CZ20004218A3 - Benzofuran compounds, pharmaceutical compositions in which they are comprised and process for preparing active component therefor - Google Patents

Abstract

The present invention relates to benzofuran derivatives of formula I, a process for preparing such compounds, pharmaceutical compositions containing said active ingredients, intermediates thereof preparing and treating a patient suffering from heart disease or central nervous system disease.

Description

Technical field

The present invention relates to novel benzofuran derivatives, to pharmaceutical compositions containing them, and to a process for preparing the active ingredient. Said novel compounds affect the circulatory system and heart activity, and further affect the central nervous system.

SUMMARY OF THE INVENTION

More particularly, the invention relates to a novel benzofuran derivative of the formula (I)

R ¹ and R ² independently represent a hydrogen atom or a C 1-4 alkyl group,

X represents an oxygen atom or a sulfur atom,

Y represents a hydrogen atom or a hydroxy group,

Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein:

R ³ represents a hydrogen atom or a C ₄ alkyl group, • · · · · · · · · ·· ······ • • · · · · · ·

R ⁴ represents a C _1-4 alkyl group, or

R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more sulfur atoms.

A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above,

B represents a methylene group, or

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

Ar is hydrogen, C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, the latter being optionally substituted with C _1-4 alkoxy or C _1-4 alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; 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; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein

R ⁵ and R ⁶ are independently selected from the group consisting ATCM hydrogen, halogen, trifluoromethyl, C ₄ alkyl, methylenedioxy, phenoxy optionally substituted by • · ·· ·· ····

J ········ ············

C _1-4 alkoxy or halogen; C ₂ -4alkenyl,

-4alkenyloxy C _2, C ₄ alkoxy optionally substituted by di (Ci_4alkyl) amino or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted by C ₄ alkyl, or

A represents a group of formula N (CH _{2) n} ^- Ar 'wherein

Ar 'is selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, wherein said last group is optionally substituted by C ₁ _ ₄ alkoxy or C _2-4 alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, and pharmaceutically acceptable acid addition salts thereof.

BACKGROUND OF THE INVENTION

Literature data suggest that certain furancarboxamides have antidepressant effects (Yakugaku Zasshi, 97 (5), 540 (1977); CA, 8, 7, 152125d (1997)), while benzofuran derivatives containing furan ring substituents from the group consisting of amino, amidino, thiocarboxamidino or dialkylaminoalkyl are H ₂ receptor antagonists and thereby have anti-ulcer effects (PCT Publication No. WO 86 02550; CA, 105, 226586u (1986)).

DE-OS No. 22 35 597 discloses tetrahydronaptoxy derivatives having hypotensive effects. The chemical structure of these known compounds is similar to that of the piperazinylalkylbenzofuran derivatives of formula Ia.

1-Phenoxyalkylpiperidine derivatives useful for the treatment of cerebrovascular diseases are described in FR-A-2681319.

4-substituted piperidine derivatives are known from WO-A9723216. Known compounds are NMDA receptor subtype antagonists and may also be useful as neuroprotective agents in a variety of cardivascular and CNS diseases.

It is an object of the present invention to provide novel benzofuran derivatives, some of which affect the circulatory system, while others have central nervous system effects.

It has been found that the novel benzofuran derivatives of formula (I) are able to achieve the above objective.

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

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

C _2-4 alkenyl group is preferably a group consisting of vinyl, allyl, methallyl or crotyl, preferably an allyl or methallyl group.

C _1-4 alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy or butoxy, preferably methoxy or isopropoxy.

• ·

C _2-4 alkenyloxy group is suitably an allyloxy or methallyloxy.

The C _1-4 alkoxy substituted with di (C _1-4 alkyl) amino is primarily a group selected from the group consisting of

2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylamincethoxy, 3-diethylaminopropoxy or

4-dimethylamino or butoxy, preferably represents 2-dimethylamino.

AND

A partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms means 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, preferably means a heterocyclic group containing a nitrogen atom, or an oxygen atom, or a sulfur atom, or a nitrogen atom and atom and wherein the heterocyclic group contains no double bond or contains one or more double bonds. The heterocyclic group is, for example, pyrrolyl, pyrrolidinyl, piperidinyl, pyridyl, morpholinyl, furyl or thienyl. It 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 preferably represents a group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl or morpholino, the nitrogen atom being linked by a C _1-4 alkoxy carbon atom.

• ·

A 5-10 membered saturated or unsaturated heterocyclic group is, for example, pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl, piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolinyl, pyrazolidinyl, thienyl, hexamethyleniminimin-1-yl, heptamethyl -l-yl etc.

A pharmaceutically acceptable acid addition salt means, for example, 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, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, etc.

The invention includes all isomers of the compounds of formula I that are possible and mixtures thereof.

A preferred subgroup of benzofuran derivatives of the invention includes compounds of formula I wherein:

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

R ² is hydrogen,

X is an oxygen atom,

Y represents a hydrogen atom or a hydroxy group,

Z is hydrogen, halogen or nitro,

A is CH, COH or C-CN,

B represents a methylene group, or

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

Ar is hydrogen, benzyl, phenyl substituted with R, R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C _1-4 alkoxy; or thienyl, wherein R ⁵ , R 0 and R ⁷ , independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyloxy, phenoxy, and methylenedioxy, and pharmaceutically acceptable addition salts thereof salts with an acid.

Within the above subgroup, preferred benzofuran derivatives of the invention include those compounds of formula I wherein:

R ¹ represents a methyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

A is CH, COH or C-CN,

B represents a methylene group, or

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

Ar is phenyl optionally substituted with halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, and pharmaceutically acceptable acid addition salts thereof.

Particularly preferred benzofuran derivatives of formula I are the following:

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4-phenyl-piperidine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-chloro-phenyl) -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-yl-oxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine, 1- [3- (2,2 -dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2,2-dimethyl-2) 3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine, - [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) - oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine, or - [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2- hydroxypropyl] -4-hydroxy-4- (6-methoxy-1-naphth-2-yl) piperidine and pharmaceutically acceptable acid addition salts thereof.

Another preferred subgroup of benzofuran derivatives of the invention includes piperazinylalkylbenzofuran derivatives of formula (Ia)

where

R ¹ represents a C _1-4 alkyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms, which is condensed with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁵ , R ⁷ , wherein

R ⁵ , R 0, R ^{7 are} independently hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C 1-4 alkoxy, or methylenedioxy; n is 0 or 1; and pharmaceutically acceptable acid addition salts thereof.

Within the subgroup of compounds of formula (Ia), suitable piperazinylalkylbenzofuran derivatives of the invention include compounds of formula Ia wherein:

R ¹ represents a methyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 'is diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted with one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and pharmaceutically acceptable salts thereof acceptable acid addition salts.

Particularly preferred benzofuran derivatives of formula Ia include the following compounds:

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (diphenylmethyl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (4-fluoro-phenyl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine, 1- [3- (2,2-dimethyl-2, 2-hydroxypropyl) piperazine]; 3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (benzo-1,3-dioxolan-5-yl) piperazine, 1- [3- (2,2-dimethyl-2,3) -dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-benzyl-piperazine,

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2 2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (2-pyridyl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (2-methoxy-phenyl) -piperazine, or

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine, and pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention are:

a) a halide of the formula

where R ¹ , R, X, Y and Z have Hal is a halogen atom, with an amine of formula (IV) as defined for formula (I), reacted with a secondary

wherein A, B and Ar are as defined for formula (I); or

b) in the preparation of a benzofuran derivative of the general formula (I) wherein Y represents a hydroxy group, R ¹ , R ² , X, Z, A, B and Ar are as defined for the formula (I), the epoxide is reacted

III

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

c) a compound of formula (V)

wherein R ¹ , X and Z are as defined for formula (I), are reacted with a halogen compound of formula (XI),

wherein R ² , Y, A, B and Ar are as defined for formula (I) and Hal is a halogen atom;

d) in the preparation of a benzofuran derivative of formula (I) wherein R ¹ , R 2, X, Z, A, B and Ar are as defined for formula (I), a compound of formula (V) wherein R ¹ , X and Z are as defined above, to react with an epoxide of formula (XII)

wherein R ^2, A, B and Ar are as defined above; or

e) a benzofuran derivative of the formula (I) wherein A forms a group B = -C = C- with B and R ¹ , R ² , X, Y, Z and Ar are as defined for formula (I) are prepared by dehydrating the benzofuran derivative (I) wherein a represents COH, B represents a methylene group and R ^1, R ^2, X, Y, Z and Ar are as defined above; or

f) the preparation of a benzofuran derivative of the formula (I) wherein A represents COH, B represents a methylene group, R ^1, R ^2, X, Y, Z and Ar are as defined for formula (I), provided that Ar is other than hydrogen, the ketone of formula (XV)

wherein R ¹ , R ', X, Y and Z are as defined above, reacted with an aryl magnesium halide of formula (XVI)

Hal-Mg-Ar XVI wherein Ar is as defined above, Hal represents a halogen atom and wherein the formed adduct is decomposed with water; or

g) a benzofuran derivative of the general formula (I) in which A represents a COH group, B represents a methylene group, R @ ¹ , R @ ² , X @ 1. 9 9 9 9 9 9 10 11 12 13 14

Y, Z and Ar are as defined for formula (I), provided that Ar is other than hydrogen, is prepared by reacting a ketone of formula (XV) wherein R ¹ , R ² , X, Y and Z are as defined above , with an aryllithium compound of formula ((XVII),

Li-Ar XVII wherein Ar is as defined above and wherein the resulting adduct is decomposed with water; or

h) a benzofuran derivative of formula (I) wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for formula (I), is prepared by hydrogenating a compound of formula (I) ), wherein a forms with B a group of the formula -C = C-, R ^1, R ^2, X, Y, Z and Ar are as defined above; or

(i) a benzofuran derivative of the formula (I) wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, and Ar are as defined for formula (I) are prepared by reacting an epoxide of formula (III) R ¹ , R ² , Z and X are as defined above, with a secondary amine of formula (IV) wherein A is CHOH, B and Ar are as defined above, under dehydration conditions and formation of a compound of formula (I), which A forms with B a group of the formula -C = C-, and R ¹ , R ² , X, Y,

Z and Ar are as defined above, and the compound thus prepared is hydrogenated in the reaction mixture in which it was prepared; and, if desired, the base of formula (I) obtained is reacted with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt of the compound or may be released from the acid addition salt of the compound with a base.

• · ·· •

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

As the solvent in this reaction, for example, alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, halogenated solvents, preferably dichloromethane, 1,2-dichloroethane or chlorobenzene can be used.

The base used in this reaction may be an inorganic base such as an alkali metal hydroxide or an alkaline earth metal hydroxide, preferably sodium hydroxide or potassium hydroxide, or an organic base, preferably a trialkylamine or tetraalkylammonium hydroxide. A particularly preferred base is triethylamine. The base is used in an amount of 0.8-1.1 molar equivalents, preferably in an amount of 0.9-1.0 molar equivalents, calculated per compound of formula (II).

The resulting product of formula (I) is separated from the reaction mixture by any method known in the art. When the product crystallizes from the solvent used for the reaction mixture or can be precipitated with another solvent miscible with the solvent initially used, the product can then be filtered off and purified by recrystallization or chromatography.

If the product does not crystallize from the reaction mixture, the solution can be evaporated and the residue recrystallized from a suitable solvent.

· *

In some cases, it is convenient to treat the evaporation residue by partitioning it between water and a water-immiscible organic solvent, then basifying the mixture, separating the phases, evaporating the organic phase and purifying the base as a residue by recrystallization.

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

As solvent for said reaction, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, water or mixtures with water, preferably ethanol, isopropanol or 5-20% (w / w) thereof, preferably 10% (w / w) solutions in water.

One mole of epoxide of formula (III) is reacted with 0.82.0, preferably 0.85-1.2 moles of secondary amine of formula (IV). When used in base form, the secondary amine of formula IV is added directly to the reaction mixture. When a secondary amine salt of formula IV is used, the base can be liberated in situ in the reaction mixture by adding an equivalent molar amount of an inorganic or organic base based on the amount of the secondary amine salt.

The inorganic base is generally a 5-40% (w / w), preferably a 10-25% (w / w) alkali metal or alkaline earth metal hydroxide solution, preferably sodium hydroxide or potassium hydroxide in water.

The organic base used is preferably trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine.

• · · · · · · · · · · · · · · · ·

Usually 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 above for process (a).

In process (c) of the invention, the reaction of a compound of formula (V) with a halo compound of formula (XI) is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.

The inorganic base is generally an alkali metal or alkaline earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. The organic base used is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is used in an amount of 1-2 moles, preferably in an amount of 1.2 moles, based on the compound of formula (V).

The halo compound of formula (XI) is used in an amount of 1-3, preferably in an amount of 1.8-2 moles relative to the compound of formula (V).

As the solvent for the above reaction, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methyl ethyl ketone can be used.

As the phase transfer catalyst, tetraalkylammonium hydroxide or a halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylamoulum hydrogen sulphate can be used.

• ·

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

The separation of the product is carried out in a manner known per se. After completion of the reaction, for example, the reaction mixture is evaporated under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated and dried, evaporated to dryness and the residue purified by recrystallization from a suitable solvent or vacuum distillation.

Using method (d) of the invention, the compound of formula (V) is reacted with an epoxide of formula XII in an indifferent solvent.

As solvent, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, water or a mixture of water, preferably ethanol, isopropanol or a mixture thereof at a concentration of 5-20% (w / w), preferably 10% ( %) in water.

The compound of formula (V) is used in this reaction in an amount of 0.8-2.0 preferably in an amount of 0.85-1.2 moles relative to the epoxide of formula (XII).

Usually, the reaction is carried out at or below the boiling point of the solvent used.

The product can be isolated from the reaction mixture as described above for method (c).

In process (e) according to the invention, the compound of formula (I) in which A represents a group of formula COH, B represents a methylene group is dehydrated by means of a strong mineral acid, preferably hydrochloric acid, in an indifferent solvent, preferably alcohol, especially preferably in ethanol, with heating, preferably at boiling point. The starting compound is suitably used in the form of a solution having a concentration of 5-40%, preferably 15-25%. If, after cooling, the product falls out of solution, it is filtered off; otherwise, a solution is used in which the product does not dissolve but is miscible with the solvent used in the reaction, preferably ether is added to the reaction mixture, and the precipitated crystalline product is filtered off.

Using methods (f) and (g) of the invention, a ketone of formula (XV) is reacted with an arylmagnesium halide of formula (XVI) or an arylllithium compound of formula (XVII) in an indifferent aprotic organic solvent, preferably ether, tetrahydrofuran or dioxane, at in the range of -10 ° C to the boiling point of the solvent, preferably at 10 to 30 ° C. The product is then obtained after decomposition of the acid reaction complex and evaporation of the solvent by simple crystallization or salt formation. If the product or salt does not crystallize, the acid-quenched reaction mixture is rendered alkaline, the product is dissolved in a water-immiscible organic solvent, the organic phase is dried and the base obtained is purified by crystallization or chromatography.

In methods (h) and (i) of the invention, a compound of formula (I) wherein A forms a group of formula -C = C- with B is suitably reduced by catalytic hydrogenation using a noble metal catalyst on a carbon support, preferably palladium on carbon , in particular a catalyst in the form of 10% palladium on carbon, in an alcohol, preferably methanol. The catalyst is then removed by filtration and the product isolated by evaporation of the solvent and crystallization of the residue. Alternatively, the evaporation residue can be converted to a salt.

If the product or salt does not crystallize, the reaction mixture is partitioned between water and a water-immiscible organic solvent, the organic phase is dried, evaporated, the base-containing residue is purified by crystallization or chromatography.

Said reduction can also be carried out in the reaction mixture in which the starting component has been prepared.

Halides of formula (II) are novel compounds and are also encompassed by the invention.

Halides of formula (II) may be prepared by reacting a compound of formula (V) with a dihaloalkane of formula (VI)

wherein Y, R ² and Hal are as defined above.

Alternatively, a halide of formula (II) is prepared by reacting a compound of formula (V) with a haloalkanol derivative of formula (VII)

Y

R ³

VII wherein Y, R‘ and Hal are as defined above, wherein the hydroxy group of the resulting hydroxyalkyl derivative of formula (VIII)

R '

Y • k- ° ^H

R ³

0 '

VIII

Where R ¹ , R ² , X, Y and Z are as defined above, is converted to an atom halogen.

The reaction of a compound of formula (V) with a dihaloalkane of formula (VI) is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.

The inorganic base used is, in particular, an alkali metal or alkaline earth metal hydroxide or a carbonate, preferably sodium hydroxide or potassium hydroxide. The organic base used is trialkylamine or tetraalkylammonium hydroxide, preferably triethylamine. The base is used in an amount of 1 to 1.5 moles relative to the compound of formula (V).

The allogene alkane of formula (VI) is used in an amount of 1-3, preferably in an amount of 1.8-2 moles, relative to the compound of formula (V).

The solvent used in the reaction may be, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, preferably ethanol, acetone or methyl ethyl ketone.

The phase transfer catalyst in the reaction may be tetraalkylammonium hydroxide or a halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrogen chloride.

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

Low: 14 ° C.

• ·

The product is isolated from the mixture by any of the known methods. For example, after completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residue purified by recrystallization from a suitable solvent or vacuum distillation.

The reaction of a compound of formula (V) with a haloalkanol derivative of formula (VII) is carried out in an analogous manner to that described for the reaction of a compound of formula (V) with a dihaloalkane of formula VI.

The prepared hydroxyalkyl derivatives of formula (VIII) are converted to the desired halides of formula (II) by halogenating agents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus tribromide, phosphorus iodide, phosphorus tribromide, preferably thionyl chloride.

The halogenating agent is used in an excess of 1-4 moles, preferably 1.2-2.2 moles per mole of the starting hydroxyalkyl derivative of formula VIII.

The reaction is carried out in an indifferent solvent, preferably in halogenated alkanes, in particular chloroform, dichloromethane or 1,2-dichloroethane, or an excess of halogenating agent is used as solvent.

The product is isolated after evaporation of the solvent in the same manner as described for the reaction of a compound of formula V with a dihaloalkane of formula VI.

Some epoxides of formula (III) are described in the literature [Japanese patent application published under No. 6 0258-174-A;

C.A., 104, 207136k (1986)]. They are prepared from compounds of formula

In reaction with epichlorohydrin in alkaline medium.

Alternatively, they can be prepared by reacting a compound of formula (V) with a halide of formula (IX)

R

IX wherein R ² and Hal are as defined above, and by oxidizing the prepared allyl derivative of formula (X)

wherein R ¹ , R ² , X and Z are as defined above.

In said reaction, the compound of formula (V) is reacted with 1-3 molar equivalents of epichlorohydrin in the presence of an alkali metal or alkaline earth metal hydroxide, preferably sodium hydroxide or potassium hydroxide used in 1-3 molar equivalent amounts.

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

The epoxide of formula (III) formed in said reaction may be separated by any of the methods known in the art. After completion of the reaction, for example, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated, dried and evaporated under reduced pressure. Usually the residue is of sufficient purity for use in further reactions. If necessary, the product can be purified by chromatography or crystallization.

One of allyl derivatives of formula (X) wherein X is oxygen, R ¹ is methyl, R ² is hydrogen and Z is hydrogen is described in the literature [Aust.J.Chem., 36 (6), 1263 ( 1983)]. It is prepared from a compound of formula V, which is reacted with a halide of formula IX in an alkaline medium in the presence of a phase transfer catalyst.

In said reaction, the alkaline medium is achieved with an alkali metal or alkaline earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. The bases are used in an amount of 12 molar equivalents.

The solvent used in the reaction is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethylformamide, water or mixtures with water, preferably ethanol, acetone or methyl ethyl ketone.

The phase transfer catalyst in said reaction may be tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrogen sulphate.

• * «· ·

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

The product is isolated from the mixture by any of the known methods. For example, after completion of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is partitioned between water and a water-immiscible organic solvent, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and purified by recrystallization from a suitable solvent or vacuum distillation.

The allyl derivative of formula (X) is oxidized to the corresponding epoxide of formula (III) by 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 is used at a temperature of 0 to 40 ° C, preferably at 20 to 30 ° C.

Dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2-trichlorethylene, chlorobenzene, preferably dichloromethane or 1,2-dichloroethane are used as solvent in the reaction.

The separation of the product is carried out by one of the known methods. For example, after completion of the reaction, water is added to the reaction mixture, the solution is made alkaline by addition of sodium carbonate, the phases are separated, the organic phase is dried and then evaporated under reduced pressure. The residue is purified by recrystallization from a suitable solvent or by chromatography.

Some halogen compounds of formula (XI) are known [Peltz

K., Protiva M., Coil.Czech.Chem.Commun. 32 (8), 2840 (1967).

US-P No. 4,110,536; Chem.Abstr., 90, P121596r)]. They are prepared by reacting an appropriate secondary amine of formula (IV) with an appropriate dihaloalkane of formula (VI). Other halogen compounds of formula (XI) may also be readily prepared by the above methods.

Also, some epoxides of formula (XII) are known.

They are prepared by reacting the corresponding compound of formula (IV) with epichlorohydrin in an alkaline medium [CH-P No. 474,511; Chem. Astr., 72, 55506m (1970)]. Certain compounds of formula (XII) may also be prepared by reacting the corresponding secondary amine of formula (IV) with the corresponding halide of formula (IX), and converting the double bond of the resulting compound of formula (XIV)

wherein R ² , A, B and Ar are as defined above, to an epoxy group under the conditions described above for the oxidation of compounds of formula (X). Other epoxides of formula (XII) may also be readily prepared by the above methods.

The ketones of formula (XV) are novel compounds and are also included in the present invention. They are prepared by reacting a halide of formula (II) or an epoxide of formula (III) with a piperidone of formula (XIII)

XIII

HN J

The reaction conditions are identical to those described for processes (a) and (b) of the invention.

The reaction of the ketone of formula (XV) with the arylmagnesium halide of formula (XVI) is carried out as described in the literature [J-P].

No. 14,632 ('67); Chem. Astr., 68, 114618s (1968)].

The reaction of aryllithium derivatives of formula (XVII) with a ketone of formula (XV) can also be carried out by methods known in the literature [Elpern B., Wetteran W., Carabates Ph., Grunbach L.,

J. Am. Chem., 8, 4916 (1958)].

Said arylmagnesium halides of formula (XVI) and arylllithium derivatives of formula (XVII) are commercially available.

Secondary amines of formula (IV) are usually commercially available or can be readily prepared by known methods.

The biological assets of the compounds of the invention were evaluated by the following tests.

1. Determination of cardioprotective effect on ischemized rat heart (according to Langendorff)

Cardioprotective compounds protect the myocardium from damage caused by ischemia or reperfusion. Among the multiple methods used to determine cardioprotective effect, the most well-known and frequently used assays are isolated perfused heart tests subjected to general ischemia [Longman S.D. and Hamilton T.C., Medicinal Research Reviews, 12). During general ischemia, myocardial contraction is probably due to an increase in myocardial calcium concentration. The time from onset of general ischemia to contraction (i.e., time to contraction = TTC) is increased by the administration of various cardioprotective compounds, and

thus, the efficacy of test compounds can be evaluated by determining TTC.

Male Sprague-Dawley rats weighing 300-350 g are injected ip with 2500 IU (0.5 ml) heparin, and after 10 minutes the animals are anesthetized with sodium pentobarbital [sodium 5-ethyl-5- (1-methylbutyl) -2] 4.6 (1H, 3H, 5H) -pyrimidinium trione] at an ip dose of 60 mg / kg. Then the heart is quickly removed and the aorta attaches to the cannula associated with the Langendorff device. The heart is perfused at constant pressure (8000 Pa) with modified carbogenized KrebsHenseleite solution. The composition of this solution is as follows (in mM): NaCl 118, KCl 4.7, MgSO ₄ 1.6, CaCl ₂ 2.5, NaHCO ₃ 24.88, KH 2 PO 4 1.18, EDTA 0.5, glucose 11. Partial the CO ₂ pressure and the pH of the solution are maintained in the physiological range (pCO ₂ 4000-4650 Pa, pH = 7.3-7.45).

A hole is cut into the left atrial wall and a plastic balloon filled with water connected to a metal cannula is inserted into the left ventricle. The internal diastolic pressure in the left ventricle is adjusted to 666-1333 Pa during equilibration by varying the volume of fluid in the balloon, but then this amount does not change.

After 20 minutes equilibrium of the alignment perfused hearts of the control group 10 minutes with vehicle (0.04% DMSO) and the test group with the test compound at a concentration of 10 ^-6 M or 10 ^-5 M. Evaluation of activity of test compound is terminated when the end of the 10 minute interval, the left ventricular systolic pressure decreases by more than 20% compared to the pre-perfusion control value.

Total ischemia is initiated by complete interruption of perfusate flow and carbogenisation for 25 minutes. The TTC is measured from the onset of ischemia to myocardial contraction, i.e. a 666 Pa increase in left ventricular diastolic pressure in the left ventricle. .

Three concurrent determinations for each concentration were performed with the test compounds, and 3 additional concurrent determinations were performed on vehicle-treated hearts (0.04% dimethylsulfoxide) at the same time.

Mean TTCs are calculated and the effect of test compounds is expressed as a percentage change relative to the vehicle treated group. Compounds with prolonged TTC relative to the control group are cardioprotective. Lemacalim, i.e. (3S) -trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4- (2-oxo-1-pyrrolidinyl) -2H- 1-benzpyran-6-carbonitrile. The results are shown in Table I.

Table I

Prolongation effect on TTC determined on Langendorff-isolated rat heart

compound (example number) TTC change (%) 10 ' ⁵ ext 10 ^{- <ϊ} | ν | lemakalim 55 20 May 9 - 90 8 90 43 20 May 65 18 24 - 47 16 78 5 26 - 43 25 59 2

Table I (continued)

compound (example number) TTC change (%) io ⁵ m 10 '* m 41 53 32 63 111 -3 66 66 5 68 43 0 73 49 19 Dec 76 80 25

Several benzofuran derivatives tested showed a remarkably higher TTC prolongation at a concentration of 10 ^-6 than the reference compound lemakalim.

The compounds of the invention elicited significant prolongation of TTC on isolated perfused rat heart during ischemia.

This confirms their cardioprotective effect. The compound of Example 9 also remarkably outperforms the effect of lemacalin when assayed at a concentration of 10 ^-6 M. Thus, the cardioprotective effect of the compounds of the invention can be utilized in human therapy. The above cardioprotective effect increases the possibilities of preventing unwanted severe coronary arrhythmias, which often occur in ischemic heart disease, by prolonged administration of the active ingredients. In particular, in patients with unstable angina, said treatment appears appropriate because the disease is considered to be prior to myocardial infarction, and said treatment may reduce the rate of irreversible myocardial damage caused by a later myocardial infarction. Other compounds of the present invention may be used in cardioprotective therapy prior to:

surgery, for example in the case of temporarily blocked coronary circulation (in coronary balloon dilation) or in cardiac arrest during surgery. Cardioprotective treatment of the heart ready for transplantation can also achieve faster or more complete regulation of cardiac function. In this case, the compound of the invention is added to a nutritional solution for heart storage.

2. Determination of influence on serotonin neurotransmission

Determination of 5-HT _1A receptor binding

Determination of 5-HT _1A receptor binding by the method of Peroutka [Peroutka SJ, J. Neurochem., 47, 529 (1986)]. Binding assays were performed on membrane fragments prepared from rat frontal cortex using tritium-labeled 8-hydroxy-N, N-dipropyl-2-aminotetralin as a specific ligand.

Non-specific binding is determined in the presence of 10 μΜ 5-HT (5-hydroxytryptamine). The final volume for incubation is 250 microliters. The test samples were incubated at 25 ° C for 30 minutes. The reaction is terminated by the addition of 9 ml of an ice-cold solution of tris (hydroxymethyl) aminomethane hydrochloride, pH 7.7, followed by filtration under reduced pressure. Filtration is performed through Whatman GFIB glass fiber filter paper, which is pre-soaked 2-3 hours before use with a 0.05% polyethyleneimine solution. Radioactivity is measured by scintillation counting in a liquid scintillator.

The 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 reference compound.

Table II

Effect of compounds of the invention on the 5-HT _1A receptor

compound inhibition of receptor binding (example #) Ki in nmol / L 9 20 May 20 May 6 24 12 30 5 14 10 16 3 26 3 23 12 25 0.7 28 9 buspiron 19 Dec

The data in Table II shows that the compounds of the invention have significant affinity for serotonin 5-HT _1A receptors. Most of the compounds tested had better effects than buspirone used as reference compound.

Increased plus-maze test in rats

The test is performed in a modified manner according to Pelow et al. [J. Neurosci. Methods, 14, 149 (1985)]. The raised plus-maze consists of two open and two 40 cm wall-closed arms of the same size (50 x 15 cm) arranged in the shape of a cross. The arms of the same type are placed opposite each other. Thus, a central square area of 15 x 15 cm) is formed at the crossing of the four arms. The whole device is made of wood up to a height of 50 cm and • · · ·

is illuminated from above by dim light. Sprague-Dawley rats weighing 220-260 g were used alone.

minutes before the start of the test, rats are treated with test or reference compounds. The animals are then placed in the central area of the maze and evaluated within 5 minutes. The following 4 different parameters are determined:

- time spent in the open arms;

- time spent in closed shoulders;

- number of entrances to open arms;

- number of entrances to the closed arms;

A compound is considered to be effective if a significant increase is found compared to control animals (in%) either at the time spent in the open arms (s) or in the number of entries into the open arms. Minimum effective doses (MED) are determined for each compound based on the time spent in the open arms. The results are shown in Table III. Buspirone was used as reference compound.

Table III

compound MED (mg / kg) (example #) after. 16 1 23 3 24 3 25 0.3 buspiron 3

• · · · · · ·

It can be seen from Table III that the compound of Example 25 is one order of magnitude better than buspirone in the above-described anxiolytic effect test. It should be noted that buspirone shows intense binding to the 5-ΗΤχ _Α receptor and is widely used in clinical practice.

Based on the results obtained in studies related to the effect on serotoninone neurotransmission, the compounds of the invention can be used in the treatment of various diseases, particularly those of the central nervous system.

Many clinical and preclinical studies suggest that 5-HT _1A receptors are involved in various pathological processes. Buspirone, used in the studies of the compounds of the invention as a reference compound and acting through

5-HT _1A receptors, inhibits the aggressive behavior of rhesus monkeys [Tomkins EC, Clemento AJ, Taylor DP, Perlach J., Res.Commun.Physiol.Psychiat.Behav., 5, 337 (1980)] and has shown anxiolytic in clinical trials effect [Goldberg

H.L. and Finnerty R.J., Am.J.Psychiatry, 136, 1184 (1979)]. In evaluating the compounds of the invention, several compounds of the invention overcome the anxiolytic activity of buspirone.

5-HT _1A receptors are believed to have been implicated in the clinical manifestations of depression since animal testing has demonstrated the antidepressant potential of 5-ΗΤχ _Α ligands [Porsolt RD, Roux S., and Wettstein JG, Pharmacol. Res. 31, 169 (1995)]. Another therapeutic option for drugs acting at the 5-HT _1A receptor includes therapy for cognitive deficiency. Administration of 8-hydroxy-N, N-dipropyl-2-aminotetraline to rats improves their memory and learning ability. (Carli, M. and Samanin, R., Br. J. Pharmacol., 105, 720 (1992)). In addition to the clinical manifestations listed above, the compounds acting at the 5-HT _1A receptor can be used for various diseases associated with eating disorders.

This hypothesis is based on the finding that 8-hydroxy-N, N-dipropyl-2-aminotetraline acting on the 5-HT _1A receptor promotes food intake under certain conditions while reducing food intake under other conditions [Dourish CT, Hutson PH and Curzon G Psychopharmacology, 86: 197 (1985)]; [Dourish CT,

Hutson P.H and Curzon G., Brain Res.Bull., 15, 377 (1985)]. Thus, the compounds of the invention may be effective in several clinical manifestations associated with a central nervous system disease manifesting symptoms including anxiety, depression, cognitive deficiency or eating disorder.

The following test confirms the above hypothesis.

3. Determination of anxiolytic effect in Vogel conflict test

The anxiolytic effect was evaluated according to the method of Vogel et al. [Vogel, J.R., Beer, B., Clody, D.E., Psychopharmacologia (Berl.), 21, 1 (1971)]. Male Wistar rats weighing 180-200 g are left free of fluids for 48 hours prior to the experiment and 24 hours prior to the experiment. Compounds to be evaluated and their carriers alone are administered to the animals half an hour prior to evaluation. In the test chamber, the rats may be connected from a fluid delivery tube drawn into the chamber. After each 20 licking of the tube, the device emits an electrical shock pulse of 0.7 mA through the supply tube. During the test, which lasts 5 minutes, the number of electrical shocks received by the animals to be watered is registered. The effect of the test compounds is expressed by increasing the tolerated number of electric shocks in percent. The minimum effective dose (MED) is determined for each test compound.

• ·

Meprobamate (2-methyl-2-propyltrimethylenecarbamate) was used as a reference compound in the evaluation of the compounds of the invention, and the results are summarized in Table IV.

Table IV Anxiolytic effect

compound COPPER (example #) in mg / kg i.p. 68 20 May meprobamat 50

It is evident from Table IV that the benzofuran derivative evaluated overcomes the effect of meprobamate used in the Vogel conflict test as a comparative compound by a factor greater than 2.

A summary of the results of the above tests undoubtedly shows the beneficial effect of the compounds of the invention on the heart. At the same time, due to their mechanism of action, the compounds of the invention may be useful in the treatment of central nervous system disorders such as depression, anxiety, cerebral ischemia, schizophrenia, etc.

The novel benzofuran derivatives of the invention can be used as active ingredients in compositions for pharmaceutical preparations.

The pharmaceutical compositions of the invention comprise a therapeutically active amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, and one or more conventional carriers.

·. ·· *. · »

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

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

Liquid pharmaceutical compositions suitable for oral administration may be in the form of solutions, suspensions or emulsions and may contain, for example, 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 carrier.

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

The dosage forms listed above as well as other dosage forms are generally known in the art, see for example Remington's Pharamceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA.

The pharmaceutical compositions of the invention generally comprise

0.1 to 95.0 weight percent of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. The usual dose for an adult patient is from 0.1 to 1000 mg of the compound 4 mg. «·· ·« · «····

...................

of formula (I) or a pharmaceutically acceptable acid addition salt thereof daily. The above dosage may be administered in one or more divided doses. The actual dose is dependent on many factors and will be determined by your doctor.

The pharmaceutical compositions of the invention are prepared by admixing a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, with one or more carriers, and converting the resulting mixture into a pharmaceutical formulation in a manner generally known in the art. Suitable methods are described in the literature, see for example Remington's Pharmaceutical Sciences.

A preferred subgroup of pharmaceutical compositions of the invention comprises a benzofuran derivative of formula (I) wherein

R ¹ represents hydrogen or C ₄ alkyl group,

R ² is hydrogen,

X is an oxygen atom,

Y represents a hydrogen atom or a hydroxy group,

Z is hydrogen, halogen or nitro,

A is CH, COH or C-CN,

B represents a methylene group, or

A forms a group of formula -C = C- with B;

'·::: ..: ..: ..: ..: ..: ..: ..

Ar is selected from the group consisting of hydrogen, benzyl, phenyl substituted from the group consisting of R ^5,

R ⁶ and R ⁷ , biftylyl, naphthyl optionally substituted with C _1-4 alkoxy; sky thienyl, wherein R ^5, R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, C ₄ alkyl, C _{4 4} alkoxy, C _2-4 alkenyloxy, phenoxy and methylenedioxy, or a pharmaceutically an acceptable acid addition salt as the active ingredient.

Within the above subgroup, the pharmaceutical compositions of the invention preferably comprise a benzofuran derivative of the general formula (I) wherein

R ¹ represents a methyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

A is CH, COH or C-CN,

B represents a methylene group, or

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

Ar is phenyl optionally substituted with halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, or a pharmaceutically acceptable acid addition salt thereof, as the active ingredient.

Another preferred subgroup of pharmaceutical compositions of the invention comprises a piperazinylalkylbenzofuran derivative of formula (Ia) wherein:

R ¹ represents a C _1-4 alkyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 1 represents a diphenylmethyl group, a pyridyl group, partially saturated with a heterocyclic group containing two oxygen atoms, which is condensed with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁶ , R ⁷ , wherein

R ⁵ , R ⁶ , R ^{7 are} independently hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, and methylenedioxy; n is 0 or 1; and a pharmaceutically acceptable acid addition salt thereof as the active ingredient.

Within the above subgroup, the compositions of the invention comprise a piperazinylalkylbenzofuran derivative of the general formula (Ia) wherein:

R ¹ represents a methyl group,

R ² is hydrogen,

X is an oxygen atom,

Y is hydroxy,

Z represents a hydrogen atom,

Ar 'represents diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or

phenyl optionally substituted with one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and a pharmaceutically acceptable acid addition salt thereof.

Particularly preferred pharmaceutical compositions of the invention comprise one of the following benzofuran derivatives or pharmaceutically acceptable acid addition salts thereof as the active ingredient:

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine, 1- [3- (2,2 -dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -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-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) - oxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine;

1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3) -dihydro-benzofuran-7-yl-oxy) -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-methoxy-naphth-2-yl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro- benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (diphenylmethyl) piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperazine, 1- [ 3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (benzo-1,3-dioxolan-5-yl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (4-chloro-phenyl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-benzyl-piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4- (2,4-dichloro-phenyl) -piperazine,

1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine, 1- [3- (2,2 -dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (2-pyridyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro- benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine; or 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl) - oxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine

The invention further encompasses a method of treating diseases comprising administering to a patient suffering from cardiac or central nervous system diseases, a therapeutically effective non-toxic amount of a benzofuran derivative of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

The invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of halides of formula (II)

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

To a solution of 32.8 g (0.2 mol) 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 600 ml acetone was added 80.8 g (0.4 mol)

1,3-dibromopropane and 83.0 g (0.6 mol) of anhydrous potassium carbonate, and the reaction mixture is heated to boiling under stirring for 24 hours. After cooling, the inorganic salts are filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue was recrystallized from methanol, filtered and then dried at room temperature.

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

Preparation of epoxides of formula (III)

2) 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydro-4-benzofuran

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

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 was added 12.2 g (0.12 mol) of acetic anhydride and the reaction mixture. The mixture is heated at boiling point for 30 minutes and then evaporated to dryness under reduced pressure. The oily residue is triturated with 60 ml of ice-water and the white crystalline product is filtered off, washed with ice-water and dried under reduced pressure.

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

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

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

This afforded 22.0 g (77%) of the title compound, mp .: 76 ° C.

c) 5-bromo-2,2-dimethyl-2,3-dihydro-benzofuran-7-ol

24.2 g (0.085 mol) of 7-acetoxy-5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran are stirred for 3 hours at 20-25 ° C in a mixture of 70 ml of methanol and 68 ml of 10 ml. % aqueous sodium hydroxide. The reaction mixture was then acidified to pH 2 with concentrated hydrochloric acid, the methanol was distilled off under reduced pressure, and the residue was extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed twice with 20 ml of water each time to remove acid residues, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue is triturated with hexane and the crystalline substance is filtered off and dried under reduced pressure.

19.9 g (96.4%) of the title compound are obtained, m.p .: 70 ° C.

d) 5-bromo-2,2-dimethyl-7-oxiranyl-methoxy-2,3-dihydrobenzofuran

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

Thus, 23.5 g (98%) of the title compound are obtained in the form of a honey-like product which is used directly for the preparation of the compounds of formula (I). After prolonged standing, the product crystallizes, m.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-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of 10% aqueous sodium hydroxide is added 20.0 g (0.216 mol) of epichlorohydrin and reaction mixture. the mixture was stirred at 48-50 ° 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 with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The title compound is obtained in the form of a thick honey-like product which is triturated with 60 ml of hexane to give white crystals. The precipitated crystals are filtered off and dried under reduced pressure.

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

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

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 was added 0.35 g of 82% m-chloroperbenzoic acid and the reaction mixture was stirred for 10 hours . 5 ml of 10% aqueous sodium bicarbonate solution are added to the reaction mixture, the phases are separated, the organic phase is dried over anhydrous sodium sulphate, filtered and the solvent is removed under reduced pressure. The oily residue was purified by column chromatography (silica gel column, eluting with a mixture of 24 volumes of dichloromethane and 1 volume of acetone).

Thus, 0.068 g (31%) of the title compound is obtained. Mp: 4951 ° C.

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

(a) 7-acetuxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

Λ ·

Κ of a solution of 16.5 g (0.08 mol) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran in 60 ml of chloroform is added, with stirring and cooling to 15 to 20 ° C, over 30 minutes 6 ml (0 (06 mol) of acetic anhydride. To the stirred and cooled solution obtained, 4 ml (5.53 g, 0.06 mol) of concentrated nitric acid (density: 1.42; 65%) was added dropwise over 30 to 40 minutes, taking care that the temperature the mixture should be in the range of 25 to 28 ° C. The reaction mixture is stirred for a further 10 minutes, then 100 ml of ice water are added, the phases are separated, the organic phase is washed with ice water until neutral, dried over anhydrous sodium sulphate, filtered and the solvent is removed under reduced pressure. The crystalline product obtained is suspended in 40 ml of methanol at 0 DEG C., filtered off and dried under reduced pressure.

Thus, 14.8 g (74%) of the title compound are obtained. Mp: 142143 ° C.

b) 2,2-dimethyl-5-nitro-2,3-dihydro-benzofuran-7-ol

13.3 g (0.053 mol) of 7-acetoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran are stirred in a mixture of 40 ml of methanol and

42.5 ml of 10% aqueous sodium hydroxide at 20-25 ° C for 30 minutes. The resulting purple solution was acidified to pH 1 with concentrated hydrochloric acid, the methanol was distilled off under reduced pressure, and the residue was extracted with 50 ml of dichloromethane. The phases are separated, the aqueous phase is extracted twice with 25 ml of dichloromethane each time. The combined organic phases were extracted twice with 20 ml of water each time to remove the acid, then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was triturated with hexane to give a crystalline product which was filtered off and dried under reduced pressure.

• *

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

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

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

Thus, 13.3 g (96.7%) of the title compound are obtained. Mp: 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 was added 12.1 g (0.12 mol) of allyl bromide and 20.75 g ( Anhydrous potassium carbonate (0.15 mol) was heated to boiling for 12 hours with stirring. After cooling, the inorganic salts are filtered off and the filtrate is concentrated by evaporation of the solvent. The residue, in the form of an oily product, is purified by vacuum distillation.

Thus, 9.20 g (90%) of the title compound are obtained. M.P .: 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-yl in 100 ml of acetone was added 7.63 g (0.10 mol) of allyl chloride and 20.7 g ( Anhydrous potassium carbonate (0.15 mol) was added and the reaction mixture was heated to boiling with stirring for 12 hours. After cooling, the inorganic salts are filtered off, and the filtrate is evaporated under reduced pressure to remove the solvent. The oily residue is purified by vacuum distillation.

Thus, 8.90 g (87%) of the title compound are obtained. M.P .: 77 ° C / 53.3 Pa.

Preparation of compounds of formula (X)

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

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

This afforded 25.0 g (76.5%) of the title compound. M.P .: 80-83 ° C / 27-4C Pa.

Preparation of Benzciurane Derivatives of Formula (I)

Example 1

- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine hydrochloride

To a solution of 4.0 g (0.14 mol) of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydroxybenzofuran in 60 ml of dichloromethane was added 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 is extracted twice with 50 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 30 ml of ethanol containing 5% hydrogen chloride and evaporated in a water bath under reduced pressure. The residue is triturated with 40 ml of ethyl acetate and the precipitated crystalline product is filtered off.

Thus, 3.75 (72.8%) of the title compound are obtained. Mp: 165 ° C.

Example 2

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine

A mixture of 2.15 g (0.005 mol) of 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 are stirred for 10 minutes. The phases are separated, the organic phase is extracted twice with 5 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The evaporation residue is recrystallized from a small amount of ethanol.

Thus, 1.54 (78, 5%) of the title base are obtained. Mp: 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 was added 2.07 g (0.01 mol) of 4-hydroxy Of 4- (4-methoxyphenyl) piperidine and 5 ml of 10% aqueous sodium hydroxide, and the reaction mixture was stirred at room temperature for 14 hours. The phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.15 g) was dissolved at 40 ° C in 30 ml of ethanol containing 5% hydrogen chloride and held at the above temperature for 5 minutes, and then evaporated again under reduced pressure. The residue is triturated with 30 ml of ethyl acetate, filtered off and dried under reduced pressure.

Thus, 2.79 (85%) of the title compound are obtained. Mp: 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) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine The mixture was stirred in 10 ml of ethanol containing 5% hydrogen chloride for 5 minutes at 40 ° C, and then the solution was evaporated under reduced pressure. The residue is then triturated with 30 ml of ethyl acetate, filtered and dried under reduced pressure.

Thus, 0.75 (87%) of the title compound are obtained. Mp: 165 ° C.

• ·

Example 5 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 0.57 g (0.002 mol) of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran in 10 ml of dichloromethane is added 0.41 g (0.002 mol) of 4-hydroxy-4- ( 4-methoxyphenyl) piperidine and 1 mL of 10% aqueous sodium hydroxide. The reaction mixture was then stirred at room temperature for 14 hours and then the phases were separated. The organic phase is then extracted twice with 5 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue was recrystallized from 3 ml of ethanol.

Thus, 0.35 (43%) of the title compound are obtained. Mp: 116117 ° C.

Example 6 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4- (3-trifluoromethylphenyl) -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 is added 2.63 g (0.01 mol) of 4- ( 3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 10 mL of 10% aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours and the phases are separated. The organic phase is extracted twice with 10 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.68 g) was dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness again under reduced pressure.

• *

The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.86 (82.5%) of the title compound are obtained. Mp: 186187 ° C.

Example 7 - [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) propyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine hydrochloride

To a solution of 7- (3-bromopropyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran (3.0 g, 0.0105 mol) in dichloromethane (50 ml) was added 4-hydroxy (2.45 g, 0.01 mol). Of 4- (3-trifluoromethylphenyl) -piperidine and 5 ml of 10% aqueous sodium hydroxide. The reaction mixture is stirred at room temperature for 24 hours and the phases are separated. The organic phase is extracted twice with 10 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue (4.91 g) was dissolved in 20 ml of ethanol containing 5% hydrogen chloride and evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.30 (67.9%) of the title compound are obtained. Mp: 154155 ° 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 was added 1.30 g (0.005 mol) of 4- (3-trifluoromethylphenyl) -1 , 2,3,6 • *

-tetrahydropyridine hydrochloride and 1.1 ml of 20% aqueous sodium hydroxide. The reaction mixture was then heated at reflux for 5 hours and then evaporated under reduced pressure. The residue was partitioned between 15 mL of dichloromethane and 10 mL of water, then the organic was extracted twice with 10 mL of water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent.

The residue (2.42 g) was dissolved in 15 ml of ethanol containing 5% hydrogen chloride and the solution was evaporated again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 2.02 g (83.5%) of the title compound are obtained. Mp: 160162 ° 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

To a solution of 4.40 g (0.02 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-diynylbenzofuran in 30 ml of isopropanol was added 4.90 g (0.02 mol) of 4-hydroxy-4. - (3-trifluoromethylphenyl) piperidine. The reaction mixture is heated at boiling for 6 hours and then evaporated under reduced pressure. The oily residue was dissolved in 15 ml of methanol and 3 ml of concentrated hydrochloric acid and 3 ml of water were added to the solution cooled to 15-20 ° C. The precipitated crystals are filtered off, washed with cold methanol and dried under reduced pressure.

Thus, 3.06 g (86%) of the title compound are obtained. Mp: 156-158 ° C (after recrystallization 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 was added 2.30 g (0.01 mol) of 4- (4-chlorophenyl) -1 2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20% aqueous sodium hydroxide. The reaction mixture was then heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent.

The residue (4.3 g) was dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution was evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.48 g (77.3%) of the title compound are obtained. Mp: 164166 ° C (after recrystallization from isopropanol).

Example 11 - [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 was added 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. The reaction mixture was then heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and

ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent.

The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution is evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.50 g (82%) of the title compound are obtained. Mp: 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 was added

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. The reaction mixture was then heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent.

The residue is dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution is evaporated to dryness again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 3.2 g (73.8%) of the title compound are obtained. Mp: 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-oxiranyl-methoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added 2.62 g (0.015 mol) of 4-oenzylpiperidine. The reaction mixture was then heated at reflux for 6 hours and then evaporated under reduced pressure. The residue is partitioned between 20 ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 15 ml of ethanol containing 10% hydrogen chloride and the solution was evaporated again under reduced pressure to dryness. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 2.67 g (62%) of the title compound are obtained. Mp: 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 was added 3.15 g (0.015 mol) of 4-hydroxy-4- (4-chlorophenyl). piperidine. The reaction mixture is heated at reflux for 6 hours, then cooled, the precipitated crystals are filtered off, washed with isopropanol and dried under reduced pressure.

This afforded Ξ, 40 g (83.4%) of the title compound. Mp: 148150 ° C (recrystallized from acetone).

• 99 9 • 9 9 • 9 9

9 9 · 9 9

999 ···· · * ··

Example 15 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine hydrochloride

Dissolve 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 in 10 ml of methanol and 2 ml of methanol containing 5% hydrogen chloride are added under ice-cooling. The solution was then evaporated to dryness under reduced pressure, the crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 0.87 (93%) of the title compound are obtained. Mp: 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 was added 2.53 g (0.013 mol) of 4-hydroxy-4- (4-fluorophenyl) of piperidine and the reaction mixture is heated at reflux for 4 hours. The isopropanol is then distilled off under reduced pressure, the residue is triturated with 120 ml of petroleum ether (b.p .: 60 ° C), the precipitated crystals are filtered off, washed with acetone / petroleum ether (1 vol. + Vol) and dried under reduced pressure.

Thus, 4.55 g (84%) of the title compound are obtained. Mp: 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 β

0.83 g (0.002 mol) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) piperidine Dissolve in 10 ml of methanol and add 2 ml of methanol containing 5% hydrogen chloride under ice-cooling. This solution was evaporated to dryness under reduced pressure, the crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 0.79 g (87.5%) of the title compound are obtained. Mp: 173175 ° 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 is added 0.98 g (0.005 mol) of 4- (4-phenyl) -1 2,3,6-tetrahydropyridine hydrochloride and 1.1 ml of 20% aqueous sodium hydroxide. The reaction mixture was then heated at reflux for 5 hours and then evaporated under reduced pressure. The residue is partitioned between 10 ml of chloroform and 10 ml of water, the organic phase is extracted twice with 10 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 15 ml of ethanol containing 5% hydrogen chloride and the solution was evaporated again under reduced pressure. The crystalline residue was triturated with ether, filtered and dried under reduced pressure.

Thus, 1.93 g (92.8%) of the title compound are obtained. Mp: 166167 ° 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 was added 0.85 g (0.01 mol) of piperidine. The solution obtained is heated at reflux for 3 hours, then cooled and 20 ml of isopropanol containing 5% hydrogen chloride are added under cooling to 15-25 ° C. Then the reaction mixture is evaporated to dryness under reduced pressure, the residue is recrystallized from a mixture of ethanol and ether, the crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 2.60 g (76%) of the title compound are obtained. Mp: 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 was added 2.5 g (0.014 mol) of 4-hydroxy-4-phenylpiperidine. The solution obtained is heated at boiling for 3 hours, then cooled to 15 ° C and 10 ml of ethanol containing 10% hydrogen chloride are added under cooling to 15-20 ° C. The reaction mixture is then evaporated to dryness under reduced pressure, the residue is triturated with ether, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.62 g (60%) of the title compound are 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 are dissolved in 50 ml of water. ml of hot water and 5 ml of 10% aqueous sodium hydroxide are added. The precipitated crystals are filtered off, washed with water and then recrystallized from methanol.

Thus, 1.00 g (78%) of the title base are obtained. Mp: 127-129 ° C.

Example 22 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (2-methoxyphenyl) -piperidine hydrochloride

To a solution of 3.40 g (0.0153 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added

3.10 g (0.015 mol) of 4-hydroxy-4- (2-methoxyphenyl) piperidine. The solution obtained is heated at boiling for 5 hours, then cooled to 15 DEG C. and, with cooling to 15 DEG-25 DEG C., 4 ml of ethanol containing 15% hydrogen chloride are added. The solution was evaporated to dryness under reduced pressure, and the residue was recrystallized from ethanol-ether. The precipitated crystals are filtered off and dried under reduced pressure.

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

Example 23 ···· ··· ’

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (6-methoxynaphth-2-yl) -piperidine hydrochloride

To a solution of 2.42 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 2.6 g (0.01 mol) of 4-hydroxy-4- (6- methoxynaphth-2-yl) piperidine. The resulting solution was heated at reflux for 6 hours, then cooled to 15 ° C and 3 ml of ethanol containing 15% hydrogen chloride were added. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, 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 are obtained. Mp: 125-127 ° C.

Example 24

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) -piperidine hydrochloride

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol is added 2.12 g (0.01 mol) of 4-hydroxy-4- (3- chlorophenyl) piperidine. The resulting solution was heated at reflux for 6 hours, then cooled to 15 ° C and 3 ml of ethanol containing 15% hydrogen chloride were added under cooling to 15-25 ° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, 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 are obtained. Mp: 138-140 ° C.

Example 25

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-methoxyphenyl) -piperidine hydrochloride

To a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol was added

3.10 g (0.015 mol) of 4-hydroxy-4- (3-methoxyphenyl) piperidine. The resulting solution was heated at reflux for 4 hours and then evaporated to dryness under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate, then cooled to 15 ° C and 6 ml of ethanol containing 15% hydrogen chloride are added under cooling to 15-20 ° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from a mixture of acetone and ether and dried under reduced pressure.

Thus, 5.90 g (84.8%) of the title compound are obtained. Mp: 128130 ° 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) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 3.10 g (0.015 mol) of 4-hydroxy-4- (4- methoxyphenyl) piperidine. The resulting solution was heated for 4 hours and then evaporated to dryness under reduced pressure. The residue is triturated with 40 ml of ethyl acetate, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 4.70 g (73.4%) of the title compound are obtained. Mp: 144146 ° C.

Example 27 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (5-fluoro-2-methoxyphenyl) -piperidine hydrochloride

To a solution of 3.80 g (0.0173 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol was added 3.37 g (0.015 mol) of 4-hydroxy-4- (5-). fluoro-2-methoxyphenyl) piperidine. The solution obtained is heated at boiling for 6 hours and then, at 15 DEG C. and with cooling to 15 DEG-20 DEG C., 4 ml of ethanol containing 15% hydrogen chloride are added. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off, recrystallized from 40 ml of ethyl acetate.

Thus, 5.60 g (77.5%) of the title compound are obtained. Mp: 156158 ° C.

Example 28 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperidine hydrochloride

To a solution of 3.96 g (0.018 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of ethanol is added 3.34 g (0.015 mol) of 4- (3-trifluoromethylphenyl) piperidine hydrochloride and 2 ml of 40% aqueous sodium hydroxide. The reaction mixture was then heated at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 30 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is separated twice.

extract with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was dissolved in 25 ml of ethanol containing 5% hydrogen chloride and the solution was evaporated to dryness under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 5.15 g (77.1%) of the title compound are obtained. Mp: 172174 ° C.

Example 29

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine

To a solution of 3.4 g (0.0153 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 2.86 g (0.015 mol) of 4-hydroxy-4- (4- methylphenyl) piperidine. The solution obtained is heated at reflux for 5 hours. After cooling, the solution was further cooled to 5 ° C in an ice bath, and then the precipitated crystals were filtered off and dried under reduced pressure.

Thus, 5.17 g (83.8%) of the title compound are obtained. Mp: 138139 ° 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) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) The piperidine is dissolved in 15 ml of methanol and 12 ml of methanol containing 5% hydrogen chloride are added to the obtained solution which is cooled with ice. This 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 are obtained. Mp: 164-166 ° C.

Example 31 - [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 is added 3.37 (0.015 mol) of 4- (4-methoxyphenyl) -1,2, Of 3,6-tetrahydropyridine hydrochloride and 2 ml of 40% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 6 hours and then evaporated to dryness under reduced pressure, the residue is diluted with 50 ml of water, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 6.1 g (92.8%) of the title compound are obtained. Mp: 104-105 ° C (after recrystallization from petroleum ether, b.p. 120 °).

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

Thus, 4.05 g (91%) of the title compound are obtained. Mp: 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) of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) -1,2, 3,6-tetrahydropyridine is dissolved in 5 ml of ethanol containing 20% hydrogen chloride and the solution is heated at boiling for 10 minutes. After cooling, the solution is diluted with 50 ml of ether, the precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

Thus, 0.98 g (93%) of the title compound are obtained. Mp: 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

To a solution of 3.60 g (0.0165 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 3.45 g (0.015 mol) of 4-hydroxy-4- (3, 2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran). 5-dimethyl-4-methoxyphenyl) piperidine. The reaction mixture is allowed to react for 2 hours at 55 to 60 ° C, then cooled to 0 ° C and 5 ml of ethanol containing 10% hydrogen chloride are added under cooling. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with ether. The precipitated crystals are filtered off and dried under reduced pressure.

Thus, 6.42 g (87%) of the title compound are obtained. Mp: 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 is added 1.18 g (0.015 mol) of 4-hydroxy-4 (3,5-dimethyl-4- methoxyphenyl) -piperidine and the reaction mixture is allowed to react at 60 ° C for 1 hour. The mixture was cooled, dissolved in ether and treated with 1 mL of ethanol containing 20% hydrogen chloride. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

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

Example 36

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (3,4-methylenedioxyphenyl) piperidine

To a solution of 2.42 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 2.57 g (0.01 mol) of 4-hydroxy-4- (3, 2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran). 4-methylenedioxyphenyl) piperidine hydrochloride and 4.2 mL of 10% aqueous sodium hydroxide. The reaction mixture is then heated at reflux for 5 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 20 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane, the precipitated crystals were filtered off and dried under reduced pressure.

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

Example 37 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- [4- (2-methyl-2-propenyloxy) 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 is added 4.94 g (0.02 mol) of 4-hydroxy-4- [4- (2-methyl-2-propenyloxy) phenyl] piperidine. The reaction mixture is heated at reflux for 6 hours, then cooled to 0 ° C and the precipitated crystals are filtered off, washed with diisopropyl ether and dried under reduced pressure.

⁷ are obtained 95 g (85%) of the title compound. Mp: 108-110 ° C.

Example 38 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-biphenyl) piperidine hydrochloride

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol was added 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 then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ether and 1.5 ml of ethanol containing 20% hydrogen chloride are added to the obtained solution while cooling. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

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

Example 39 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-phenoxyphenyl) piperidine

To a solution of 2.64 g (0.012 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol was added 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 residue was recrystallized from a small amount of methanol, filtered off and dried under reduced pressure.

Thus, 4.47 g (91%) of the title compound are obtained. Mp: 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

To a solution of 3.90 g (0.0177 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 4.19 g (0.015 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 residue is dissolved in 60 ml of ether and 2.5 ml of ethanol containing 20% hydrogen chloride are added. The precipitated crystals are filtered off, washed with ether and dried under reduced pressure.

···· · · · · • · • · · · • · · · · · · · «· ·« «« «

Thus, 7.00 g (88%) of the title compound are obtained. Mp: 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) sodium hydroxide in 15 ml isopropanol was added 1.21 g (0.0055 mol) 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.11 g (0.005 mol). mol)

4-cyano-4-phenylpiperidine hydrochloride. The reaction mixture is then heated to boiling under stirring for 6 hours and then evaporated to dryness under reduced pressure. The residue is then partitioned between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml of ether and 1 ml of ethanol containing 20% hydrogen chloride was added thereto while cooling. The precipitated crystals are filtered off, washed with ether, and dried under reduced pressure.

Thus, 1.60 g (74%) of the title compound are obtained. Mp: 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 was added 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.40 g (0.005 mol). mol) • 9 * 9

4-Cyano-4- (3-trifluoromethylphenyl) piperidine hydrochloride. The reaction mixture is then heated to boiling under stirring for 6 hours and then evaporated to dryness under reduced pressure. The residue is then partitioned between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. ml of ether and 1 ml of ethanol containing 20% hydrogen chloride are added. The precipitated crystals are filtered off, washed with ether, and dried under reduced pressure.

Thus, 1.48 g (59.2%) of the title compound are obtained. Mp: 213216 ° C.

Example 43

1- [3- (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine

To a solution of 2.63 g (0.0088 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol was added 1.66 g (0.008 mol) of 4-hydroxy-4. - (4-methoxyphenyl) piperidine. The reaction mixture is heated to boiling under stirring for 10 hours and then cooled to 0 ° C. The precipitated crystals are filtered off, washed with cold isopropanol and dried under reduced pressure.

Thus, 2.67 g (66%) of the title compound are obtained. Mp: 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- (chloro-3-trifluoromethylphenyl) -piperidine hydrochloride

To a solution of 3.30 g (0.011 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol is added 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, then evaporated to dryness under reduced pressure. The residue is then dissolved in 60 ml of ether, and 2.5 ml of ethanol containing 20% hydrogen chloride are added thereto under cooling. The crystals were filtered off, washed with ether and dried under reduced pressure.

Thus, 4.86 g (79%) of the title compound are obtained. Mp: 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

To a solution of 2.62 g (0.01 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 8 ml of isopropanol was added 1.86 g (0.009 mol) of 4-hydroxy-4. - (4-methoxyphenyl) piperidine. The reaction mixture is heated to boiling under stirring for 2 hours and then cooled to 2 ° C. The precipitated crystals are filtered off, washed with cold isopropanol and dried under reduced pressure.

Thus, 3.48 g (81.8%) of the title compound are obtained. Mp: 136138 ° 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

To a solution of 2.46 g (0.012 mol) of 2,2-dimethyl-5-nitro-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol was added 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. The reaction mixture is then heated with stirring at boiling point for 5 hours and then evaporated under reduced pressure.

The residue is partitioned between 30 ml of dichloromethane and 10 ml of water, the organic phase is extracted twice with 20 ml of water each, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 50 ml of ethanol containing 5% hydrogen chloride and the solution is evaporated to dryness under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 3.89 g (73.7%) of the title compound are obtained. Mp: 162165 ° 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

A solution of 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (6-methoxynaphth-2-yl) piperidine hydrochloride in 15 ml of ethanol containing 20% of hydrogen chloride is heated at boiling for 20 minutes and then evaporated to dryness under reduced pressure. The crystalline residue is triturated with 30 ml of ether, filtered and dried under reduced pressure.

Thus, 2.96 g (92%) of the title compound are obtained. Mp: 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

To a solution of 2.63 g (0.0088 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol was added 2.11 g (0.008 mol) of 4- (3- trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride and 3.2 mL of 10% aqueous sodium hydroxide. The reaction mixture is then heated with stirring at boiling for 6 hours and then evaporated under reduced pressure.

The residue was partitioned between 50 mL of dichloromethane and 50 mL of water. The organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to remove the solvent. The residue was dissolved in 10 ml of ethanol containing 10% hydrogen chloride and the solution was evaporated to dryness under reduced pressure. The crystalline residue is heated with 50 ml of ethyl acetate to boiling, the crystals are filtered off from the hot mixture and dried under reduced pressure.

Thus, 3.78 g (89.8%) of the title compound are obtained. Mp: 112114 ° 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

To a solution of 2.30 g (0.0077 mol) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol was added 1.72 g (0.007 mol) of 4- (3- trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine and the reaction mixture is heated to boiling under stirring for 6 hours and then evaporated under reduced pressure. The residue was heated to boiling in 10 ml of ethanol containing 20% hydrogen chloride for 30 minutes and the mixture was again evaporated under reduced pressure. The crystalline residue is heated at boiling point with 30 ml of ethyl acetate for 5 minutes, then the crystals are filtered off and dried under reduced pressure.

Thus, 3.42 g (92.8%) of the title compound are obtained. Mp: 112114 ° C.

Example 50 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine hydrochloride

A solution of 1.78 g (0.004 mol) of 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 is hydrogenated in the presence of 0.1 g of 10% palladium / carbon catalyst at atmospheric pressure. Once the calculated amount of hydrogen (96 ml) was taken up, the catalyst was filtered off and the solution was evaporated under reduced pressure. The crystalline residue is triturated with 20 ml of ether, the crystals are filtered off and dried under reduced pressure.

Thus, 1.75 g (98%) of the title compound are obtained. Mp: 172-174 ° C.

Example 51 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-hydroxy- (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 was added. The mixture is melted for 1 hour at λ ° C and then dissolved in 10 ml of ethanol containing 20% hydrogen chloride, and the resulting mixture is heated at boiling point for 45 minutes. The solution was then diluted with 10 mL of ethanol, cooled to 30 ° C, and hydrogenated in the presence of 0.1 g of 10% palladium / carbon catalyst. Once the calculated amount of hydrogen (240 ml) was taken up, the catalyst was filtered off and the solution was evaporated under reduced pressure. The crystalline residue is triturated with ether, the crystals are filtered off and dried under reduced pressure.

Thus, 4.05 g (91%) of the title compound are obtained. Mp: 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 terahydrofuran was added 0.55 g (0.0055 mol) of 4-hydroxypiperidine. The reaction mixture is heated under stirring at boiling point for 3 hours and then evaporated under reduced pressure. The residue is dissolved in a mixture of 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16% hydrogen chloride and the solution is evaporated under reduced pressure, the residue is dissolved in 8 ml of 2-propanol and left at 0 for 5 days. C. The precipitated crystals are then filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.22 g (57%) of the title compound are obtained. Mp: 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)

4-methylpiperidine and 8 ml of water are heated at reflux for 9 hours. The oily phase formed in the mixture was dissolved in 20 ml of ether, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure and the residue was dissolved in 3 ml.

2-propanol containing 16% hydrogen chloride and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, precipitated with ether, then the precipitated crystals were filtered off, dissolved in hot 2-propanol, reprecipitated with ether, filtered off and dried under reduced pressure.

Thus, 1.25 g (59%) of the title compound are obtained. Mp: 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 are dissolved in 25 ml of 10% aqueous sodium hydroxide.

To this solution was added 3.70 g (0.04 mol) of epichlorohydrin and the reaction mixture was stirred for 3 hours at 45-50 °. The oily product is separated by cooling, dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, thick honey-like epoxide (3.78 g, 85.3%) was dissolved in 40 mL of ethanol and 3.80 g (0.0155 mol) was added.

4-hydroxy-4- (3-trifluoromethylphenyl) piperidine, and the reaction mixture is heated at reflux for 6 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride were added to the solution obtained below 15 DEG C. and the mixture was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized from ethanol / ether, filtered and washed with ether.

Thus, 5.60 g (72%) of the title compound are obtained. Mp: 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 except that the epoxide prepared in the first step (3.75 g, 85.2%) was dissolved in 50 mL of ethanol. To this solution was added 3.94 g (0.0153 mol) of 4-hydroxy-4- (6-methoxy-naphth-2-yl) piperidine and the reaction mixture was heated at reflux for 4 hours. After cooling, 13 ml of ethanol containing 5% hydrogen chloride were added to the solution, and the reaction mixture was evaporated to dryness under reduced pressure. The residual crystalline product is recrystallized from a mixture of ethanol and ether.

Thus, 5.35 g (68%) of the title compound are obtained. Mp: 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 are dissolved in 30 ml of an aqueous solution containing 3 g of sodium hydroxide. To this solution was added 3.70 g (0.04 mol) of epichlorohydrin and the reaction mixture was stirred for 3 hours at 48-50 °. The oily product is separated by cooling, dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, a thick waxy epoxide (3.85 g, 87.3%) was dissolved in 50 mL of ethanol and 3.80 g (0.0155 mol) of 4-hydroxy-4- (3-trifluoromethylphenyl) piperidine was added, and the reaction mixture is heated at reflux for 5 hours. After cooling, 15 ml of ethanol containing 5% hydrogen chloride were added to the solution below 15 DEG C. and the mixture was evaporated to dryness under reduced pressure. The crystalline residue was recrystallized from ethanol / ether, filtered and washed with ether.

Thus, 4.97 g (64%) of the title compound are obtained. Mp: 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 (1.01 mol) of 2,2-dimethyl-2,3-dihydrobenzofuran-6-ol are dissolved in 15 ml of 10% aqueous sodium hydroxide solution. To this solution was added 1.85 g (0.02 mol) of epichlorohydrin and the reaction mixture was stirred at 48-50 ° for 2.5 hours. The oily product is separated by cooling, dissolved in 25 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 15 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue, thick honey-like epoxide (2.10 g, 95%) was dissolved in 10 mL of ethanol and 1.52 g (0.0086 mol, 4-hydroxy-4-phenyl) piperidine was added thereto, and the reaction mixture was heated. 6 hours at boiling point. After cooling, 10 ml of ethanol containing 5% hydrogen chloride are added to the solution obtained at a temperature below 15 DEG C. and the mixture is evaporated to dryness under reduced pressure. The crystalline residue was recrystallized from ethanol / ether, filtered and washed with ether.

Thus, 4.97 g (64%) of the title compound are obtained. Mp: 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 was added 1.21 g (0.0055 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.48 g (0.005 mol). mol)

4-methoxy-4- (3-trifluoromethylphenyl) piperidine hydrochloride.

The reaction mixture was then heated at reflux for 6 hours with stirring and then evaporated to dryness under reduced pressure. The residue is partitioned between 52 ml of water and 50 ml of dichloromethane, the phases are separated, and the organic phase is extracted twice with 20 ml of water each time.

Dry with anhydrous sodium sulphate, filter and evaporate to dryness under reduced pressure. The residue was dissolved in 50 ml of ether and to this solution was added, while cooling, 1 ml of ethanol containing 20% hydrogen chloride, the precipitated crystals were filtered off, washed with ether and dried under reduced pressure.

Thus, 1.62 g (62.8%) of the title compound are obtained. Mp: 192195 ° C.

Example 59

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

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 is heated at boiling 6 hours. The solution was then evaporated to dryness under reduced pressure, the residue was triturated with hexane and filtered. The crude product thus obtained (4.53 g) was then recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

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

Example 60

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

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 is melted at 80 ° C and held at this temperature for one hour. The mass that solidifies is then •

recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

Thus, 3.42 g (83%) of the title compound are obtained. Mp: 129-130 ° C.

Example 61 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

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 is melted at 60 ° C and it is maintained at this temperature for one hour. The solid which solidified is then recrystallized from 25 ml of ethanol, filtered off and dried under reduced pressure.

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

Example 62 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4-diphenylmethylpiperazine

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

Thus, 3.87 g (81%) of the title compound are obtained. Mp: 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 is treated with is heated at boiling point for 5 hours. The solution was then evaporated to dryness under reduced pressure, and the residue was chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fractions were evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 7.30 g (91%) of the title compound are obtained. Mp: 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 is melted at 60 ° C and it is maintained at this temperature for one hour. The melt obtained is then chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fractions were evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 3.72 g (93%) of the title compound are obtained. Mp: 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 is melted at 70 ° C and it is maintained at this temperature for one hour. 60 ml of hexane are added to the obtained melt, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.26 g (81%) of the title compound are obtained. Mp: 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 is heated at boiling point for 4 hours. The solution was then evaporated to dryness under reduced pressure, and the residue was chromatographed on a Kieselgel 60 column using a mixture of chloroform and ethanol (30 vol. + 1 vol.) As eluent. The product-containing fractions were evaporated, the residue was triturated with hexane, filtered off and dried under reduced pressure.

Thus, 3.76 g (84%) of the title compound are obtained. Mp: 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 is melted at 70 ° C, and is maintained at this temperature for 1.5 hours. 60 ml of hexane are added to the obtained melt, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 3.77 g (84%) of the title compound are obtained. Mp: 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 is added. The mixture is heated at the boiling point for 8 hours and then cooled to 0 ° C. The precipitated crystals are then filtered off and dried under reduced pressure.

Thus, 5.21 g (84%) of the title compound are obtained. Mp: 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 is melted at 80 ° C and maintained at this temperature for one hour. To the hot melt is added 10 ml of methyl tert-butyl ether, the mixture is cooled, the precipitated crystals are filtered off and dried under reduced pressure.

Thus, 1.88 g (91%) of the title compound are obtained. Mp: 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 are heated at boiling point for 10 hours. The solution was evaporated to dryness under reduced pressure and the residue (8.0 g) was dissolved in 30 ml of ethanol containing 4.0 g of hydrogen chloride. Crystals start to precipitate from the homogeneous solution. The suspension is then diluted with 60 ml of methyl tert-butyl ether and the crystals are dried under reduced pressure.

Thus, 5.40 g (70%) of the title compound are obtained. Mp: 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 are heated at reflux for 6 hours. The solution is then evaporated to dryness under reduced pressure and the residue is dissolved in 20 ml of ethanol containing 15% hydrogen chloride. Crystals start to precipitate from the homogeneous solution. The suspension is then diluted with 60 ml of methyl tert-butyl ether and the crystals are dried under reduced pressure.

Thus, 5.43 g (71%) of the title compound are obtained. M.P .: 216-218

C.

• · i

......

Example 72 - [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) of piperazine in 30 ml of disopropyl ether was heated at boiling for 6 hours and then 7 ml of ethanol containing 20% hydrogen chloride were added. The precipitated crystals are cooled, filtered off and dried under reduced pressure.

Thus, 4.41 g (86%) of the title compound are obtained. Mp: 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 ethanol, 3 ml of water and 0.9 g (0.0225 mol) of sodium hydroxide are heated under stirring at reflux for 6 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 80 ml of dichloromethane and 50 ml of water, the organic phase is extracted twice with 30 ml of water each time, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue is recrystallized from 8 ml of methanol, the precipitated crystals are filtered off and dried under reduced pressure.

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

• ·

Example 74 - [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 was added 3 ml of water and 0.9 g (0.0225 mol) of sodium hydroxide was heated for 10 minutes at a temperature of boiling. 2.40 g (0.011 mol) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran are then added to the reaction mixture with stirring and the mixture is heated at reflux for a further 4 hours, then evaporated to dryness under reduced pressure. . 50 ml of water are added to the residue, which is decanted from the substance which slowly precipitates, and the residue is triturated with another portion of water. The precipitated crystals are filtered off, washed with water, recrystallized from methanol, filtered off and dried under reduced pressure.

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

Example 75 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-chlorophenyl) piperazine dihydrochloride

To a solution of 0.40 g (0.001 mol) of 1- [3- (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 is added and the mixture is evaporated to dryness under reduced pressure. The residue was heated with boiling point 5 ml of ethyl acetate for 5 minutes, the hot suspension was filtered off, and the crystals were dried under reduced pressure.

• · · ·

Thus, 0.43 g (91%) of the title compound are obtained. Mp: 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 are heated at reflux 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 residue was dissolved in 3 ml of 2-propanol and 3 ml of 2-propanol containing 16% hydrogen chloride was added to the obtained solution and the reaction mixture was kept at 0 ° for 5 days. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.48 g (60%) of the title compound are obtained. Mp: 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-benzylperazine and 8 ml of 2-propanol is heated for 4 hours and then The reaction mixture was cooled to 20 ° C. 20 ml of petroleum ether are then added to the reaction mixture, the mixture is kept at 0 ° C for 5 days, the crystals formed are filtered off and then recrystallized. from hexane. The precipitated crystals were dissolved in 15 ml of 2-propanol and 1.5 ml of 2-propanol containing 16% hydrogen chloride were added thereto. After cooling, the precipitated crystalline salt is filtered off and dried under reduced pressure.

Thus, 1.50 g (58%) of the title compound are obtained. Mp: 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 is added. The mixture is heated at reflux for 5 hours and then cooled to 20 ° C. To the reaction mixture was then added 3.6 ml of 2-propanol, 2.4 ml of 2-propanol containing 16% hydrogen chloride, and the mixture was stirred at room temperature for 5 hours. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.19 g (45%) of the title compound are obtained. Mp: 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-chloro-92). Phenyl) piperazine and 16 ml of 2-propanol are heated. 3 hours at boiling point. After cooling, 7 ml of 2-propanol containing 16% hydrogen chloride were added to the solution obtained at 20 ° C. The reaction mixture is then left at 0 ° C for 2 days, the precipitated crystals are filtered off, recrystallized. The mixture was filtered from 2-propanol, filtered again and dried under reduced pressure.

Thus, 2.88 g (53%) of the title compound are obtained. Mp: 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 2, 2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran (1.32 g, 0.006 mol), 1- (2-pyridyl) piperazine (0.78 g, 0.0048 mol) and petroleum ether (8 ml) was heated for 6 hours. hours at boiling point. After cooling to 20 ° C, the phases are separated and 20 ml of 2-propanol and 4.5 ml of 2-propanol containing 16% hydrogen chloride are added to the lower phase and the reaction mixture is left at 0 ° C for 5 days. The precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.68 g (71%) of the title compound are obtained. Mp: 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-dihydrofcenzofuran, 2.36 g (0.011 mol) of 1- (2-methoxyphenyl) piperazine and 16 ml of 2-propanol is heated for 5 hours. 5 hours at boiling point. 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 left at 0 ° C for 2 days. The precipitated crystals are filtered off 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 are obtained. Mp: 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 is heated for 6 hours. hours at boiling point. After cooling to 20 ° C, the reaction mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. 5 ml of 2-propanol containing 16% hydrogen chloride are added to the residue, the reaction mixture is left at 0 ° C for 2 days, the precipitated crystals are filtered off, recrystallized from 2-propanol, filtered again and dried under reduced pressure.

Thus, 1.50 g (62%) of the title compound are obtained. Mp: 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-pyrimidyl94 piperazine and 8 ml of tetrahydrofuran is heated at reflux for 12 hours and then is cooled to 20 ° C. 20 ml of ether and 1.5 ml of 2-propanol containing 30% hydrogen chloride were added to the oil formed, the reaction mixture was left at 0 ° C for 5 days, the precipitated crystals were filtered off, dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.50 g (82%) of the title compound are obtained. Mp: 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) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.27 g (0.008 mol) of 1- (4-chloro-2-methylphenyl) piperazine hydrochloride, 0, 64 (0.016 mol) of sodium hydroxide and 16 ml of water were heated at reflux for 3 hours and then cooled to 20 ° C. The aqueous phase was removed by decantation and 30 ml of ether was added to the organic phase and the reaction mixture was stirred for 1 hour. The precipitated crystals are filtered off, dried under reduced pressure and recrystallized. from acetonitrile.

Thus, 2.07 g (60%) of the title compound are obtained. Mp: 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 is heated at reflux for 3 hours and then cooled to 20 ° C. 4 ml are then added to the mixture.

Of 2-propanol containing 30% hydrogen chloride and the reaction mixture is left at -15 ° C for 2 days, the precipitated crystals are filtered off, dried under reduced pressure, dissolved in hot 2-propanol, and precipitated from solution with diethyl ether.

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

Example 86

1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (trifluoromethylbenzyl) piperazinedihydrochloride

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 ( 0.009 mol) of sodium hydroxide and 8 ml of water are heated at boiling point for 2.5 hours and then cooled to 20 DEG C., the aqueous phase is removed by decantation and 2 ml of propan-2-ol containing 30% hydrogen chloride are added to the organic phase. , dried under reduced pressure and recrystallized from 2-propanol.

Thus, 1.39 g (57%) of the title compound are obtained. Mp: 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 is heated at reflux for 3 hours at a boiling point and then cooled to 20 ° C. A mixture of 2-propanol (10 ml), 2-propanol (2 ml) containing 30% hydrogen chloride was added to the mixture, and the reaction mixture was stirred for 5 hours, the precipitated crystals were filtered off, dried under reduced pressure, and recrystallized. of 2-propanol.

Thus, 1.63 g (62%) of the title compound are obtained. Mp: 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, 32 (0.008 mol) of sodium hydroxide and 8 ml of water are heated at boiling for 2 hours and then cooled to 20 ° C. The aqueous phase formed in the mixture is removed by decantation and 2.5 ml of 2-propanol containing 30% hydrogen chloride are added to the organic phase, the reaction mixture is left at -15 ° C for 2 days, then 10 ml of 2-propanol is added and the precipitated crystals are filtered. dried under reduced pressure and recrystallized! with 2-propanol.

Thus, 1.00 g (41%) of the title compound are obtained. Mp: 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) of 1-bromo-3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-propanol, 0.45 g (0.0016 mol)

4-chloro-2-dimethylphenylpiperazine, 0.25 g (0.0063 mol) of sodium hydroxide and 6.5 ml of water are heated at reflux for 3 hours and then cooled to 20 ° C. The aqueous phase was removed by decantation and the residual oil was mixed 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 are obtained. Mp: 68-70 ° C.

Claims (17)

A benzofuran compound of formula (I) wherein R ¹ and R ² independently represent hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C _1-4 alkyl group, R ⁴ represents a C _1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more more sulfur atoms • <······ * A is CH, COH, C-CN, C-COOR ³ or COR wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is selected from the group consisting of hydrogen, C ₄ alkyl, phenyl (C _C4 alkyl), biphenyl, naphthyl, wherein the groups mentioned last may be optionally substituted by C ₄ alkoxy, or c _{2. 4} alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; 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; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein 5 6 7 R, R, and R independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, methylenedioxy, phenoxy optionally substituted C _1-4 alkoxy or halogen; C _2-4 alkenyl, C _2-4 alkenyloxy, C _1-4 alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted with C 1-4 alkyl, or A represents a group of formula N (CH _{2) n} -Ar 'wherein 100 ·· «· ···· Ar 'is selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter being optionally substituted with C _1-4 alkoxy or C _2-4 alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, and pharmaceutically acceptable acid addition salts thereof. The benzofuran derivative according to claim 1, wherein in formula (I) R ¹ represents a hydrogen atom or a C _1-4 alkyl group, R ² is hydrogen, X is an oxygen atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen or nitro, A is CH, COH or C-CN, B represents a methylene group, or 101 • · · · · · · · · · · · · · · · · · · · A forms with the group B a group of the formula -C = C-, Ar is hydrogen, benzyl, phenyl substituted with R ⁵ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C _1-4 alkoxy; or thienyl, wherein R, R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, C ₄ alkyl, C _{4 4} alkoxy, C 2 ₄ alkenyloxy, phenoxy and methylenedioxy, and pharmaceutically acceptable addition salts with acids. The benzofuran compound according to claim 1 or 2, wherein in formula (I) R ¹ represents a methyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, A is CH, COH or C-CN, B represents a methylene group, or A forms a group B with the formula -C = C-, Ar is phenyl optionally substituted with halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, and pharmaceutically acceptable acid addition salts thereof. A piperazinylalkylbenzofuran compound of formula (Ia) according to claim 1, 102 ·. ♦. Where R ¹ represents a C _1-4 alkyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms, which is fused to a phenyl group, or a phenyl group substituted by a group selected from R ⁵ , R ⁶ , R ⁷ , wherein R ⁵ , R ⁶ , R ^{7 are} independently hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, or methylenedioxy, n represents 0 or 1 and pharmaceutically acceptable acid addition salts thereof. A piperazinylalkylbenzofuran compound according to claim 4, wherein in formula (Ia) R ¹ represents a methyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, 103 ·· ·· · fr · fr · Z represents a hydrogen atom, Ar 'is diphenylmethyl, pyridyl, benzo-1,3-dioxolanyl or phenyl optionally substituted with one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, and a pharmaceutically acceptable salt thereof acceptable acid addition salts. 6. 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine, 1- [ 3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4-phenyl-piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (3-chlorophenyl) piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-methoxy-phenyl) -piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (4-methoxy-phenyl) -piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (3-trifluoromethyl-phenyl) -piperidine, 1- [3- (2,2-dimethyl-2, 3-trifluoromethyl-phenyl) -piperidine]; 3-dihydro-benzofuran-7-yl-oxy) 104 * (*) -2-hydroxypropyl] -4-hydroxy-4- (4-methylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] 4-Cyano-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -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-methoxy-naphth-2-yl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (diphenylmethyl) piperazine, 1- [3- (2, 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-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperazine, 1- [3] - (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -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-yl) —Oxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl -4- (3-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -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) 105 -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine, and pharmaceutically acceptable acid addition salts thereof. A process for the preparation of a benzofuran compound of formula (I) wherein R ¹ , R ² , Z, X, Y, A, B, and Ar are as defined in claim 1, or a pharmaceutically acceptable acid salt thereof, wherein: that a) a halide of formula (II) wherein R ¹ , R ² , X, Y and Z have Hal is a halogen atom, with an amine of formula (IV) as defined for formula (I), react with a secondary wherein A, B and Ar is as defined for formula (I); or b) in the preparation of a benzofuran derivative of the general formula (I) wherein Y represents a hydroxy group, R ¹ , R ² , X, Z, A, B and Ar are as defined for the formula (I), reacting the epoxide of the general formula (III) III 106 wherein R ¹ , R ² , Z and X are as defined above _f with a secondary amine of formula (IV), wherein A, B and Ar are as defined above; or c) reacting a compound of formula (V) wherein R ¹ , X and Z are as defined for formula (I) with a halogen compound of formula (XI), Hal XI wherein R ² , Y, A, B and Ar are as defined for formula (I) and Hal represents a halogen atom; d) in the preparation of a benzofuran derivative of formula (I) wherein R ¹ , R, X, Z, A, B and Ar are as defined for formula (I), a compound of formula (V) wherein R ¹ , X is left and Z are as defined above, to react with an epoxide of formula (XII) N XII where R, A, B and Ar are as defined above; or e) a benzofuran derivative of the general formula (I) wherein A forms a group B = -C = C- with B and R ¹ , R ² , X, Y, Z and Ar have the meaning 107 shown for formula (I), is prepared by dehydrating a benzofuran derivative of formula (I) wherein A is COH, 3 is methylene and R ¹ , R ² , X, Y, Z and Ar are as defined above; or f) the preparation of a benzofuran derivative of the formula (I) wherein A represents COH, B represents a methylene group, R ^1, Fi, X, Y, Z and Ar are as defined for formula (I), provided that Ar is other a ketone of formula (XV) wherein R ¹ , R ² , X, Y and Z are as defined above, is reacted with an arylmagnesium halide of formula (XVI) Hal-Mg-Ar XVI wherein Ar is as defined above, Hal represents a halogen atom and wherein the formed adduct is decomposed with water; or (g) a benzofuran derivative of the formula (I) wherein A is COH, B is methylene, R ¹ , R ² , X, Y, Z and Ar are as defined for formula (I), with Ar being otherwise than hydrogen, is prepared by reacting a ketone of formula (XV), wherein R ¹ , R ² , X, Y and Z are as defined above, with an aryllithium compound of formula (XVII), Li-Ar XVII • · Wherein Ar is as defined above and wherein the resulting adduct is decomposed with water; or h) a benzofuran derivative of formula (I) wherein A is CH, B is methylene, R, R, X, Y, and Ar are as defined for formula (I) are prepared by hydrogenation of a compound of formula (I) wherein: A forms with B a group of the formula -C =C-, and R ¹ , R ² , X, Y, Z are as defined above; or (i) a benzofuran derivative of the formula (I) wherein A is CH, B is a methylene group, R ¹ , R ² , X, Y, Z and Ar are as defined for formula I are prepared by reaction of an epoxide of formula (III); wherein R ¹ , R ² , Z and X are as defined above, with a secondary amine of formula (IV) wherein A is CHOH, B and Ar are as defined above, under dehydration conditions to form a compound of formula (I) wherein A forms a group of formula -C = C- with B and R ¹ , R ² , X, Y, Z and Ar are as defined above, and the compound thus prepared is hydrogenated in the reaction mixture in which it was prepared; and, if desired, the base of formula (I) obtained is reacted with an inorganic or organic acid to form a pharmaceutically acceptable acid addition salt of the compound or may be released from the acid addition salt of the compound with a base. 8. A pharmaceutical composition comprising a benzofuran compound of the general formula wherein R ¹ and R ² independently represent hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C _1-4 alkyl group, R ⁴ represents a C _1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more more sulfur atoms ^ A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is hydrogen, C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, the latter being optionally substituted with C _1-4 alkoxy or C _1-4 alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two 110 oxygen atoms, wherein said heterocyclic group is optionally substituted with one to three C _1-4 alkyl groups; 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; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, methylenedioxy, phenoxy optionally substituted C _1-4 alkoxy or halogen; C _2-4 alkenyl, C _2-4 alkenyloxy, C ₄ alkoxy optionally substituted by di (C ₄ alkyl) amino or a 5- or β-membered saturated heterocyclic group containing one or two nitrogen atoms or a nitrogen atom and an oxygen atom, said heterocyclic group is optionally substituted with a C _1-4 alkyl group, or A represents a group of formula N (CH _{2) n} ^_ Ar ', wherein Ar 'is selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, wherein said last group is optionally substituted C ₄ alkoxy or C _2-4 alkenyloxy; partially saturated 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C ₁ _ ₄ alkyl groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R 6 and R ⁷ are as defined above, n is 0 or 1, Or a pharmaceutically acceptable acid addition salt thereof as an active ingredient and one or more conventional carriers. 9. A pharmaceutical composition according to claim 8 wherein _f in that it comprises benzofuranovovou compound of formula (I) wherein R ¹ represents a hydrogen atom or a C 1-4 alkyl group, R ² is hydrogen, X is an oxygen atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen or nitro, A is CH, COH or C-CN, B represents a methylene group, or A forms with the group B a group of the formula -C = C-, Ar is hydrogen, benzyl, phenyl substituted with R ⁵ , R ⁶ and R ⁷ , biphenylyl, naphthyl optionally substituted with C _1-4 alkoxy; or thienyl, R ^5, R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, C _4-4 alkyl, C ₄ alkoxy, C _2-4 alkenyloxy, phenoxy and methylenedioxy, 112 ................... or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. Pharmaceutical composition according to claim 8 or 9, characterized in that it comprises a benzofuran compound of formula (I), wherein: R ¹ represents a methyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, A is CH, COH or C-CN, B represents a methylene group, or A forms a group B with the formula -C = C-, Ar is phenyl optionally substituted with halogen, trifluoromethyl, methyl or methoxy; or a methoxynaphthyl group, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient. Pharmaceutical composition according to claim 8, characterized in that it comprises a piperazinylalkylbenzofuran compound of the formula (Ia) 113 where R ¹ represents a C _1-4 alkyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, Ar 1 represents a diphenylmethyl group, a pyridyl group, a partially saturated 2-heterocyclic group containing two oxygen atoms which is fused with a phenyl group, or a phenyl group substituted with a group selected from R ⁵ , R ⁶ , R ⁷ , wherein R ⁵ , R 0, R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, or methylenedioxy; n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, as the active ingredient. Pharmaceutical composition according to claim 11, characterized in that it comprises a piperazinylalkylbenzofuran compound of formula (Ia), wherein: R ¹ represents a methyl group, R ² is hydrogen, X is an oxygen atom, Y is hydroxy, Z represents a hydrogen atom, Ar 'is diphenylmethyl, pyridyl, 114 is a benzo-1,3-dioxolanyl or phenyl group optionally substituted by one or two halogen atoms, one or two methyl groups, methylenedioxy, trifluoromethyl or methoxy, n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof as active folder. A pharmaceutical composition according to claim 8, comprising one of the following compounds: 1- [3- (2,2-Dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (3-trifluoromethyl-phenyl) -piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-fluorophenyl) -piperidine, 1- [3 - (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4-phenylpiperidine, 1- [3- (2,2-dimethyl-2, 3-dihydrobenzofuran-7-yl-oxy) -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-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-methoxyphenyl) piperidine, 1- [3- (2,2- dimethyl-2,3-dihydro-benzofuran-7-yloxy) 115 -2-hydroxypropyl] -4- (3-trifluoromethylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy -4- (4-methylphenyl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-cyano-4-phenylpiperidine 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (4-chlorophenyl) piperidine, 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxy-propyl] -4-hydroxy-4- (6-methoxy-naphth-2-yl) piperidine, 1- [3- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy) -2-hydroxypropyl] -4- (diphenylmethyl) piperazine, 1- [3- (2, 2 2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (4-fluorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro) -benzofuran-7-yl-oxy) -2-hydroxypropyl] -4-hydroxy-4- (3-trifluoromethylphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran- 7-yl-oxy) -2-hydroxypropyl] -4- (4-methoxyphenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (benzo-1,3-dioxolan-5-yl) piperazine, 1 - [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -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-yl) - oxy) -2-hydroxypropyl] -4- (2,4-dichlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (3-chlorophenyl) piperazine, 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) -2-hydroxypropyl] -4- (2-pyridyl) piperazine 1- [3- (2,2-dimethyl-2,3-dihydro-benzofuran-7-yl-oxy) - 116 -2-hydroxypropyl] -4- (2-methoxyphenyl) piperazine; 1- [3- (2,2-Dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl] -4- (3-methoxyphenyl) piperazine, or a pharmaceutically acceptable acid addition salt thereof such as active ingredient. 14. A method of treating a patient, in particular a patient suffering from a heart or central nervous system disorder, wherein the patient is treated with a non-toxic dose of a benzofuran compound of formula (I) wherein R ¹ and R ² independently represent hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C ₄ alkyl group, R ⁴ represents a C _1-4 alkyl group, or 117 Φ 100 • · R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more more sulfur atoms, A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is selected from the group consisting of hydrogen, C ₄ alkyl, phenyl (C _C4 alkyl), biphenyl, naphthyl, wherein the groups mentioned last may be optionally substituted by C ₄ alkoxy or C ₂ '_ ₄ alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; 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; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, methylenedioxy, phenoxy optionally substituted C _1-4 alkoxy or halogen; C ₂ _ ₄ alkenyl, C _2-4 alkenyloxy, C - _C4 alkoxy optionally substituted by di (C ₄ alkyl) amino or a 5- or 6-membered saturated heterocyclic group containing one or two atoms • · nitrogen or nitrogen and oxygen, said the heterocyclic group is optionally substituted with a C _1-4 alkyl group, or A represents a group of formula N (CH _{2) n} -Ar 'wherein Ar 'is a group selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, the latter being optionally substituted by C _1-4 alkoxy or C _2-4 alkenyloxy; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C _1-4 alkyl groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof. A process for the preparation of a pharmaceutical composition which has a particularly cardioprotective effect or is suitable for the treatment of a central nervous system disease, characterized in that the benzofuran compound of the formula (I) wherein: R ¹ and R ² independently represent hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is selected from the group consisting of hydrogen, halogen, C _4-4 alkyl, C _C4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ^3, -NHCOR ^3, and -SC> 2 NR ³ R ^4, wherein R ³ represents a hydrogen atom or a C ₄ alkyl group, R ⁴ represents a C _1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 5 to 10 members and optionally containing as further heteroatom (s) one or more nitrogen atoms and / or one or more oxygen atoms, and / or one or more more sulfur atoms _/ A is CH, COH, C-CN, C-COOR ³ or COR ⁴ wherein R ³ and R ⁴ are as defined above, B represents a methylene group, or A forms together with the group B a group of the formula -C = C-, Ar is hydrogen, C _1-4 alkyl, phenyl (C _1-4 alkyl), biphenylyl, naphthyl, the latter being optionally substituted with C 1-4 alkoxy or C _1-4 alkenyl; a partially saturated 5- or 6-membered heterocyclic group fused to a phenyl group and containing one or two 120 oxygen atoms, wherein said heterocyclic group is optionally substituted with one to three C _1-4 alkyl groups; 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; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ independently represent hydrogen, halogen, trifluoromethyl, C _1-4 alkyl, methylenedioxy, phenoxy optionally substituted C _1-4 alkoxy or halogen; _C2-C4 alkenyl, C _2-4 alkenyloxy, C _1-4 alkoxy optionally substituted by a di (C _1-4 alkyl) amino group or a 5- or 6-membered saturated heterocyclic group containing one or two nitrogen atoms, or a nitrogen atom and an oxygen atom, said heterocyclic group being optionally substituted C _1-4 alkyl; A represents a group of formula N (CH _{2) n} ^- Ar 'wherein Ar 'is selected from the group consisting of diphenylmethyl, pyridyl, pyrimidinyl, naphthyl, wherein said last group is optionally substituted C ₄ alkoxy or C _2-4 alkenyloxy; partially saturated 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atoms, said heterocyclic group being optionally substituted with one to three C ₁ _ ₄ alkylcvými groups; or a phenyl group substituted with substituents including R ⁵ , R ⁶ and R ⁷ , wherein R ⁵ , R ⁶ and R ⁷ are as defined above, n is 3 or 1, 121, or a pharmaceutically acceptable acid addition salt thereof, is formulated into a pharmaceutical composition using one or more pharmaceutical carriers commonly used in the pharmaceutical art. A halide of formula (II) wherein Hal II R ¹ and R ² independently represent hydrogen or C ₄ alkyl group, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ₂ NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C ₄ alkyl group, R ⁴ is C ^ ₄ alkyl, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 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, 122 • · Hal represents a halogen atom. A ketone of formula (XV) wherein R ¹ and R ² independently, X represents an oxygen atom or a sulfur atom, Y represents a hydrogen atom or a hydroxy group, Z is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, amino, nitro, cyano, trifluoromethyl, -COOR ³ , -NHCOR ³ , and -SO ² NR ³ R ⁴ , wherein: R ³ represents a hydrogen atom or a C ₄ alkyl group, R ⁴ represents a C _1-4 alkyl group, or R ³ and R ⁴ together with the associated nitrogen atom form a saturated or unsaturated heterocyclic group containing 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,