were partitioned between 20 ml of water and 50 ml of dichloromethane, the phases were separated, the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were recrystallized from a mixture of ethyl acetate and n-hexane, the settled crystals were filtered and dried under reduced pressure.

Thus, 3.01 g (73 %) of the title compound were obtained. T.p.: 128-130°C.

Example 37

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-/4-(2-methyl-2-ropenyloxy)phenyl/piperidine

To a solution of 4.8 g (0.022 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of diisopropyl ether, 4.94 g (0.02 mol) of 4-hydroxy-4-/4 -(2-methyl-2-propenyloxy)phenylpiperidine. The reaction mixture was boiled for 6 hours, then cooled to 0°C, the settled crystals were filtered, washed with diisopropyl ether, and dried under reduced pressure.

Thus, 7.95 g (85 %) of the title compound were obtained. T.p.: 108-110°C.

Example 38

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-biphenylyl)piperidine hydrochloride

2.53 g (0.01 mol) of 4-hydroxy-4-(4- biphenylyl)piperidine. The reaction mixture was stirred at 70°C for 1 hour and evaporated to dryness under reduced pressure. The residues were dissolved in 50 ml of ether, and 1.5 ml of ethanol containing 20% hydrogen chloride was added to the resulting solution while cooling. The settled crystals were filtered, washed with ether, and dried under reduced pressure.

Thus, 4.45 g (87 %) of the title compound were obtained. M.p.: 166-167°C.

Example 39

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-phenoxyphenyl)piperidine

2.70 g (0.01 mol) of 4-hydroxy-4-(4- phenoxyphenyl) piperidine. The reaction mixture was stirred at 70°C for 1 hour and then evaporated to dryness under reduced pressure. The residues were recrystallized from a small amount of methanol, filtered and dried under reduced pressure.

Thus, 4.47 g (91 %) of the title compound were obtained. T.p.: 113-115°C.

Example 40

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl-4-hydroxy-4-(4-chloro-3-trifluoromethylphenyl)piperidine hydrochloride

4.19 g (0.015 mol) of 4-hydroxy-4-(4- chloro-3-trifluoromethylphenyl)piperidine. The residues were stirred at 60°C for 2 hours and then evaporated to dryness under reduced pressure. The residues were dissolved in 60 ml of ether, and 2.5 ml of ethanol containing 20% hydrogen chloride was added to the resulting solution. The precipitated crystals were filtered, washed with ether and dried under reduced pressure.

Thus, 7.00 g (88%) of the title compound were obtained. T.p.: 146-148°C.

Example 41

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-phenylpiperidine hydrochloride

To a solution of 0.20 g (0.005 mol) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.11 g (0.005 mol) of 4-cyano-4-phenylpiperidine hydrochloride. The reaction mixture was boiled with stirring for 6 hours and then evaporated to dryness under reduced pressure. The residues were partitioned between 50 ml of water and 50 ml of dichloromethane, the phases were separated, the organic phase was extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were dissolved in 50 ml of ether, and 1 ml of ethanol containing 20% hydrogen chloride was added to the resulting solution while cooling. The settled crystals were filtered, washed with ether, and dried under reduced pressure.

Thus, 1.60 g (74 %) of the title compound were obtained. T.p.: 204-206°C.

Example 42

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-(3-trifluoromethylphenyl)piperidine hydrochloride

To a solution of 0.20 g (0.005 mol) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.40 g (0.005 mol) of 4-cyano-4-(3-trifluoromethylphenyl)piperidine hydrochloride. The reaction mixture was stirred for 6 hours and then evaporated to dryness under reduced pressure. The residue was partitioned between 50 ml of water and 50 ml of dichloromethane, the phases were separated, the organic phase was extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were dissolved in 50 ml of ether, and 1 ml of ethanol containing 20% hydrogen chloride was added to the obtained solution. The settled crystals were filtered, washed with ether, and dried under reduced pressure.

Thus, 1.48 g (59.2 %) of the title compound were obtained. M.p.: 213-216°C.

Example 43

1-/3-(5-bromo-2,2-dimethyl-2,3-3ihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine

1.66 g (0.008 mol) of 4-hydroxy-4 -(4-Methoxyphenyl)piperidine. The reaction mixture was boiled with stirring for 10 hours and then cooled to 0°C. The precipitated crystals were filtered, washed with cold isopropanol and dried under reduced pressure.

Thus, 2.67 g (66%) of the title compound were obtained. M.p.: 120-121°C (after recrystallization from isopropanol).

Example 44

1-(3-(5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chloro-3-trifluoromethylphenyl)piperidine hydrochloride

2.80 g (0.01 mol) of 4-hydroxy-4 -(4-chloro-3-trifluoromethylphenyl)piperidine. The reaction mixture was stirred at 60°C for 2 hours and then evaporated to dryness under reduced pressure. The residues were dissolved in 60 ml of ether, and 2.5 ml of ethanol containing 20% hydrogen chloride was added to the resulting solution while cooling. The separated crystals were filtered, washed with ether and dried under reduced pressure.

Thus, 4.86 g (79 %) of the title compound were obtained. T.p.: 108-110°C.

Example 45

1-(3-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine

1.86 g (0.009 mol) of 4-hydroxy-4 -(4-Methoxyphenyl)piperidine. The reaction mixture was boiled for 2 hours with stirring and then cooled to 2°C. The settled crystals were filtered, washed with cold isopropanol, and dried under reduced pressure.

Thus, 3.48 g (81.8 %) of the title compound were obtained. T.p.: 136-138°C.

Example 46

1-/3-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

2.11 g (0.01 mol) of 4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide solution. The reaction mixture was stirred for 5 hours and then evaporated under reduced pressure. The residue was partitioned between 30 ml of dichloromethane and 10 ml of water, the organic phase was then extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 50 ml of ethanol containing 5% hydrogen chloride, and the resulting solution was also evaporated to dryness under reduced pressure. The crystalline residues were triturated with ether, filtered and dried under reduced pressure.

Thus, 3.89 g (73.7 %) of the title compound were obtained. T.p.: 162-165°C.

Example 47

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl)-4-(6-methoxynaphth-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride

Solution 3.34 g (0.0065 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl)-4-(6-methoxynaphth-2-yl) of piperidine hydrochloride in 15 ml of ethanol containing 20% hydrogen chloride was boiled for 20 minutes and then evaporated to dryness under reduced pressure. The crystalline residues were triturated with 30 ml of ether, filtered and dried under reduced pressure.

Thus, 2.96 g (92 %) of the title compound were obtained. M.p.: 186-188°C.

Example 48

1-/3-(5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

2.11 g (0.008 mol) of 4-(3- trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 3.2 ml of 10% aqueous sodium hydroxide solution. The reaction mixture was stirred for 6 hours and evaporated under reduced pressure. The residue was partitioned between 50 ml of dichloromethane and 50 ml of water, the organic phase was then extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residues were dissolved in 10 ml of ethanol containing 10% hydrogen chloride, and the resulting solution was also evaporated to dryness under reduced pressure. The crystalline residues were boiled with 50 ml of ethyl acetate, the crystals were filtered from the hot mixture and dried under reduced pressure.

Thus, 3.78 g (89.8 %) of the title compound were obtained. T.p.: 112-114°C.

Example 49

1-/3-(5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

1.72 g (0.007 mol) of 4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, and the reaction mixture was boiled for 6 hours with stirring, and then evaporated under reduced pressure. The residues were boiled in 10 ml of ethanol containing 20% hydrogen chloride for 30 minutes, and the mixture was also evaporated under reduced pressure. The crystalline residues were boiled with 30 ml of ethyl acetate for 5 minutes, the crystals were filtered and dried under reduced pressure.

Thus, 3.42 g (92.8 %) of the title compound were obtained. T.p.: 112-114°C.

Example 50

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine hydrochloride

Solution 1.78 g (0.004 mol) 1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl)-4-(3-trifluoromethylphenyl)-1,2,3 ,6-tetrahydropyridine hydrochloride in 20 ml of methanol was hydrogenated in the presence of 0.1 g of 10% palladium/carbon catalyst at 20°C and atmospheric pressure. When the calculated amount of hydrogen (96 ml) was consumed, the catalyst was removed by filtration and the solution was evaporated under reduced pressure. The crystalline residues were triturated with 20 ml of ether, the crystals were filtered and dried under reduced pressure.

Thus, 1.75 g (98%) of the title compound was obtained.

M.p.: 172-174°C.

Example 51

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine hydrochloride

A mixture of 2.31 g (0.0105 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.45 g (0.01 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine melted was at 80°C for 1 hour, then it was dissolved in 10 ml of ethanol containing 20% hydrogen chloride, and the mixture was boiled for 45 minutes. The solution was diluted with 10 ml of ethanol, cooled to 30°C, 0.1 g of 10% palladium/carbon catalyst was added and the mixture was hydrogenated. As soon as the calculated amount of hydrogen (240 ml) was consumed, the catalyst was removed by filtration and the solution was evaporated under reduced pressure. The crystalline residues were triturated with ether, the crystals were filtered and dried under reduced pressure.

Thus, 4.05 g (91 %) of the title compound were obtained. M.p.: 172-174°C.

Example 52

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxypiperidine hydrochloride

To a solution of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of tetrahydrofuran was added 0.55 g (0.0055 mol) of 4-hydroxypiperidine. The reaction mixture was boiled for 3 hours with stirring and then evaporated to dryness under reduced pressure. The residues were dissolved in a mixture of 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16% hydrogen chloride, the resulting solution was evaporated under reduced pressure, the residues were dissolved in 8 ml of 2-propanol and left to stand at 0°C during 5 days. The precipitated crystals were filtered, recrystallized from 2-propanol, filtered and dried under reduced pressure.

Thus, 1.22 g (57 %) of the title compound were obtained. M.p.: 139-141°C.

Example 53

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-methylpiperidine hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.44 g (0.0045 mol) of 4-methyl-piperidine and 8 ml of water was boiled for 9 hours. The oily phase of the resulting mixture was dissolved in 20 ml of ether, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, dissolved in 3 ml of 2-propanol containing 16% hydrogen chloride, and evaporated under reduced pressure. The residues were dissolved in ethyl acetate, settled with ether, the crystals were filtered, dissolved in hot 2-propanol, settled again with ether, then the crystals were filtered and dried under reduced pressure.

Thus, 1.25 g (59%) of the title compound was obtained. T.p.: 146-148°C.

Example 54

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-4-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-trifluoromethylphenyl)piperidine hydrochloride

3.28 g (0.02 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-4-ol was dissolved in 25 ml of 10% aqueous sodium hydroxide solution. 3.70 g (0.04 mol) of epichlorohydrin was added to the solution, and the reaction mixture was stirred at 45 to 50°C for 3 hours. After cooling, the separated oily product was dissolved in 30 ml of dichloromethane, the phases were separated, and the organic phase was washed twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The remaining epoxide in the form of honey (3.78 g, 85.3%) was dissolved in 40 ml of ethanol, and 3.80 g (0.0155 mol) of 4-hydroxy-4-(3-trifluoromethylphenyl) was added to the resulting solution. piperidine, so the reaction mixture was boiled for 6 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride was added to the resulting solution at a temperature below 15°C, and the mixture was evaporated to dryness under reduced pressure. The crystalline residues were recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 5.60 g (72 %) of the title compound were obtained. M.p.: 162-164°C.

Example 55

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-4-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine hydrochloride

The procedure of Example 54 was followed, with the difference that the epoxide obtained in the first reaction step (3.75 g, 85.2%) was dissolved in 50 ml of ethanol. 3.94 g (0.0153 mol) of 4-hydroxy-4-(6-methoxy-naphth-2-yl)piperidine was added to the solution and the reaction mixture was boiled for 4 hours. After cooling, 13 ml of ethanol containing 5% hydrogen chloride was added to the reaction mixture, and the reaction mixture was evaporated to dryness under reduced pressure. The last crystalline product was recrystallized from a mixture of ethanol and ether.

Thus, 5.35 g (68 %) of the title compound were obtained.

T.p.: 118-120°C.

Example 56

1-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-trifluoromethylphenyl)piperidine hydrochloride

3.28 g (0.02 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-5-ol were dissolved in 30 ml of an aqueous solution containing 3 g of sodium hydroxide. 3.70 g (0.04 mol) of epichlorohydrin was added to the resulting solution and the reaction mixture was stirred at 48 to 50°C for 3 hours. After cooling, the separated oily product was dissolved in 30 ml of dichloromethane, the phases were separated, the organic phase was washed twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The remaining epoxide in the form of wax (3.85 g, 87.3%) was dissolved in 50 ml of ethanol, 3.80 g (0.0155 mol) of 4-hydroxy-4-(trifluoromethylphenyl)piperidine was added to the solution, and the reaction the mixture boiled for 5 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride was added to the resulting solution at a temperature below 15°C, and the mixture was evaporated to dryness under reduced pressure. The crystallized residues were recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 4.97 g (64 %) of the title compound were obtained. M.p.: 172-173°C.

Example 57

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-6-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride

1.64 g (0.01 mol) of 2,2-dimethyl-2,3-dihydro-benzofuran-6-ol was dissolved in 15 ml of 10% aqueous sodium hydroxide solution. 1.85 g (0.02 mol) of epichlorohydrin was added to the solution, and the reaction mixture was stirred at 48 to 52°C for 2.5 hours. After cooling, the separated oily product was dissolved in 25 ml of dichloromethane, the phases were separated, and the organic phase was washed twice, each time with 15 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to zero under reduced pressure. The last epoxide in the form of honey (2.10 g, 95%) was dissolved in 10 ml of ethanol, 1.52 g (0.0086 mol) of 4-hydroxy-4-phenylpiperidine was added to the resulting solution, and the reaction mixture was boiled for 6 hours . After cooling, 10 ml of ethanol containing 5% hydrogen chloride was added to the resulting solution at a temperature lower than 15°C, and the mixture was evaporated to dryness under reduced pressure. The crystallized residues were recrystallized from a mixture of ethanol and ether, filtered and washed with ether.

Thus, 4.97 g (64 %) of the title compound were obtained. M.p.: 184-186°C.

Example 58

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-methoxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride

To a solution of 0.20 g (0.005 mol) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.48 g (0.005 mol) of 4-methoxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride. The reaction mixture was stirred for 6 hours and then evaporated to dryness under reduced pressure. The residues were partitioned between 50 ml of water and 50 ml of dichloroethane, the phases were separated, the organic phase was extracted twice, each time with 20 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were dissolved in 50 ml of ether, and 1 ml of ethanol containing 20% hydrogen chloride was added to the cooling solution, the settled crystals were filtered, washed with ether, and dried under reduced pressure.

Thus, 1.62 g (62.8 %) of the title compound were obtained. M.p.: 192-195°C.

Example 59

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine

A solution of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1-(diphenylmethyl)piperazine in 30 ml of isopropanol was boiled during 6 hours. The solution was evaporated to dryness under reduced pressure, the final product was triturated with n-hexane and filtered. The thus obtained crude product (4.53 g) was recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

Thus, 3.89 g (82 %) of the title compound were obtained. T.p.: 129-130°C.

Example 60

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1-(diphenylmethyl)piperazine was melted at 80°C and maintained at that temperature for one hour. The solidified mass obtained was recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

Thus, 3.92 g (83 %) of the title compound were obtained. T.p.: 129-130°C.

Example 61

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 mol) of 1-(diphenylmethyl)piperazine was melted at 60°C and maintained at that temperature for one hour. The solidified mass obtained was recrystallized from 25 ml of ethanol, filtered and dried under reduced pressure.

Thus, 3.82 g (81 %) of the title compound were obtained. T.p.: 129-130°C.

Example 62

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine

To a solution of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.52 g (0.01 mol) of 1-(diphenylmethyl)piperazine was added, and the reaction mixture was boiled for 4 hours. After cooling, the settled crystals were filtered and dried under reduced pressure.

Thus, 3.87 g (81 %) of the title compound were obtained. T.p.: 129-130°C.

Example 63

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine

A solution of 4.40 g (0.02 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.60 g (0.02 mol) of 1-(4-fluorophenyl)piperazine in 30 ml of ethanol it boiled for 5 hours. The solution was evaporated to dryness under reduced pressure, the final product was subjected to chromatography on a column packed with Kieselgel 60 using a mixture of 30 parts by volume of chloroform and 1 part by volume of ethanol as eluent. Fractions containing the product were evaporated, the last product was triturated with n-hexane, filtered, and dried under reduced pressure.

Thus, 7.30 g (91%) of the title compound were obtained. T.p.: 80-82°C.

Example 64

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine

A mixture of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 mol) of 1-(4-fluorophenyl)piperazine was melted at 60°C, and maintained at that temperature for one hour. The obtained melt was subjected to chromatography on a column filled with Kieselgel 60 using a mixture of 30 parts by volume of chloroform and 1 part by volume of ethanol as eluent. Fractions containing the product were evaporated, the last product was triturated with n-hexane, filtered, and dried under reduced pressure.

Thus, 3.72 g (93 %) of the title compound were obtained. T.p.: 80-82°C.

Example 65

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine

A mixture of 2.20 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 mol) of 1-(4-fluorophenyl)piperazine was melted at 70°C and maintained at that temperature for 1 hour. 60 ml of n-hexane was added to the resulting melt, the mixture was cooled, the settled crystals were filtered, and dried under reduced pressure.

Thus, 3.26 g (81 %) of the title compound were obtained. T.p.: 80-82°C.

Example 66

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-fluorophenyl)piperazine

A solution of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 mol) of 1-(3-trifluoromethylphenyl)piperazine in 20 ml of isopropanol was boiled is during 4 hours. The solution was evaporated to dryness under reduced pressure, the final product was subjected to chromatography on a column packed with Kieselgel 60 using a mixture of 30 parts by volume of chloroform and 1 part by volume of ethanol as eluent. Fractions containing the product were evaporated, the last product was triturated with n-hexane, filtered, and dried under reduced pressure.

Thus, 3.76 g (84 %) of the title compound were obtained. T.p.: 82-84°C.

Example 67

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-fluorophenyl)piperazine

A mixture of 2.20 g (0.01 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 mol) of 1-(3-trifluoromethylphenyl)piperazine was melted at 70° C, and maintained at that temperature for 1.5 hours. 60 ml of n-hexane was added to the obtained melt, the mixture was cooled, the settled crystals were filtered and dried under reduced pressure.

Thus, 3.77 g (84 %) of the title compound were obtained. T.p.: 82-84°C.

Example 68

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.88 g (0.015 mol) of 1-(4-methoxyphenyl)piperazine in 40 ml of methyl tert-butyl ether was boiled is 8 hours and then cooled to 0°C. The precipitated crystals were filtered and dried under reduced pressure.

Thus, 5.21 g (84 %) of the title compound were obtained. T.p.: 93-94°C.

Example 69

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine

A mixture of 1.10 g (0.005 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 0.96 g (0.005 mol) of 1-(4-methoxyphenyl)piperazine was melted at 80°C and maintained at that temperature for 1 hour. 10 ml of methyl tert-butyl ether was added to the obtained warm melt, the mixture was cooled, the settled crystals were filtered and dried under reduced pressure.

Thus, 1.88 g (91 %) of the title compound were obtained. T.p.: 93-94°C.

Example 70

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine dihydrochloride

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 mol) of 1-(benzo-1,3-dioxolan-5-yl)piperazine in 30 ml of ethanol was boiled for 10 hours. The solution was evaporated to dryness under reduced pressure, the residue (8.0 g) was dissolved in 30 ml of ethanol containing 4.0 g of hydrogen chloride. Crystals began to separate from the homogeneous solution. The suspension was diluted with 60 ml of methyl tert-butyl ether, filtered and the crystals were dried under reduced pressure.

Thus, 5.40 g (70 %) of the title compound were obtained. T.p.: 216-218°C.

Example 71

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine dihydrochloride

A solution of 3.80 g (0.017 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 mol) of 1-(benzo-1,3-dioxolan-5-yl)piperazine in 30 ml of isopropanol boiled for 6 hours. The solution was evaporated to dryness under reduced pressure, the residues were dissolved in 20 ml of ethanol containing 15% hydrogen chloride. Crystals began to separate from the homogeneous solution. The suspension was diluted with 60 ml of methyl tert-butyl ether, filtered and the crystals were dried under reduced pressure.

Thus, 5.43 g (71 %) of the title compound were obtained. T.p.: 216-218°C.

Example 72

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine dihydrochloride

A solution of 2.31 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.20 g (0.01 mol) of 1-(benzo-1,3-dioxolan-5-yl) piperazine in 30 ml of diisopropyl ether was boiled for 6 hours, and 7 ml of ethanol containing 20% hydrogen chloride was added. The settled crystals were cooled, filtered and dried under reduced pressure.

Thus, 4.41 g (86 %) of the title compound were obtained. T.p.: 216-218°C.

Example 73

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine

A mixture of 2.42 g (0.0115 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.70 g (0.01 mol) of 1-(4-chlorophenyl)piperazine dihydrochloride, 26 ml of ethanol, 3 ml of water and 0.9 g (0.0225 mol) of sodium hydroxide were boiled for 6 hours with stirring, and evaporated to dryness under reduced pressure. The residues were partitioned between 80 ml of dichloromethane and 50 ml of water, the organic phase was extracted twice, each time with 30 ml of water, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residues were recrystallized from 8 ml of methanol, the settled crystals were filtered and dried under reduced pressure.

Thus, 3.25 g (78%) of the title compound were obtained. T.p.: 96-98°C.

Example 74

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine

To a solution of 2.70 g (0.01 mol) of 1-(4-chlorophenyl)piperazine dihydrochloride in 26 ml of ethanol, 3 ml of water and 0.9 g (0.0225 mol) of sodium hydroxide were added, and the mixture was boiled for 10 minutes . Then, with stirring, 2.40 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran was added to the reaction mixture, and the reaction mixture was boiled for another 4 hours, and evaporated to dryness under reduced pressure . 50 ml of water was added to the residues, the water above the slowly hardening substance was decanted, and the residues were diluted with the next portion of water. The precipitated crystals were filtered, washed with water, recrystallized from methanol, filtered and dried under reduced pressure.

Thus, 3.17 g (80 %) of the title compound were obtained. T.p.: 96-98°C.

Example 75

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine dihydrochloride

Solutions of 0.40 g (0.001 mol) of 1-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine in 5 ml of ethanol, 1 ml of ethanol containing 20% hydrogen chloride was added, and the mixture was evaporated to dryness under reduced pressure. The residues were boiled with 5 ml of ethyl acetate for 5 minutes, then the hot suspension was filtered, and the crystals were dried under reduced pressure.

Thus, 0.43 g (91%) of the title compound was obtained. T.p.: 168-170°C.

Example 76

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-methoxyphenyl)piperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.46 g (0.0055 mol) of 1-(3-methoxyphenyl)piperazine dihydrochloride, 0.44 g ( 0.011 mol) of sodium hydroxide, 5 ml of ethanol, 3 ml of dimethylformamide and 10 ml of water was boiled for 3 hours. The reaction mixture was cooled to 20°C, the phases were separated, the lower (organic) phase was dissolved in 20 ml of ether, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residues were dissolved in 3 ml of 2-propanol, 3 ml of 2-propanol containing 16% hydrogen chloride was added to the resulting solution, and the reaction mixture was kept at 0°C for 5 days. The settled crystals were filtered, recrystallized from 2-propanol, filtered again, and dried under reduced pressure.

Thus, 1.48 g (60 %) of the title compound were obtained. T.p.: 168-170°C.

Example 77

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-benzylpiperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.97 g (0.0055 mol) of 1-benzylpiperazine and 8 ml of 2-propanol was boiled for 4 hours, then is cooled to 20°C. 20 ml of petroleum ether was added to the reaction mixture, the mixture was kept at 0°C for 5 days, and the resulting crystals were filtered and recrystallized from n-hexane. The settled crystals were dissolved in 15 ml of 2-propanol, and 1.5 ml of 2-propanol containing 16% hydrogen chloride was added to the obtained solution. After cooling, the settled crystalline salt was filtered and dried under reduced pressure.

Thus, 1.50 g (58 %) of the title compound were obtained. M.p.: 188-191°C.

Example 78

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)piperazine hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.15 g (0.005 mol) of 1-(2,4-dichlorophenyl)piperazine and 8 ml of 2-propanol was boiled is 5 hours, and is cooled to 20°C. 3.6 ml of 2-propanol and 2.4 ml of 2-propanol containing 16% hydrogen chloride were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 hours. The precipitated crystals were filtered, recrystallized from 2-propanol, filtered and dried under reduced pressure.

Thus, 1.19 g (45 %) of the title compound were obtained. M.p.: 169-171°C.

Example 79

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)piperazine hydrochloride

A mixture of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.012 mol) of 1-(3-chlorophenyl)piperazine and 16 ml of 2-propanol was boiled for 3 an hour. After cooling, 7 ml of 2-propanol containing 16% hydrogen chloride was added to the resulting solution at 20°C. The reaction mixture was kept at 0°C for 2 days, the settled crystals were filtered, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 2.88 g (53 %) of the title compound were obtained. T.p.: 187-190°C.

Example 80

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-pyridyl)piperazine trihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.78 g (0.0048 mol) of 1-(2-pyridyl)piperazine and 8 ml of petroleum ether was boiled for 6 hours. After cooling to 20°C, the resulting phases were separated, and 20 ml of 2-propanol and 4.5 ml of 2-propanol containing 16% hydrogen chloride were added to the lower phase, and the reaction mixture was kept at 0°C for 5 days. The separated crystals were filtered, recrystallized from 2-propanol, filtered and dried under reduced pressure.

Thus, 1.68 g (71 %) of the title compound were obtained. T.p.: 133-136°C.

Example 81

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperazine dihydrochloride

A mixture of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.011 mol) of 1-(2-methoxyphenyl)piperazine and 16 ml of 2-propanol was boiled for 5 ,5 hours. After cooling to 20°C, 10 ml of 2-propanol and 8 ml of 2-propanol containing 16% hydrogen chloride were added to the reaction mixture, and the reaction mixture was maintained at 0°C for 2 days. The precipitated crystals were filtered under reduced pressure, washed with 2-propanol, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 2.53 g (47 %) of the title compound were obtained. T.p.: 128-130°C.

Example 82

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3,4-dimethylphenyl)piperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.95 g (0.005 mol) of 1-(3,4-dimethylphenyl)piperazine and 8 ml of ethanol was boiled for 6 hours. After cooling to 20 °C, the reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. 5 ml of 2-propanol containing 16% hydrogen chloride was added to the residues, the reaction mixture was maintained at 0°C for 2 days, the settled crystals were filtered, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.50 g (62%) of the title compound was obtained. T.p.: 119-122°C.

Example 83

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-pyrimidyl)piperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.65 g (0.004 mol) of 2-pyrimidylpiperazine and 8 ml of tetrahydrofuran was boiled for 12 hours and cooled to 20 °C. 20 ml of ether and 1.5 ml of 2-propanol containing 30% hydrogen chloride were added to the resulting oil, the reaction mixture was kept at 0°C for 5 days, the settled crystals were filtered, dried under reduced pressure, and recrystallized from 2-propanol.

Thus, 1.50 g (82 %) of the title compound were obtained. T.p.: 128-130°C.

Example 84

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chloro-2-methylphenyl)piperazine hydrochloride

A mixture of 2.64 g (0.012 mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.27 g (0.008 mol) 1-(4-chloro-2-methylphenyl)piperazine hydrochloride, 0.64 g (0.016 mol) of sodium hydroxide and 16 ml of water was boiled for 3 hours and cooled to 20°C. The aqueous phase was decanted, 30 ml of ether was added to the organic phase, and it was stirred for one hour. The precipitated crystals were filtered, dried under reduced pressure, and recrystallized from acetonitrile.

Thus, 2.07 g (60%) of the title compound were obtained. T.p.: 68-70°C.

Example 85

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-methylpiperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.45 g (0.0045 mol) of 4-methylpiperazine and 8 ml of ethanol was boiled for 3 hours and cooled. at 20°C. 4 ml of 2-propanol containing 30% hydrogen chloride was added to the mixture, the reaction mixture was kept at -15°C for 2 days, the settled crystals were filtered, dried under reduced pressure, dissolved in hot 2-propanol, and precipitated from the solution using diethyl ether .

Thus, 1.15 g (65 %) of the title compound were obtained. T.p.: 119-122°C.

Example 86

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(trifluoromethylbenzyl)piperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.43 g (0.0045 mol) of 4-(3-trifluoromethyl)benzylpiperazine dihydrochloride, 0.36 g ( 0.009 mol) of sodium hydroxide and 8 ml of water was boiled for 2.5 hours, then it was cooled to 20°C, the aqueous phase was removed by decantation, 2 ml of 2-propanol containing 30% hydrogen chloride was added to the organic phase, the settled crystals were filtered, dried under reduced pressure, and recrystallized from 2-propanol.

Thus, 1.39 g (57 %) of the title compound were obtained. M.p.: 209-211°C.

Example 87

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3,4-dichlorophenyl)piperazine hydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.04 g (0.0045 mol) of 1-(3,4-dichlorophenyl)piperazine and 8 ml of 2- of propanol was boiled for 3 hours and cooled to 20°C. A mixture of 10 ml of 2-propanol and 2 ml of 2-propanol containing 30% hydrogen chloride was added to the reaction mixture, the reaction mixture was stirred for 5 hours, the settled crystals were filtered, dried under reduced pressure, and recrystallized from 2-propanol.

Thus, 1.63 g (62 %) of the title compound were obtained. T.p.: 180-182°C.

Example 88

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,6-dimethylphenyl)piperazine dihydrochloride

A mixture of 1.32 g (0.006 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.90 g (0.004 mol) of 1-(2,6-dimethylphenyl)piperazine hydrochloride, 0.32 g ( 0.008 mol) of sodium hydroxide and 8 ml of water was boiled for 2 hours and then cooled to 20°C. The aqueous phase of the resulting mixture was removed by decantation, 2.5 ml of 2-propanol containing 30% hydrogen chloride was added to the organic phase, and the reaction mixture was kept at -15°C for 2 days, and then 10 ml of 2-propanol was added, settled the crystals were filtered, dried under reduced pressure, and recrystallized from 2-propanol.

Thus, 1.00 g (41%) of the title compound was obtained. T.p.: 115-117°C.

Example 89

1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-{4-chloro-2-methylphenyl)piperazine

A mixture of 0.5 g (0.0016 mol) 1-bromo-3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-propanol, 0.45 g (0.0016 mol) 4 -chloro-2-methylphenylpiperazine, 0.25 g (0.0063 mol) of sodium hydroxide and 6.5 ml of water was boiled for 3 hours and then cooled to 20°C. The aqueous phase was removed by decantation, the remaining oil was triturated with ether, the precipitated crystals were filtered off, dried under reduced pressure and recrystallized from acetonitrile.

Thus, 0.25 g (40%) of the title compound was obtained. T.p.: 68-70°C.

Claims (17)

1. A new benzofuran derivative, indicated by its formula [image] AND where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms as the following heteroatoms , A denotes a group of the formula CH, COH, C-CN, C-COOR3 or COR4, where R3 and R4 are as previously defined, B denotes a methylene group, or A gives, together with B, a group of the formula -C=C-, Ar denotes a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl-4 alkyl) group, a biphenyl group, a naphthyl group, where the last mentioned species can be arbitrarily substituted with a C1-4 alkoxy group or a C2-4 alkenyl group, partially saturated, a 5- or 6-membered heterocyclic group which is condensed with a phenyl group and contains one or more oxygen atoms, and said heterocyclic group is optionally substituted with one to three C1-4 alkyl groups; A 5- or 6-membered, saturated or unsaturated heterocyclic group contains a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group which is arbitrarily substituted with a C1-4 alkoxy group or a halogen atom; a C2-4 alkenyl group, a C2-4 alkenyloxy group, a C1-4 alkoxy group which is optionally substituted with a di(C1-4 alkyl)amino group or with a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom; wherein said heterocyclic group is optionally substituted with a C1-4 alkyl group, or A denotes a group of the formula N-(CH2)n-Ar', where Ar' denotes a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, where the last group is optionally substituted with a C1-4 alkoxy group or a C2-4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group which is fused with a phenyl group and contains one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C1-4 alkyl groups; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 are as previously defined, n has the value 0 or 1, or pharmaceutically acceptable acid addition salts thereof. 2. Benzofuran derivative according to claim 1, characterized in that in formula I R1 denotes a hydrogen atom or a Cl-4 alkyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom or a nitro group, A denotes a group of formula CH, COH or C-CN, B denotes a methylene group, or A forms with B a group of the formula -C=C-, Ar denotes a hydrogen atom, a benzyl group, a phenyl group substituted with the substituents R5, R6 and R7, a biphenyl group, a naphthyl group substituted with a C1-4 alkoxy group; or a thienyl group, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group, a C2-4 alkenyloxy group, a phenoxy group or a methylenedioxy group, and their pharmaceutically acceptable acid addition salts. 3. Benzofuran derivative according to claims 1 or 2, indicated by the fact that in formula I R1 denotes a methyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, A is a group of formula CH, COH or C-CN, B denotes a methylene group, or A forms with B a group of the formula -C=C-, Ar denotes a phenyl group which is optionally substituted with a halogen atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, and their pharmaceutically acceptable acid addition salts. 4. Derivative of piperazinylalkylbenzofuran, indicated by its formula [image] Ia where R1 denotes a C1-4 alkyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, Ar' denotes a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and which is condensed with a phenyl group, or a phenyl group which is substituted by R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group or a methylenedioxy group, n has the value 0 or 1, and their pharmaceutically acceptable acid addition salts. 5. Piperazinylalkylbenzofuran derivative according to claim 4, characterized in that in formula Ia R1 denotes a methyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, Ar' denotes a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group which is optionally substituted with one or two halogen atoms, one or two methyl groups, a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has the value 0 or 1, and their pharmaceutically acceptable acid addition salts. 6. The following compounds, indicated by their composition: 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-methoxyphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-phenylpiperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl-4-(diphenylmethyl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-benzylpiperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-pyridyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperazine or 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl)-4-(3-methoxyphenyl)piperazine. and their pharmaceutically acceptable acid addition salts. 7. Process for the preparation of benzofuran derivatives of formula I, where R1, R2, Z, X, Y, A, B and Ar are as defined in claim 1, or their pharmaceutically suitable acid addition salts, characterized in that a) halide of the following formula [image] II where R1, R2, X, Y and Z are as defined in relation to formula I, Hal denotes a halogen atom, reacts with a secondary amine of the following formula [image] IV where A, B and Ar are as defined in formula I; or b) for the preparation of benzofuran derivatives of formula I, where Y denotes a hydroxyl group, R1, R2, X, Z, A, B and Ar are defined in connection with formula I, an epoxide of the following formula [image] III wherein R 1 , R 2 , Z and X are as above, reacted with a secondary amine of formula IV, where A, B and Ar are as above; or c) a compound of the following formula [image] V wherein R 1 , X and Z are as defined in relation to formula I, reacts with a halogen compound of the following formula [image] XI wherein R 2 , Y, A, B and Ar are as defined in relation to formula I, Hal denotes a halogen atom; d) to prepare a benzofuran derivative of formula I, where R1, R2, X, Z, A, B and Ar are as defined in relation to formula I, a compound of formula V, where R1, X and Z are as mentioned above, is reacted with epoxy of the following formula [image] XII where R 2 , A, B and Ar are as previously stated; or e) for the preparation of benzofuran derivatives of formula I, where A gives with B a group of formula -C=C-, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, benzofuran of formula I, where A denotes a group of the formula COH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as previously stated, is dehydrated; or f) for the preparation of benzofuran derivatives of formula I, where A denotes a COH group, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in relation to formula I, however Ar is not a hydrogen atom, a ketone formulas [image] XV where R1, R2, X, Y and Z are as previously defined, reacts with an arylmagnesium halide of the formula Hal-Mg-Ar XVI where Ar is previously defined, Hal denotes a halogen atom, and the resulting adduct decomposes with water; or g) for the preparation of benzofuran derivatives of formula I, where A denotes a COH group, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in relation to formula I, however Ar is not a hydrogen atom, a ketone of formula XV, where R1, R2, X, Y and Z are as previously defined, reacts with an aryllithium compound of the following formula Li-Ar XVII where Ar is previously defined, and the resulting adduct decomposes with water; or h) for the preparation of a benzofuran derivative of formula I, where A denotes a group of formula CH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, a compound of formula I, where A gives with B a group of the formula -C=C-, R1, R2, X, Y, Z and Ar are as previously defined, is hydrogenated; or i) for the preparation of a benzofuran derivative of formula I, where A denotes a group of formula CH, B denotes a methylene group, R1, R2, X, Y, Z and Ar are as defined in connection with formula I, an epoxide of formula III, where R1, R2, Z and X as previously defined, react with a secondary amine of formula IV, where A denotes the CHOH group, B and Ar are as defined above, under dehydrating reaction conditions, and is a compound of formula I, where A gives with B group of the formula -C=C-, R1, R2, X, Y, Z and Ar are, as previously defined, hydrogenated in the reaction mixture in which it was prepared; and if desired, the resulting base of formula I is reacted with an inorganic or organic acid to give its pharmaceutically acceptable acid addition salt, or to be liberated from the acid addition salt by means of a base. 8. Pharmaceutical composite containing a benzofuran derivative, indicated by the following formula [image] AND where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms as the following heteroatoms , A denotes a group of formula CH, COH, C-CN, C-COOR3 or COR4, where R3 and R4 are as previously defined, B denotes a methylene group, or A gives, together with B, a group of the formula -C=C-, Ar denotes a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl-4 alkyl) group, a biphenyl group, a naphthyl group, where the last mentioned species can be arbitrarily substituted with a C1-4 alkoxy group or a C2-4 alkenyl group, partially saturated, a 5- or 6-membered heterocyclic group which is condensed with a phenyl group and contains one or more oxygen atoms, and said heterocyclic group is optionally substituted with one to three C1-4 alkyl groups; A 5- or 6-membered, saturated or unsaturated heterocyclic group contains a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group which is arbitrarily substituted with a C1-4 alkoxy group or a halogen atom; a C2-4 alkenyl group, a C2-4 alkenyloxy group, a C1-4 alkoxy group which is optionally substituted with a di(C1-4 alkyl)amino group or with a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom; wherein said heterocyclic group is optionally substituted with a C1-4 alkyl group, or A denotes a group of the formula N-(CH2)n-Ar', where Ar' denotes a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, where the last group is optionally substituted with a C1-4 alkoxy group or a C2-4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group which is fused with a phenyl group and contains one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C1-4 alkyl groups; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 are as previously defined, n has the value 0 or 1, or its pharmaceutically acceptable acid addition salt as an active ingredient and one or more carriers. 9. Pharmaceutical composite according to claim 8, characterized in that it contains a benzofuran derivative of formula I, where R1 denotes a hydrogen atom or a Cl-4 alkyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom or a nitro group, A denotes a group of formula CH, COH or C-CN, B denotes a methylene group, or A forms with B a group of the formula -C=C-, Ar denotes a hydrogen atom, a benzyl group, a phenyl group substituted with the substituents R5, R6 and R7, a biphenyl group, a naphthyl group substituted with a C1-4 alkoxy group; or a thienyl group, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group, a C2-4 alkenyloxy group, a phenoxy group or a methylenedioxy group, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. 10. Pharmaceutical composite according to claims 8 or 9, characterized in that it contains a benzofuran derivative of formula I, where R1 denotes a methyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, A is a group of formula CH, COH or C-CN, B denotes a methylene group, or A forms with B a group of the formula -C=C-, Ar denotes a phenyl group which is optionally substituted with a halogen atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. 11. Pharmaceutical composite according to claim 8, characterized in that it contains a piperazinyl-alkylbenzofuran derivative of the following formula: [image] Ia where R1 denotes a C1-4 alkyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, Ar' denotes a diphenylmethyl group, a pyridyl group, a partially saturated 5-membered heterocyclic group containing two oxygen atoms and which is condensed with a phenyl group, or a phenyl group which is substituted by R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a C1-4 alkoxy group or a methylenedioxy group, n has the value 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. 12. Pharmaceutical composite according to claim 11, characterized in that it contains a piperazinyl-alkylbenzofuran derivative of formula Ia, where R1 denotes a methyl group, R2 denotes a hydrogen atom, X denotes an oxygen atom, Y is a hydroxyl group, Z denotes a hydrogen atom, Ar' denotes a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group which is optionally substituted with one or two halogen atoms, one or two methyl groups, a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has the value 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. 13. Pharmaceutical composite according to claim 8, characterized in that it contains one of the following compounds: 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-methoxyphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-cyano-4-phenylpiperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chlorophenyl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(6-methoxynaphth-2-yl)piperidine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl-4-(diphenylmethyl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(benzo-1,3-dioxolan-5-yl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-benzylpiperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)piperazine, 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-pyridyl)piperazine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperazine or 1-(3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl)-4-(3-methoxyphenyl)piperazine. and their pharmaceutically acceptable acid addition salts as the active ingredient. 14. Method for treatment, indicated by this, in which a patient suffering, in particular, from a disease of the central nervous system, is treated with a non-toxic dose of a benzofuran derivative of the following formula: [image] AND where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms as the following heteroatoms , A denotes a group of formula CH, COH, C-CN, C-COOR3 or COR4, where R3 and R4 are as previously defined, B denotes a methylene group, or A gives, together with B, a group of the formula -C=C-, Ar denotes a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl-4 alkyl) group, a biphenyl group, a naphthyl group, where the last mentioned species can be arbitrarily substituted with a C1-4 alkoxy group or a C2-4 alkenyl group, partially saturated, a 5- or 6-membered heterocyclic group which is condensed with a phenyl group and contains one or more oxygen atoms, and said heterocyclic group is optionally substituted with one to three C1-4 alkyl groups; A 5- or 6-membered, saturated or unsaturated heterocyclic group contains a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group which is arbitrarily substituted with a C1-4 alkoxy group or a halogen atom; a C2-4 alkenyl group, a C2-4 alkenyloxy group, a C1-4 alkoxy group which is optionally substituted with a di(C1-4 alkyl)amino group or with a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom; wherein said heterocyclic group is optionally substituted with a C1-4 alkyl group, or A denotes a group of the formula N-(CH2)n-Ar', where Ar' denotes a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, where the last group is optionally substituted with a C1-4 alkoxy group or a C2-4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group which is fused with a phenyl group and contains one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C1-4 alkyl groups; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 are as previously defined, n has the value 0 or 1, or a pharmaceutically acceptable acid addition salt thereof. 15. Process for the preparation of a pharmaceutical composite that has a particularly protective effect on the heart or that is suitable for treating diseases of the central nervous system, indicated by the fact that it is a benzofuran derivative of the following formula [image] AND where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, amino group, nitro group, cyano group, trifluoromethyl group, group of formula -COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms as the following heteroatoms , A denotes a group of formula CH, COH, C-CN, C-COOR3 or COR4, where R3 and R4 are as previously defined, B denotes a methylene group, or A gives, together with B, a group of the formula -C=C-, Ar denotes a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl-4 alkyl) group, a biphenyl group, a naphthyl group, where the last mentioned species can be arbitrarily substituted with a C1-4 alkoxy group or a C2-4 alkenyl group, partially saturated, A 5- or 6-membered heterocyclic group that is fused with a phenyl group and contains one or more oxygen atoms, and said heterocyclic group is optionally substituted with one to three C1-4 alkyl groups; A 5- or 6-membered, saturated or unsaturated heterocyclic group contains a nitrogen atom and/or an oxygen atom and/or a sulfur atom as a heteroatom; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 denote, independently, a hydrogen atom, a halogen atom, a trifluoromethyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group which is arbitrarily substituted with a C1-4 alkoxy group or a halogen atom; a C2-4 alkenyl group, a C2-4 alkenyloxy group, a C1-4 alkoxy group which is optionally substituted with a di(C1-4 alkyl)amino group or with a 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom; wherein said heterocyclic group is optionally substituted with a C1-4 alkyl group, or A denotes a group of the formula N-(CH2)n-Ar', where Ar' denotes a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, where the last group is optionally substituted with a C1-4 alkoxy group or a C2-4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group which is fused with a phenyl group and contains one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C1-4 alkyl groups; or a phenyl group which is substituted by the substituents R5, R6 and R7, where R5, R6 and R7 are as previously defined, n has the value 0 or 1, or a pharmaceutically acceptable acid addition salt thereof translated into a pharmaceutical composite using one or more carriers that are standardly used in the manufacture of drugs. 16. Halide of the following formula, indicated by [image] II where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms, Hal denotes a halogen atom. 17. Ketone of the following formula, indicated by [image] XV where R1 and R2 denote, independently, a hydrogen atom or a C1-4 group, X denotes an oxygen atom or a sulfur atom, Z denotes a hydrogen atom or a hydroxyl group, Z denotes a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula –COOR3, -NHCOR3 or SO2NR3R4, where R3 denotes hydrogen or a C1-4 alkyl group, R4 is a C1-4 alkyl group, or R3 and R4 give, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally containing one or more nitrogen atoms and/or one or more oxygen atoms and/or one or more sulfur atoms.